Clinical trial NCT02631538
Conditions: Sjogren's Syndrome
Keywords: Subcutaneous Rituximab Intravenous Safety Efficacy Sjogren's syndrome Belimumab
Sponsor: GlaxoSmithKline
Start date: 2016-02-17; Completion date: 2020-06-23
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multi-national, multi-center, double-blind (sponsor open), randomized, placebo-controlled trial in subjects with active primary Sjögren's syndrome designed to understand the safety and tolerability profile of belimumab/ rituximab co-administration and of belimumab monotherapy; and to evaluate whether either co-administration therapy or belimumab monotherapy has a substantive effect on disease activity.

This study will consist screening period, double blind treatment period, a general follow-up period and individualized follow-up period. Approximately 70 subjects will be recruited into the study initially. At Day 0, subjects will be randomized 1:2:2:2 to one of the four treatment arms placebo arm, belimumab monotherapy arm, co-administration therapy arm and rituximab monotherapy arm. Once a sufficient number of subjects have completed the Week 24, interim analyses and sample size re-estimation will be conducted. The total number of subjects randomized may increase following sample size re-estimation up to a maximum of 120 recruited into the study.

Subjects in all arms will receive investigational product (IP) until Week 52 (completion of the treatment phase). All subjects will enter a 16-week general follow-up period after the Week 52 visit or after discontinuation if a subject discontinues IP and withdraws from the treatment phase visits prior to Week 52.

After completing the general follow-up period, subjects with cluster of differentiation (CD)19+ B-cell levels below the lower limit of normal (or less than 90 percent \[%\] of baseline, if baseline value was below lower limit of normal \[LLN\]) will enter an individualized safety follow-up phase and return to the clinic for visits every 12 weeks with monthly calls between visits to evaluate subjects for any serious adverse events (SAEs) related to IP or study participation, fatal SAEs, and designated adverse event of special interests (AESIs) (i.e., infections, malignancies, or depression, suicide/self-injury), and to check concomitant medications.

The total duration of participation of a subject in this study will be approximately up to a maximum of 2 years (i.e., up to Week 104).

Detailed description:

Arms: arm 1: Subjects will receive belimumab placebo weekly subcutaneous injections to Week 52 and rituximab placebo infusions at Weeks 8 and 10. arm 2: Subjects will receive 200 mg weekly subcutaneous injections of belimumab to Week 52 and placebo rituximab infusions at Weeks 8 and 10. arm 3: Subjects will receive belimumab 200 mg SC weekly for 24 weeks followed by weekly placebo belimumab injections to Week 52 with rituximab 1000 mg intravenously at Weeks 8 and 10. arm 4: Subjects will receive 1000 mg IV rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of placebo belimumab to Week 52.
Interventions: intervention 1: Belimumab intervention 2: Rituximab intervention 3: Placebo belimumab intervention 4: Placebo rituximab
Intervention descriptions: intervention 1: Belimumab will be provided as a 200 mg sterile, liquid product in a prefilled syringe. Each syringe contains 1.0 mL of 200 mg/mL belimumab. Each syringe will be a single use. intervention 2: Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid. intervention 3: The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use. intervention 4: Placebo rituximab will be provided as solution for infusion. It is a clear, colorless liquid.

Protocol documents:
Prot_000.pdf: 
2014N220285_06
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1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomized, double blind (sponsor open), comparative, multi-
center study to evaluate the safety and efficacy of subcutaneous 
belimumab (GSK1550188) and intravenous rituximab co-
administration in subjects with primary Sjögren’s syndrome.
Compound Number:
GSK1550188
Development Phase:
II
Effective Date:
25-JUN-2019
Protocol Amendment Number:  6
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1 for 
Sweden
Protocol amended in response to comments received from Swedish regulatory 
authority.
Local
2014N220285_02
2015-NOV-20
Amendment No. 2 for 
Norway
Protocol amended in response to comments received from Norwegian regulatory 
authority.
Local
2014N220285_03
2016-JAN-04
Amendment No. 3 for Italy
Protocol amended in response to comments received from Italian regulatory authority.
Global
2014N220285_04
2016-JUN-13
Amendment No. 4
The primary reason for this amendment is to modify the subject selection criteria 
(specifically exclusion criterion #30 pertaining to exclusionary laboratory thresholds) 
to better align with the intended population characteristics.
Other amendments include the following:

Greater clarity is provided regarding the committees involved in monitoring 
subject safety and review of study data as well as the governance of the study.

It has been made clear that a single formal interim analysis is planned.

The subject withdrawal and study stopping criteria have been modified.

Greater detail is provided regarding prohibited and permitted medications.

Additional guidance is provided regarding vaccination.

Guidance has been provided for tuberculosis assessment during the screening 
period.

The pregnancy section has been modified to clarify the duration of follow up 
required.
 
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GlaxoSmithKline Document 
Number
Date
Version
This amendment incorporates country-specific changes required by Regulatory 
Authorities during prior review. In addition, changes have been made throughout to 
provide clarity for the conduct of the study and correct typographical errors.
All changes made in Amendment 4 are summarized, rationalized and detailed in 
Appendix 13 (Section 12.13).
Global
2014N220285_05
2018-MAY-11
Amendment No. 5
The primary reason for this amendment is to clarify the definition of “sponsor open” in 
Section 6.3, with respect to study blinding. Additional minor clarifications have been 
made throughout the protocol.
Global
2014N220285_06
2019-JUN-25
Amendment No. 6
The primary reason for this amendment is to clarify the timing of unblinding for GSK 
staff and site staff.  Additional minor updates have been made in several sections of the 
protocol.
 
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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 
Numbe
r
Site 
Address
Primary 
Medical 
Monitor *
Mobile: 
NA
Stevenag
e, 
UNITED 
KINGDO
M
Secondar
y Medical 
Monitor*
Mobile: 
NA
Upper 
Providenc
e
US
SAE 
contact  
informatio
n 
Case 
Management 
Group, Global 
Clinical Safety 
and 
Pharmacovigilan
ce (GCSP)
 
NA
 
 
NA
*Medical monitor name and contact information can also be found in the Study Reference Manual
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):  EudraCT number 2015-000400-26
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201842
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
SPONSOR SIGNATORY ................................................................................................4
1.
PROTOCOL SYNOPSIS FOR STUDY 201842......................................................10
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Follow up Periods .......................................................................................20
4.3.1.
General Follow up Period ............................................................20
4.3.2.
Individualized Follow up Period....................................................20
4.4.
Type and Number of Subjects.....................................................................20
4.5.
Design Justification.....................................................................................21
4.6.
Dose Justification........................................................................................21
4.7.
Benefit:Risk Assessment ............................................................................22
4.7.1.
Risk Assessment for Dual Biologics in pSS .................................24
4.7.2.
Vaccinations ................................................................................29
4.7.3.
Benefit Assessment.....................................................................29
4.7.4.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
General Criteria ...........................................................................35
5.4.2.
Early Withdrawal Visit ..................................................................37
5.4.3.
Detailed Adverse Event Criteria...................................................37
5.4.4.
Study Stopping Criteria................................................................38
5.4.5.
Liver Chemistry Stopping Criteria ................................................38
5.4.5.1.
Study Treatment Restart ............................................39
5.5.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................40
6.1.
Investigational Product and Other Study Treatment....................................40
6.1.1.
Belimumab...................................................................................40
6.1.1.1.
Self Administered Subcutaneous Injections and 
Log Book....................................................................40
6.1.1.2.
Missed Doses.............................................................41
6.1.2.
Rituximab.....................................................................................41
6.2.
Treatment Assignment................................................................................43
6.3.
Blinding.......................................................................................................43
6.4.
Packaging and Labeling..............................................................................44
6.5.
Preparation/Handling/Storage/Accountability..............................................44
6.6.
Compliance with Study Treatment Administration.......................................45
6.7.
Treatment of Study Treatment Overdose....................................................45
 
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6.8.
Treatment after the End of the Study ..........................................................46
6.9.
Concomitant Medications and Non-Drug Therapies....................................46
6.9.1.
Permitted Medications and Non-Drug Therapies..........................46
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................47
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
7.1.
Time and Events Table...............................................................................48
7.2.
Screening and Critical Baseline Assessments ............................................52
7.3.
Efficacy.......................................................................................................54
7.3.1.
Patient-Reported Outcomes Assessments...................................55
7.4.
Safety .........................................................................................................55
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........55
7.4.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................56
7.4.1.2.
Method of Detecting AEs and SAEs ...........................56
7.4.1.3.
Follow-up of AEs and SAEs........................................56
7.4.1.4.
Adverse Events of Special Interest.............................57
7.4.1.5.
Cardiovascular and Death Events ..............................57
7.4.1.6.
Regulatory Reporting Requirements for SAEs............57
7.4.2.
Pregnancy ...................................................................................58
7.4.3.
Physical Exams ...........................................................................58
7.4.4.
Vital Signs....................................................................................59
7.4.5.
Electrocardiogram (ECG).............................................................59
7.4.6.
Clinical Safety Laboratory Assessments ......................................59
7.4.7.
Progressive Multifocal Leukoencephalopathy (PML)....................61
7.4.8.
Suicidal Risk Monitoring...............................................................62
7.5.
Pharmacokinetics .......................................................................................62
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................62
7.6.1.
Novel Biomarkers ........................................................................63
7.6.1.1.
Assessment of the Salivary Gland Cellular 
Composition ...............................................................63
7.6.1.2.
Peripheral Blood Leukocyte Analysis..........................63
7.6.1.3.
Serological Biomarkers...............................................63
7.6.1.4.
Additional Exploratory Biomarkers..............................64
7.6.1.4.1.
Saliva Proteomics...................................64
7.6.1.4.2.
Transcriptomic Analysis..........................64
7.6.1.4.3.
B and T Cell Receptor Clonal 
Analysis..................................................64
7.6.1.5.
Immunogenicity ..........................................................64
7.7.
Genetics .....................................................................................................64
8.
DATA MANAGEMENT ...........................................................................................64
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................65
9.1.
Hypotheses and Treatment Comparisons...................................................65
9.2.
Sample Size Considerations.......................................................................65
9.2.1.
Sample Size Assumptions ...........................................................65
9.2.2.
Sample Size Sensitivity................................................................67
9.2.3.
Sample Size Re-estimation..........................................................67
9.3.
Data Analysis Considerations .....................................................................67
9.3.1.
Analysis Populations....................................................................67
9.3.2.
Interim Analysis ...........................................................................67
 
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9.4.
Key Elements of Analysis Plan ...................................................................68
9.4.1.
Primary Analysis and Follow Up Analysis ....................................68
9.4.2.
Analysis of Primary Endpoints .....................................................68
9.4.3.
Analysis of Secondary Endpoints.................................................68
9.4.4.
Analysis of Other Endpoints.........................................................69
9.4.4.1.
Health Outcome Analyses ..........................................69
9.4.4.2.
Pharmacokinetic Analyses..........................................69
9.4.4.3.
Pharmacokinetics/Pharmacodynamic Analyses..........70
10. STUDY GOVERNANCE CONSIDERATIONS........................................................70
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............70
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................70
10.3.
Quality Control (Study Monitoring) ..............................................................71
10.4.
Quality Assurance.......................................................................................71
10.5.
Study and Site Closure ...............................................................................71
10.6.
Records Retention......................................................................................72
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................72
10.8.
Review Committees....................................................................................73
10.8.1.
Internal Safety Review Committee (iSRC) and Therapeutic 
Area Data Assessment Committee (TA-DAC)..............................73
10.8.2.
PML Adjudication Committee.......................................................73
11. REFERENCES.......................................................................................................74
12. APPENDICES........................................................................................................77
12.1.
Appendix 1: Abbreviations and Trademarks................................................77
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................80
12.3.
Appendix 3: Liver Safety – Study Treatment Restart Guidelines.................83
12.4.
Appendix 4: PML Algorithm.........................................................................85
12.5.
Appendix 5: Neurological Symptoms Questionnaire ...................................86
12.6.
Appendix 6: Genetic Research ...................................................................87
12.7.
Appendix 7: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................90
12.7.1.
Definition of Adverse Events........................................................90
12.7.2.
Definition of Serious Adverse Events...........................................91
12.7.3.
Definition of Cardiovascular Events .............................................92
12.7.4.
Recording of AEs and SAEs ........................................................93
12.7.5.
Evaluating AEs and SAEs............................................................93
12.7.6.
Reporting of SAEs to GSK...........................................................95
12.8.
Appendix 8: Collection of Pregnancy Information........................................96
12.9.
Appendix 9: American-European Consensus Group Classification .............97
12.10. Appendix 10: Protocol changes in Amendment 1........................................98
12.11. Appendix 11: Protocol changes in Amendment 2......................................103
12.12. Appendix 12: Protocol changes in Amendment 3......................................106
12.13. Appendix 13: Protocol changes in Amendment 4......................................108
12.14. Appendix 14: Protocol changes in Amendment 5......................................153
12.15. Appendix 15: Protocol changes in Amendment 6......................................169
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201842
Rationale
Primary Sjögren’s syndrome (pSS) is a common autoimmune disease characterized by 
oral and ocular dryness as well as systemic manifestations. B cells are thought to play a 
central pathogenic role. There are no disease modifying treatments for this disease and 
existing approved therapies consist of symptomatic treatments that do not address the 
autoimmune pathology. Therefore, substantial unmet medical need exists for a disease 
modifying therapy; one that can stop B-cell mediated autoimmune damage, alleviate 
glandular as well as constitutional symptoms, and ameliorate extra-glandular target organ 
manifestations.
Clinical studies suggest that targeting B-cells with belimumab or rituximab may improve 
disease symptoms of patients with Sjögren’s syndrome. In addition, scientific evidence 
suggests that dual B-cell targeted immunotherapy with both B lymphocyte stimulator 
(BLyS) blockade (i.e., belimumab) and B cell depletion (i.e., rituximab; anti-CD20) may 
be more efficacious than targeting either mechanism alone. Therefore, this proof of 
mechanism study will assess whether either dual B-cell immunotherapy (i.e., co-
administration of belimumab and rituximab) or belimumab monotherapy demonstrates a 
favorable safety and tolerability profile and results in improvements in clinical status, 
functional outcomes and mechanistic endpoints in comparison to placebo or rituximab 
monotherapy.
Overall Design
The primary efficacy comparison for this study at Week 24 will be between the co-
administration therapy arm and the placebo arm. Once approximately 35 subjects have 
 
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completed week 24, a formal interim analysis will be performed on the available data. 
Following this interim analysis, a number of actions could be taken: the study could 
continue as planned; one or more treatment arms may be dropped; the number of subjects 
in some or all treatment arms may be increased following sample size re-estimation up to 
a maximum of 120 total subjects in the study. 
Key Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

Safety and tolerability of anti-
BLyS / anti-CD 20 co-
administration therapy and anti-
BLyS and anti-CD 20 
monotherapies

Safety and tolerability; including 
incidence of SAEs and AESIs
Secondary

Clinical efficacy of anti-BLyS / 
anti-CD 20 co-administration 
therapy and anti-BLyS and anti-
CD 20 monotherapies

Assessment of anti-BLyS / anti-
CD 20 co-administration therapy 
and anti-BLyS and anti-CD 20 
monotherapies on tissue B-cells

ESSDAI score over time

Stimulated salivary flow over time

Oral dryness numeric response scale over 
time

B cell quantification within salivary 
gland biopsy at Week 24
Exploratory

Assessment of mechanism and 
durability of effect of anti-
BLyS/anti-CD 20 co-
administration therapy and anti-
BLyS and anti-CD20 
monotherapies
Sustained efficacy of anti-BLyS/anti-CD 
20 co-administration at Week 52
Extended mechanistic assessment of anti-
BLyS/anti-CD20 co-administration and 
monotherapies in blood, tissue and saliva 
at Week 24 and 52
Treatment Arms and Duration
Approximately 70 subjects will be recruited into the study initially. At Day 0, subjects 
will be randomized 1:2:2:2 to one of the four treatment arms below. 
1. Placebo Arm: Approximately 10 subjects will receive belimumab placebo weekly 
subcutaneous injections to Week 52 and rituximab placebo infusions at Weeks 8 
and 10. 
 
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2. Belimumab Monotherapy Arm: Approximately 20 subjects will receive 200 mg 
weekly subcutaneous injections of belimumab to Week 52 and placebo rituximab 
infusions at Weeks 8 and 10.
3. Co-administration Therapy Arm: Approximately 20 subjects will receive 
belimumab 200 mg weekly subcutaneous injections for 24 weeks followed by 
weekly placebo belimumab injections to Week 52 with rituximab 1,000 mg 
intravenously at Weeks 8 and 10. 
4. Rituximab Monotherapy Arm: Approximately 20 subjects will receive 1,000 mg 
IV rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of 
placebo belimumab to Week 52.
General Follow up Period
Subjects in all arms will receive investigational product (IP) until Week 52 (completion 
of the treatment phase). All subjects will enter a 16-week general follow-up period after 
the Week 52 visit or after discontinuation, if a subject discontinues IP and withdraws 
from the treatment phase visits prior to Week 52. 
Individualized Follow up Period
After completing the general follow-up period, subjects with CD19+ B-cell levels below 
the lower limit of normal (LLN) (or less than 90% of baseline, if baseline value was 
below LLN) will enter an individualized safety follow-up phase and return to the clinic 
for visits every 12 weeks up to a maximum of two years (i.e., up to Week 104).
Type and Number of Subjects
Adult subjects with symptomatic and systemically active disease as well as evidence of 
glandular reserve function will be recruited. Initially, approximately 70 subjects will be 
randomized. Withdrawn subjects may be replaced, and there is potential to further 
increase the number of subjects in one or more arms following sample size re-estimation, 
up to a maximum of 120 recruited into the study. The randomization ratio will vary 
dependent on the number of treatment arms continuing following the interim analysis
Analysis
Hypotheses and Treatment Comparisons: The primary objective of the study is to 
investigate the safety and tolerability of the co-administration of belimumab with 
rituximab and of belimumab monotherapy. No formal statistical comparisons will be 
conducted to assess this objective. If deemed appropriate, to investigate the secondary 
efficacy and mechanistic endpoints, the following comparisons may be conducted:

Co-administration belimumab/rituximab treatment arm vs. Placebo arm

Co-administration belimumab/rituximab treatment arm vs. Rituximab 
monotherapy arm
 
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
Co-administration belimumab/rituximab treatment arm vs. Belimumab 
monotherapy arm

Belimumab monotherapy arm vs. Placebo arm

Belimumab monotherapy arm vs. Rituximab monotherapy arm
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI score, stimulated salivary flow, oral dryness numeric response scale and a 
subset of salivary gland histology assessments and B cell quantification. For all other 
parameters, no formal statistical comparisons will be made, although trends over time 
will be investigated across all treatment arms.
Sample Size Calculations: Initially approximately 70 subjects will be recruited into the 
study. The study is not powered to detect pre-defined differences.
Interim Analysis: Once  half of the planned subjects (i.e.: approximately 35 subjects) 
have completed their Week 24 assessments, a formal interim analysis will take place. 
Appropriate available safety and efficacy data will be included in the interim analysis. 
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, preliminary efficacy analysis may be conducted. to enable a 
sample size re-estimation and obtain an initial estimate of the effect size of the co-
administration therapy and belimumab monotherapy. Following the interim analysis, a 
number of actions could be  taken: the study may continue as planned; one or more 
treatment arms may be dropped; the number of subjects in some or all treatment arms 
may be increased following sample size re-estimation, up to a maximum of 120 subjects 
in the study
Data Analysis Considerations: All data will be descriptively summarized, graphically 
presented and listed appropriately. The relationship between the mechanistic endpoints 
(e.g., salivary gland B cell quantification) and clinical effects (e.g., ESSDAI score) will 
be graphically presented The consistency in the changes over time between the endpoints 
will be assessed and further exploratory analyses to characterize relationships between 
endpoints may be conducted. Comparisons between treatment groups will be conducted if 
deemed appropriate. For example, the change from baseline in ESSDAI score will be 
statistically analyzed using a mixed effect model repeated measurement (MMRM) 
analysis comparing the co-administration with placebo at each time point. Similar 
analyses may be conducted for other secondary endpoints. In addition, based on the data 
that we observe in the study, probabilities of success may be determined, for example, 
what is the probability that we would observe a certain change in ESSDAI score (i.e., 
comparator rate), based on the data that we have observed in the study?
 
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2.
INTRODUCTION
2.1.
Study Rationale
Primary Sjögren’s syndrome (pSS) is a common autoimmune disease characterized by 
oral and ocular dryness as well as systemic manifestations. B cells are thought to play a 
central pathogenic role. There are no disease modifying treatments for this disease and 
existing approved therapies consist of symptomatic treatments that do not address the 
autoimmune pathology. Therefore, substantial unmet medical need exists for a disease 
modifying therapy; one that can stop B-cell mediated autoimmune damage, alleviate 
glandular as well as constitutional symptoms and ameliorate extra-glandular target organ 
manifestations.
Clinical studies suggest that targeting B-cells with belimumab or rituximab may improve 
disease symptoms of patients with Sjögren’s syndrome. In addition, scientific evidence 
suggests that dual B-cell targeted immunotherapy with both B lymphocyte stimulator 
(BLyS) blockade (i.e., belimumab) and B cell depletion (i.e., rituximab) may be more 
efficacious than targeting either mechanism alone. Therefore, this proof of mechanism 
study will assess whether either dual B-cell immunotherapy (i.e., co-administration of 
belimumab and rituximab) or belimumab monotherapy demonstrates a favorable safety 
and tolerability profile and results in improvements in clinical status, functional outcomes 
and mechanistic endpoints in comparison to placebo or rituximab monotherapy.
2.2.
Brief Background
Sjögren’s syndrome is manifest by sicca symptoms, constitutional findings, and 
potentially severe, life-threatening organ-specific extra-glandular manifestations. It is 
characterized by a combination of features including oral and ocular dryness, which can 
be disabling; ocular signs including objective evidence for involvement; salivary gland 
involvement including abnormal appearance of salivary glands; and presence of 
antibodies to Ro and/or La. Patients may also experience severe, variable and 
unpredictable fatigue, which is similar in character and severity to that of patients with 
systemic lupus erythematosus (SLE). Similarly, fibromyalgia and widespread chronic 
pain are found in 5% of pSS patients, again, comparable to SLE. Extra-glandular 
manifestations occur in 20 to 40% of patients and include rashes, peripheral neuropathy, 
Hashimoto’s thyroiditis, non-erosive arthritis, arthralgia, vasculitis, interstitial lung 
disease, B-cell lymphoma, pancreatitis, primary biliary cirrhosis, autoimmune hepatitis 
and renal disease.
BLyS (also known as BAFF) promotes B-cell maturation, proliferation and survival. 
Transgenic mice that over-express this cytokine develop features of SLE, and go on to 
develop clinical characteristics of primary Sjögren’s syndrome [Mackay, 1999]. In recent 
years, several studies have focused on elucidating the role of BLyS in primary Sjögren’s 
syndrome. Serum BLyS levels were demonstrated to be increased, and to correlate with, 
levels of anti-Ro/SS-A antibodies and rheumatoid factor (RF) in patients with primary 
Sjögren’s syndrome [Mariette, 2003] and elevated levels of BLyS have been detected in 
saliva [Daridon, 2007; Lavie, 2008]. 
 
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Belimumab, an anti-BLyS therapy, has been studied in patients with Sjögren’s syndrome. 
In the open label, Phase II BELISS trial of belimumab in patients (n = 30) with primary 
Sjögren’s syndrome, 60% of subjects (18/30) met the primary endpoint - improvement in 
at least two of the following five parameters: dryness, fatigue, pain, systemic activity or 
B-cell biomarkers - measured at 28 weeks [Mariette, 2015]. This study will allow the 
opportunity to test the efficacy of belimumab in a placebo controlled, randomized trial 
and will extend the observations of the BELISS study in assessing the effects on disease 
activity in patients treated with belimumab for 12 months.
Rituximab, an anti-CD 20 therapy, has also been studied in patients with Sjögren’s 
syndrome. In general, these studies - despite being heterogonous, especially with respect 
to the patient populations recruited - have shown evidence of temporary beneficial effects 
on symptoms of dryness and fatigue [Meijer, 2010; Devauchelle-Pensec, 2014; Dass, 
2008]. Furthermore, additional studies have raised the possibility of rituximab positively 
impacting systemic disease, salivary histology and biomarkers such as beta2 
microglobulin [Carubbi, 2014]. As a result, rituximab has been recommended as a 
potential treatment [Ramos-Casals, 2012] in subjects with systemic disease.
Administration of anti-CD20 therapy has been shown to result in an increase in serum 
BLyS [Cambridge, 2006; Lavie, 2007; Pers, 2007]. This increase is linked both to the 
disappearance of BLyS-binding B cells in peripheral blood, as well as to a true 
homeostatic feedback characterized by increased BLyS mRNA expression in monocytes 
after rituximab [Toubi, 2007; Lavie, 2007]. This increase in BLyS after rituximab could 
favor the stimulation of new autoimmune B cells and, possibly explains the waning 
clinical improvement over time seen in clinical studies of rituximab in patients with 
Sjögren’s syndrome. 
Anti-BLyS and anti-CD20 therapeutics operate through different but complementary 
mechanisms: anti-BLyS (e.g., belimumab) therapeutics rapidly increase peripheral 
memory B cells (possibly by mobilization/redistribution of tissue B cells), decrease 
naive, activated and plasma B cell subsets, and increase stringency on B cell selection 
during reconstitution; while anti-CD20 (e.g., rituximab) therapeutics eliminate peripheral 
B cells through complement dependent cytotoxicity (CDC) and antibody-dependent cell-
mediated cytotoxicity (ADCC). Paired together, these two mechanisms may achieve 
synergistic effects through improved depletion of memory and germinal center tissue B 
cells and increased stringency during B cell reconstitution with additive effects through 
more efficient targeting of circulating plasma cells.
Pre-clinical evidence supporting the hypothesis that dual B-cell targeted immunotherapy 
maybe more efficacious than monotherapy, has been generated in a human-CD20 
expressing mouse model. This model demonstrated limited tissue depletion with anti-
CD20 antibody mono-therapy but increased efficacy of anti-CD20 therapy when B cells 
were mobilized into the peripheral blood through concomitant inhibition of adhesion 
[Gong, 2005]. The combined effect of administration of mouse BLyS receptor (BR3)-Fc 
and anti-hCD20 in this model leads to more effective tissue B cell depletion. Similar 
observations have been made in SLE models [Lin, 2015] where dual targeting resulted in 
greater efficacy with increased tissue B cell depletion, greater reduction in a range of 
auto-antibody levels and significant decreases in total IgG1, IgG2b, IgG3, IgM and IgA 
 
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when compared to BLyS inhibition and CD20 B-cell depletion alone. Total plasma cells 
in the long lived bone marrow niche, thought to be less sensitive to immunotherapy, were 
not affected relative to monotherapy with the exception of IgG1+ plasma cells. 
Assessment of the translatability of the IgG reductions to humans are difficult to make 
due to species differences in B-cell biology and different treatments; however the mouse 
data raises the hypothetical risk that immunoglobulin levels may reduce more with 
combination treatment. 
There also exists limited clinical evidence that dual B-cell targeted immunotherapy with 
both BLyS blockade and B cell depletion may be more efficacious than monotherapy. 
One subject in the BELISS trial [Mariette, 2015; De Vita, 2014] had severe refractory 
Sjögren’s syndrome including parotid B-cell MALT lymphoma and cryoglobulinemic 
vasculitis. Previous treatment (prior to BELISS) with rituximab, steroids, 
cyclophosphamide, azathioprine, plasmapheresis, hyperbaric therapy and surgery had 
failed. Administration of belimumab to this patient in the BELISS study was also 
ineffective. However, 49 days after her last infusion with belimumab, the subject was 
again treated with rituximab. She experienced complete and sustained remission of her 
lymphoma, regression of her previously non-healing cutaneous ulcer and complete 
normalization of her serologic biomarkers. Although this is a limited, single-case study, it 
raises the possibility of profound effects achievable through concomitant exposure to 
anti-BLyS and anti-CD20 therapeutics. 
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

Safety and tolerability of anti-
BLyS / anti-CD 20 co-
administration therapy and anti-
BLyS and anti-CD 20 
monotherapies

Safety and tolerability; including 
incidence of SAEs and AESIs.
Secondary

Clinical efficacy of anti-BLyS / 
anti-CD 20 co-administration 
therapy and anti-BLyS and anti-
CD 20 monotherapies

Assessment of anti-BLyS / anti-
CD 20 co-administration therapy 
and anti-BLyS and anti-CD 20 
monotherapies on tissue B-cells.

ESSDAI score over time

Stimulated salivary flow over time

Oral dryness numeric response scale over 
time

B cell quantification within salivary 
gland biopsy at Week 24
 
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Objectives
Endpoints
Exploratory

Assessment of mechanism and 
durability of effect of anti-
BLyS/anti-CD 20 co-
administration therapy and anti-
BLyS and anti-CD20 
monotherapies.
Ocular dryness numeric response scale 
over time
Lacrimal gland function as measured by 
Schirmer’s test.
Physician’s Global Assessment (PGA) of 
disease activity over time
Serologic markers over time
Change in peripheral blood leukocytes 
including B cell subsets over time
BLyS levels in blood
Immunogenicity of rituximab and 
belimumab
Pharmacokinetics of rituximab and 
belimumab
Change from baseline in the cellular 
composition of the salivary gland
Sustained efficacy of anti-BLyS/anti-CD 
20 co-administration at Week 52
Additional exploratory biomarkers may 
be evaluated
o Transcriptomic analysis of blood 
and salivary gland
o B and T cell receptor clonal 
analysis in peripheral blood and 
salivary gland
o Proteomic assessment of the 
saliva
Health Outcomes

Gather preliminary information 
on patient reported outcomes of 
anti-BLyS/anti-CD 20 co-
administration therapy and anti-
BLyS and anti-CD 20 
monotherapies
ESSPRI score (and individual scale sub-
scores) over time
Fatigue and Discomfort- SICCA 
Symptom Inventory (PROFAD SSI SF) 
over time
Patient Global Assessment (PtGA) of 
disease activity over time
Subject exit interviews
 
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4.
STUDY DESIGN
4.1.
Overall Design
This will be a multi-national, multi-center, double-blind (sponsor open) (see Section 6.3), 
randomized, placebo-controlled trial in subjects with active primary Sjögren’s syndrome. 
The study design is shown in the schematic above. 
This study is designed to understand the safety and tolerability profile of belimumab/ 
rituximab co-administration and of belimumab monotherapy; and to evaluate whether 
either co-administration therapy or belimumab monotherapy has a substantive effect on 
disease activity. It is also designed to understand the underlying immunological 
mechanisms impacted by belimumab monotherapy compared to placebo or rituximab 
monotherapy and to determine if there is a mechanistic difference between monotherapy 
and co-administration therapy. Disease activity assessment at Week 52 will allow 
determination of whether any clinical effects of co-administration therapy achieved at 
Week 24 are sustained after discontinuation of therapy and/or whether chronic treatment 
with belimumab monotherapy is effective. 
Study data will be reviewed in a confidential manner during the conduct of the trial. In 
line with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on an 
ongoing basis during the study conduct by an internal GSK Safety Review Team (SRT).
An internal GSK Safety Review Committee (iSRC), independent of the study team, will 
maintain governance of the study and will periodically review all available data in an un-
blinded manner with a focus on key safety parameters.  A Therapeutic Area (Immuno-
Inflammation) Data Assessment Committee (TA DAC), independent of the study team, 
will periodically review un-blinded efficacy data and at the interim analysis will advise 
 
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the iSRC on adaptive design changes should such changes be required.  An iSRC charter 
details the activities of these committees, including when and which data will be 
reviewed, how the integrity of the study will be maintained, and the membership of both 
committees. Once approximately half of the planned subjects (i.e.: approximately 35 
subjects) have completed their Week 24 assessments, a formal interim analysis will take 
place. Appropriate available safety and efficacy data will be included in the interim 
analysis. The main purpose of the interim analysis is to assess the safety and tolerability 
of the study drugs. In addition, preliminary efficacy data will be evaluated.  .  Following 
the interim analysis, a number of actions could be mandated by the iSRC: the study may 
continue as planned; one or more treatment arms may be dropped; the number of subjects 
in some or all treatment arms may be increased following sample size re-estimation, up to 
a maximum of 120 subjects in the study.
4.2.
Treatment Arms and Duration
Approximately 70 subjects will be recruited into the study initially. Withdrawals may be 
replaced. At Day 0, subjects will be randomized 1:2:2:2 to one of the four treatment arms 
below. 
1.
Placebo Arm: Approximately 10 subjects will receive belimumab placebo 
weekly subcutaneous injections to Week 52 and rituximab placebo infusions at 
Weeks 8 and 10. 
2.
Belimumab Monotherapy Arm: Approximately 20 subjects will receive 200 mg 
weekly subcutaneous injections of belimumab to Week 52 and placebo rituximab 
infusions at Weeks 8 and 10.
3.
Co-administration Therapy Arm: Approximately 20 subjects will receive 
belimumab 200 mg SC weekly for 24 weeks followed by weekly placebo 
belimumab injections to Week 52 with rituximab 1,000 mg intravenously at 
Weeks 8 and 10. 
4.
Rituximab Monotherapy Arm: Approximately 20 subjects will receive 1,000 mg 
IV rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of 
placebo belimumab to Week 52.
The subjects will be stratified based on their baseline disease activity severity [ESSDAI 
5-12 (moderate) vs. ESSDAI >12 (severe)] ensuring that within each disease severity 
there is an allocation across all treatment groups.
The total number of subjects recruited will be determined through an ongoing review of 
the data and sample size re-estimation. Following interim analysis, a number of actions 
could be taken: the study may continue as planned; one or more treatment arms may be 
dropped; the number of subjects in some or all treatment arms may be increased 
following sample size re-estimation, up to a maximum of 120 total subjects in the study 
where up to a maximum of 25, 45, 30 and 20 will be randomized to placebo, belimumab 
monotherapy, co-administration therapy and rituximab monotherapy respectively. The 
randomization ratio will vary dependent on the number of treatment arms continuing 
following the interim analysis. 
 
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4.3.
Follow up Periods
4.3.1.
General Follow up Period
Subjects in all arms will receive investigational product (IP) until Week 52 (completion 
of the treatment phase). All subjects will enter a 16-week general follow-up period after 
the Week 52 visit or after discontinuation if a subject discontinues IP and withdraws from 
the treatment phase visits prior to Week 52. Assessments to be performed are included in 
the Time and Events Table, Section 7.1. During the general follow up period subjects will 
remain off of investigational product, endeavor not to change concomitant medication 
regimen, receive monthly safety follow up phone calls, and will return to the clinic for a 
site visit at the end of the general follow up period.
Monthly telephone calls for urine pregnancy test results, neurological questionnaire and 
to evaluate AEs, SAEs, and concomitant medications will be required during the 16-week 
general follow-up period.
4.3.2.
Individualized Follow up Period
After completing the general follow-up period, subjects with CD 19+ B-cell levels below 
the lower limit of normal (or less than 90% of baseline, if baseline value was below LLN) 
will enter an individualized safety follow-up phase and return to the clinic for visits every 
12 weeks with monthly calls between visits to evaluate subjects for any SAEs related to 
IP or study participation, fatal SAEs, and designated AESIs (i.e., infections, 
malignancies, or depression, suicide/self-injury), and to check concomitant medications. 
Each subject will be followed until either “normalization” of CD 19+ B cell count occurs 
or, at the investigator’s discretion the subject starts receiving disease modifying therapy 
that may affect B-cell numbers, or for up to a maximum of 2 years (i.e., up to Week 104) 
– whichever comes first. “Normalization” is defined as return of CD 19+ B cell count 
above LLN or within 10% of baseline (in cases where the baseline value itself was below 
LLN). When a decision is made for subjects to exit the individualized safety follow up 
phase, they will attend a final site visit within 28 days of that decision for final efficacy 
assessments to help explore the durability of any treatment response.
Subjects who prior to the Week 68 visit receive a disease modifying therapy that may 
affect B-cell numbers are not required to enter the IFU.
Finally, as this is an exploratory clinical trial and neither agent is licensed for Sjögren’s 
syndrome there are no plans to provide either agent following completion of the 
treatment phase of the study.
4.4.
Type and Number of Subjects
Adult subjects with symptomatic and systemically active disease as well as evidence of 
glandular reserve function will be recruited. A screen failure rate of 25% is anticipated. 
This implies 94 subjects must be screened in order to randomize approximately 70 
subjects into the trial. 
 
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The total number of subjects randomized may increase following sample size re-
estimation up to a maximum of 120 recruited into the study.  The sample size re-
estimation will be conducted at the interim analysis.
In addition, if subjects prematurely discontinue the study, additional subjects may be 
randomized and assigned to the next treatment in the randomization schedule at the 
discretion of the Sponsor. 
4.5.
Design Justification
This is a randomized, double-blind (sponsor open), placebo-controlled trial. Stable, low 
dose steroids (≤10 mg prednisone or equivalent) and hydroxychloroquine will be 
permitted in all treatment arms. The use of pilocarpine and cevimeline (at stable doses) as 
well as symptomatic therapies (such as ophthalmic lubricants, chewing gum) may be 
used for symptom relief during the treatment and follow up phases but would be 
prohibited within a period of time prior to endpoint assessments (see Section 6.9.1 for 
details). Considering that there are no disease modifying treatments for Sjögren’s 
syndrome and that approved therapies consist of symptomatic treatments, inclusion of a 
placebo-controlled arm is ethically justifiable – especially considering these subjects will 
be allowed to continue stable low doses of standard of care treatments (steroids, 
hydroxychloroquine and symptomatic topical therapies). 
4.6.
Dose Justification
Dose Selection:
The belimumab 200 mg SC weekly dose was selected because it delivers a substantial 
molar excess of belimumab above free BLyS levels in the blood, resulting in rapid 
suppression of BLyS levels and is understood to be equivalent (by area under the curve, 
AUC) to the belimumab 10 mg/kg IV dose which has been shown to be safe and effective 
in patients with active SLE. A Phase III study with 200 mg belimumab administered SC 
weekly in SLE patients is currently ongoing.  The double blind phase of this study was 
recently completed; the belimumab 200 mg SC weekly dose plus standard of care 
significantly improved SLE Response Index (SRI) and decreased time to severe flare 
compared with placebo plus standard of care.  Furthermore, safety findings 
withbelimumab plus standard of care were similar to that of placebo plus standard of care 
[Stohl, 2017].  In addition, a completed belimumab trial in patients with Sjögren’s 
syndrome [BELISS study; Mariette, 2015] used the 10 mg/kg IV dose without 
unexpected adverse events. 
The rituximab 1,000 mg IV dose (x2, 2 weeks apart) was selected because it causes rapid 
depletion of peripheral B cells to below the lower limit of quantification. Also, this 
regimen is the approved treatment course for patients with rheumatoid arthritis (RA). In 
addition, published trials of rituximab in patients with Sjögren’s syndrome have used this 
regimen.
 
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Dose Duration and Selection of Key Time Points:
In the co-administration therapy arm, rituximab treatment will commence at Week 8, two 
months after the start of belimumab. This will provide an opportunity to observe the 
anticipated increase in the memory B cell population in peripheral blood (mobilization 
endpoint) expected with belimumab and to determine whether greater increases in 
peripheral B cells correlate with greater efficacy for individual subjects in the co-
administration therapy arm. 
Following the last dose of rituximab therapy (which will be at Week 10 for the co-
administration arm), B cell levels are predicted to remain suppressed below the level of 
quantification for at least 14 weeks [Emery, 2006; Meijer, 2010]. Therefore, Week 24 is a 
time point at which both anti-CD 20 and anti-BLyS pharmacodynamic effects are 
maximal, and was selected as the time point for primary efficacy comparison. 
In the co-administration therapy arm, continuing belimumab treatment to Week 24 
provides an opportunity to assess peripheral B cell reconstitution in the presence of 
prolonged BLyS suppression.
The Week 52 assessment provides an opportunity to determine whether treatment effects 
achieved at Week 24 in the co-administration therapy group can be maintained or 
improved after a drug-free follow up period (persistence of effect after treatment 
discontinuation) and to evaluate the effects of chronic (52 week) belimumab treatment on 
clinical, functional and mechanistic endpoints.
The primary efficacy comparison for this study at Week 24 will be between the co-
administration therapy arm and the placebo arm. 
4.7.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1550188 and rituximab can be found in the Investigator’s Brochure and product 
label, respectively. 
There is an unmet medical need in pSS for a disease modifying therapy that can prevent 
B-cell mediated autoimmune damage, alleviate glandular as well as constitutional 
symptoms, and ameliorate extra-glandular target organ manifestations. There are no 
disease-modifying treatments for this disease. Rituximab controlled trials have shown 
temporary but not sustained effects on glandular function and constitutional symptoms 
[Meijer, 2010; Devauchelle-Pensec, 2014]. In an open label belimumab study (BELISS, 
n=30) 60% of subjects met the primary endpoint defined as improvement in at least two 
of five parameters including dryness, fatigue, pain, measures of systemic disease activity 
and B cell biomarkers; however, the study did not demonstrate change in objective 
measures of glandular function [Mariette, 2015]. A single clinical case has been reported 
where sequential belimumab and rituximab appeared to yield dramatic results. The 
subject had severe refractory pSS including parotid B-cell MALT lymphoma and 
cryoglobulinemic vasculitis. While numerous previous treatments, including rituximab 
and belimumab monotherapy, had failed, the patient responded to therapy when 
 
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rituximab was administered 49 days following a treatment course of belimumab [De Vita, 
2014].
The safety profile of belimumab in the open-label study described above appeared 
consistent with that in the SLE population. The safety profile of rituximab in pSS 
suggests an elevated incidence of serum sickness compared with RA, SLE or lymphoma 
[Meijer, 2010] and has ranged from 6-38% [Carubbi, 2014]. The increased risk could be 
related to the disease itself or less intensive background steroid/immunosuppressant 
regimens. Hypergammaglobulinemia, which is common in pSS, could also contribute. 
Potential increased risks associated with the co-administration of belimumab and 
rituximab include more prolonged B-cell suppression and more profound 
hypogammaglobulinemia that could put subjects at increased risk for serious infections 
(including PML and Hepatitis B reactivation), malignancy, as well as greater interaction 
with immunizations. 
There are no clinical trial data for the co-administration of belimumab with rituximab; 
however, the following data were reviewed and no new safety risks beyond what would 
be expected for either agent alone was suggested from the very limited data available 
from patients (n=39) who may have had overlapping exposures to belimumab and 
rituximab:

The GSK Safety Database of adverse events from clinical trials and post-
marketing experience

An insurance claims database (SafetyWorks)

In-stream, blinded data from an ongoing GSK study of belimumab in subjects 
with vasculitis who were induced with high dose corticosteroids and either 
rituximab or cyclophosphamide.
Given that the experience of co-administered anti-CD20 and anti-BLyS to date is very 
limited, coupled with the introduction of dual biologic therapy in this new indication of 
pSS, robust safety monitoring and stopping rules are being implemented to safeguard 
subject safety. The key risk assessment and mitigation strategy for this protocol is 
outlined in Section 4.7.1. 
 
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4.7.1.
Risk Assessment for Dual Biologics in pSS
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [belimumab (GSK1550188) & rituximab]
Infections:
Prolonged B-cell suppression 
and more complete B-cell 
depletion expected; potential 
for more profound 
hypogammaglobulinemia 
with increased risk for 
serious infections including 
opportunistic infections 
(OIs), PML, and HBV re-
activation.
Rituximab: The rate of 
serious infections with 
rituximab in the RA 
population is 4/100 per 
year.
Reactivation of hepatitis B 
has also been very rarely 
reported in RA patients 
receiving rituximab. 
Late onset neutropenia 
occurs rarely in patients 
treated with rituximab.
Belimumab: The rate for 
belimumab in SLE is 5% of 
subjects receiving either 
belimumab or placebo.
Belimumab and Rituximab:
Infections are expected 
events for both belimumab 
and rituximab.
Cases of PML have been 
very rarely reported, 
including fatal events, for 
both rituximab and 
belimumab in autoimmune 
diseases. 
Dual Belimumab and 
Rituximab: There is pre-
clinical evidence for 
prolonged B-cell 
suppression and more 
complete B-cell depletion 
as well as effect on IgG1+ 
plasma cells in the long-
lived bone marrow niche 
thought to be less sensitive 
Exclusions based on 
significant infection history, 
serologic evidence of past or 
present HBV or HCV 
infection; IgG < 550 mg / 
dL, IgA deficiency, 
neutrophils <1.5X109/L.
A PML management plan 
including neurologic 
questionnaire and patient 
alert card.
Individual subject’s 
treatment will be 
discontinued for (a) life-
threatening infection; (b) 
IgG <400mg/dL (or 
<550mg/dL if associated 
with a serious infection); (c) 
neutrophils < 1X109/L
Subjects will be monitored 
for up to 2 years or until B-
cells return to LLN and 
monitored for late onset 
neutropenia at 6 months 
post-rituximab.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
to immunotherapy [Lin, 
2015] with dual B-cell 
immunotherapy. 
Assessment of the 
translatability of the IgG 
reductions to humans is 
difficult to make due to 
species differences in B-cell 
biology and different 
treatments; however, the 
mouse data raises the 
hypothetical risk that 
immunoglobulin levels may 
reduce more with co-
administration treatment.
Systemic Infusion / 
Injection Reactions, 
Hypersensitivity Reactions 
and Immunogenicity
There is a potential risk for 
increased ADA due to cross 
reactivity which could lead 
to increased frequency of 
hypersensitivity reactions, 
particularly of the delayed 
type.
Serum Sickness: The 
incidence of serum sickness 
associated with rituximab is 
higher in autoimmune 
indications and likely greater 
in Sjögren’s Syndrome vs. 
RA [Meijer, 2010]. 
Rituximab: The incidence 
of serum sickness 
associated with rituximab in 
pSS studies has ranged from 
6-38% [Carubbi, 2014].
Belimumab and Rituximab:
Administration of 
belimumab and rituximab 
may result in infusion and 
hypersensitivity reactions, 
which can be severe and 
can be fatal. Delay in the 
onset of serious 
hypersensitivity reactions 
can occur. Both rituximab 
and belimumab have been 
associated with delayed 
type non-acute HSR/serum 
sickness, although no 
relationship to ADA has 
been established. 
Dual Belimumab and 
Rituximab: Incidences of 
hypersensitivity and 
infusion reactions have 
been noted to be higher 
with co-administration vs. 
ADA will be monitored 
with collection at baseline, 
Weeks 8, 24, and 52
A pre-medication regimen 
will be given before each 
rituximab/rituximab 
placebo infusion: 
methylprednisolone 100 mg 
IV, an oral antihistamine 
and analgesic.
Patients will be given an 
alert card for HSR and 
delayed HSR/serum 
sickness.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
mono-biologic therapy but 
no association with ADA 
has been established 
[Weinblatt, 2006].
Malignancy
There is an increased risk of 
B-cell lymphoma in pSS. 
There is a theoretical 
increased risk of malignancy 
with combination 
immunosuppressive 
mechanisms; however, the
potential synergistic effect of 
rituximab/belimumab would 
be assumed to result in a 
prolonged b-cell depletion 
that would not be dissimilar 
to repeat doses of rituximab.
Belimumab and Rituximab:
Immunomodulatory drugs 
like rituximab and 
belimumab may increase 
the risk of malignancy. To 
date, no causal relationship 
to belimumab or rituximab 
to malignancy, including B-
cell lymphoma, has been 
detected with either agent, 
both of which have been 
administered long term and 
in combination with other 
immunosuppressants of 
various mechanisms. 
Subjects with a history of 
malignancy in the 5 yrs 
prior to randomization will 
be excluded (see Section 
5.2, criterion #4).
Interaction with 
Vaccinations
There is a risk of reduced 
antibody titers with mono 
and dual B cell 
immunotherapy. The 
potential synergistic effect of 
rituximab and belimumab 
may result in a prolonged B-
cell depletion that should 
have a similar impact on 
vaccine response as 
administering repeated doses 
of rituximab.
Rituximab: Median 
antibody titers (tetanus, 
diphtheria, pneumococcus) 
at Week 32 were reduced 
from baseline in atacicept 
but not placebo-treated 
patients who had been 
previously treated with 
rituximab. However, these 
values recovered close to 
baseline by Week 16 of the 
follow-up, there were few 
shifts to below protective 
titres, and no between-
group differences with 
respect to the frequency of 
shifts.
Belimumab: the efficacy of 
concurrent vaccination in 
patients receiving 
belimumab is not known; 
Live vaccination is 
prohibited from 30 days 
prior to Day 0 until the end 
of the general follow up 
period or IFU, if 
appropriate. 
Subjects’ vaccination status 
should be assessed and 
current immunization 
guidelines followed; all 
necessary vaccinations 
should be administered if 
possible no later than 30 
days prior to Day 0.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
however, in the belimumab 
vaccination trial (study 
115470, see GSK Clinical 
Study Register at www.gsk-
clinicalstudyregister.com), 
evaluation of the impact of 
belimumab treatment on 
response to on-treatment 
vaccination with 23-valent 
pneumococcal vaccine 
revealed that immune 
responses to the different 
serotypes were similar in 
SLE patients receiving 
belimumab compared with 
those not receiving 
treatment at the time of 
vaccination.
Psychiatric Events
There is a potential risk of 
psychiatric events with 
belimumab and rituximab.
Rituximab: Depression and 
anxiety were common 
adverse events in rituximab 
RA trials.
Belimumab: There have 
been reports of depression 
and suicidality in patients 
receiving belimumab. A 
causal relationship to 
belimumab has not been 
established.
Subjects who, in the 
investigator’s opinion, pose 
a significant suicide risk 
will be excluded. 
The C-SSRS will be 
completed at each visit 
during which the subject 
may potentially be exposed 
to belimumab. 
Subjects will be monitored 
closely for signs and 
symptoms of psychiatric 
illness including depression 
and suicidal ideation. 
Subjects displaying such 
signs and symptoms will be 
treated appropriately and 
referred as necessary to 
specialty psychiatric care.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Cardiac disorders
Rituximab: Angina pectoris, 
cardiac arrhythmias such as 
atrial flutter and fibrillation, 
heart failure and/or 
myocardial infarction have 
occurred in patients treated 
with rituximab. There is no 
data on the safety of 
rituximab in patients with 
moderate to severe heart 
failure or severe, 
uncontrolled CV disease. 
Belimumab and Rituximab:
Hypotension may 
accompany infusion/post-
injection systemic reactions 
with both rituximab and 
belimumab.
Exclude subjects with 
severe heart failure (New 
York Heart Association, 
Class IV) or other severe, 
uncontrolled cardiac 
disease.
Closely monitor any 
patients with cardiac history 
or those who have 
experienced prior 
cardiopulmonary adverse 
reactions during 
administration of 
rituximab/rituximab 
placebo. Consider 
withholding anti-
hypertensive medications 
12 hours prior to 
rituximab/rituximab 
placebo infusion.
Skin reactions
Rituximab: Severe skin 
reactions such as Toxic 
Epidermal Necrolysis and 
Stevens-Johnson syndrome; 
some with fatal outcome, 
have been reported with 
rituximab. 
Permanently discontinue 
treatment in the case of 
such an event with 
suspected relationship to 
treatment.
Posterior Reversible 
Encephalopathy Syndrome
(PRES)
Rituximab: Cases of PRES / 
reversible posterior
leukoencephalopathy 
syndrome (RPLS) have 
been reported. Signs and 
symptoms included visual 
disturbance, headache, 
seizures and altered mental 
status, with or without 
associated hypertension. A 
diagnosis of PRES/RPLS 
Medical monitor will be 
notified of any new 
neurologic symptoms (see 
Section 5.4.3). Medical 
monitor and investigator 
will consider the possibility 
of PRES in differential 
diagnosis.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
requires confirmation by 
brain imaging. The reported 
cases had recognized risk 
factors for PRES/RPLS, 
including the patients’ 
underlying disease, 
hypertension, 
immunosuppressive therapy 
and/or chemotherapy.
Study Procedures
Salivary gland Biopsy
This procedure is associated 
with (a low) incidence of 
complications including 
bleeding and hematoma 
formation. 
The reported incidence of 
bleeding and hematoma 
were 7.5% and 2.7%, 
respectively in a large case 
series [Santiago, 2012].
Subjects will be instructed 
to stop anticoagulant 
therapy (i.e., aspirin, 
NSAIDs, warfarin) prior to 
the procedure. Also, the 
biopsy will be performed by 
qualified physicians, 
surgeons or dentists and the 
personnel performing the 
biopsy will be required to 
undergo study-specific 
training in the performance 
of this procedure. 
4.7.2.
Vaccinations
The vaccination risk mitigation strategy detailed in the table above recommends that all 
necessary vaccinations should be administered if possible no later than 30 days prior to 
day 0 and requires that no live vaccine be given from 30 days prior to day 0 until the end 
of the general follow up period or IFU, if appropriate.  In determining which vaccinations 
are necessary, investigators should follow guidelines such as the EULAR 
recommendations for vaccination in adult patients with autoimmune inflammatory 
rheumatic diseases (van Assen, 2011).  If indicated for standard of care, non live vaccines 
(e.g., inactivated influenza vaccines) may be administered while on study based on an 
assessment of the benefit:risk (e.g.: theoretical risk of decreased responsiveness).
4.7.3.
Benefit Assessment
This study provides an opportunity for subjects with moderate to severely active 
Sjögren’s syndrome to benefit from a potentially disease modifying regimen that may 
stop B-cell mediated autoimmune damage, alleviate glandular as well as constitutional 
symptoms, and ameliorate extra-glandular target organ manifestations. Additionally this 
 
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study is designed for active Sjögren’s syndrome patients who are not experiencing relief 
despite their current medications, including topical symptomatic medications, oral 
muscarinic agonists, steroids and hydroxychloroquine (which are permitted in all arms) to 
benefit from the addition of potentially beneficial biological therapy.
4.7.4.
Overall Benefit:Risk Conclusion
Taking into account the measures that will be implemented to minimize risk to subjects 
participating in this study, the potential risks associated with belimumab and rituximab 
are justified by the anticipated benefits that may be afforded to patients with Sjögren’s 
syndrome who choose to participate in this trial.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement and 
product label.
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:
AGE
1.
Age ≥18 years, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2.
Documented Primary Sjögren’s Syndrome by American European Consensus Group 
criteria including:
-
either SS-A or SS-B positive.
3.
Baseline unstimulated salivary flow >0.0 mL/min or evidence of glandular reserve 
function (stimulated baseline salivary flow >0.05 mL/min).
4.
Symptomatic oral dryness (5/10 on subject completed Numeric Response Scale)
5.
Systemically active disease, ESSDAI ≥5 points.
OR (for sites in ITALY ONLY)
Systemically active disease, ESSDAI≥5 points and with at least:
a) 1 extraglandular domain moderate,
 
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OR
b) 2 extraglandular domains low.
SEX
6.
Male and female subjects; females of child bearing potential are eligible if using 
effective contraception: 
Female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotropin (hCG) test), not lactating, and at least 
one of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)]. Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study; otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed below in the 
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP) requirements from 30 days prior to the 
first dose of study medication up to Week 68 after Day 0.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label

Combined estrogen and progestogen oral contraceptive
 
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
Injectable progestogen

Contraceptive vaginal ring

Percutaneous contraceptive patches

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.
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.
INFORMED CONSENT
7.
Ability to understand and comply with the protocol-required procedures and 
provision of informed consent.
OTHER CRITERIA
8.
For FRANCE ONLY, a subject will be eligible for inclusion in this study if he /she
is either affiliated to or beneficiary of a social security category. It is the 
investigator’s responsibility to ensure and to document (in source document - patient 
notes) that the patient is either affiliated to or beneficiary of a social security 
category.
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 
1.
Diagnosis of secondary Sjögren’s syndrome.
2.
Active life-threatening or organ-threatening complications of SS disease at the time 
of screening based on treating physician evaluation including but not restricted to (a) 
vasculitis with renal, digestive, cardiac, pulmonary or CNS involvement 
characterized as severe, (b) active CNS or PNS involvement requiring high dose 
steroids, (c) severe renal involvement defined by objective measures, (d) lymphoma.
3.
History of major organ transplant (including hematopoietic stem cell transplant).
4.
History of malignancy within past 5 years [with the exception of adequately treated: 
(a) cervical carcinoma Stage 1B or less, (b) non-invasive basal cell and squamous 
cell skin carcinoma].
5.
History of infection requiring long term systemic therapy including: (a) history of 
positive HIV serology, (b) positive serology for Hepatitis C (HCV), (c) positive 
serology for Hepatitis B (HB), defined as: (i) HB surface antigen positive (HBsAg+) 
 
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OR (ii) HB core antibody positive (HBcAb+). 
6.
Previous serious opportunistic or atypical infections or hospitalization for treatment 
of infection within 364 days of Day 0 or use of parenteral (IV or IM) antibacterials, 
antivirals, anti-fungals, or anti-parasitic agents within 364 days of prior to Day 0.
7.
Patients in a severely immunocompromised state.
8.
History of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies.
9.
History of significant medical illness (or planned surgical procedure) which in the 
opinion of the investigator would interfere with the study procedures and / or 
assessments - including but not limited to IgG4 disease or prior head or neck 
irradiation.
10. Severe heart failure (New York Heart Association, Class IV) or other severe, 
uncontrolled cardiac disease.
11. Tuberculosis (TB), defined as: (a) prior history of TB infection, (b) suspicion of TB 
infection or (c) current TB infection.
12. At risk of suicide, as indicated by a lifetime history of attempted suicide or 
significant suicidal ideation over the 6 months prior to the screening visit; or, if in 
the Investigator’s judgment, the subject is at risk for a suicide attempt.
13. Neurological findings consistent with Progressive Multifocal Leukoencephalopathy 
(PML) - not otherwise explained - or confirmed PML.
14. Electrocardiogram (ECG) showing a clinically significant abnormality at Screening 
or showing an average QTcB or QTcF interval 450 msec (480 msec for subjects 
with a Bundle Branch Block) over 3 consecutive ECGs (refer to Section 7.4.5) 
15. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 
16. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
CONCOMITANT MEDICATIONS
17. Use of systemic immunosuppressive or immunomodulatory agents including 
methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate 
mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), 
mizoribine, calcineurin inhibitors (e.g., tacrolimus, cyclosporine), sirolimus, 6-
mercaptopurine, or thalidomide) within 60 days prior to Day 0.
18. Have received cyclophosphamide within 180 days prior to Day 0.
19. Have received anti-BLyS, anti-CD 20, anti-CD22 or anti-CD52 or any other B-cell 
depleting agent within 364 days prior to Day 0. 
20. Have received abatacept or any biologic agent within 180 day prior to Day 0 
21. Have received IVIG or plasmapheresis within 90 days prior to Day 0.
22. Have received oral steroid >10 mg prednisone equivalent/day within 30 days prior to 
 
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Day 0 or oral steroid >20 mg prednisone equivalent / day for a minimum of two 
consecutive weeks within 60 days prior to Day 0. Have received parenteral steroid 
within 60 days prior to Day 0.
23. Have received a live vaccine within 30 days of Day 0.
24. Current participation in any other interventional trial.
25. Planned blood donation during the treatment and follow up periods of the study.
RELEVANT HABITS
26. Subjects who are unable or unwilling to administer, or to have a caregiver administer 
subcutaneous injections.
27. Drug or alcohol abuse or dependence.
CONTRAINDICATIONS 
28. History of hypersensitivity to belimumab and/or rituximab or known to have titers of 
human anti-mouse antibody or human anti-chimeric antibody or history of 
hypersensitivity reactions when treated with other diagnostic or therapeutic 
monoclonal antibodies.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
29. Have an IgA deficiency (IgA level <10 mg/dL). 
30. Any of the following screening laboratory values:

White blood cells (WBC) <2 x 109/L

Neutrophils <1.5 x 109/L

Circulating IgG < 550 mg / dL 

Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

Bilirubin >1.5 times the upper limit of normal (unless direct bilirubin fraction is 
< 35%)

CD 19+ B-lymphocyte counts <0.1 x 109/L (<100 per CMM) (applies only to 
subjects previously exposed to B cell depleting therapies)
31. For FRANCE ONLY, subjects with legal or administrative guardianship (“tutelle” 
or “curatelle”), or subjects deprived of liberty, or subjects receiving psychiatric care, 
or subjects hospitalized in an Health and Social Establishment for purposes other 
than participation in this study.
 
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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 
failures meet the Consolidated Standards of Reporting Trials publishing requirements, 
and respond to queries from Regulatory authorities, a minimal set of screen failure 
information is required including Demography, Screen Failure details, Eligibility Criteria, 
and any Serious Adverse Events.
Rescreening:  Subjects who fail screening may be rescreened once at the discretion of 
the investigator.
Repeat assessments during the 35 day screening period: assessments (see Section 
7.1), including laboratory assessments, may be repeated if determined necessary by the 
investigator, for example: (a) in cases of technical malfunction (e.g., loss of laboratory 
specimen), (b) in the event of a value close enough to the exclusionary threshold that it 
may reasonably lie within the degree of variability of the assay; (c) if there is reason to 
believe the result may be false (i.e.: contradicts recent  result for the same parameter). 
These are repeat assessments and not rescreening events.  If the original result was 
exclusionary and is confirmed by repeat testing, the subject will be excluded.
In the specific case of an indeterminate result from autoantibody (SS-A, SS-B) 
assessment during the 35 day screening period, this assessment may be repeated once. If 
the result from the repeat assessment is either indeterminate or negative, the subject will 
be excluded.
5.4.
Withdrawal/Stopping Criteria
5.4.1.
General Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
 
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administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to study agent and could potentially be 
exacerbated by the next dose, the investigator may delay IP dosing by up to one week or 
withhold one dose (or single dose co-administration). If a similar concern is present at the 
time of the next scheduled dose, the investigator should contact the Medical Monitor to 
determine whether treatment with belimumab or rituximab should be discontinued. 
Subjects who discontinue IP (i.e., during the treatment phase prior to Week 52) should be 
encouraged to continue to participate in study visits in accordance with the Time and 
Events schedule, especially all remaining safety evaluations. All subjects, including those 
who decline to complete the treatment phase visits through Week 52, are required to 
participate in the general follow up phase (and the individualized follow up phase, if 
applicable).
In addition, for a subset of subjects who receive rituximab/placebo at the Week 8 visit, or 
at both the Weeks 8 and 10 visits, but who discontinue treatment prior to Week 46, 
maintenance of contraception and monthly telephone calls for urine pregnancy test results 
will be required until approximately 52 weeks after the last dose of rituximab/pbo was 
administered.
Week 46 is an important threshold for withdrawal as it is only beyond week 46 that 
continued exposure to belimumab/placebo dictates a longer follow up for pregnancy 
evaluation (Section 7.4.2).
 
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Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before Week 46 
Subject discontinues 
treatment at or after Week 
46 
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the
16-week general follow-
up period
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period.
maintenance of 
contraception and 
monthly telephone calls 
for urine pregnancy test 
results will be required 
until approximately 52 
weeks after the last dose 
of rituximab/pbo was 
administered.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general 
follow-up period.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
Please refer to Section 5.4.4 of the study reference manual for further consideration of 
scenarios which may be encountered in terms of the timing and circumstances of subject 
withdrawal and the steps which need to be followed.
5.4.2.
Early Withdrawal Visit
Subjects that withdraw consent prior to the week 68 visit should, if possible, complete an 
early withdrawal visit. The early withdrawal visit is identical to the week 68 visit (see 
Section 7.1) but also includes the exit interview (Section 7.3.1).
5.4.3.
Detailed Adverse Event Criteria
All subjects should be monitored closely for infection. Patients who develop 
IgG <400 mg/dL confirmed by repeat test 1 week (>2 days) after the initial result, will be 
withdrawn from study treatment. In addition, increased vigilance for infection is 
recommended in subjects who develop IgG <550 mg/dL. Those with a decrease in IgG 
below 550 mg/dL that is associated with a serious infection (i.e., an infection reported as 
 
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an SAE) will be withdrawn from study treatment. In addition, any subject who develops a 
life-threatening infection, regardless of IgG status, will be promptly withdrawn from IP. 
Finally, subjects will be withdrawn from study treatment for the following lab 
abnormality: neutrophils <1X109/L (confirmed by repeat test 1 week [>2 days] after the 
initial result).
A questionnaire-based neurological examination to detect any signs or symptoms 
consistent with the diagnosis of PML will be conducted at each visit (see Appendix 5). If 
any question is answered ‘yes’ and the reason for the symptom is unknown (i.e., is not 
definitely explained by other known cause), the subject will be referred to a neurologist 
for evaluation. An MRI with gadolinium enhancement (pending renal function 
evaluation) and/or cerebrospinal fluid (CSF) JCV PCR are recommended to be performed 
to confirm the diagnosis. In addition, the investigator should contact the Medical Monitor 
within 2 business days if any question is answered ‘yes,’ regardless of suspected cause, to 
discuss appropriate management of the patient. If PML is confirmed, investigational 
product will be discontinued.
Severe skin reactions such as Toxic Epidermal Necrolysis and Stevens-Johnson 
syndrome, some with fatal outcome, have been reported with the use of rituximab. In 
case of such an event with a suspected relationship to IP, treatment should be 
permanently discontinued.
A subject will be withdrawn from study treatment if he or she meets liver stopping 
criteria (defined below), presents with suicidal ideation of type 4 or 5 on the C-SSRS or, 
if in the investigator’s judgment, the subject is at risk for a suicide attempt. Female 
subjects who become pregnant will be withdrawn from IP but may continue in the trial 
for safety reporting and outcomes assessments, including infant status.
Lymphoma discovered on evaluation of baseline biopsy post randomization is a finding 
to be reviewed by the GSK medical monitor and investigator but does not necessarily 
mandate subject withdrawal.
5.4.4.
Study Stopping Criteria
The un-blinded iSRC will review the safety data on a regular basis. The study would be 
stopped if 2 of the first 5 co-administration therapy (belimumab + rituximab) subjects to 
complete Week 10 have IgG <400 mg/dL (confirmed by repeat test 1 week (>2 days) 
after the initial result) that is associated with a serious infection or if there are 2 fatal 
infections. After this point, the un-blinded iSRC will stop the study if the rate of IgG 
<400 mg/dL associated with serious infection or fatal infection rate exceeds 20% in the 
co-administration therapy arm.
5.4.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
The Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.5.1.
Study Treatment Restart
If a subject meets liver chemistry stopping criteria, do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
Refer to Appendix 3 for full guidance. 
5.5.
Subject and Study Completion
A completed subject is one who has completed the treatment and general follow up phase 
of the study including the final visit at Week 68 as defined in the Time and Events Table.
The end of the study is defined as the last subject’s last visit.
 
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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the co-administration of those study 
treatments. Two investigational products, belimumab and rituximab, will be utilized in 
this study.
6.1.1.
Belimumab
The trade name is Benlysta. The generic (USAN/INN) name is belimumab; the GSK 
code for the drug is GSK1550188. Belimumab is a recombinant, fully human, IgG1λ 
monoclonal antibody which is specific for soluble human B lymphocyte stimulator 
(BLyS, also referred to as BAFF and TNFSF13B). Belimumab is produced by 
recombinant DNA technology in a mammalian cell expression system.
Belimumab drug product is provided as a 200 mg sterile, liquid product in a prefilled 
syringe containing a safety shield. Each syringe contains 1.0 mL (deliverable) of 200 
mg/mL belimumab in 0.65 mg/mL L-histidine, 1.2 mg/mL L-histidine 
monohydrochloride, 6.7 mg/mL sodium chloride, 5.3 mg/mL L-arginine hydrochloride, 
0.1 mg/mL polysorbate 80, with pH 6.0. Each syringe is single use.
The placebo control is provided as a sterile liquid product in a prefilled syringe 
containing a safety shield. Each syringe contains 1.0 mL (deliverable) of 0.65 mg/mL L-
histidine, 1.2 mg/mL L-histidine monohydrochloride, 6.7 mg/mL sodium chloride, 5.3 
mg/mL L-arginine hydrochloride, 0.1 mg/mL polysorbate 80, with pH 6.0. Each syringe 
is single use.
Belimumab should be stored in a refrigerator at 2-8°C with protection from light. Placebo 
should be stored in a refrigerator at 2-8°C with protection from light.
The first two doses of belimumab/placebo will be administered under supervision in the 
clinic with monitoring of subjects in clinic for 3 hours following the first and second 
dose. A patient alert card should be sent home with the subject each time 
belimumab/placebo is dispensed for home administration.
Detailed instructions on the storage and administration of study agent will be provided to 
the study site in the Pharmacy Manual and to subjects in a patient-friendly format.
6.1.1.1.
Self Administered Subcutaneous Injections and Log Book
On Day 0, the subject will be randomized. Qualified study site personnel must review 
study agent handling and administration techniques with the subject prior to the first self-
injection of the study agent. Subject will self-administer the study agent by SC injection, 
under supervision at the study site for the first administration on Day 0 and the second 
administration at Day 7 (1 day). In the post-marketing setting with IV belimumab, 
delayed onset of symptoms of acute hypersensitivity reactions has been observed.
 
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Subjects will remain at the clinic for 3 hours following the first and the second dose of 
belimumab/placebo for observation. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgement. Subjects 
should be made aware of the potential risk, the signs and symptoms of such reactions, 
and the importance of immediately seeking medical attention. At the discretion of the 
investigator, subjects who are adequately trained will self-administer all subsequent doses 
at home following the instructions provided on the dosing cards. After the first and the 
second dose, subjects who do not feel adequately trained with self injection may return to 
the site for further training.
Patients who cannot self-administer the study agent must have a reliable resource (e.g., a 
caregiver) to administer the subcutaneous injection. Patients or their caregivers should 
not administer the study agent until they receive proper training in subcutaneous injection 
technique.
Subjects will be provided with a self-injection log book (refer to Appendices of Study 
Reference Manual). Subjects will fill out the injection log immediately after 
administering the injection, recording the date of injection, the injection site and whether 
or not the entire dose was administered. If the entire dose was not administered, an 
explanation should be provided, and the estimated amount injected should be recorded. 
The injection site should be rotated between the left or the right thigh and the abdomen. 
Dosing compliance should be reviewed with the subject monthly at the site study visit 
and self-injection log books reviewed by study site staff. Subjects are also required to 
return all unused syringes at each study visit. Used syringes should be placed in a sharps 
container and returned to the site as described in Section 2 of the Study Reference 
Manual.
6.1.1.2.
Missed Doses
Study agent should be administered weekly. If the subject misses 3 or more consecutive 
doses the missed doses must be documented as a protocol deviation, the next dose should 
be administered at the study site and the subject should remain at the clinic for 3 hours 
following the injection for observation.
6.1.2.
Rituximab
The trade name is MabThera or Rituxan. The generic (USAN/INN) name is rituximab. 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody 
representing a glycosylated immunoglobulin with human IgG1 constant regions and 
murine light-chain and heavy chain variable region sequences. The antibody is produced 
by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity 
chromatography and ion exchange.
Rituximab is a 500 mg concentrated solution which requires dilution prior to infusion. It 
is a clear, colorless liquid. Rituximab and placebo (0.9% NaCl, sterile, pyrogen free) will 
be prepared at the study site by an unblinded pharmacist according to the procedure 
defined in the Pharmacy Manual. Rituximab treatment will consist of two 1000 mg 
intravenous infusions, a first 1000 mg intravenous infusion followed by a second 1000 
 
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mg intravenous infusion 2 weeks later. Please refer to the study reference manual for 
guidance regarding missed doses of rituximab.
Rituximab/placebo will be administered intravenously by an experienced healthcare 
professional under physician supervision, and in an environment where full resuscitation 
facilities are immediately available. Premedication consisting of an oral anti-pyretic and 
an oral antihistamine, e.g., paracetamol and diphenhydramine (approximately 60 minutes 
prior to rituximab) and intravenous methylprednisolone (100 mg) (at least 30 minutes 
prior to rituximab), will be given before each administration of rituximab/placebo.
The rituximab/placebo solution prepared by the unblinded pharmacist should be 
administered as an intravenous infusion through a dedicated line. It should not be 
administered as an intravenous push or bolus. As detailed in the rituximab summary of 
product characteristics, patients should be closely monitored for the onset of infusion 
reactions during the rituximab/placebo infusion. Vital signs (heart rate, blood pressure, 
temperature and respiratory rate) should be regularly measured and subjects should be 
observed closely for any signs that might be consistent with a hypersensitivity reaction 
(e.g. development of skin rash, fever). Patients who develop evidence of severe reactions, 
especially severe dyspnea, bronchospasm or hypoxia should have the infusion interrupted 
immediately. In all patients, the infusion should not be restarted until complete resolution 
of all symptoms, and normalization of clinical investigations including laboratory values. 
At this time, the infusion can be initially resumed at not more than one-half the previous 
rate. If the same severe adverse reactions occur for a second time, the decision to stop the 
treatment should be seriously considered on a case by case basis. Mild or moderate 
infusion-related reactions usually respond to a reduction in the rate of infusion. The 
infusion rate may be increased upon improvement of symptoms.
First infusion (Week 8):
The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be 
escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.
Second infusion (Week 10):
Rituximab can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h 
increments at 30 minute intervals, to a maximum of 400 mg/h. 
Patients who have clinically significant cardiovascular disease, including arrhythmias, or 
previous serious infusion reactions to any prior biologic therapy or to rituximab, should 
not be administered the more rapid infusion.
Subjects will remain at the clinic for 1 hour following the first and the second dose of the 
rituximab for observation. Should symptoms of acute hypersensitivity occur, an extended 
period of monitoring may be appropriate based on clinical judgement. Subjects should be 
made aware of the potential risks, the signs and symptoms of a reaction, and the 
importance of immediately seeking medical attention. Patients treated must be given the 
patient alert card after each infusion of rituximab or rituximab placebo.
Refer to the Pharmacy Manual for detailed instructions on the administration and storage 
of rituximab.
 
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6.2.
Treatment Assignment
Subjects will be assigned to the relevant treatment, as outlined below, in accordance with 
the randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using the validated internal software RandAll NG. The randomization will be centrally 
controlled.
Subjects will be assigned to either the co-administration arm (A), belimumab arm (B), 
rituximab arm (C), or placebo arm (P) initially in a 2:2:2:1 ratio. A description of each 
regimen is provided in the table below:
Treatment Code
Treatment Description
A
Co-administration therapy
B
Belimumab 200 mg SC injection
C
Rituximab 1,000 mg IV infusion
P
Placebo
The subjects will be stratified based on his/her baseline disease activity severity [ESSDAI 
5-12 (moderate) vs. ESSDAI >12 (severe)] ensuring that within each disease severity 
there is an allocation to each treatment group.
Note that the randomization allocation ratio may change following the interim analysis if 
it is decided that one or more treatment arms are dropped or the sample size within a 
treatment arm is increased.
6.3.
Blinding
This will be a double blind (sponsor open) study and the following will apply: 

All study staff involved in clinical assessments (which includes the investigator, sub-
investigators, other site staff), and the subject will be blinded to the treatment 
allocated to individual subjects until the primary and follow up analyses have been 
completed (see Section 9.4.1). 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 
 
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
The date and reason for the unblinding must be fully documented in the eCRF.

An unblinded pharmacist will be used at each study site to prepare rituximab and its 
placebo for intravenous administration. Unblinded monitors will be assigned to 
review all pharmacy records, storage and procedures.

An unblinded member of staff at each site will be assigned to use the randomization 
software (RAMOS NG) and to receive all drug shipments and notifications.

Following discussion with GSK medical monitor, a subject may continue in the 
study if that subject’s treatment assignment is unblinded. The primary reason for 
unblinding (the event or condition which led to the unblinding) will be recorded in 
the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.

During the treatment and follow up phases (see Section 4.3.1 and Section 4.3.2), all 
study staff (which includes the investigator, sub-investigators, other site trial staff,
and the subject) will remain blinded to central laboratory data that have the potential 
to unblind a subject’s treatment assignment. Such data may include but is not 
necessarily limited to:

B-cell lymphocyte counts including results from flow cytometry

IgM and IgA levels
Refer to the central laboratory manual for additional information.

The iSRC will perform safety reviews of laboratory data during the conduct of the 
study, as outlined within the iSRC charter.

Sponsor open refers to those members of the iSRC and the TA DAC who are 
unblinded, as outlined in the iSRC charter. The GSK study team will remain blinded 
until the primary analysis (see Section 9.4.1) except for those in unblinded roles e.g., 
unblinded monitor for monitoring the pharmacy etc, as well as a restricted number of 
team members required for interpretation of data at the interim analysis (Section 
9.3.2), as specified in the iSRC Charter.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of and reconstitution 
of rituximab and its placebo will be detailed in a Study Specific Technical 
Agreement/Memo or Pharmacy Manual which will be accompanied by a Quality 
Agreement.
 
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
Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records). 

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure, notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the investigative site with belimumab or matching placebo 
subcutaneously, they will receive study treatment directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the 
clinic will be recorded in the source documents. The dose of study treatment and study 
subject identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study treatment. 
When subjects self-administer study treatment(s) at home, compliance with belimumab 
or matching placebo treatment will be assessed through review of the self-injection log 
book with the subject during site visits and documented in the source documents and 
eCRF. A record of the number of belimumab syringes dispensed to and taken by each 
subject must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the eCRF.
Rituximab will be intravenously administered to subjects at the site. Administration will 
be documented in the source documents and reported in the eCRF.
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of subcutaneous belimumab in excess of 200 mg per week (7 ± 2 
days) will be considered an overdose. GSK does not recommend specific treatment for an 
overdose. 
 
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For this study, any dose of rituximab in excess of 1,000 mg IV within a 24 hour period 
will be considered an overdose. Please refer to the rituximab approved product label for 
advice on the management of overdose.
In the event of an overdose, the investigator or treating physician should:
1. contact the Medical Monitor immediately
2. monitor the subject closely for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities.
3. obtain a sample for pharmacokinetic (PK) analysis if requested by the Medical 
Monitor (determined on a case-by-case basis)
4. document the quantity of the excess dose as well as the duration of the overdosing 
in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor and based on the clinical evaluation of the 
subject.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies

Oral steroids (provided subject is on a stable regimen for at least 30 days at a dose no 
greater than 10 mg prednisone equivalent daily prior to Day 0 and continues this 
dose for the duration of the study).

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd (ie daily) for 30 days prior to Day 0 and continues this dose for the duration of 
the study).

Topical symptomatic therapies are detailed below:

Ophthalmic lubricants [(e.g. glucane or saline eye drops); subjects will be 
required to withhold dosing 4hrs prior to efficacy assessments].

Ophthalmic lubricating ointments [(e.g. Dry Eyes, LacriLube); subjects will be 
required to withhold dosing 24hrs prior to efficacy assessments].

Hydroxyl cellulose ophthalmic  insert  [(e.g. Lacrisert); subjects will be required 
to withhold dosing 24hrs prior to efficacy assessments].
 
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
Non-pharmacologic saliva stimulants  [(e.g. gums, drinks, teeth washing); 
subjects will be required to withhold dosing 90 minutes prior to efficacy 
assessments].

Saliva substitutes [(e.g. Xialine, Oral Balance , Saliva Orthana , Salinum mouth 
rinses, Chlorhexidine mouth rinses); subjects will be required to withhold dosing 
90 minutes prior to efficacy assessments.

Oral muscarinic agonists (such as pilocarpine and cevimiline) provided subjects are 
on a stable regimen for at least 30 days prior to Day 0 and continue this dose for the 
duration of the study. Subjects will be required to withhold dosing with these agents 
in the 24h prior to all efficacy assessments.

Anticholinergic agents, such as tricyclic antidepressants, bupropion, antihistamines, 
phenothiazines, antiparkinsonian drugs, anti-asthmatic medications, or 
gastrointestinal (GI) medications that cause xerostomia in more than 10% of patients, 
provided that a subject is on a stable regimen for at least 30 days prior to Day 0. 
6.9.2.
Prohibited Medications and Non-Drug Therapies

Concomitant biologic treatments (see SRM for examples)

Conventional systemic immunosuppressive treatments and DMARDs (such as 
methotrexate and azathioprine) (see SRM for examples)

Pharmacological topical ophthalmic agents (e.g. NSAIDs, corticosteroids, 
cyclosporine, diquafosal) are excluded from use in the study.

Non muscarinic secretagogues (e.g.  Anetholtritione, Bromhexine3 N-acetylcystein) 
are excluded from use in the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table, Section 7.1.
 
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7.1.
Time and Events Table
Study Day
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period
General
follow 
up 
period1
Individ
ualized 
follow 
up 
period 
(IFU)6
IFU 
Final 
Visit
Day 0
7 ± 1 days
28 ± 7days
56 ± 7days
70 ± 7 days
84 ± 7 days
112 ± 7days
140 ± 7days
168 ± 7days
196± 7days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
W -5
W1
W4
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
W68
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical exam
X
X3
X
X
X
Abbreviated physical exam symptom 
directed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Past & current medical conditions 
[including AECG criteria & CV medical 
history] 
X
Urine pregnancy test (WCBP) in clinic9
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review
X10
X3
X
X
X
X
X10
X
X
X10
X
X
X10
X
X
X
X10
X10
X
X10
Study Treatments
Randomization
X
Belimumab/placebo.(weekly, home, except 
1st & 2nd dose), last dose wk 51
X11
X11
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor in clinic after dosing for 3hrs (1st & 
2nd dose of belimumab/pbo)
X
X
Rituximab/placebo (at site) 
X8
X8
Monitor in clinic after dosing for 1h post 
rituximab/placebo
X
X
 
 
 
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Study Day
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period
General
follow 
up 
period1
Individ
ualized 
follow 
up 
period 
(IFU)6
IFU 
Final 
Visit
Day 0
7 ± 1 days
28 ± 7days
56 ± 7days
70 ± 7 days
84 ± 7 days
112 ± 7days
140 ± 7days
168 ± 7days
196± 7days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
W -5
W1
W4
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
W68
Efficacy, pharmacokinetics and pharmacodynamics
ESSDAI16
X
X
X
X
X
X
X
ESSPRI 
X
X
X
X
X
X
X
Oral Dryness numerical resp. scale
X
X
X
X
X
X
X
Ocular Dryness numerical resp. scale
X
X
X
X
X
X
X
Salivary gland biopsy
X5
X12
X13
Lacrimal function (Schirmer's) test
X
X
X
X
X
Fatigue- (PROFAD SSI SF)
X
X
X
X
Patient Global Assessment (PtGA) 
X
X
X
X
Physicians Global Assessment (PGA) 
X
X
X
X
Exit interview19
X
Stimulated Salivary Flow
X
X
X
X
X
X
X
Unstimulated Salivary Flow 
X
X
X
X
X
X
X
Blood: Leukocyte population2
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
Serological biomarkers
X
X3
X
X
X
X
X
X
X
X
X
X
X
Saliva sample for proteomics
X
X
X
X
X
Blood: BLyS levels2
X3
X
X
X
X
X
X
X
X
X
X
X
Blood: Transcriptomics
X3
X
X
X
X
Salivary gland: Transcriptomics
X
X
X13
Blood: PBMC exploratory endpoints
X3
X
X
Blood: Belimumab PK2
X
X
X
X
Blood: Rituximab PK2
X7
X7
X
X
X
 
 
 
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Study Day
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period
General
follow 
up 
period1
Individ
ualized 
follow 
up 
period 
(IFU)6
IFU 
Final 
Visit
Day 0
7 ± 1 days
28 ± 7days
56 ± 7days
70 ± 7 days
84 ± 7 days
112 ± 7days
140 ± 7days
168 ± 7days
196± 7days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
W -5
W1
W4
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
W68
Safety & Laboratory Assessments
AE/SAE review 
X17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X18
X
Vital signs
X
X3,4
X4
X
X4
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
CSSRS (suicidality assessment) 
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological assessment
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X3
X
X
X
X
X
X
Blood: Immunoglobulin levels (IgG, IgA2, 
IgM2)
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood: Cryoglobulins
X
X
X
X
X
X
X
Blood chemistry
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B and Hep C screen
X14
X
Pharmacogenetics blood sample15
X
Blood: Belimumab Immunogenicity2
X3
X
X
X
X
Blood: Rituximab Immunogenicity2
X3
X
X
Footnotes:
1. All subjects, including subjects who are withdrawn from the study (See Section 5.4.1) and decline to complete the treatment phase visits through Week 52, are required to enter 
the general follow up period. During this 16-week general follow up period, subjects will receive calls every 4 weeks (±7 days) to evaluate AEs, to check concomitant medications 
and to complete the neurological assessment (Appendix 5).
2. In order to maintain the blind, sites will be blinded to these data following screening - including B-cell flow cytometry panels and IgA, IgM levels.
3. To be measured or collected pre-dose.
4. Subjects will be monitored post study treatment as detailed in protocol.
 
 
 
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5. Biopsy can occur on Day 0 or at any time during the screening period provided the subject has met all other entry criteria prior to the biopsy.
6. Subjects will enter the IFU if, following the general follow up period, their CD19+ B-cell levels remain below the lower limit of normal (or less than 90% of baseline, if baseline 
value was below LLN). During the IFU, subjects will be seen in the clinic every 12 weeks (7 days), with calls every 4 weeks (±7 days) between visits to evaluate subjects for 
AEs & concomitant medications. Subjects will exit the IFU when: CD19+ B-lymphocyte counts are within normal range or 10% of baseline levels (if baseline < LLN), OR at the 
investigator’s discretion the subject starts receiving disease modifying therapy that may affect B-cell numbers OR or for up to a maximum of 2 years (i.e., up to Week 104) –
whichever comes first. Subjects exiting IFU period will attend a final visit (within 28 days of that decision) for final assessments (IFU Final Visit) as detailed in the Table.
7. Obtain samples post-dose only, within 10 minutes after end of infusion.
8. Both doses of rituximab/placebo will be administered in the clinic. Approximately 60 minutes prior to rituximab/placebo, subjects will receive orally an antipyretic and an 
antihistamine. At least 30 minutes prior to administration of rituximab/placebo, subjects will receive IV 100mg methylprednisilone .The 2nd rituximab/placebo administration at the 
Week10 visit must be given 14 days (13-18 days, see SRM) after the first administration (given at the Week 8 visit). A patient alert card should be sent home with the subject 
following each dose of rituximab/placebo.
9. If urine test is positive, confirm with serum test. Pregnancy testing & contraception are required until 16 weeks post last administration of study treatment for those subjects who 
complete Weeks 46- 52 or withdraw from treatment prior to Week 8 dosing. Pregnancy testing and contraception are required for approximately 12 months after the 
administration of the final rituximab/placebo dose for the subset of subjects who discontinue treatment from Week 8 up to Week 46. 
10. Subjects will receive a reminder phone call 48 hours prior to efficacy assessment visits to remind them that they should not be using certain symptomatic therapies prior to visit 
(see Section 4.1 of Study Reference Manual for details); in addition subjects should document their last use of symptomatic therapies in their self injection log book.
11. First & second dose of belimumab will be administered in clinic by subject or caregiver. A patient alert card will be sent home with the subject each time belimumab is dispensed 
for home administration. 
12. Week 24 biopsy may be taken on a separate day from the other required assessments within the Week 24 study visit window.
13. Week 52 biopsy is optional. Trancriptomics will only be performed if biopsy is taken.
14. If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required.
15. Informed consent for optional substudies e.g.,genetics must be obtained before collecting a sample. 
16. If additional tests (e.g., pulmonary function tests, EMG, MRI) are required to complete ESSDAI assessment, these should be scheduled as close as possible to the stipulated 
study visit window.
17. From signing of consent until initiation of study treatment, only SAEs related to study participation will be collected.
18. From the end of general follow-up phase through the last contact (including the individualized safety follow-up phase), only designated AESIs (i.e., infections, malignancies, and 
depression/suicidality/self-injury), fatal SAEs, and SAEs assessed as related to the investigational product or to study participation will be collected.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Information collected during the Screening Phase assessments described below represents 
key data that identifies and defines subject baseline status. This information is critical for 
the evaluation and comparison of subsequent safety and efficacy assessments.
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 enter a screening period of up to 35 
days.  A subject may be randomized when all screening procedures have been completed 
and eligibility criteria confirmed. During the screening period 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. 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, and will impact the safety monitoring assessments during the study. 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:

Past or current conditions.

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, 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).
Urine Pregnancy Test: A test will be performed for women of child-bearing potential: 
monthly during the double blind treatment with investigational product (up to Week 52) 
and then at each clinic visit during the general and individualized follow up phases (see 
Time and Events Table in Section 7.1). Refer to the pregnancy section (Section 7.4.2).
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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Electrocardiogram: 12-lead ECGs will be obtained at screening. A single method 
(Bazett’s or Fredericia’s) must be used when calculating the corrected QT interval for 
determining subject eligibility, as described in the study reference manual (SRM).
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.
Unstimulated and stimulated salivary flow: Unstimulated and stimulated salivary flow 
rate will both be assessed as an entry criteria to ensure that subjects entered into the study 
have residual glandular function. Subjects with 0.0 mL/min unstimulated salivary flow 
rate may qualify for the study on the basis of stimulated salivary flow greater than 
0.05 mL/min. Details of the collection procedure will be further specified in the SRM.
Oral dryness Numerical Response Scale (NRS): subjects are required to have 
symptomatic oral dryness as assessed by a score of at least 5 points on the 10 point NRS. 
The oral dryness NRS will be detailed in the SRM. 
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 treating physician (preferably the same 
physician at each visit). 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, 2015].
Serological Biomarkers: Quantification of serum analytes, autoantibodies [including 
anti-SS-A, SS-B], markers of B cells activation [may include but not limited to Beta-
microglobulin, free kappa and lambda light chain], BLyS and other cytokines [may 
include but not limited to BLyS/Belimumab complex, IL-6, IL-21], chemokines [may 
include but not limited to CXCL13 and CCL19] and other analytes associated with 
immune activation or inflammation [may include but not limited to complement C3, C4, 
CH50, Cryoglobulin, CRP] or Sjögren’s biology will be performed.
Urinalysis: will be performed as related to the eligibility criteria listed in Section 5.
Blood immunoglobulin (IgG, IgA, IgM) screening: will be performed as related to the 
eligibility criteria listed in Section 5.
Tuberculosis: Assessment of TB in the screening period is to be done via evaluation of 
the subject’s history, physical examination of the subject and, if judged necessary by the 
Investigator, local  laboratory testing. For subjects in Argentina only, the central lab will 
perform Quantiferon Gold testing.
Hematology and blood chemistry (clinical safety laboratory assessments): will be 
performed as related to the eligibility criteria listed in Section 5.
 
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HIV, Hepatitis B and C screening: will be performed as related to the eligibility criteria 
listed in Section 5.
Salivary gland biopsy: The salivary gland biopsy surgical technique is described in the 
SRM. Training reference materials will be provided to site personnel who will perform 
this procedure. 
Biopsy tissue will be shipped to a central histopathology laboratory for processing and 
assessment. The baseline biopsy can occur on Day 0 or at any time during the screening 
period provided the subject has met all other entry criteria prior. After the interim 
analysis, dependent on data, the biopsy may no longer be a mandatory requirement.
7.3.
Efficacy
Planned time points for all efficacy assessments are listed in the Time and Events Table 
in Section 7.1. Time windows are provided for each study visit to allow flexibility in site 
and subject scheduling. All study visits should occur within the visit window of the 
scheduled study visit. Details regarding the execution of the efficacy assessments 
described below can be found in the SRM.
ESSDAI: The ESSDAI [Seror, 2014] is an assessment of disease activity across 12 
different clinically relevant domains for subjects with Sjögren’s syndrome. ESSDAI will 
be assessed by the treating physician (preferably the same physician at each visit). A 
recent user’s guide has also been published [Seror, 2015].
Un-stimulated and stimulated salivary flow: Unstimulated salivary flow rate and 
stimulated salivary flow will be measured. Details of the collection procedure will be 
further specified in the SRM.
Salivary gland biopsy: The salivary gland biopsy surgical technique is described in the 
SRM. Training reference materials will be provided to site personnel who will perform 
this procedure. 
Biopsy tissue will be shipped to a central histopathology laboratory for processing and 
assessment. After an interim analysis, dependent on data, the biopsy may no longer be a 
mandatory requirement.
Schirmer’s test: is an assessment of lacrimal gland function 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. 
PGA: the Physician’s Global Assessment is a physician reported visual analogue scale 
that provides an overall measure of the subject’s current disease activity. The assessment 
instrument and technique for administration will be described in the SRM.
Oral dryness NRS: A description of the anchors and directions for administering this 
scale will be provided in the SRM.
 
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7.3.1.
Patient-Reported Outcomes Assessments
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified.
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 0-10 NRS for each symptom. The ESSPRI assessment tool will be detailed 
in the SRM..
Oral and Ocular Dryness: will be reported by subjects on a NRS from 0 to 10. The 
NRS will be translated into local languages. A description of the instrument anchors and 
technique for administering these scales will be described in the SRM. 
PROFAD-SSI-SF: the Profile of Fatigue and Discomfort - Sicca Symptoms Inventory 
(Short Form) questionnaire is an assessment of fatigue, discomfort, and SICCA 
symptoms, on a 0-7 NRS for each item. Details will be provided in the SRM.
PtGA: the Patient Global Assessment is a patient reported numeric rating scale that 
provides an overall measure of disease severity. The assessment instrument and technique 
for administration will be described in the SRM. 
Exit Interviews: Exit interviews will be conducted as shown in the Schedule of Events 
(Section 7.1) to explore subjects’ experience with study treatment. Exit interviews are 
qualitative interviews conducted with study subjects to capture subject experiences in 
drug development on completion of participation in a clinical study. Interview questions 
designed to fully assess a subject’s experience with a study medication are administered 
in a semi-structured format by a trained interviewer. Subject feedback will be captured in 
a data collection sheet as well as being audio-taped for subsequent transcription and 
qualitative analysis. The Exit interview technique and questions will be described in the 
SRM and training as well as training material references will be provided to site 
personnel who will administer the Exit interviews.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table in 
Section 7.1. Additional time points for safety tests may be added during the course of the 
study based on newly available data to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 7.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
 
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7.4.1.1.
Time Period and Frequency for Collecting AE and SAE Information

AEs and SAEs will be collected from the start of Study Treatment through the 
general follow-up period (see Section 4.3 and the Time and Events Table in Section 
7.1)

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

During the individualized safety follow-up phase (if applicable, see Section 4.3 and 
the Time and Events Table in Section 7.1), only SAEs assessed as related to the 
investigational product or to study participation, fatal SAEs, and designated AESIs 
(i.e., infections, malignancies, and depression/suicidality/self-injury) will be 
collected.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 7.

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 7.
7.4.1.2.
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?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(as defined in Section 7.4.1.4) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
 
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(as defined in Section 5.4.1). Further information on follow-up procedures is given in 
Appendix 7.
7.4.1.4.
Adverse Events of Special Interest
A number of adverse events of special interest have been identified as part of the risk 
assessment outlined in Section 4.7.1 due to the co-administration of two biologics and 
will be monitored for the duration of the study.  These AESIs include infections 
(including opportunistic), systemic infusion / injection reactions, hypersensitivity 
reactions, malignancy, psychiatric events (including suicidality), severe skin reactions 
(including Toxic Epidermal Necrolysis and Stevens-Johnson syndrome), 
immunogenicity, cardiac disorders, posterior reversible encephalopathy syndrome 
(PRES), PML, and AE’s related to the biopsy procedure.  The analyses of these events 
will be described in the Reporting and Analysis Plan. 
7.4.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 7 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment 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. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
 
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7.4.2.
Pregnancy

Pregnancy testing and contraception are required until 16 weeks post last 
administration of study treatment for those subjects who complete Weeks 46-52 or 
withdraw from treatment prior to Week 8 dosing. Pregnancy testing and 
contraception are required for approximately 12 months after the administration of 
the final rituximab/placebo dose for the subset of subjects who discontinue treatment 
from Week 8 up to Week 46. 

Details of all pregnancies in female subjects will be collected for pregnancies 
occurring after the start of dosing and until either (a) 16 weeks post last 
administration of study treatment for those who complete Weeks 46-52 or withdraw 
from treatment prior to Week 8 dosing or (b) 12 months after the last administration 
of rituximab/placebo for subjects who discontinue treatment from Week 8 up to 
Week 46. 

If a pregnancy is reported, then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures as outlined in 
Appendix 8.

Women who become pregnant while on active treatment will be withdrawn from 
therapy but will continue in the trial for safety reporting and outcomes assessments. 
The pregnancy must be followed up to determine outcome (including premature 
termination), and status of mother and child including a one-year pediatric follow-up.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Head and Neck, Skin, Cardiovascular, Respiratory, Gastrointestinal, Musculoskeletal 
and Neurological systems. Height and weight will also be measured and recorded. 

An abbreviated physical examination will include, at a minimum, assessments of the 
eyes, mouth, skin, joints, lungs, cardiovascular system, and abdomen (liver and 
spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

A questionnaire-based neurological examination to detect any signs or symptoms 
consistent with the diagnosis of PML will be conducted at each visit. The 
questionnaire is shown in Appendix 5. If any question is answered ‘yes’ and the 
reason for the symptom is unknown (i.e., is not definitively explained by other 
known cause), the subject will be referred to a neurologist for evaluation. An MRI 
with gadolinium enhancement (pending renal function evaluation) and/or 
Cerebrospinal Fluid (CSF) JCV PCR are recommended to be performed to confirm 
the diagnosis. In addition, the investigator should contact the Medical Monitor within 
2 business days if any question is answered ‘yes,’ regardless of suspected cause, to 
discuss appropriate management of the patient. Any findings should be reported as 
an adverse event and the PML reporting procedures followed, as in Section 7.4.7. A 
PML Adjudication Committee will review all cases of PML and suspected PML, and 
will provide their opinion to the sponsor.
 
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7.4.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate. 

Three readings of blood pressure and pulse rate will be taken.

First reading should be rejected.

Second and third readings should be averaged to give the measurement to be 
recorded in the eCRF. 
7.4.5.
Electrocardiogram (ECG)

12-lead ECGs will be obtained at screening. If the ECG demonstrates a QTcB or 
QTcF interval ≥ 450 msec (≥ 480 msec for subjects with a Bundle Branch Block), 
there is a requirement to obtain two additional, consecutive ECGs (for a total of 
three). The investigator will then average the three QTc (and QT) intervals obtained 
and document the following from the 1st ECG:
o
Rate
o
PR interval
o
QRS axis
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in the Time and Events Table (in
Section 7.1) must be conducted in accordance with the Laboratory Manual and Protocol 
Time and Events Schedule. Laboratory requisition forms must be completed and samples 
must be clearly labeled with the subject number, protocol number, site/center number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
the laboratory and will be detailed in the SRM or the laboratory manual. Reference 
ranges for all safety parameters will be provided to the site by the laboratory responsible 
for the assessments.
If additional, non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE) the results must be 
recorded in the eCRF. 
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws. 
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
 
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to make either a treatment or response evaluation, the results must be entered into the 
eCRF.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1. 
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
CBC:
RBC Indices:
WBC Differential:
WBC Count
RBC Count
Neutrophils
Hemoglobin
MCV
Lymphocytes
Hematocrit
MCH
Monocytes
Platelet Count
Eosinophils
Basophils
Clinical 
Chemistry
Sodium 
Chloride
BUN 
Glucose 
Potassium 
Bicarbonate
Creatinine 
Calcium 
Total and 
direct bilirubin
ALT (SGPT)
AST (SGOT)
Alkaline phosphatase 
Total Protein 
Albumin
Creatine Kinase
Uric acid 
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick 
o
Microscopic examination (if blood observed or protein is abnormal)
o
Urine protein quantitative analysis (if indicated)
Additional 
safety tests

IgG, IgM, IgA.

CD19 B cell counts, CD4 & CD8 cell counts
Other 
Screening Tests

HIV, Hepatitis B (HBsAg) and HbcAb

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing potential only)

Serum or urine hCG Pregnancy test (as needed for women of child bearing 
potential)2
NOTES:
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments 
after liver stopping or monitoring event are given in Section 5.4.5 and Appendix 2.
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or ethics committee.
With the exception of CD19+ B-cell levels (see “Follow up period” in Section 4.3), all 
laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment should 
be repeated until the values return to normal or baseline. If such values do not return to 
normal within a period judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified.
 
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7.4.7.
Progressive Multifocal Leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating infection of 
the CNS caused by initial infection or reactivation of the John Cunningham virus (JCV). 
Asymptomatic primary infection with JCV typically occurs in childhood with latent virus 
remaining dormant in the kidneys and lymphoid organs. In the context of 
immunosuppression, the virus can reactivate and involve the brain. Prior to 2000, most 
cases of PML had a fatal outcome. PML has been recently associated with
immunosuppressive therapy, notably natalizumab, rituximab, efalizumab, mycophenolate 
mofetil, and tacrolimus [Schmedt, 2012].
In order to accommodate potential development of PML, neurological examinations will 
be conducted at the time points indicated in Section 7.1, the Time and Events Table.
Signs and symptoms of PML include visual disturbances, ocular movements, ataxia, and 
changes in mental status such as disorientation or confusion. These symptoms are not an 
exhaustive list and the investigator should exercise judgment in deciding to report signs 
and symptoms to sponsor promptly. 
If a subject develops neurological signs or symptoms consistent with PML, treatment 
with investigational product should be halted and the subject referred to a neurologist or 
PML specialist for evaluation. Neurological evaluation for PML should focus on clinical 
symptoms, imaging studies and evidence of the virus in the CSF. The PML algorithm
should be followed for all suspected cases of PML (See Appendix 4).
If the assessments are positive, the patient should proceed to the Follow-Up Period. All 
such patients will be followed until resolution. Any patient with a diagnosis of PML will 
be withdrawn from IP.
An independent PML Adjudication Committee will be utilized in this study to confirm 
any PML events. The PML Adjudication Committee will review blinded data for any 
subject with suspected PML and report the outcome of their adjudication review to the 
sponsor.
Note: The GSK Medical Monitor must be informed within 2 business days in the event a 
subject is identified as having neurological signs and symptoms suggestive of a diagnosis 
of PML. If PML is not confirmed, the investigator will inform the Medical Monitor of the 
relevant diagnosis and any action taken. 
Refer to the SRM for further information and detailed guidance for completing and 
transmitting these and other SAE reports for patients who experience a serious infection, 
malignancy, death, sign or symptom of PML.
The investigator will do the following when reporting a serious infection (including 
PML) or sign/symptom consistent with PML.
 
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Promptly report the event, as with any other SAE, as per Section 7.4.1.
Provide key source documentation for the Sponsor to assist with the safety 
evaluation process.
Examples of key source documents include but are not limited to: hospitalization records, 
discharge summaries, laboratory evaluations, biopsy results, culture/sensitivity results, 
death certificates, and autopsy reports.
If the patient has not otherwise been withdrawn from the study, then the investigator 
should contact the Sponsor to discuss the appropriate course of action regarding study 
continuation.
7.4.8.
Suicidal Risk Monitoring
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation 
[Bachen, 2009; Timonen, 2003; Stenager, 1992]. For this reason, in studies of patients 
with autoimmune disease, patients should be clinically assessed for suicidal ideation 
and/or behavior at each visit. In this study, the Columbia Suicidality Severity Rating 
Scale (C-SSRS ( www.cssrs.columbia.edu) will be used to assess suicidal ideation and 
behavior. It is recommended that the Investigator consider mental health consultation or 
referral for subjects who experience signs of suicidal ideation or behavior. The Medical 
Monitor should be notified when these events occur. In addition, a “yes” to any suicidal 
behavior or ideation question on the C-SSRS prompts the completion of the Possible 
Suicidality Related Adverse Event Questionnaire (PSRAE) Details of the C-SSRS and 
PSRAE questionnaires will be provided in the SRM.
7.5.
Pharmacokinetics
All randomized subjects will be sampled for serum belimumab and rituximab levels. 
Assessment of belimumab and rituximab concentrations will be performed at the time 
points indicated in Section 7.1, Time and Events Table. Details of blood sample 
collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM.
7.6.
Biomarker(s)/Pharmacodynamic Markers
Samples for biomarkers and pharmacodynamic markers will be collected as indicated in 
Section 7.1, Time and Events Table. 
The timing of collections may be adjusted based on emerging PK or PD data from this 
study or other information in order to ensure optimal evaluation of the PD endpoint.
Details of blood sample collection (including volume to be collected), processing, and 
storage will be provided in the SRM.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
 
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7.6.1.
Novel Biomarkers
A secondary endpoint will be the quantification of B cells, such as a change in B/T cell 
ratio measured by immunohistochemistry (IHC) analysis of B and T cell numbers within 
lymphoid foci in the salivary gland as assessed at Day 0 and Week 24 and as described in 
Section 7.6.1.1.
An exploratory endpoint is to identify other mechanistic measures that may be more 
sensitive in detecting the effects of, or may provide more insight into, the effect of the co-
administration treatment on the immune system and is described in Section 7.6.1.1
through Section 7.6.1.4. For all Biomarkers/PD assays and procedures, further details are 
provided in the SRM. Details of the analyses performed can be found in the RAP. 
7.6.1.1.
Assessment of the Salivary Gland Cellular Composition
Histological analysis of biopsy samples will include assessment of lymphocyte infiltrate, 
B cell and T cell subsets assessed through analysis of foci scoring, and IHC. IHC 
assessments may include B cell markers: CD20, IgG, IgM, IgA and CD38; T cell 
markers: CD3, markers of germinal center formation, CD21 and markers of dividing 
cells, Ki67. Changes in lymphocytes populations in glandular tissue may be further 
evaluated using epigenetic quantification or other equivalent technology and/or additional 
IHC markers of leukocyte infiltration and activation and/or glandular biology. Sections of 
salivary gland will be assessed by a pathologist to score glandular pathology. 
7.6.1.2.
Peripheral Blood Leukocyte Analysis
B cell flow cytometry panels will be used to measure changes over the course of therapy 
in the transitional, naive, memory and plasma B cell compartments. For subsets of 
interest, absolute numbers of cells and proportions relative to all B cells will be 
determined as well as activation status. 
Peripheral blood mononuclear cells (PBMCs) may be collected and stored to allow for 
further evaluation of leukocyte populations to further support mechanistic understanding 
of treatment.
7.6.1.3.
Serological Biomarkers
The quantification of serum analytes, autoantibodies [including anti-SSA and SSB], 
markers of B cells activation [may include but not limited to Beta-microglobulin, free 
kappa and lambda light chain], cytokines [may include but not limited to BLyS, IL-6, IL-
21], chemokines [may include but not limited to CXCL13 and CCL19] and other analytes 
associated with immune activation [may include but not limited to complement C3, C4, 
and CH50] or Sjögren’s biology will be performed using Luminex, ELISA or other 
appropriate technologies on serum or other assay appropriate blood matrix. Serum may 
be further analyzed for novel biomarkers and correlation with transcriptomic analysis of 
blood and glandular tissue. Serum for longitudinal analysis will be collected and stored 
for analysis at the end of the study. 
 
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7.6.1.4.
Additional Exploratory Biomarkers
7.6.1.4.1.
Saliva Proteomics
Saliva may be analyzed for novel biomarkers and correlation with transcriptomic and 
serologic analysis of blood and glandular tissue. Saliva for longitudinal analysis will be 
collected and stored as described in the SRM and may be analyzed at the end of the 
study. 
7.6.1.4.2.
Transcriptomic Analysis
Transcriptome studies on blood and salivary gland tissue may be conducted using 
microarray and/or alternative equivalent technologies including RNA sequencing (RNA-
seq), which facilitates the simultaneous measurement of the relative abundance of 
thousands of RNA species, resulting in a transcriptomic profile for each blood and 
glandular sample. This will enable the evaluation of the changes in transcripts relevant to 
leukocyte activation, cellular composition and ectopic lymphoid structure development.
7.6.1.4.3.
B and T Cell Receptor Clonal Analysis
An additional analysis of the effect of treatment on B and T antigen receptor clonal usage 
may be performed to assess the degree of expansion of B and T subpopulations in the 
blood and salivary gland tissue and the effect of treatment on expanded populations. 
7.6.1.5.
Immunogenicity
Serum samples will be collected for belimumab and rituximab immunogenicity 
assessment prior to dosing and after treatment start as indicated in Section 7.1, Time and 
Events Table.
7.7.
Genetics
Information regarding genetic research is included in Appendix 6.
8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined electronic case report forms 
(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 MedDRA (Medical Dictionary for Regulatory Activities) and an 
internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit 
trails) will be retained by GSK, and copies will be sent to the investigator to maintain as 
the investigator copy. In all cases, subject initials will not be collected or transmitted to 
GSK according to GSK policy.
 
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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses and Treatment Comparisons
The primary objective of the study is to investigate the safety and tolerability of the co-
administration of belimumab with rituximab and belimumab monotherapy. No formal 
statistical comparisons will be conducted to assess this objective. 
Secondary efficacy and mechanistic endpoints will be investigated. The following 
exploratory comparisons may be conducted:

Co-administration belimumab/rituximab treatment arm vs. Placebo arm

Co-administration belimumab/rituximab treatment arm vs. Rituximab 
monotherapy arm

Co-administration belimumab/rituximab treatment arm vs. Belimumab 
monotherapy arm

Belimumab monotherapy arm vs. Placebo arm

Belimumab monotherapy arm vs. Rituximab monotherapy arm
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI, stimulated salivary flow, oral dryness numeric response scale and a subset of 
salivary gland and plasma B cell parameters.  Full details will be included in the RAP.
For all other parameters, no formal statistical comparisons will be made, although trends 
over time will be investigated across all treatment arms.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences. Initially, approximately 
70 subjects will be recruited.
Following interim analysis the number of subjects in some or all treatment arms may be 
increased following sample size re-estimation, up to a maximum of 120 total subjects in 
the study where up to a maximum of 25, 45, 30 and 20 will be randomized to placebo, 
belimumab monotherapy, co-administration therapy and rituximab monotherapy, 
respectively. This will be dependent on variability and placebo rates for certain 
parameters. More details will be included in the RAP.
The primary objective of the study is safety, where a number of safety events are of 
interest. Using a Bayesian approach to determine the confidence interval around an 
observed safety event in the co-administration group, we would have a flat Beta(1,1) 
 
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prior, and if we were to observe 1 safety event in 20 then the posterior distribution would 
be Beta (2,20), as outlined below:
We can be 95% certain that the true probability of the safety event lies between 0.01 and 
0.24.
For supportive information, with 20 patients randomized to belimumab or the belimumab 
/ rituximab arm and 10 to placebo, the smallest difference in ESSDAI between the two 
treatment groups that would be statistically significant would be -3.30, assuming a 
placebo change from baseline of -1.7 [TEARS, Devauchelle-Pensec, 2014], a standard 
deviation of 4.192 [BELISS, Mariette, 2015] and alpha=5%.
Following the interim analysis, if the number of subjects were to increase to those 
outlined above then the following would apply for the continuous ESSDAI score, 
assuming a placebo change from baseline of -1.7 [TEARS, Devauchelle-Pensec, 2014], a 
standard deviation of 4.192 [BELISS, Mariette, 2015] and alpha=5%:
Placebo
Active
Difference
Placebo N
Active N
Power to detect 
difference
-1.7
-4.7
3
25
45
82%
-1.7
-4.7
3
25
40
80%
-1.7
-4.7
3
25
35
78%
-1.7
-4.7
3
25
30
75%
For responder endpoints, including the proportion of patients who achieve a 30% 
improvement in oral dryness response scale; or the proportion of patients who achieve a 
30% improvement in stimulated salivary flow, then the smallest difference between the 
2 treatment groups that would be statistically significant is 33%, assuming a placebo 
response of 14%, for example.
Twenty subjects randomized to the rituximab arm, would enable a reasonable evaluation 
of the impact of treatment on the underlying immunological mechanisms but not the 
clinical efficacy.
 
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9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates. If the number of subjects who completed the 24 
weeks is lower than 20 in the co-administration group, then the true incidence rates of 
safety events that could not be ruled out (as outlined in Section 9.2.1) would change. 
These changes are outlined in the table below:
N 
completing 
study
Number of particular 
safety events observed 
with co-administration
Upper limit of exact 95% CI indicating 
that a true incidence rate of x% could 
not be ruled out
18
0 / 18
18%
18
1 / 18
26%
16
0 / 16
20%
16
1 / 16
29%
14
0 / 14
22%
14
1 / 14
32%
9.2.3.
Sample Size Re-estimation
At the interim analysis, the sample size may be re-estimated based on the emerging data 
from the study. The sample size may need to be re-estimated if higher variability or 
differing placebo means are observed for the ESSDAI, a key secondary endpoint.  
Therefore, any significant deviation from the assumptions used to design the study may 
result in changes to the number of subjects to be randomized. Further details will be 
included in the RAP and guidance document for interim decision making. A maximum of 
120 subjects will be recruited into the study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least 
one dose of study medication. This population is used for the summary of all data 
including safety efficacy and pharmacodynamic (PD) data but excluding PK data. 
Pharmacokinetic Population: The ‘PK Population’ is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a pharmacokinetic sample was 
obtained and analyzed. This population is used for the summary of PK data only. In the 
case of PK/PD, the Safety Population is used so that subjects receiving placebo can be 
included.
9.3.2.
Interim Analysis
In line with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on 
an ongoing basis during the study conduct by an internal GSK Safety Review Team 
(SRT).
 
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An internal GSK Safety Review Committee (iSRC), independent of the study team, will 
maintain governance of the study and will periodically review all available data in an un-
blinded manner with a focus on key safety parameters.  A Therapeutic Area (Immuno-
Inflammation) Data Assessment Committee (TA DAC), independent of the study team, 
will periodically review un-blinded efficacy data and at the interim analysis will advise 
the iSRC on adaptive design changes should such changes be required.  An iSRC charter 
details the activities of these committees, including when and which data will be 
reviewed, how the integrity of the study will be maintained, and the membership of both 
committees. Once half of the planned subjects (i.e.: approximately 35 subjects) have 
completed their Week 24 assessments, a formal interim analysis will take place.  
Appropriate available safety and efficacy data will be included in the interim analysis. 
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, on an exploratory basis, preliminary efficacy analysis may be 
conducted to enable a sample size re-estimation and obtain an initial estimate of the effect 
size of the co-administration therapy and belimumab monotherapy. Following the interim 
analysis, a number of actions could be mandated by the iSRC: the study may continue as 
planned; one or more treatment arms may be dropped; the number of subjects in some or 
all treatment arms may be increased following sample size re-estimation, up to a 
maximum of 120 subjects in the study.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analysis and Follow Up Analysis
In addition to the interim analysis, there will be additional analyses for this study, 
corresponding to the primary analysis and the follow-up analyses. The primary analysis 
will occur after the data through the Week 52 visit (or withdrawal visit for those subjects 
who withdraw during double-blind treatment) for all subjects has been collected, verified 
and validated. The follow up analyses will occur after data through the 16-week 
generalized follow-up period and IFU periods for all subjects has been collected, verified 
and validated. All subjects and study site personnel (except the unblinded site 
pharmacist) will remain blinded until the follow up analyses have been completed.
9.4.2.
Analysis of Primary Endpoints
No formal statistical testing will be performed on safety data.
All safety evaluations will be based on the safety population. Clinical interpretation will 
be based upon review and displays of AEs,  laboratory values and vital signs. The 
principle consideration in this evaluation will be the investigator-reported relationships of 
either AEs or laboratory abnormalities to IP.
Safety data will be presented in tabular and/or graphical format.
9.4.3.
Analysis of Secondary Endpoints
All data will be descriptively summarized, graphically presented and listed appropriately.
 
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Each endpoint will be considered individually and at the treatment level where 
comparisons between treatment groups would be made on any changes observed. 
The relationship between the mechanistic (e.g., salivary gland B cell quantification) and 
clinical effects (e.g., ESSDAI score) will be graphically presented. The consistency in the 
changes over time between the endpoints will  be assessed and further exploratory 
analyses to characterise relationships between endpoints may be conducted.
The ESSDAI, stimulated salivary flow and oral dryness numeric response scale change 
from baseline scores will be statistically analyzed using a mixed model repeated 
measures approach  Point estimates and corresponding 95% confidence intervals will be 
estimated for all the comparisons of interest (see Section 9.1) at weeks 24 and 52. 
Distributional assumptions underlying the analyses will be assessed. Additional models 
may be investigated.
Non-parametric statistical analyses will also be conducted to assess the comparisons of 
interest for a subset of salivary gland histology assessments, and B cell quantification in 
plasma. These analyses will be described in the RAP.    
In addition, based on the data that we observe in the study, probabilities of success of the 
co-administration therapy and belimumab monotherapy may be determined. For example, 
what is the probability that we would observe a certain change in the ESSDAI score (i.e., 
comparator rate), based on the data that we have observed in the study?
Further details regarding the statistical analysis will be outlined in the RAP.
9.4.4.
Analysis of Other Endpoints
9.4.4.1.
Health Outcome Analyses
Pain, dryness, and fatigue will be assessed over time using the ESSPRI total score and 
subscale scores. In addition, the PROFAD-SSI-SF will assess fatigue, discomfort and 
sicca symptoms. The PtGA and PGA will be performed to assess disease activity. At the 
end of the study, patients will participate in an exit interview where they will be asked to 
report on their experience with treatment during the clinical trial. Questions will be asked 
regarding treatment benefit, side effects, and study design (in terms of patient burden). 
The interview data will be qualitatively analyzed and will serve to inform expected 
magnitude of treatment benefit, risk tolerance, and future study design considerations.
All health outcome measures will be listed, summarized and presented graphically over 
time where appropriate. Further details will be included in the RAP. 
9.4.4.2.
Pharmacokinetic Analyses
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.
 
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9.4.4.3.
Pharmacokinetics/Pharmacodynamic Analyses
The relationship between B-cells and belimumab concentrations will be explored 
graphically. A PK/PD modeling approach may be used to quantify the relationship.
More details of any exploratory pharmacokinetic/pharmacodynamic analyses will be 
provided 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 enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments, as applicable

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

Regulatory Agency review and favorable opinion/approval of the study protocol and 
substantial amendments.

GSK will provide full details of the above procedures, either verbally, in writing, or 
both

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. 
 
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
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 eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that:

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. GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicenter studies, this can occur at one or more or at all 
sites. If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where applicable). 
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action. If the study is 
 
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suspended or prematurely discontinued for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable) and/or institution(s) 
conducting the study. GSK will also promptly inform the relevant regulatory authorities 
of the suspension or premature discontinuation of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location. The records must 
be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit or 
regulatory inspection) and must be available for review in conjunction with assessment of 
the facility, supporting systems, and relevant site staff. Where permitted by local 
laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution 
needs to be exercised before such action is taken. The investigator must ensure that all 
reproductions are legible and are a true and accurate copy of the original and meet 
accessibility and retrieval standards, including re-generating a hard copy, if required. 
Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 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 Publicly 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. GSK will provide the investigator with the randomization codes 
for their site only after completion of the full statistical analysis. The procedures and 
timing for public disclosure of the results summary and for development of a manuscript 
for publication will be in accordance with GSK Policy. A manuscript will be progressed 
for publication in the scientific literature if the results provide important scientific or 
medical knowledge.
 
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10.8.
Review Committees
10.8.1.
Internal Safety Review Committee (iSRC) and Therapeutic Area 
Data Assessment Committee (TA-DAC)
An internal GSK Safety Review Committee (iSRC), independent of the study team, will 
maintain governance of the study and will periodically review all available data in an un-
blinded manner with a focus on key safety parameters.  A Therapeutic Area (Immuno-
Inflammation) Data Assessment Committee (TA DAC), independent of the study team, 
will periodically review un-blinded efficacy data and at the interim analysis will advise 
the iSRC on adaptive design changes should such changes be required.  An iSRC charter 
details the activities of these committees, including when and which data will be 
reviewed, how the integrity of the study will be maintained, and the membership of both 
committees.
The overall responsibility of the iSRC is to protect the ethical and safety interests of 
subjects recruited into the study while also protecting the scientific validity of the data. 
The iSRC has the primary governance role for the study.
10.8.2.
PML Adjudication Committee
An independent PML Adjudication Committee will be utilized in this study to confirm 
any PML events. The PML Adjudication Committee will review blinded data for any 
subject with suspected PML and report the outcome of their adjudication review to the 
sponsor.
 
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11.
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADA
Anti-drug antibodies
ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity
AE
Adverse Event
AECG
American European Consensus Group
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the Curve
BLyS
B lymphocyte stimulator
CBC
Complete Blood Count
CMM
Cubic Millimeter
CNS
Central Nervous System
CRP
C-Reactive Protein
C-SSRS
Columbia Suicidality Severity Rating Scale
CV
Cardiovascular
eCRF
Electronic Case Report Form
CSF
Cerebrospinal Fluid
DMARD
Disease-modifying anti-rheumatic drugs
ECG
Electrocardiogram
ESSPRI
EULAR Sjögren’s Syndrome Patient Reported Index
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
DILI
Drug Induced Liver Injury
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FRP
Females of Reproductive Potential
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HBV
Hepatitis B virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HSR
Hypersensitivity reactions
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
 
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INN
International Nonproprietary Name
IP
Investigational Product
IRB
Institutional Review Board
iSRC
Internal Safety Review Committee
IVIG
Intravenous Immunoglobulin
JCV PCR
John Cunningham virus polymerase chain reaction test
LLN
Lower Limit of Normal
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
MMRM
Mixed Effect Model Repeat Measurement
MRI
Magnetic Resonance Imaging
NRS
Numerical Response Scale
NSAID
Non steroidal anti-inflammatory drug
OI
Opportunistic Infection
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamic
PGA
Physicians Global Assessment
PK
Pharmacokinetic
PML
Progressive multifocal leukoencephalopathy
PNS
Peripheral Nervous System
PRES
Posterior Reversible Encephalopathy Syndrome
PROFAD-SSI-SF
Profile of Fatigue and Discomfort Sicca Symptoms 
Inventory Short Form
PSRAE
Possible Suicidality Related Adverse Event Questionnaire
pSS
Primary Sjögren’s Syndrome
PtGA
Patient Global Assessment of Disease Activity
QD
Once a day
R&D
Research and Development
RAMOS NG
Randomization and Medication Ordering System Next 
Generation
RA
Rheumatoid Arthritis
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RF
Rheumatoid Factor
RPLS
Reversible Posterior Leukoencephalopathy Syndrome
SAE
Serious Adverse Event
SLE
Systemic Lupus Erythematosus
SRM
Study Reference Manual
SRT
Safety Review Team
SS-A
Anti-Sjögren’s-syndrome-related antigen A
SS-B
Anti-Sjögren’s-syndrome-related antigen B
TA-DAC
Therapeutic Area – Data Assessment Committee
TB
Tuberculosis
ULN
Upper Limit of Normal
USAN
United States Adopted Names
WBC
White Blood Cell
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BENLYSTA
Chiron RIBA
Luminex
MabThera
Rituxan
SAS
WinNonlin
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Appendix 3) 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 6 weeks after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.) 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart 
Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart subject with study treatment is not
granted, then subject must permanently discontinue study treatment and may continue in 
the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury) or study treatment has an 
HLA genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death. 

The subject must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study 
chart. 

Study treatment must be administered at the dose specified by GSK.
 
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
Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 7.4.1.1.
 
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12.4.
Appendix 4: PML Algorithm
 
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12.5.
Appendix 5: Neurological Symptoms Questionnaire
YES
NO
If any of the above are answered “Yes” at any visit, the investigator will contact the 
medical monitor.
Any neurological symptom that cannot be attributed to a concurrent medical condition or 
concomitant medication must be referred to a neurologist.
 
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collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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12.6.
Appendix 6: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including belimumab, ritixumab or any concomitant 
medicines;

Sjögren’s syndrome susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response. 

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample. 
The genetic sample is labeled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to the 
 
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subject by the investigator or site staff. Coded samples do not carry personal identifiers 
(such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner. GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research. 

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
 
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Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance, a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
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12.7.
Appendix 7: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.7.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
 
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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.
12.7.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a. 
Results in death
b. 
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.7.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack
 
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
Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.7.4.
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 patient reported outcome questionnaires and the collection of AE 
data are independent components of the study.

Responses to each question in the patient reported outcome questionnaires 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.
12.7.5.
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 
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
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.
12.7.6.
Reporting of SAEs to GSK
SAE reporting to GSK via InForm

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 designee.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

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 designee 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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12.8.
Appendix 8: Collection of Pregnancy Information

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 for 1 year to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

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 
as described in this appendix. 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.
Any female subject who becomes pregnant while participating

will be withdrawn from therapy but will continue in the trial for safety reporting and 
outcomes assessments.
 
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12.9.
Appendix 9: American-European Consensus Group 
Classification
References
Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a 
revised version of the European criteria proposed by the American-European Consensus 
Group. Ann Rheum Dis. 2002; 61:554–8.
 
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12.10.
Appendix 10: Protocol changes in Amendment 1
Amendment 1: Specific amendment for Sweden (all sites)
Protocol Amendment 01, 15 October 2015
Summary of Modifications (relative to original protocol) and Rationale:
1.
Section 5.1 (Inclusion Criteria). This section has been updated to amend the list of 
acceptable methods of contraception. 
2.
Section 5.4 (Withdrawal/Stopping Criteria). The detailed Adverse Event Criteria 
(within Section 5.4.2) have been clarified to confirm that subjects will be withdrawn 
from investigational products in the event of a life- threatening infection. 
3.
Section 6.9.1 (Permitted Medications and Non-Drug Therapies). Correction of 
typographical error regarding the permitted dose of hydroxychloroquine.
4.
Section 1 (Synopsis), Section 4.1 (Overall Design) and Section 9.3.2 (Interim 
Analysis). These sections have been updated to clarify both the timing and number of 
interim analyses.
5.
Section 10.2 (Regulatory and Ethical Considerations, Including the Informed 
Consent Process). Updated to clarify that regulatory agency approval is required for 
the protocol AND for substantial amendments to the protocol. 
6.
Appendix 9 has been added to protocol and contains the American European Group 
Consensus Criteria for Primary Sjögren’s Syndrome.
Associated Protocol Modifications:
Protocol Cover Page
Add:
Protocol Amendment Number: 1
Updated:
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1
Protocol amended in response to comments received from Swedish regulatory authority. 
 
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Protocol synopsis (Section 1)
Change from:
An iSRC charter will detail their activities, including when and which data will be 
reviewed, how the integrity of the study will be maintained in addition to the iSRC group 
membership. Once an appropriate number of subjects have completed the Week 24 
assessments interim analyses and sample size re-estimation will be conducted to assess 
the effect of the monotherapy belimumab or co-administration therapy when compared to 
placebo and rituximab monotherapy at Week 24.
Change to:
An iSRC charter will detail their activities, including when and which data will be 
reviewed, how the integrity of the study will be maintained in addition to the iSRC group 
membership. An interim analysis by the independent safety review committee will 
be conducted once at least 35 subjects have completed their Week 24 assessment.  
An additional interim analysis may be performed and this will be specified 
prospectively in the reporting and analysis plan.  Once an appropriate number of 
subjects have completed the Week 24 assessments Interim analyses and sample size re-
estimation will be conducted to assess the effect of the monotherapy belimumab or co-
administration therapy when compared to placebo and rituximab monotherapyat Week 
24.
Overall Design (Section 4.1)
Change from:
Once a sufficient number of subjects have completed Week 24, interim analyses and 
sample size re-estimation will be conducted.
Change to:
An interim analysis by the independent safety review committee will be conducted once 
at least 35 subjects have completed their Week 24 assessment.  An additional interim 
analysis may be performed and this will be specified prospectively in the reporting and 
analysis plan.  
Inclusion Criteria (Section 5.1)
Change from:

Oral Contraceptive, either combined or progestogen alone
Change to:

Combined Oral Contraceptive (note: progestogen only oral contraceptive is 
considered inadequate.)
 
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Delete:

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).
Detailed adverse event criteria (Section 5.4.2)
Change from:
In addition, if any subject develops a life-threatening infection regardless of IgG status, 
the investigator must contact the Medical Monitor to determine whether treatment with IP 
should be continued.
Change to:
In addition, if any subject who develops a life-threatening infection, regardless of IgG 
status, will be promptly withdrawn from IP.the investigator must contact the Medical 
Monitor to determine whether treatment with IP should be continued.
Permitted medications and non-drug therapies (Section 6.9.1)
Change from:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 40 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Change to:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
 
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Interim Analysis (Section 9.3.2)
Change from:
Once an appropriate number of subjects have completed their Week 24 assessment, 
interim analyses and sample size re-estimation will be conducted to assess the effect of 
the monotherapy belimumab or co-administration therapy when compared to placebo and 
rituximab monotherapy at Week 24.
Change to:
An interim analysis by the independent safety review committee will be conducted 
once at least 35 subjects have completed their Week 24 assessment.  An additional 
interim analysis may be performed and this will be specified prospectively in the 
reporting and analysis plan.    Once an appropriate number of subjects have completed 
their Week 24 assessment, Interim analysis and sample size re-estimation will be 
conducted to assess the effect of the monotherapy belimumab or co-administration 
therapy when compared to placebo and rituximab monotherapy at Week 24.
Regulatory and ethical considerations (Section 10.2)
Added:

Regulatory Agency review and favorable opinion/approval of the study protocol and 
substantial amendments.
Appendices
Added:
Appendix 9: American-European Consensus Group Classification
References
Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a 
revised version of the European criteria proposed by the American-European Consensus 
Group. Ann Rheum Dis. 2002; 61:554–8.
 
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12.11.
Appendix 11: Protocol changes in Amendment 2
Amendment 2: specific amendment for Norway (all sites)
Protocol Amendment 02, 20th November 2015
Summary of Modifications (relative to original protocol) and Rationale:
1.
Section 5.1 (Inclusion Criteria). This section has been updated to amend the list of 
acceptable methods of contraception.
2.
Section 7.2 (Screening and Critical Baseline Assessments). This section has been 
updated to define how assessment of subjects for tuberculosis should be carried out 
during the screening period.
3.
Section 1 (Synopsis) and Section 9.3.2 (Interim Analyses). These sections have been 
edited to clarify the number of subjects required for the interim analysis and the basis 
for the recalculation of sample size following the interim analysis. 
4.
Section 6.9.1 (Permitted Medications and Non-Drug Therapies). Correction of 
typographical error regarding the permitted dose of hydroxychloroquine.
Associated Protocol Modifications:
Protocol Cover Page
Add:
Protocol Amendment Number: 02
Add:
Author: 
Updated:
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1
Protocol amended in response to comments received from Swedish regulatory 
authority.
 
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GlaxoSmithKline 
Document Number
Date
Version
2014N220285_02
2015-NOV-20
Amendment No. 2
Protocol amended in response to comments received from Norwegian regulatory 
authority.
Section 1, Synopsis, Page 11 
Delete:
Once an appropriate number of subjects have completed the Week 24 assessments, 
interim analyses and sample size re-estimation will be conducted to assess the effect of 
the monotherapy belimumab or co-administration therapy when compared to placebo and 
rituximab monotherapy at Week 24. Appropriate available data will be included in the 
interim analyses; the results of which will be reviewed by the iSRC.
Add:
The interim analysis is planned once approximately half of the subjects (i.e.  35 subjects) 
complete their week 24 assessment. The main purpose of the interim analysis is to assess 
the safety and tolerability of the study drug.  In addition, on an exploratory basis, 
preliminary efficacy analysis will be conducted to enable a sample size re-estimation and 
obtain an initial estimate of the effect size of the dual immunotherapy.
Inclusion Criteria (Section 5.1)
Delete:

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).
Screening and Critical Baseline Assessments (Section 7.2)
Added:

Tuberculosis: Assessment of TB in the screening period is to be done via 
evaluation of the subject’s history, physical examination of the subject and, if 
judged necessary by the Investigator, local laboratory (screening and 
confirmatory) testing.
Permitted medications and non-drug therapies (Section 6.9.1)
Change from:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 40 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
 
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Change to:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Interim Analysis (Section 9.3.2)
Delete:
Once an appropriate number of subjects have completed their Week 24 assessment, 
interim analyses and sample size re-estimation will be conducted to assess the effect of 
the monotherapy belimumab or co-administration therapy when compared to placebo and 
rituximab monotherapy at Week 24. Appropriate available data will be included in the 
interim analyses, the results of which will be reviewed by the iSRC. 
Add:
The interim analysis is planned once approximately half of the subjects (i.e.  35 subjects) 
complete their week 24 assessment. The main purpose of the interim analysis is to assess 
the safety and tolerability of the study drug.  Adverse events and serious adverse events, 
immunoglobulin levels, vital signs, blood chemistry and hematology data will be 
summarized by treatment. 
Preliminary efficacy data will also be assessed during the interim analysis on an 
exploratory basis. Data such as: ESSDAI, stimulated salivary flow, oral dryness numeric 
response, and B cell quantification within salivary gland biopsies will be summarized by 
treatment and week. The purpose of this efficacy exploration is to conduct a sample size 
re-estimation and obtain an initial estimate of the effect size of the dual immunotherapy. 
As such, the variability estimates will be updated based on the emerging data with the 
potential of enrolling up to 120 subjects into the study to accommodate for higher than 
expected variability in the aforementioned efficacy endpoints. A Bayesian predictive 
modeling approach may be adopted to calculate predictive probabilities of success for a 
range of true treatment differences between the monotherapy belimumab, monotherapy 
rituximab and combination therapy when compared to placebo at week 24.
 
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12.12.
Appendix 12: Protocol changes in Amendment 3
Amendment 3: specific amendment for Italy (all sites)
Protocol Amendment 03, 4th January 2016
Summary of Modifications (relative to original protocol) and Rationale:
1.
Section 5.1 (Inclusion Criteria). This section has been updated to amend the list of 
highly effective methods of contraception.
2.
Section 6.9.1 (Permitted Medications and Non-Drug Therapies). Correction of 
typographical error regarding the permitted dose of hydroxychloroquine.
Associated Protocol Modifications:
Protocol Cover Page
Add:
Protocol Amendment Number: 03
Updated:
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1
Protocol amended in response to comments received from Swedish regulatory authority.
2014N220285_02
2015-NOV-20
Amendment No. 2
Protocol amended in response to comments received from Norwegian regulatory 
authority.
2014N220285_03
2016-JAN-04
Amendment No. 3
Protocol amended in response to comments received from Italian regulatory authority.
 
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Inclusion Criteria (Section 5.1)
Delete:

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).
Permitted medications and non-drug therapies (Section 6.9.1)
Change from:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 40 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Change to:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
 
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12.13.
Appendix 13: Protocol changes in Amendment 4
Amendment 4: global amendment (all sites).
Protocol Amendment 04, 13th June 2016
Summary of Modifications (relative to original protocol) and rationale:
1. Protocol Synopsis (Section 1)

The study design schematic/figure has been replaced with a revised figure which 
makes it easier for the reader to understand the study design. This change has also 
been made in Section 4 (study design).

Clarification that a single interim analysis is planned, when that interim analysis 
will occur and what actions may be taken following the interim analysis.
2. Study Design (Section 4)

Clarifications regarding the committees involved in monitoring subject safety and 
review of study data, the governance of the study and how these committees will 
work with each other during the interim analysis.

Clarification that a single interim analysis is planned, when that interim analysis 
will occur and what actions may be taken following the interim analysis.

Clearer guidance has been provided regarding the prohibition on use of topical 
symptomatic medications prior to efficacy assessments.

Further information has been added in support of the use of the subcutaneous 
formulation of belimumab.

The Table (Section 4.7.1) summarising the risk assessment for dual biologic 
therapy in primary Sjögren’s syndrome has been changed, specifically the 
sections dealing with mitigation strategy for infections and vaccinations.
o
For the infection mitigation strategy, the protocol no longer mandates that 
subjects are excluded or discontinued with CD4 <400cells/mm3 or CD8 
<150cells/mm3. In addition, the exclusion level for IgG is now set at 
<550mg/dL rather than <LLN (<694mg/dL). Please refer to point 3 below 
for the rationale underlying these changes.
o
For the vaccination mitigation strategy, clarification is provided that live 
vaccination is prohibited until the end of the general or (if appropriate) the 
individualized follow up period. This clarification is made for practical 
reasons because subjects may enter the trial with B cell counts lower than 
the lower limit of normal, in which case they will be followed only until 
their B cell levels return to baseline (not until “normalization”). The 
individualized follow up period ends when the subject’s B cell count 
returns to baseline (or the subject reaches week 104, whichever comes 
first). In addition, additional text has been added to summarise previous 
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
A new sub-section (Section 4.7.2) has been added to make clearer the vaccination 
guidance and the EULAR recommendations which underlie this guidance.
3. Selection of study population and withdrawal criteria (Section 5)

The inclusion criteria have been changed.
o
Inclusion criterion #5. A change has bee made which was mandated by the 
Italian Regulatory Authority (AIFA) and which applies only to Italian 
sites.
o
Inclusion criterion #6. The list of highly effective methods of 
contraception has been updated in to reflect most recent CTFG 
recommendations (2014_09_15) and GSK standards.
o
An additional mandatory inclusion criterion (#8) for FRANCE only, has 
been added.

The exclusion criteria have been changed.
o
Exclusion criterion #20. The exception of denosumab relative to the 
overall exclusion of biological agents for 180days prior to Day 0 has been 
removed. The rationale for this is to avoid any potential increased risk of 
infection.
o
Exclusion criterion #30 was amended to:
-
Reduce the IgG exclusionary threshold to 550mg/dL. This level 
allows patients with a modest IgG hypogammaglobulinemia to enter 
the study. This is supported by the pivotal phase 3 study of belimumab 
in SLE, HGS1006-C1056 (and its long term continuation study, 
112233 (C1066)) in which an IgG exclusionary threshold of 
<400mg/dL was used (http://www.gsk-clinicalstudyregister.com) and 
by the study of rituximab in RA (Emery, 2010; Ann Rheum Dis; 
69:1629–1635) in which an IgG exclusionary threshold of 500 mg / 
dL was used. In the belimumab studies, 8 / 635 subjects developed 
IgG < 400 mg / dL and no subjects experiencing treatment–emergent 
hypogammaglobulinemia (IgG < 400 mg / dL) developed serious 
infection. In the rituximab study, 1.9% of rituximab treated subjects’ 
IgG levels declined below the lower limit of normal and no serious 
infections occurred in patients receiving rituximab while IgG levels 
were below the lower limit of normal (Emery et al., 2010; Ann Rheum 
Dis; 69:1629–1635).
-
Remove the IgM exclusion criteria.  This is supported by the 
Rituximab Expert Consensus Committee which observed that 
“decreases in IgM have not been associated with increased rates of 
infection” and whose recommendation is to monitor IgG – but not 
IgM – levels during rituximab therapy  (Buch et al, 2011; Ann Rheum 
Dis 2011;70:909–920).
-
Remove the CD4 and CD8 exclusion criteria and associated subject 
specific stopping criteria.  Many patients with primary Sjogren’s 
 
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syndrome have low CD4/CD8 T-cells as part of their disease 
pathology.  Of the first 13 potential subjects screened for this study 
under the original protocol, 10 potential subjects failed screening on 
the basis of low CD4/CD8 T-cells.  Among these potential subjects 
CD4 T-cells ranged as low as 273 / mm³ (reference range: 490-1740 / 
mm³) and CD8 T-cells ranged as low as 76 / mm³ (reference range: 
180-1170 / mm³).  Furthermore, the Rituximab Expert Consensus 
Committee does not recommend T-cell monitoring  (Buch et al, 2011; 
Ann Rheum Dis 2011;70:909–920). Moreover, use of CD4/CD8 T-cell 
selection and monitoring parameters  are not part of standard clinical 
practice in the use of rituximab and belimumab or in the care of 
primary Sjögren’s patients.
-
Clarify that the CD19 restriction applies only to subjects previously 
treated with B cell depleting therapy.  Potential subjects who have 
received B cell depleting therapy within 364 days of Day 0 are 
excluded from entry into this trial (Exclusion criterion # 19).  Subjects 
whose B cells fail to reconstitute (i.e.: remain persistently below <0.1 
x 109/L) a year or more after B cell depleting therapy should not 
participate in this study.
o
An additional mandatory exclusion criterion (#31) for FRANCE only, has 
been added.

The section on screening (Section 5.3) has been amended to clarify when and how 
often rescreening of subjects is allowed and to clarify the criteria for repeat 
assessments during the screening period.

The Section (5.4) on withdrawal/stopping criteria has been amended to:
o
Remove reference to a Week 46 “visit” which does not exist and to clarify 
the importance of Week 46 as a threshold for subject withdrawal with 
respect to pregnancy evaluation.
o
Clarify that the neurology questionnaire is a required assessment in 
subjects who have discontinued treatment but not withdrawn consent.
o
Added a new sub-section (Section 5.4.2) to describe the early withdrawal 
visit.
o
Indicate that subjects who develop a life threatening infection must be 
withdrawn from investigational product, regardless of IgG status.
o
Remove the stipulation that subjects will be withdrawn from 
investigational product based upon CD4 <300cells/mm3 or CD8 
<100cells/mm3.
4. Study Treatment (Section 6)

The requirements for return (by the subjects) of used and unused 
belimumab/placebo syringes have been clarified.

The description of rituximab (Section 6.1.2) has been corrected and a description 
of the rituximab placebo (sterile saline) has been added.
 
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
Guidance has been added for the monitoring of subjects following administration 
of rituximab/placebo.

A clarification has been made regarding the meaning of “sponsor open” in the 
Section (6.3) describing blinding.

The section on permitted medications (Section 6.9.1) has been amended to:
o
Correct a typographical error regarding the dose of hydroxychloroquine.
o
Provide greater detail regarding allowable topical symptomatic therapies.

The section on prohibited medications (Section 6.9.2) has been amended to 
provide additional details of prohibited medications.
5. Study Assessments and Procedures (Section 7)

The Time and Events Table (Section 7.1) has been modified by the addition of 
“cryoglobulins” to help clarify the timing of this existing required assessment.

Minor modifications have been made to the footnotes of the Time and Events 
Table to provide greater clarity and define the time window in which subjects 
should receive calls from the sites during the general follow up and individualized 
follow up phase.

Section 7.2 and Section 7.4.5 have been altered to clarify the circumstances upon 
which triplicate ECG measurements should be obtained during screening. In 
addition, the mandatory requirement to use an ECG machine has been removed as 
experienced sites will be allowed to manually calculate ECG intervals.

A new paragraph has been added to Section 7.2 to provide guidance regarding 
tuberculosis assessment during screening.

Greater detail has been added to Section 7.4.1.4 regarding adverse events of 
special interest.

The pregnancy Section (7.4.2) has been amended to clarify the duration of follow 
up.

Some additional minor language corrections have been made throughout Section 
7 to provide greater accuracy and clarity.
6. Statistical Considerations and Data Analysis (Section 9)

Clarification that a single interim analysis is planned, when that interim analysis 
will occur and what actions may be taken following the interim analysis. Detail 
has also been provided regarding the committees involved in unblinded data 
review at the interim analysis and what actions may be taken.

Some changes have been made to Section 9.4.1, Section 9.4.2 & Section 9.4.3 to 
clarify the data analysis plans for the study. The reference to “disease related 
events” has been removed. This was a typographical error as there was never 
intention to collect data on disease related events.
 
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7. Study Governance Considerations (Section 10)

The language of Section 10.2 (Regulatory and ethical considerations) has been 
edited to avoid duplication and to make clear that substantial amendments are also 
subject to regulatory agency approval.

Section 10.8.1 has been amended to clarify the roles of two committees which 
will be involved in review of unblinded data as the study progresses and to 
highlight that the primary governance role lies with the internal safety review 
committee.
8. References (Section 11)

Two additional references have been added. 
9. Appendices (Section 12)

An additional abbreviation has been added to Appendix 1.

Appendix 8 (Collection of Pregnancy Information) has been amended to clarify 
that subjects will be followed for 1 year to determine the outcome of any 
pregnancy.

Appendix 9 (American European Consensus Group classification for Primary 
Sjögren’s Syndrome) has been added.

Appendix 10-Appendix 13 have been added. These detail changes made to the 
protocol in previous country specific amendments and in the current protocol 
amendment (version 4).
Protocol Amendment 04: Modifications in detail:
(New text is in bold and deleted text is marked with strikethrough).
PROTOCOL COVER PAGE
Add:
Protocol Amendment Number: 04
Add:
IND (US only):
009970
Change author list:
Author (s):
 
 
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Updated:
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1 for 
Sweden
Protocol amended in response to comments received from Swedish regulatory authority.
Local
2014N220285_02
2015-NOV-20
Amendment No. 2 for 
Norway
Protocol amended in response to comments received from Norwegian regulatory 
authority.
Local
2014N220285_03
2016-JAN-04
Amendment No. 3 for Italy
Protocol amended in response to comments received from Italian regulatory authority.
Global
2014N220285_04
2016-JUN-13
Amendment No. 4
The primary reason for this amendment is to modify the subject selection criteria 
(specifically exclusion criterion #30 pertaining to exclusionary laboratory 
thresholds) to better align with the intended population characteristics.
Other amendments include the following:
-
Greater clarity is provided regarding the committees involved in monitoring 
subject safety and review of study data as well as the governance of the 
study.
-
It has been made clear that a single formal interim analysis is planned.
-
The subject withdrawal and study stopping criteria have been modified.
-
Greater detail is provided regarding prohibited and permitted medications.
-
Additional guidance is provided regarding vaccination.
-
Guidance has been provided for tuberculosis assessment during the 
screening period.
-
The pregnancy section has been modified to clarify the duration of follow up 
 
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required.
This amendment incorporates country-specific changes required by Regulatory 
Authorities during prior review. In addition, changes have been made throughout to 
provide clarity for the conduct of the study and correct typographical errors.
All changes made in Amendment 4 are summarized, rationalized and detailed in 
Appendix 13 (Section 12.13).
PROTOCOL SYNOPSIS FOR STUDY 201842 (Section 1)
Clarification of study schematic:
Change from:
 
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Change to:
Overall Design, Paragraph:
Change from:
The primary efficacy comparison for this study at Week 24 will be between the co-
administration therapy arm and the placebo arm. Interim analyses will be performed on 
the accumulating data. Following any of the interim analyses, a number of actions could 
be taken: the study could continue as planned; one or more treatment arms may be 
dropped; the number of subjects in some or all treatment arms may be increased 
following sample size re-estimation up to a maximum of 120 total subjects in the study.
Overall Design, Change to:
The primary efficacy comparison for this study at Week 24 will be between the co-
administration therapy arm and the placebo arm. Once approximately 35 subjects have 
completed week 24, a formal interim analysis will be performed on the available
accumulating data. Following any of this interim analysis, a number of actions could be 
taken: the study could continue as planned; one or more treatment arms may be dropped; 
the number of subjects in some or all treatment arms may be increased following sample 
size re-estimation up to a maximum of 120 total subjects in the study.
Interim Analysis, Change from:
Interim Analysis: Study data will be reviewed in a confidential manner during the trial 
conduct by an internal GSK Safety Review Committee (iSRC). Reviews may include un-
blinded efficacy, pharmacodynamic and safety data. An iSRC charter will detail their 
 
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activities, including when and which data will be reviewed, how the integrity of the study 
will be maintained in addition to the iSRC group membership. Once an appropriate 
number of subjects have completed the Week 24 assessments, interim analyses and 
sample size re-estimation will be conducted to assess the effect of the monotherapy
belimumab or co-administration therapy when compared to placebo and rituximab 
monotherapy at Week 24. Appropriate available data will be included in the interim 
analyses; the results of which will be reviewed by the iSRC. Following interim analyses, 
a number of actions could be taken: the study will continue as planned; one or more 
treatment arms may be dropped; the number of subjects in some or all treatment arms 
may be increased following sample size re-estimation, up to a maximum of 120 subjects 
in the study.
Change to:
Interim Analysis: Study data will be reviewed in a confidential manner during the trial 
conduct by an internal GSK Safety Review Committee (iSRC)., Reviews may include un-
blinded efficacy, pharmacodynamic and safety data. An iSRC charter will detail their  
activities, including when and which data will be reviewed, how the integrity of the study 
will be maintained in addition to the iSRC group membership. Once an appropriate 
number of half of the planned subjects (i.e.: approximately 35 subjects) subjects have 
completed their Week 24 assessments, a formal interim analysis and sample size re-
estimation will be conducted to assess the effect of the monotherapy belimumab or co-
administration therapy when compared to placebo and rituximab monotherapy at Week 
24will take place. Appropriate available safety and efficacy data will be included in the 
interim analysis. The main purpose of the interim analysis is to assess the safety and 
tolerability of the study drugs. In addition, preliminary efficacy analysis will be 
conducted to enable a sample size re-estimation and obtain an initial estimate of the 
effect size of the co-administration therapy and belimumab monotherapy. Following 
the interim analysis, a number of actions could be taken: the study will continue as 
planned; one or more treatment arms may be dropped; the number of subjects in some or 
all treatment arms may be increased following sample size re-estimation, up to a 
maximum of 120 subjects in the study.
STUDY DESIGN (Section 4)
Overall design (Section 4.1)
Change from:
Unblinded study data will be reviewed during trial conduct by an internal Safety Review 
Committee (iSRC), where a charter will detail their activities and membership. In line 
with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on an 
ongoing basis during the study conduct by an internal GSK Safety Review Team (SRT).
Once a sufficient number of subjects have completed Week 24, interim analyses and 
sample size re-estimation will be conducted. The results of the interim analyses will be 
reviewed by the iSRC, details of which will be outlined in the iSRC charter. Dependent 
on these results, the study will continue as planned, continue with modifications or may 
be stopped.
 
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Change to:
Study data will be reviewed in a confidential manner during the conduct of the 
trial.Unblinded study data will be reviewed during trial conduct by an internal Safety 
Review Committee (iSRC), where a charter will detail their activities and membership. In 
line with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on an 
ongoing basis during the study conduct by an internal GSK Safety Review Team (SRT).
Once a sufficient number of subjects have completed Week 24, interim analyses and 
sample size re-estimation will be conducted. The results of the interim analyses will be 
reviewed by the iSRC, details of which will be outlined in the iSRC charter. Dependent 
on these results, the study will continue as planned, continue with modifications or may 
be stopped.
An internal GSK Safety Review Committee (iSRC), independent of the study team, 
will maintain governance of the study and will periodically review all available data 
in an un-blinded manner with a focus on key safety parameters.  A Therapeutic 
Area (Immuno-Inflammation) Data Assessment Committee (TA DAC), independent 
of the study team, will periodically review un-blinded efficacy data and at the 
interim analysis will advise the iSRC on adaptive design changes should such 
changes be required.  An iSRC charter details the activities of these committees, 
including when and which data will be reviewed, how the integrity of the study will 
be maintained, and the membership of both committees. Once approximately half of 
the planned subjects (i.e.: approximately 35 subjects) have completed their Week 24 
assessments, a formal interim analysis will take place. Appropriate available safety 
and efficacy data will be included in the interim analysis. The main purpose of the 
interim analysis is to assess the safety and tolerability of the study drugs. In 
addition, preliminary efficacy analysis will be conducted to enable a sample size re-
estimation and obtain an initial estimate of the effect size of the co-administration 
therapy and belimumab monotherapy. Following the interim analysis, a number of 
actions could be mandated by the iSRC: the study will continue as planned; one or 
more treatment arms may be dropped; the number of subjects in some or all 
treatment arms may be increased following sample size re-estimation, up to a 
maximum of 120 subjects in the study.
Type and number of subjects (Section 4.4)
Add:
The sample size re-estimation will be conducted at the interim analysis.
Design Justification (Section 4.5)
Change from:
The use of pilocarpine and cevimeline (at stable doses) as well as topical therapies (such 
as ophthalmic lubricants, chewing gum) may be used for symptom relief during the 
treatment and follow up phases but would be prohibited within 24 hours of endpoint 
assessments.
 
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Change to:
The use of pilocarpine and cevimeline (at stable doses) as well as topical symptomatic
therapies (such as ophthalmic lubricants, chewing gum) may be used for symptom relief 
during the treatment and follow up phases but would be prohibited within 24 hours
within a period of time prior to of endpoint assessments (see Section 6.9.1 for details).
Dose justification (Section 4.6)
Dose Selection:
Added:
The double blind phase of this study was recently completed; the belimumab 200 mg 
SC weekly dose plus standard of care significantly improved SLE Response Index 
(SRI) and decreased time to severe flare compared with placebo plus standard of 
care.  Furthermore, safety findings with belimumab plus standard of care were 
similar to that of placebo plus standard of care [Stohl, 2015].
Risk Assessment for dual biologics in pSS (Section 4.7.1)
The table has been reformatted and the text edited to reflect revised exclusion and 
stopping criteria. In addition, the section on vaccination now includes further rationale 
with respect to belimumab.
Change from:
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [belimumab (GSK1550188) & rituximab]
Infections
Prolonged B-cell suppression 
and more complete B-cell 
depletion expected; potential 
for more profound 
hypogammaglobulinemia 
with increased risk for 
serious infections including 
opportunistic infections 
(OIs), PML, and HBV re-
activation.
Rituximab: The rate of 
serious infections with 
rituximab in the RA 
population is 4/100 per 
year.
Reactivation of hepatitis B 
has also been very rarely 
reported in RA patients 
receiving rituximab. 
Late onset neutropenia 
occurs rarely in patients 
treated with rituximab.
Belimumab: The rate for 
belimumab in SLE is 5% of 
Exclusions based on 
significant infection history, 
serologic evidence of past or 
present HBV or HCV 
infection; IgG or IgM below 
the LLN, IgA deficiency, 
neutrophils <1.5X109/L, 
CD4 < 400cells/mm3, or 
CD8<150cells/mm3.
A PML management plan 
including neurologic 
questionnaire and patient 
alert card.
Individual subject’s 
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
subjects receiving either 
belimumab or placebo.
Belimumab and Rituximab:
Infections are expected 
events for both belimumab 
and rituximab.
Cases of PML have been 
very rarely reported, 
including fatal events, for 
both rituximab and 
belimumab in autoimmune 
diseases. 
Dual Belimumab and 
Rituximab: There is pre-
clinical evidence for 
prolonged B-cell 
suppression and more 
complete B-cell depletion 
as well as effect on IgG1+ 
plasma cells in the long-
lived bone marrow niche 
thought to be less sensitive 
to immunotherapy [Lin, 
2015] with dual B-cell 
immunotherapy. 
Assessment of the 
translatability of the IgG 
reductions to humans are 
difficult to make due to 
species differences in B-cell 
biology and different 
treatments; however, the 
mouse data raises the 
hypothetical risk that 
immunoglobulin levels may 
reduce more with co-
administration treatment.
treatment will be 
discontinued for (a) life-
threatening infection; (b) 
IgG <400mg/dL (or 
<550mg/dL if associated 
with a serious infection); 
neutrophils < 1X109/L, CD4 
<300 cells/mm3, or CD8 
<100 cells/mm3
Subjects will be monitored 
for up to 2 years or until B-
cells return to LLN and 
monitored for late onset 
neutropenia at 6 months 
post-rituximab.
Systemic Infusion / Injection Reactions, Hypersensitivity Reactions and 
Immunogenicity
There is a potential risk for 
increased ADA due to cross 
reactivity which could lead 
to increased frequency of 
Rituximab: The incidence 
of serum sickness 
associated with rituximab in 
pSS studies has ranged from 
ADA will be monitored 
with collection at baseline, 
Weeks 8, 24, and 52
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
hypersensitivity reactions, 
particularly of the delayed 
type.
Serum Sickness: The 
incidence of serum sickness 
associated with rituximab is 
higher in autoimmune 
indications and likely greater 
in Sjögren’s Syndrome vs. 
RA [Meijer, 2010]. 
6-38% [Carubbi, 2014].
Belimumab and Rituximab:
Administration of 
belimumab and rituximab 
may result in infusion and 
hypersensitivity reactions, 
which can be severe and 
can be fatal. Delay in the 
onset of serious 
hypersensitivity reactions 
can occur. Both rituximab 
and belimumab have been 
associated with delayed 
type non-acute HSR/serum 
sickness, although no 
relationship to ADA has 
been established. 
Dual Belimumab and 
Rituximab: Incidences of 
hypersensitivity and 
infusion reactions have 
been noted to be higher 
with co-administration vs. 
mono-biologic therapy but 
no association with ADA 
has been established 
[Weinblatt, 2006].
A pre-medication regimen 
will be given before each 
rituximab/rituximab 
placebo infusion: 
methylprednisolone 100 mg 
IV, an oral antihistamine 
and analgesic.
Patients will be given an 
alert card for HSR and 
delayed HSR/serum 
sickness.
Malignancy
There is an increased risk of 
B-cell lymphoma in pSS. 
There is a theoretical 
increased risk of malignancy 
with combination 
immunosuppressive 
mechanisms; however, the 
potential synergistic effect of 
rituximab/belimumab would 
be assumed to result in a 
prolonged b-cell depletion 
that would not be dissimilar 
to repeat doses of rituximab.
Belimumab and Rituximab:
Immunomodulatory drugs 
like rituximab and 
belimumab may increase 
the risk of malignancy. To 
date, no causal relationship 
to belimumab or rituximab 
to malignancy, including B-
cell lymphoma, has been 
detected with either agent, 
both of which have been 
administered long term and 
in combination with other 
immunosuppressants of 
various mechanisms. 
Subjects with a history of 
malignancy in the 5 yrs 
prior to randomization will 
be excluded (see Section 
5.2, criterion #4).
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Interaction with Vaccinations
There is a risk of reduced 
antibody titers with mono 
and dual B cell 
immunotherapy. The 
potential synergistic effect of 
rituximab and belimumab 
may result in a prolonged B-
cell depletion that should 
have a similar impact on 
vaccine response as 
administering repeated doses 
of rituximab.
Rituximab: Median 
antibody titers (tetanus, 
diphtheria, pneumococcus) 
at Week 32 were reduced 
from baseline in atacicept 
but not placebo-treated 
patients who had been 
previously treated with 
rituximab. However, these 
values recovered close to 
baseline by Week 16 of the 
follow-up, there were few 
shifts to below protective 
titres, and no between-
group differences with 
respect to the frequency of 
shifts.
Live vaccination is 
prohibited from 30 days 
prior to Day 1 until 
normalization of peripheral 
B cells. 
Subjects’ vaccination status 
should be assessed and 
current immunization 
guidelines followed; all 
necessary vaccinations 
should be administered if 
possible no later than 30 
days prior to Day 0.
Psychiatric Events
There is a potential risk of 
psychiatric events with 
belimumab and rituximab.
Rituximab: Depression and 
anxiety were common 
adverse events in rituximab 
RA trials.
Belimumab: There have 
been reports of depression 
and suicidality in patients 
receiving belimumab. A 
causal relationship to 
belimumab has not been 
established.
Subjects who, in the 
investigator’s opinion, pose 
a significant suicide risk 
will be excluded. 
The C-SSRS will be 
completed at each visit 
during which the subject 
may potentially be exposed 
to belimumab. 
Subjects will be monitored 
closely for signs and 
symptoms of psychiatric 
illness including depression 
and suicidal ideation. 
Subjects displaying such 
signs and symptoms will be 
treated appropriately and 
referred as necessary to 
specialty psychiatric care.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Cardiac disorders
Rituximab: Angina pectoris, 
cardiac arrhythmias such as 
atrial flutter and fibrillation, 
heart failure and/or 
myocardial infarction have 
occurred in patients treated 
with rituximab. There is no 
data on the safety of 
rituximab in patients with 
moderate to severe heart 
failure or severe, 
uncontrolled CV disease. 
Belimumab and Rituximab:
Hypotension may 
accompany infusion/post-
injection systemic reactions 
with both rituximab and 
belimumab.
Exclude subjects with 
severe heart failure (New 
York Heart Association, 
Class IV) or other severe, 
uncontrolled cardiac 
disease.
Closely monitor any 
patients with cardiac history 
or those who have 
experienced prior 
cardiopulmonary adverse 
reactions during 
administration of 
rituximab/rituximab 
placebo. Consider 
withholding anti-
hypertensive medications 
12 hours prior to 
rituximab/rituximab 
placebo infusion.
Skin reactions
Rituximab: Severe skin 
reactions such as Toxic 
Epidermal Necrolysis and 
Stevens-Johnson syndrome; 
some with fatal outcome, 
have been reported with 
rituximab. 
Permanently discontinue 
treatment in the case of 
such an event with 
suspected relationship to 
treatment.
Posterior Reversible Encephalopathy Syndrome (PRES)
Rituximab: Cases of PRES / 
reversible posterior 
leukoencephalopathy 
syndrome (RPLS) have 
been reported. Signs and 
symptoms included visual 
disturbance, headache, 
seizures and altered mental 
status, with or without 
Medical monitor will be 
notified of any new 
neurologic symptoms (see 
Section 5.4.3). Medical 
monitor and investigator 
will consider the possibility 
of PRES in differential 
diagnosis.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
associated hypertension. A 
diagnosis of PRES/RPLS 
requires confirmation by 
brain imaging. The reported 
cases had recognized risk 
factors for PRES/RPLS, 
including the patients’ 
underlying disease, 
hypertension, 
immunosuppressive therapy 
and/or chemotherapy.
Study Procedures
Salivary gland Biopsy
This procedure is associated 
with (a low) incidence of 
complications including 
bleeding and hematoma 
formation. 
The reported incidence of
bleeding and hematoma 
were 7.5% and 2.7%, 
respectively in a large case 
series [Santiago, 2012].
Subjects will be instructed 
to stop anticoagulant 
therapy (i.e., aspirin, 
NSAIDs, warfarin) prior to 
the procedure. Also, the 
biopsy will be performed by 
qualified physicians, 
surgeons or dentists and the 
personnel performing the 
biopsy will be required to 
undergo study-specific 
training in the performance 
of this procedure. 
Change to:
Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [belimumab (GSK1550188) & rituximab]
Infections
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Infections:
Prolonged B-cell suppression 
and more complete B-cell 
depletion expected; potential 
for more profound 
hypogammaglobulinemia 
with increased risk for 
serious infections including 
opportunistic infections 
(OIs), PML, and HBV re-
activation.
Rituximab: The rate of 
serious infections with 
rituximab in the RA 
population is 4/100 per 
year.
Reactivation of hepatitis B 
has also been very rarely 
reported in RA patients 
receiving rituximab. 
Late onset neutropenia 
occurs rarely in patients 
treated with rituximab.
Belimumab: The rate for 
belimumab in SLE is 5% of 
subjects receiving either 
belimumab or placebo.
Belimumab and Rituximab:
Infections are expected 
events for both belimumab 
and rituximab.
Cases of PML have been 
very rarely reported, 
including fatal events, for 
both rituximab and 
belimumab in autoimmune 
diseases. 
Dual Belimumab and 
Rituximab: There is pre-
clinical evidence for 
prolonged B-cell 
suppression and more 
complete B-cell depletion 
as well as effect on IgG1+ 
plasma cells in the long-
lived bone marrow niche 
thought to be less sensitive 
to immunotherapy [Lin, 
2015] with dual B-cell 
immunotherapy. 
Assessment of the 
translatability of the IgG 
reductions to humans is
Exclusions based on
significant infection history, 
serologic evidence of past or 
present HBV or HCV 
infection; IgG< 550 mg / 
dL or IgM below the LLN, 
IgA deficiency, neutrophils 
<1.5X109/L, CD4 < 
400cells/mm3, or 
CD8<150cells/mm3.
A PML management plan 
including neurologic 
questionnaire and patient 
alert card.
Individual subject’s 
treatment will be 
discontinued for (a) life-
threatening infection; (b) 
IgG <400mg/dL (or 
<550mg/dL if associated 
with a serious infection); (c)
neutrophils < 1X109/L, CD4 
<300 cells/mm3, or CD8 
<100 cells/mm3
Subjects will be monitored 
for up to 2 years or until B-
cells return to LLN and 
monitored for late onset 
neutropenia at 6 months 
post-rituximab.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
difficult to make due to 
species differences in B-cell 
biology and different 
treatments; however, the 
mouse data raises the 
hypothetical risk that 
immunoglobulin levels may 
reduce more with co-
administration treatment.
Systemic Infusion / Injection Reactions, Hypersensitivity Reactions and 
Immunogenicity
Systemic Infusion / 
Injection Reactions, 
Hypersensitivity Reactions 
and Immunogenicity
There is a potential risk for 
increased ADA due to cross 
reactivity which could lead 
to increased frequency of 
hypersensitivity reactions, 
particularly of the delayed 
type.
Serum Sickness: The 
incidence of serum sickness 
associated with rituximab is 
higher in autoimmune 
indications and likely greater 
in Sjögren’s Syndrome vs. 
RA [Meijer, 2010]. 
Rituximab: The incidence 
of serum sickness 
associated with rituximab in 
pSS studies has ranged from 
6-38% [Carubbi, 2014].
Belimumab and Rituximab:
Administration of 
belimumab and rituximab 
may result in infusion and 
hypersensitivity reactions, 
which can be severe and 
can be fatal. Delay in the 
onset of serious 
hypersensitivity reactions 
can occur. Both rituximab 
and belimumab have been 
associated with delayed 
type non-acute HSR/serum 
sickness, although no 
relationship to ADA has 
been established. 
Dual Belimumab and 
Rituximab: Incidences of 
hypersensitivity and 
infusion reactions have 
been noted to be higher 
with co-administration vs. 
mono-biologic therapy but 
no association with ADA 
has been established 
ADA will be monitored 
with collection at baseline, 
Weeks 8, 24, and 52
A pre-medication regimen 
will be given before each
rituximab/rituximab 
placebo infusion: 
methylprednisolone 100 mg 
IV, an oral antihistamine 
and analgesic.
Patients will be given an 
alert card for HSR and 
delayed HSR/serum 
sickness.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
[Weinblatt, 2006].
Malignancy
Malignancy
There is an increased risk of 
B-cell lymphoma in pSS. 
There is a theoretical 
increased risk of malignancy 
with combination 
immunosuppressive 
mechanisms; however, the 
potential synergistic effect of 
rituximab/belimumab would 
be assumed to result in a 
prolonged b-cell depletion 
that would not be dissimilar 
to repeat doses of rituximab.
Belimumab and Rituximab:
Immunomodulatory drugs 
like rituximab and 
belimumab may increase 
the risk of malignancy. To 
date, no causal relationship 
to belimumab or rituximab 
to malignancy, including B-
cell lymphoma, has been 
detected with either agent, 
both of which have been 
administered long term and 
in combination with other 
immunosuppressants of 
various mechanisms. 
Subjects with a history of 
malignancy in the 5 yrs 
prior to randomization will 
be excluded (see Section 
5.2, criterion #4).
Interaction with Vaccinations
Interaction with 
Vaccinations
There is a risk of reduced 
antibody titers with mono 
and dual B cell 
immunotherapy. The 
potential synergistic effect of 
rituximab and belimumab 
may result in a prolonged B-
cell depletion that should 
have a similar impact on 
vaccine response as 
administering repeated doses 
of rituximab.
Rituximab: Median 
antibody titers (tetanus, 
diphtheria, pneumococcus) 
at Week 32 were reduced 
from baseline in atacicept 
but not placebo-treated 
patients who had been 
previously treated with 
rituximab. However, these 
values recovered close to 
baseline by Week 16 of the 
follow-up, there were few 
shifts to below protective 
titres, and no between-
group differences with 
respect to the frequency of 
shifts.
Belimumab: the efficacy of 
concurrent vaccination in 
patients receiving 
belimumab is not known; 
however, in the 
Live vaccination is 
prohibited from 30 days 
prior to Day 0 until 
normalization of peripheral 
B cells.the end of the 
general follow up period 
or IFU, if appropriate.  
Subjects’ vaccination status 
should be assessed and 
current immunization 
guidelines followed; all 
necessary vaccinations 
should be administered if 
possible no later than 30 
days prior to Day 0.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
belimumab vaccination 
trial (study 115470, see 
GSK Clinical Study 
Register at www.gsk-
clinicalstudyregister.com), 
evaluation of the impact of
belimumab treatment on 
response to on-treatment 
vaccination with 23-valent 
pneumococcal vaccine 
revealed that immune 
responses to the different 
serotypes were similar in 
SLE patients receiving 
belimumab compared 
with those not receiving 
treatment at the time of 
vaccination.
Psychiatric Events
Psychiatric Events
There is a potential risk of 
psychiatric events with 
belimumab and rituximab.
Rituximab: Depression and 
anxiety were common 
adverse events in rituximab 
RA trials.
Belimumab: There have 
been reports of depression 
and suicidality in patients 
receiving belimumab. A 
causal relationship to 
belimumab has not been 
established.
Subjects who, in the 
investigator’s opinion, pose 
a significant suicide risk 
will be excluded. 
The C-SSRS will be 
completed at each visit 
during which the subject 
may potentially be exposed 
to belimumab. 
Subjects will be monitored 
closely for signs and 
symptoms of psychiatric 
illness including depression 
and suicidal ideation. 
Subjects displaying such 
signs and symptoms will be 
treated appropriately and 
referred as necessary to 
specialty psychiatric care.
Cardiac disorders
Cardiac disorders
Rituximab: Angina pectoris, 
cardiac arrhythmias such as 
Exclude subjects with 
severe heart failure (New 
 
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Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
atrial flutter and fibrillation, 
heart failure and/or 
myocardial infarction have 
occurred in patients treated 
with rituximab. There is no 
data on the safety of 
rituximab in patients with 
moderate to severe heart 
failure or severe, 
uncontrolled CV disease. 
Belimumab and Rituximab:
Hypotension may 
accompany infusion/post-
injection systemic reactions 
with both rituximab and 
belimumab.
York Heart Association, 
Class IV) or other severe, 
uncontrolled cardiac 
disease.
Closely monitor any 
patients with cardiac history 
or those who have 
experienced prior 
cardiopulmonary adverse 
reactions during 
administration of 
rituximab/rituximab 
placebo. Consider 
withholding anti-
hypertensive medications 
12 hours prior to 
rituximab/rituximab 
placebo infusion.
Skin reactions
Skin reactions
Rituximab: Severe skin 
reactions such as Toxic 
Epidermal Necrolysis and 
Stevens-Johnson syndrome; 
some with fatal outcome, 
have been reported with 
rituximab. 
Permanently discontinue 
treatment in the case of 
such an event with 
suspected relationship to 
treatment.
Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior Reversible 
Encephalopathy Syndrome
(PRES)
Rituximab: Cases of PRES / 
reversible posterior 
leukoencephalopathy 
syndrome (RPLS) have 
been reported. Signs and 
symptoms included visual 
disturbance, headache, 
seizures and altered mental 
status, with or without 
associated hypertension. A 
diagnosis of PRES/RPLS 
requires confirmation by 
brain imaging. The reported 
Medical monitor will be 
notified of any new 
neurologic symptoms (see 
Section 5.4.3). Medical 
monitor and investigator 
will consider the possibility 
of PRES in differential 
diagnosis.
 
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Potential Risk of Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
cases had recognized risk 
factors for PRES/RPLS, 
including the patients’ 
underlying disease, 
hypertension, 
immunosuppressive therapy 
and/or chemotherapy.
Study Procedures
Salivary gland Biopsy
Salivary gland Biopsy
This procedure is associated 
with (a low) incidence of 
complications including 
bleeding and hematoma 
formation. 
The reported incidence of 
bleeding and hematoma 
were 7.5% and 2.7%, 
respectively in a large case 
series [Santiago, 2012].
Subjects will be instructed 
to stop anticoagulant 
therapy (i.e., aspirin, 
NSAIDs, warfarin) prior to 
the procedure. Also, the 
biopsy will be performed by 
qualified physicians, 
surgeons or dentists and the 
personnel performing the 
biopsy will be required to 
undergo study-specific 
training in the performance 
of this procedure. 
Vaccinations (Section 4.7.2)
A new Section 4.7.2 has been added to emphasise the vaccination recommendations and 
reference the appropriate EULAR guidelines.
Add:
The vaccination risk mitigation strategy detailed in the table above recommends 
that all necessary vaccinations should be administered if possible no later than 30 
days prior to day 0 and requires that no live vaccine be given from 30 days prior to 
day 0 until the end of the general follow up period or IFU, if appropriate.  In 
determining which vaccinations are necessary, investigators should follow guidelines 
such as the EULAR recommendations for vaccination in adult patients with 
autoimmune inflammatory rheumatic diseases (van Assen et al., 2011).  If indicated 
for standard of care, non live vaccines (e.g., inactivated influenza vaccines) may be 
administered while on study based on an assessment of the benefit:risk (e.g.: 
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SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA 
(Section 5)
Inclusion Criteria (Section 5.1)
Criterion #5
Change from:
Systemically active disease, ESSDAI ≥5 points.
Change to:
Systemically active disease, ESSDAI ≥5 points.
OR (for sites in ITALY ONLY)
Systemically active disease, ESSDAI≥5 points and with at least:
c) 1 extraglandular domain moderate,
OR
d) 2 extraglandular domains low.
Criterion #6:
Change from:
Oral Contraceptive, either combined or progestogen alone
Change to:
Combined estrogen and progestogen oral contraceptive
Delete:
Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).
New inclusion criterion #8
Add:
For FRANCE ONLY, a subject will be eligible for inclusion in this study if he /she is 
either affiliated to or beneficiary of a social security category. It is the investigator’s 
responsibility to ensure and to document (in source document - patient notes) that 
the patient is either affiliated to or beneficiary of a social security category.
 
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Exclusion Criteria (Section 5.2)
Exclusion criterion #14
Add:
(refer to Section 7.4.5)
Exclusion criterion #20
Change from:
Have received abatacept or any biologic agent within 180 day prior to Day 0 (with 
exception of denosumab)
Change to:
Have received abatacept or any biologic agent within 180 day prior to Day 0 (with 
exception of denosumab)
Exclusion criterion #30
Change from:
Any of the following screening laboratory values:

White blood cells (WBC) <2 x 109/L

Neutrophils <1.5 x 109/L

Circulating IgG or IgM levels <lower limit of normal (according to central 
laboratory range)

Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

Bilirubin >1.5 times the upper limit of normal

CD4 count <400 cells/mm3 

CD8 count <150 cells/mm3 
CD19+ B-lymphocyte counts <0.1 x 109/L
Change to:
Any of the following screening laboratory values:

White blood cells (WBC) <2 x 109/L

Neutrophils <1.5 x 109/L

Circulating IgG < 550 mg / dL or IgM levels <lower limit of normal (according 
to central laboratory range)
 
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
Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

Bilirubin >1.5 times the upper limit of normal (unless direct bilirubin fraction 
is < 35%)

CD4 count <400 cells/mm3 

CD8 count <150 cells/mm3 

CD19+ B-lymphocyte counts <0.1 x 109/L (applies only to subjects previously 
exposed to B cell depleting therapies)
New Exclusion criterion #31
Add:
For FRANCE ONLY, subjects with legal or administrative guardianship (“tutelle” 
or “curatelle”), or subjects deprived of liberty, or subjects receiving psychiatric 
care, or subjects hospitalized in an Health and Social Establishment for purposes 
other than participation in this study.
Screening/Baseline/Run-in failures (Section 5.3)
Change from:
Subjects who fail screening as a result of negative auto-antibodies (SS-A and SS-B) or as 
a result of insufficient systemic disease activity (ESSDAI ≤5 points) may be rescreened 
once in the 12 month period following the initial screen if the investigator has reason to 
believe that the subject’s auto-antibody status or level of systemic disease activity has 
changed. Similarly, subjects who are excluded on the basis of abnormal laboratory 
screening values as detailed in Selection Criteria #30 (Section 5.2) may be re-screened 
within a 1 year period if the investigator has reason to believe the laboratory values may 
have changed. The informed consent process should be repeated in the event that a 
subject is rescreened.
Assessments may be repeated in cases of technical malfunction (e.g., loss of laboratory 
specimen). Assessments (see Section 7.1) performed during the 35 day screening period 
to determine subject suitability for entry into the study may be repeated during this 
screening period. These are repeat assessments and not rescreening events.
Change to:
Rescreening: Subjects who fail screening as a result of negative auto-antibodies (SS-A 
and SS-B) or as a result of insufficient systemic disease activity (ESSDAI ≤5 points) may 
be rescreened once in the 12 month period following the initial screen if the investigator 
has reason to believe that the subject’s auto-antibody status or level of systemic disease 
activity has changed. Similarly, subjects who are excluded on the basis of abnormal 
laboratory screening values as detailed in Selection Criteria #30 (Section 5.2) may be re-
 
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screened within a 1 year period if the investigator has reason to believe the laboratory 
values may have changed. The informed consent process should be repeated in the event 
that a subject is rescreened. Subjects who fail screening may be rescreened once at the 
discretion of the investigator.
Assessments may be repeated in cases of technical malfunction (e.g., loss of laboratory 
specimen). Assessments (see Section 7.1) performed during the 35 day screening period 
to determine subject suitability for entry into the study may be repeated during this 
screening period. These are repeat assessments and not rescreening events.
Repeat assessments during the 35 day screening period: assessments (see Section 
7.1), including laboratory assessments, may be repeated if determined necessary by 
the investigator, for example: (a) in cases of technical malfunction (e.g., loss of 
laboratory specimen), (b) in the event of a value close enough to the exclusionary 
threshold that it may reasonably lie within the degree of variability of the assay; (c) 
if there is reason to believe the result may be false (i.e.: contradicts recent  result for 
the same parameter). These are repeat assessments and not rescreening events.  If 
the original result was exclusionary and is confirmed by repeat testing, the subject 
will be excluded.
Withdrawal/Stopping Criteria/General Criteria (Section 5.4.1)
Change from:
In addition, for a subset of subjects who receive rituximab/placebo at the Week 8 visit, or 
at both the Weeks 8 and 10 visits, but who discontinue treatment prior to the Week 46 
visit, maintenance of contraception and monthly telephone calls for urine pregnancy test 
results will be required until approximately 52 weeks after the last dose of rituximab/pbo 
was administered.
 
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Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before the Week 46 
Visit
Subject discontinues 
treatment at or after the 
Week 46 Visit
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, AEs, SAEs, and 
concomitant 
medications during the 
16-week general follow-
up period
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, AEs, SAEs, and 
concomitant medications 
during the 16-week 
general follow-up period.
An additional telephone 
call for urine pregnancy 
results at approximately 
52 weeks after the last 
rituximab/placebo dose
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, AEs, SAEs, and 
concomitant 
medications during the 
16-week general 
follow-up period.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
Change to:
In addition, for a subset of subjects who receive rituximab/placebo at the Week 8 visit, or 
at both the Weeks 8 and 10 visits, but who discontinue treatment prior to the Week 
46visit, maintenance of contraception and monthly telephone calls for urine pregnancy 
test results will be required until approximately 52 weeks after the last dose of 
rituximab/pbo was administered.
Week 46 is an important threshold for withdrawal as it is only beyond week 46 that 
continued exposure to belimumab/placebo dictates a longer follow up for pregnancy 
evaluation (Section 7.4.2).
 
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Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before the Week 46 
Visit
Subject discontinues 
treatment at or after the
Week 46 Visit
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period.
An additional telephone 
call for urine pregnancy 
results at approximately 
52 weeks after the last 
rituximab/placebo dose
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general 
follow-up period.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
Please refer to Section 5.4.4 of the study reference manual for further consideration 
of scenarios which may be encountered in terms of the timing and circumstances of 
subject withdrawal and the steps which need to be followed.
Early withdrawal visit (Section 5.4.2)
A new section has been created to describe the early withdrawal visit.
Add:
Subjects that withdraw consent prior to the week 68 visit should, if possible, 
complete an early withdrawal visit. The early withdrawal visit is identical to the 
week 68 visit (see Section 7.1) but also includes the exit interview (Section 7.3.1).
Detailed adverse event criteria (Section 5.4.3)
Change from:
All subjects should be monitored closely for infection. Patients who develop 
IgG <400 mg/dL confirmed by repeat test 1 week (>2 days) after the initial result, will be 
withdrawn from study treatment. In addition, increased vigilance for infection is 
recommended in subjects who develop IgG <550 mg/dL. Those with a decrease in IgG 
 
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below 550 mg/dL that is associated with a serious infection (i.e., an infection reported as 
an SAE) will be withdrawn from study treatment. In addition, if any subject develops a 
life-threatening infection regardless of IgG status, the investigator must contact the 
Medical Monitor to determine whether treatment with IP should be continued. Finally, 
subjects will be withdrawn from study treatment for the following lab abnormalities: 
neutrophils <1X109/L, CD4 <300cells/ mm3, or CD8 <100 cells/mm3 (confirmed by 
repeat test 1 week [>2 days] after the initial result).
Change to:
All subjects should be monitored closely for infection. Patients who develop 
IgG <400 mg/dL confirmed by repeat test 1 week (>2 days) after the initial result, will be 
withdrawn from study treatment. In addition, increased vigilance for infection is 
recommended in subjects who develop IgG <550 mg/dL. Those with a decrease in IgG 
below 550 mg/dL that is associated with a serious infection (i.e., an infection reported as 
an SAE) will be withdrawn from study treatment. In addition, if any subject who
develops a life-threatening infection regardless of IgG status, will be promptly 
withdrawn from the investigator must contact the Medical Monitor to determine 
whether treatment withIPshould be continued. Finally, subjects will be withdrawn from 
study treatment for the following lab abnormalitiesabnormality: neutrophils <1X109/L, 
CD4 <300cells/ mm3, or CD8 <100 cells/mm3(confirmed by repeat test 1 week [>2 days] 
after the initial result).
STUDY TREATMENT (Section 6)
Self Administered Subcutaneous Injections and Log Book (Section 6.1.1.1)
Paragraph 2:
Change from:
Subjects will remain at the clinic for 3 hours following the first and the second dose of 
belimumab for observation.
Change to:
Subjects will remain at the clinic for 3 hours following the first and the second dose of 
belimumab/placebo for observation.
Paragraph 4:
Change from:
Subjects will be provided with a self-injection log book. Subjects will fill out the 
injection log immediately after administering the injection, recording the date of 
injection, the injection site and whether or not the entire dose was administered. If the 
entire dose was not administered, an explanation should be provided, and the estimated 
amount injected should be recorded. The injection site should be rotated between the left 
or the right thigh and the abdomen. Dosing compliance should be reviewed with the 
 
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subject monthly at the site study visit and self-injection log books collected from the 
subject by study site staff. Subjects are also required to return all used syringes at each 
visit, and all unused syringes at their final visit
Change to:
Subjects will be provided with a self-injection log book (refer to Appendices of Study 
Reference Manual). Subjects will fill out the injection log immediately after 
administering the injection, recording the date of injection, the injection site and whether 
or not the entire dose was administered. If the entire dose was not administered, an 
explanation should be provided, and the estimated amount injected should be recorded. 
The injection site should be rotated between the left or the right thigh and the abdomen. 
Dosing compliance should be reviewed with the subject monthly at the site study visit 
and self-injection log books collected from the subjectreviewed by study site staff. 
Subjects are also required to return all unused syringes at each study visit. and all 
unUused syringes should be placed in a sharps container and returned to the site as 
described in Section 2 of the Study Reference Manual.at their final visit.
Rituximab (Section 6.1.2)
Paragraph 2:
Change from:
Rituximab is a 100 mg concentrated solution for infusion. It is a clear, colorless liquid. 
Rituximab and placebo will be prepared at the study site by an unblinded pharmacist 
according to the procedure defined in the Pharmacy Manual. Rituximab treatment will 
consist of two 1000 mg intravenous infusions, a first 1000 mg intravenous infusion 
followed by a second 1000 mg intravenous infusion 2 weeks later.
Change to:
Rituximab is a 5100 mg concentrated solution which requires dilution prior tofor
infusion. It is a clear, colorless liquid. Rituximab and placebo (0.9% NaCl, sterile, 
pyrogen free) will be prepared at the study site by an unblinded pharmacist according to 
the procedure defined in the Pharmacy Manual. Rituximab treatment will consist of two 
1000 mg intravenous infusions, a first 1000 mg intravenous infusion followed by a 
second 1000 mg intravenous infusion 2 weeks later. Please refer to the study reference 
manual for guidance regarding missed doses of rituximab.
Paragraph 4:
Change from:
The rituximab/placebo solution prepared by the unblinded pharmacist should be 
administered as an intravenous infusion through a dedicated line. It should not be 
administered as an intravenous push or bolus. Patients should be closely monitored for 
the onset of cytokine release syndrome. Patients who develop evidence of severe 
reactions, especially severe dyspnea, bronchospasm or hypoxia should have the infusion 
 
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interrupted immediately. In all patients, the infusion should not be restarted until 
complete resolution of all symptoms, and normalization of clinical investigations 
including laboratory values. At this time, the infusion can be initially resumed at not 
more than one-half the previous rate. If the same severe adverse reactions occur for a 
second time, the decision to stop the treatment should be seriously considered on a case 
by case basis. Mild or moderate infusion-related reactions usually respond to a reduction 
in the rate of infusion. The infusion rate may be increased upon improvement of 
symptoms.
Change to:
The rituximab/placebo solution prepared by the unblinded pharmacist should be 
administered as an intravenous infusion through a dedicated line. It should not be 
administered as an intravenous push or bolus. As detailed in the rituximab summary of 
product characteristics, patients should be closely monitored for the onset of 
infusion reactions during the rituximab/placebo infusion. Vital signs (heart rate, 
blood pressure, temperature and respiratory rate) should be regularly measured 
and subjects should be observed closely for any signs that might be consistent with a 
hypersensitivity reaction (e.g. development of skin rash, fever). Patients should be 
closely monitored for the onset of cytokine release syndrome. Patients who develop 
evidence of severe reactions, especially severe dyspnea, bronchospasm or hypoxia should 
have the infusion interrupted immediately. In all patients, the infusion should not be 
restarted until complete resolution of all symptoms, and normalization of clinical 
investigations including laboratory values. At this time, the infusion can be initially 
resumed at not more than one-half the previous rate. If the same severe adverse reactions 
occur for a second time, the decision to stop the treatment should be seriously considered 
on a case by case basis. Mild or moderate infusion-related reactions usually respond to a 
reduction in the rate of infusion. The infusion rate may be increased upon improvement 
of symptoms.
Blinding (Section 6.3)
Final bullet point:
Change from:

Sponsor open refers only to those members of the iSRC who are unblinded for the 
interim analysis, as outlined in the iSRC charter. The GSK study team will be 
blinded except for any iSRC team members and any team members required for 
monitoring the pharmacy e.g., unblinded monitor etc.
Change to:

Sponsor open refers only to those members of the iSRC and the TA DAC who are 
unblinded for the interim analysis, as outlined in the iSRC charter. The GSK study 
team will be blinded except for any iSRC team members and any team members 
required for monitoring the pharmacy e.g., unblinded monitor etc.
 
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Permitted medications and non-drug therapies (Section 6.9.1)
Bullet point 2:
Change from:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 40 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Change to:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Bullet point 3:
Change from:

Topical symptomatic therapies (such as ophthalmic lubricants). Subjects will be 
required to withhold dosing with these agents in the 24h prior to all efficacy 
assessments.
Change to:

Topical symptomatic therapies are detailed below:

(such as Ophthalmic lubricants (e.g. glucane or saline eye drops); subjects 
will be required to withhold dosing 4hrs prior to efficacy assessments.

Ophthalmic lubricating ointments [(e.g. Dry Eyes, LacriLube); subjects will 
be required to withhold dosing 24hrs prior to efficacy assessments].

Hydroxyl cellulose ophthalmic  insert  [(e.g. Lacrisert); subjects will be required 
to withhold dosing 24hrs prior to efficacy assessments].

Non-pharmacologic saliva stimulants  [(e.g. gums, drinks, teeth washing); 
subjects will be required to withhold dosing 90 minutes prior to efficacy 
assessments].

Saliva substitutes [(e.g. Xialine, Oral Balance , Saliva Orthana , Salinum 
mouth rinses, Chlorhexidine mouth rinses); subjects will be required to 
withhold dosing 90 minutes prior to efficacy assessments.
Subjects will be required to withhold dosing with these agents in the 24 h prior to all 
efficacy assessments.
Prohibited Medications and Non-Drug Therapies (Section 6.9.2)
Change from:

Concomitant biologic treatments 
 
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
Conventional systemic immunosuppressive treatments and DMARDs (such as 
methotrexate and azathioprine)
Change to:

Concomitant biologic treatments (see SRM for examples)

Conventional systemic immunosuppressive treatments and DMARDs (such as 
methotrexate and azathioprine)

Pharmacological topical ophthalmic agents (e.g. NSAIDs, corticosteroids, 
cyclosporine, diquafosal) are excluded from use in the study.

Non muscarinic secretagogues (e.g.  Anetholtritione, Bromhexine3 N-
acetylcystein) are excluded from use in the study.
STUDY ASSESSMENTS AND PROCEDURES (Section 7)
Time and Events Table (Section 7.1)
Safety and Laboratory Assessments:
Added:
Blood: Cryoglobulins. An additional row has been added to the table to clarify when 
blood samples should be taken for cryoglobulins assessment.
Footnote 1:
Change from:
All subjects, including subjects who are withdrawn from the study (See Section 5.4.1) 
and decline to complete the treatment phase visits through Week 52, are required to enter 
the general follow up period. During this 16-week general follow up period, subjects will 
receive monthly calls to evaluate AEs, to check concomitant medications and to complete 
the neurological assessment (Appendix 5).
Change to:
All subjects, including subjects who are withdrawn from the study (See Section 5.4.1) 
and decline to complete the treatment phase visits through Week 52, are required to enter 
the general follow up period. During this 16-week general follow up period, subjects will 
receive monthly calls every 4 weeks (±7 days) to evaluate AEs, to check concomitant 
medications and to complete the neurological assessment (Appendix 5).
 
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Footnote 2:
Change from:
In order to maintain the blind, sites will be blinded to these data - including B-cell flow 
cytometry panels and IgA, IgM levels.
Change to:
In order to maintain the blind, sites will be blinded to these data following screening -
including B-cell flow cytometry panels and IgA, IgM levels.
Footnote 6, first sentence:
Change from:
Subjects will enter the IFU if, following the general follow up period, their CD19+ B-cell 
levels remain below the lower limit of normal (or less than 90% of baseline, if baseline 
value was below LLN). During the IFU, subjects will be seen in the clinic every 12 
weeks (7 days), with monthly calls between visits to evaluate subjects for AEs & 
concomitant medications.
Change to:
Subjects will enter the IFU if, following the general follow up period, their CD19+ B-cell 
levels remain below the lower limit of normal (or less than 90% of baseline, if baseline 
value was below LLN). During the IFU, subjects will be seen in the clinic every 12 
weeks (7 days), with monthly calls every 4 weeks (±7 days) between visits to evaluate 
subjects for AEs & concomitant medications.
Footnote 8:
Change from:
Both doses of rituximab/placebo will be administered in the clinic. 60 minutes prior to 
rituximab subjects will receive orally an antipyretic and an antihistamine. 30-60 minutes 
prior to administration of rituximab/placebo, subjects will receive IV 100mg 
methylprednisilone .The 2nd rituximab/placebo administration at the Week10 visit must 
be given 14 days after the first administration (given at the Week 8 visit). A patient alert 
card should be sent home with the subject following each dose of rituximab.
Change to:
Both doses of rituximab/placebo will be administered in the clinic. 60 minutes prior to 
rituximab/placebo, subjects will receive orally an antipyretic and an antihistamine. 30-60 
minutes prior to administration of rituximab/placebo, subjects will receive IV 100mg 
methylprednisilone .The 2nd rituximab/placebo administration at the Week10 visit must 
be given 14 days after the first administration (given at the Week 8 visit). A patient alert 
card should be sent home with the subject following each dose of rituximab/placebo.
 
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Footnote 10:
Change from:
Subjects will receive a reminder phone call 48 hours prior to efficacy assessment visits to 
remind them that they should not be using topical symptomatic therapy for 24 hours prior 
to visit; in addition subjects should document their last use of topical symptomatic 
therapy.
Change to:
Subjects will receive a reminder phone call 48 hours prior to efficacy assessment visits to 
remind them that they should not be usingtopical certain symptomatic therapiesy for 
24 hours prior to visit (see Section 4.1 of Study Reference Manual for details); in 
addition subjects should document their last use of topical symptomatic therapiesy in 
their self injection log book.
Screening and Critical Baseline Assessments (Section 7.2)
Electrocardiogram
Change from:
Electrocardiogram: Triplicate 12-lead ECGs will be obtained at screening using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. A single method (Bazett’s or Fredericia’s) must be used when 
calculating the corrected QT interval for determining subject eligibility, as described in 
the SRM.
Change to:
Electrocardiogram: Triplicate 12-lead ECGs will be obtained at screening using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. A single method (Bazett’s or Fredericia’s) must be used when 
calculating the corrected QT interval for determining subject eligibility, as described in 
the study reference manual (SRM).
Tuberculosis (new subsection):
Added:

Tuberculosis: Assessment of TB in the screening period is to be done via 
evaluation of the subject’s history, physical examination of the subject and, if 
judged necessary by the Investigator, local laboratory (screening and 
confirmatory) testing.
 
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Salivary gland biopsy:
Change from:
The salivary gland biopsy surgical technique will be described in the SRM and training. 
Training reference materials will be provided to site personnel who will perform this 
procedure. 
Biopsy tissue will be shipped to a central histopathology laboratory for processing and 
assessment. The baseline biopsy can occur on Day 0 or at any time during the screening 
period provided the subject has met all other entry criteria prior. After an interim 
analysis, dependent on data, the biopsy may no longer be a mandatory requirement.
Change to:
The salivary gland biopsy surgical technique will beis described in the SRMand training. 
Training reference materials will be provided to site personnel who will perform this 
procedure. 
Biopsy tissue will be shipped to a central histopathology laboratory for processing and 
assessment. The baseline biopsy can occur on Day 0 or at any time during the screening 
period provided the subject has met all other entry criteria prior. After thean interim 
analysis, dependent on data, the biopsy may no longer be a mandatory requirement.
Efficacy (Section 7.3)
Salivary gland biopsy:
Change from:
The salivary gland biopsy surgical technique will be described in the SRM and training. 
Training reference materials will be provided to site personnel who will perform this 
procedure.
Change to:
The salivary gland biopsy surgical technique will beis described in the SRM and training. 
Training reference materials will be provided to site personnel who will perform this 
procedure.
Patient Reported Outcomes Assessments (Section 7.3.1)
Change from:
PtGA: 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. 
 
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Change to:
PtGA: the Patient Global Assessment is a patient reported visual analogue numeric 
rating scale that provides an overall measure of disease severity. The assessment 
instrument and technique for administration will be described in the SRM. 
Safety (Section 7.4)
Adverse Events of Special Interest (Section 7.4.1.4)
Change from:
Adverse events of special interest are malignancies, post-injection systemic reactions,
infections, depression/suicidality/self-injury, and deaths. Please refer to Section . The 
analyses of these events will be described in the Reporting and Analysis Plan.
Change to:
A number of adverse events of special interest have been identified as part of the 
risk assessment outlined in Section 4.7.1 due to the co-administration of two 
biologics.and will be monitored for the duration of the study.  These AESIs include 
infections (including opportunistic), systemic infusion / injection reactions, 
hypersensitivity reactions, malignancy, psychiatric events (including suicidality), 
severe skin reactions (including Toxic Epidermal Necrolysis and Stevens-Johnson 
syndrome), immunogenicity, cardiac disorders, posterior reversible encephalopathy 
syndrome (PRES), PML, and AE’s related to the biopsy procedure.  The analyses of 
these events will be described in the Reporting and AnalysisPlan. 
Pregnancy (Section 7.4.2)
Final bullet point:
Change from:

Women who become pregnant while on active treatment will be withdrawn from 
therapy but will continue in the trial for safety reporting and outcomes assessments. 
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child.
Change to:

Women who become pregnant while on active treatment will be withdrawn from 
therapy but will continue in the trial for safety reporting and outcomes assessments. 
The pregnancy must be followed up to determine outcome (including premature 
termination), and status of mother and child including a one-year pediatric follow-
up.
 
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Electrocardiogram (Section 7.4.5)
Change from:

Triplicate 12-lead ECGs will be obtained at screening using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.
Change to:

Triplicate 12-lead ECGs will be obtained at screening using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
If the ECG demonstrates a QTcB or QTcF interval ≥ 450 msec (≥ 480 msec for 
subjects with a Bundle Branch Block), there is a requirement to obtain two 
additional, consecutive ECGs (for a total of three). The investigator will then 
average the three QTc (and QT) intervals obtained and document the following 
from the 1st ECG:
o
Rate
o
PR interval
o
QRS axis
Clinical Laboratory Assessments (Section 7.4.6)
Delete “Ig” from Table 1. Ig was included in the original Table in error and is not being 
measured in this study.
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS (Section 9)
Throughout Section 9, “analyses” has been replaced with “analysis”
Hypothesis and Treatment Comparisons (Section 9.1)
Paragraph 2.
Change from:
If deemed appropriate, to investigate the secondary efficacy and mechanistic endpoints, 
the following exploratory comparisons may be conducted:
Change to:
If deemed appropriate, to investigate the sSecondary efficacy and mechanistic endpoints 
will be investigated. The following exploratory comparisons may be conducted:
 
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Interim Analysis (Section 9.3.2)
Change from:
In line with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on 
an ongoing basis during the study conduct by an internal GSK Safety Review Team 
(SRT).
Study data will be reviewed in a confidential manner during the trial conduct by an 
internal GSK Safety Review Committee (iSRC). Reviews may include un-blinded 
efficacy, pharmacodynamic and safety data. An iSRC charter will detail their activities, 
including when and which data will be reviewed and how the integrity of the study will 
be maintained in addition to the iSRC group membership.
Once an appropriate number of subjects have completed their Week 24 assessment, 
interim analyses and sample size re-estimation will be conducted to assess the effect of 
the monotherapy belimumab or co-administration therapy when compared to placebo and 
rituximab monotherapy at Week 24. Appropriate available data will be included in the 
interim analyses, the results of which will be reviewed by the iSRC. Following interim 
analyses, a number of actions could be taken: the study will continue as planned; one or 
more treatment arms may be dropped; the number of subjects in some or all treatment 
arms may be increased following sample size re-estimation, up to a maximum of 120 
total subjects in the study. 
The interim analysis decision making criteria will be outlined in the iSRC Charter, where 
in parallel with all available safety data the ESSDAI score, stimulated salivary flow, oral 
dryness numeric response scale and salivary gland B cell quantification may be 
considered.
Change to:
In line with routine pharmacovigilance, subjects’ blinded safety data will be reviewed on 
an ongoing basis during the study conduct by an internal GSK Safety Review Team 
(SRT).
Study data will be reviewed in a confidential manner during the trial conduct by an 
internal GSK Safety Review Committee (iSRC). Reviews may include un-blinded 
efficacy, pharmacodynamic and safety data. An iSRC charter will detail their activities, 
including when and which data will be reviewed and how the integrity of the study will 
be maintained in addition to the iSRC group membership.
Once an appropriate number of subjects have completed their Week 24 assessment, 
interim analyses and sample size re-estimation will be conducted to assess the effect of 
the monotherapy belimumab or co-administration therapy when compared to placebo and 
rituximab monotherapy at Week 24. Appropriate available data will be included in the 
interim analyses, the results of which will be reviewed by the iSRC. Following interim 
analyses, a number of actions could be taken: the study will continue as planned; one or 
more treatment arms may be dropped; the number of subjects in some or all treatment 
 
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arms may be increased following sample size re-estimation, up to a maximum of 120 
total subjects in the study. 
An internal GSK Safety Review Committee (iSRC), independent of the study team, 
will maintain governance of the study and will periodically review all available data 
in an un-blinded manner with a focus on key safety parameters.  A Therapeutic 
Area (Immuno-Inflammation) Data Assessment Committee (TA DAC), independent 
of the study team, will periodically review un-blinded efficacy data and at the 
interim analysis will advise the iSRC on adaptive design changes should such 
changes be required.  An iSRC charter details the activities of these committees, 
including when and which data will be reviewed, how the integrity of the study will 
be maintained, and the membership of both committees. Once half of the planned 
subjects (i.e.: approximately 35 subjects) have completed their Week 24 
assessments, a formal interim analysis will take place. Appropriate available safety 
and efficacy data will be included in the interim analysis. The main purpose of the 
interim analysis is to assess the safety and tolerability of the study drugs. In 
addition, on an exploratory basis, preliminary efficacy analysis will be conducted to 
enable a sample size re-estimation and obtain an initial estimate of the effect size of 
the co-administration therapy and belimumab monotherapy. Following the interim 
analysis, a number of actions could be mandated by the iSRC: the study will 
continue as planned; one or more treatment arms may be dropped; the number of 
subjects in some or all treatment arms may be increased following sample size re-
estimation, up to a maximum of 120 subjects in the study.
The interim analysis decision making criteria will be outlined in the iSRC Charter, where 
in parallel with all available safety data the ESSDAI score, stimulated salivary flow, oral 
dryness numeric response scale and salivary gland B cell quantification may be 
considered.
Final Analysis (Section 9.4.1)
Change from:
In addition to the interim analyses, there will be 2 database locks and hence analyses for 
this study, corresponding to the primary analysis and the follow-up analysis. The 
database will be locked for the primary analysis after data through the Week 52 visit (or 
withdrawal visit for those subjects who withdraw during double-blind treatment) for all 
subjects have been collected, verified and validated. The second database lock will occur 
after data through the 16-week generalized follow-up period for all subjects have been 
collected, verified and validated. All subjects and study site personnel (except the 
unblinded site pharmacist) will remain blinded until the second database lock.
Change to:
In addition to the interim analysesanalysis, there will be 2 database locks and 
henceadditional analyses for this study, corresponding to the primary analysis and the 
follow-up analyses. The database will be locked for the primary analysis will occur after 
the data through the Week 52 visit (or withdrawal visit for those subjects who withdraw 
during double-blind treatment) for all subjects have been collected, verified and 
 
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validated. The second database lockfollow up analyses will occur after data through the 
16-week generalized follow-up period and IFU periods for all subjects have been 
collected, verified and validated. All subjects and study site personnel (except the 
unblinded site pharmacist) will remain blinded until the second database lockfollow up 
analyses have been completed.
Primary Analysis (Section 9.4.2)
2nd paragraph:
Change from:
All safety evaluations will be based on the safety population. Clinical interpretation will 
be based upon review and displays of AEs, disease related events, laboratory values and 
vital signs. The principle consideration in this evaluation will be the investigator-reported 
relationships of either AEs or laboratory abnormalities to IP.
Change to:
All safety evaluations will be based on the safety population. Clinical interpretation will 
be based upon review and displays of AEs, disease related events, laboratory values and 
vital signs. The principle consideration in this evaluation will be the investigator-reported 
relationships of either AEs or laboratory abnormalities to IP.
Secondary Analysis (Section 9.4.3)
4th and 5th paragraphs:
Change from:
The ESSDAI, stimulated salivary flow, oral dryness numeric response scale and salivary 
gland B cell quantification change from baseline scores will be statistically analyzed 
using a MMRM analysis, comparing the belimumab / rituximab or the belimumab 
monotherapy arm with placebo at each time point. Similar analyses will also be 
conducted, if deemed appropriate, comparing each monotherapy arm with placebo. The 
baseline ESSDAI scores will be investigated as a potential co-variate in the model, if 
deemed appropriate.
In addition, based on the data that we observe in the study, probabilities of success will 
be determined. For example, what is the probability that we would observe a certain 
change in the ESSDAI score (i.e., comparator rate), based on the data that we have 
observed in the study?
Change to:
The ESSDAI, stimulated salivary flow, oral dryness numeric response scale and salivary 
gland B cell quantification change from baseline scores will be statistically analyzed 
using a mixed model repeated measures approach MMRM analysis comparing the 
belimumab monotherapy, rituximab monotherapy andbelimumab / rituximab 
 
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combination therapyor the belimumab monotherapy arm with placebo at each time 
point. Similar analyses will also be conducted, if deemed appropriate, comparing each 
monotherapy arm with placebo. Point estimates and corresponding 95% confidence 
intervals will be estimated for the comparisons of interest. The baseline ESSDAI 
scores will be investigated as a potential co-variate in the model, if deemed appropriate.
Distributional assumptions underlying the analyses will be assessed. Additional 
models may be investigated.
In addition, based on the data that we observe in the study, probabilities of success of the 
combination therapy and belimumab monotherapy will be determined. For example,
what is the probability that we would observe a certain change in the ESSDAI score (i.e., 
comparator rate), based on the data that we have observed in the study?
STUDY GOVERNANCE CONSIDERATIONS (Section 10)
Regulatory and ethical considerations (Section 10.2)
Added:

Regulatory Agency review and favorable opinion/approval of the study protocol and 
substantial amendments.
Deleted to avoid duplication:

Signed informed consent must be obtained for each subject prior to participation in 
the study
Review Committees (Section 10.8.1)
Change from:
Section 10.8.1
Internal Safety Review Committee (iSRC)
Study data will be reviewed during trial conduct by an iSRC. Reviews may include un-
blinded efficacy, pharmacodynamic, and/or safety data. An iSRC charter will detail their 
activities, including when and which data will be reviewed and how the integrity of the 
study will be maintained in addition to the group membership.
Change to:
Section 10.8.1
Internal Safety Review Committee (iSRC) and Therapeutic Area 
Data Assessment Committee (TA-DAC)
Study data will be reviewed during trial conduct by an iSRC. Reviews may include un-
blinded efficacy, pharmacodynamic, and/or safety data. An iSRC charter will detail their 
activities, including when and which data will be reviewed and how the integrity of the 
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An internal GSK Safety Review Committee (iSRC), independent of the study team, 
will maintain governance of the study and will periodically review all available data 
in an un-blinded manner with a focus on key safety parameters.  A Therapeutic 
Area (Immuno-Inflammation) Data Assessment Committee (TA DAC), independent 
of the study team, will periodically review un-blinded efficacy data and at the 
interim analysis will advise the iSRC on adaptive design changes should such 
changes be required.  An iSRC charter details the activities of these committees, 
including when and which data will be reviewed, how the integrity of the study will 
be maintained, and the membership of both committees.
The overall responsibility of the iSRC is to protect the ethical and safety interests of 
subjects recruited into the study while also protecting the scientific validity of the 
data. The iSRC has the primary governance role for the study.
REFERENCES  (Section 11)
Added:
Stohl W, Schwarting A, Okada M, et al. A Randomized, Double-Blind, Placebo-
Controlled, 52-Week Study of the Efficacy and Safety of Belimumab Administered 
Subcutaneously Plus Standard Care to Patients with Systemic Lupus 
Erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
van Assen, S, Agmon-Levin, N, Elkayam, O, et al. EULAR recommendations for 
vaccination in adult patients with autoimmune infl ammatory rheumatic diseases. 
Ann Rheum Dis 2011;70: 414–422.
APPENDICES
Appendix 1 – Abbreviations and Trademarks
Added:
TA-DAC
Therapeutic Area – Data Assessment Committee
 
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Appendix 8 – Collection of Pregnancy information
Bullet point 3:
Change from:
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.
Change to:
Subject will be followed for 1 year 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.
Added:
Appendix 9: American-European Consensus Group Classification
Reference: Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for 
Sjögren's syndrome: a revised version of the European criteria proposed by the 
American-European Consensus Group. Ann Rheum Dis. 2002; 61:554–8.
 
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Added:
Appendix 10 to Appendix 13 have been added. These detail changes made to the 
protocol in previous country specific amendments and in the current global protocol 
amendment (version 4).
 
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12.14.
Appendix 14: Protocol changes in Amendment 5
Amendment 5: global amendment (all sites).
Protocol Amendment 05, 11 May 2018
Summary of Modifications (relative to protocol amendment 4) and Rationale:
1.
Protocol Cover Page

Protocol version and Revision Chronology updated in line with 
amendment 5

Author list removed as this is no longer part of the current GSK protocol 
template, furthermore authors are captured on technical approval TMF 
documentation

Medical Monitor Contact Details updated in line with GSK team changes
2.
Protocol Synopsis (Section 1)

Clarification that total subject number is approximate, in line with the rest 
of the document.

Text inserted to state that withdrawals may be replaced, in line with the 
main body of the protocol.

Clarification of Statistical Methods
3.
Study Design (Section 4)

Clarification of the purpose of the Interim Analysis

Text inserted to state that withdrawals may be replaced, in line with the 
main body of the protocol.

Clarification around process for replacing subject that withdraw early 
from treatment
4.
Selection of Study Populations (Section 5)

CD19+ threshold for exclusion provided in alternative units, to correspond 
with laboratory reporting.

Requirements for follow up of subjects withdrawn from treatment updated 
for consistency with the rest of the protocol
5.
Study Treatment (Section 6)

Clarification around timing requirements for rituximab/placebo infusion 
premedication

Clarification of the definition of “sponsor-open”, allowing designated 
team members to interpret interim analysis data.  Also deleted text to 
clarify that iSRC and TADAC are unblinded throughout the study duration

Clarification of “weekly” definition for purposes of belimumab overdose 
reporting
 
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
Clarification that qd means daily
6.
Study Assessments and Procedures (Section 7)

Clarification in Time and Events Table footnote around timing 
requirements for rituximab/placebo infusion premedication

Clarification in Time and Events Table footnote of requirements for time 
between first and second rituximab/placebo infusions

Clarification that central lab will conduct TB screening for subjects in 
Argentina
7.
Statistical Considerations and Data Analyses (Section 9)

Clarification of statistical methods
8.
References (Section 11)

Correction of publication date

Removal and replacement of a publication reference that has been updated
Protocol Amendment 05: Modifications in detail:
PROTOCOL COVER PAGE
Add:
Protocol Amendment Number: 05
Remove author list:
Author (s):
 
Updated:
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1 for 
Sweden
Protocol amended in response to comments received from Swedish regulatory 
authority.
 
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GlaxoSmithKline 
Document Number
Date
Version
Local
2014N220285_02
2015-NOV-20
Amendment No. 2 for 
Norway
Protocol amended in response to comments received from Norwegian regulatory 
authority.
Local
2014N220285_03
2016-JAN-04
Amendment No. 3 for Italy
Protocol amended in response to comments received from Italian regulatory authority.
Global
2014N220285_04
2016-JUN-13
Amendment No. 4
The primary reason for this amendment is to modify the subject selection criteria 
(specifically exclusion criterion #30 pertaining to exclusionary laboratory thresholds) 
to better align with the intended population characteristics.
Other amendments include the following:

Greater clarity is provided regarding the committees involved in monitoring 
subject safety and review of study data as well as the governance of the study.

It has been made clear that a single formal interim analysis is planned.

The subject withdrawal and study stopping criteria have been modified.

Greater detail is provided regarding prohibited and permitted medications.

Additional guidance is provided regarding vaccination.

Guidance has been provided for tuberculosis assessment during the screening 
period.

The pregnancy section has been modified to clarify the duration of follow up 
required.
This amendment incorporates country-specific changes required by Regulatory 
Authorities during prior review. In addition, changes have been made throughout to 
provide clarity for the conduct of the study and correct typographical errors.
All changes made in Amendment 4 are summarized, rationalized and detailed in 
Appendix 13 (Section 12.13).
 
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GlaxoSmithKline 
Document Number
Date
Version
Global
2014N220285_05
2018-MAY-11
Amendment No. 5
The primary reason for this amendment is to clarify the definition of “sponsor open” in 
Section 6.3, with respect to study blinding. Additional minor clarifications have been 
made throughout the protocol.
Updated:
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 *
Mobile: 
NA
Stevenage, 
UNITED 
KINGDOM
Secondary 
Medical 
Monitor*
Mobile: 
NA
Stevenage, 
UNITED 
KINGDOM
SAE 
contact  
information 
Case Management 
Group, Global 
Clinical Safety and 
Pharmacovigilance 
(GCSP)
 
NA
NA
*Medical monitor name and contact information can also be found in the Study Reference Manual
PROTOCOL SYNOPSIS FOR STUDY 201842 (Section 1)
Type and Number of Subjects
Change from:
Adult subjects with symptomatic and systemically active disease as well as evidence of 
glandular reserve function will be recruited. Initially, there will be a total of 70 subjects 
randomized with the potential to increase the number of subjects in one or more arms 
following sample size re-estimation, up to a maximum of 120 recruited into the study. 
The randomization ratio will vary dependent on the number of treatment arms continuing 
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Change to:
Adult subjects with symptomatic and systemically active disease as well as evidence of 
glandular reserve function will be recruited. Initially, there will be a total of
approximately 70 subjects will be randomized. Withdrawn subjects may be replaced, 
and there is with the potential to further increase the number of subjects in one or more 
arms following sample size re-estimation, up to a maximum of 120 recruited into the 
study. The randomization ratio will vary dependent on the number of treatment arms 
continuing following the interim analysis
Analysis
Change from
Hypotheses and Treatment Comparisons:
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI score, stimulated salivary flow, oral dryness numeric response scale and 
salivary gland B cell quantification. For all other parameters, no formal statistical 
comparisons will be made, although trends over time will be investigated across all 
treatment arms.
Change to 
Hypotheses and Treatment Comparisons:
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI score, stimulated salivary flow, oral dryness numeric response scale and a 
subset of salivary gland histology assessments and B cell quantification. For all other 
parameters, no formal statistical comparisons will be made, although trends over time 
will be investigated across all treatment arms.
Change from
Interim Analysis: Once  half of the planned subjects (i.e.: approximately 35 subjects) 
have completed their Week 24 assessments, a formal interim analysis will take place. 
Appropriate available safety and efficacy data will be included in the interim analysis. 
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, preliminary efficacy analysis will be conducted. to enable a 
sample size re-estimation and obtain an initial estimate of the effect size of the co-
administration therapy and belimumab monotherapy. Following the interim analysis, a 
number of actions could be  taken: the study may continue as planned; one or more 
treatment arms may be dropped; the number of subjects in some or all treatment arms 
may be increased following sample size re-estimation, up to a maximum of 120 subjects 
in the study
 
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Change to 
Interim Analysis: Once  half of the planned subjects (i.e.: approximately 35 subjects) 
have completed their Week 24 assessments, a formal interim analysis will take place. 
Appropriate available safety and efficacy data will be included in the interim analysis. 
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, preliminary efficacy analysis will may be conducted. to enable a 
sample size re-estimation and obtain an initial estimate of the effect size of the co-
administration therapy and belimumab monotherapy. Following the interim analysis, a 
number of actions could be  taken: the study may continue as planned; one or more 
treatment arms may be dropped; the number of subjects in some or all treatment arms 
may be increased following sample size re-estimation, up to a maximum of 120 subjects 
in the study
Change from
Data Analysis Considerations: All data will be descriptively summarized, graphically 
presented and listed appropriately. The relationship between the mechanistic endpoints 
(e.g., salivary gland B cell quantification) and clinical effects (e.g., ESSDAI score) will 
be graphically presented and analyzed using an appropriate statistical model identifying 
any trends. The model will determine whether the mechanistic effect significantly 
explains or predicts the effect on the clinical endpoints (e.g., ESSDAI score). This may
be conducted through comparing statistical models, incorporating different explanatory 
terms (i.e., mechanistic endpoints) with the ‘null’ model (no mechanistic endpoints); or, 
if deemed appropriate, multivariate statistical methods may also be applied to determine 
the relationship between the key endpoints. The consistency in the changes over time 
between the endpoints will also be assessed. Comparisons between treatment groups will 
be conducted if deemed appropriate. For example, the change from baseline in ESSDAI 
score will be statistically analyzed using a mixed effect model repeated measurement 
(MMRM) analysis comparing the co-administration with placebo at each time point. 
Similar analyses may be conducted for other secondary endpoints. In addition, based on 
the data that we observe in the study, probabilities of success will may be determined, for 
example, what is the probability that we would observe a certain change in ESSDAI 
score (i.e., comparator rate), based on the data that we have observed in the study?
Change to 
Data Analysis Considerations: All data will be descriptively summarized, graphically 
presented and listed appropriately. The relationship between the mechanistic endpoints 
(e.g., salivary gland B cell quantification) and clinical effects (e.g., ESSDAI score) will 
be graphically presented and analyzed using an appropriate statistical model identifying 
any trends. The model will determine whether the mechanistic effect significantly 
explains or predicts the effect on the clinical endpoints (e.g., ESSDAI score). This may 
be conducted through comparing statistical models, incorporating different explanatory 
terms (i.e., mechanistic endpoints) with the ‘null’ model (no mechanistic endpoints); or, 
if deemed appropriate, multivariate statistical methods may also be applied to determine 
the relationship between the key endpoints. The consistency in the changes over time 
between the endpoints will also be assessed and further exploratory analyses to 
 
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characterize relationships between endpoints may be conducted. Comparisons 
between treatment groups will be conducted if deemed appropriate. For example, the 
change from baseline in ESSDAI score will be statistically analyzed using a mixed effect 
model repeated measurement (MMRM) analysis comparing the co-administration with 
placebo at each time point. Similar analyses may be conducted for other secondary 
endpoints. In addition, based on the data that we observe in the study, probabilities of 
success will may be determined, for example, what is the probability that we would 
observe a certain change in ESSDAI score (i.e., comparator rate), based on the data that 
we have observed in the study?
STUDY DESIGN (Section 4)
Overall design (Section 4.1)
Change from:
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, preliminary efficacy analysis will be conducted to enable a 
sample size re-estimation and obtain an initial estimate of the effect size of the co-
administration therapy and belimumab monotherapy. Following the interim analysis, a 
number of actions could be mandated by the iSRC: the study may continue as planned; 
one or more treatment arms may be dropped; the number of subjects in some or all 
treatment arms may be increased following sample size re-estimation, up to a maximum 
of 120 subjects in the study.
Change to:
The main purpose of the interim analysis is to assess the safety and tolerability of the 
study drugs. In addition, preliminary efficacy data will be evaluated. analysis will be 
conducted to enable a sample size re-estimation and obtain an initial estimate of the effect 
size of the co-administration therapy and belimumab monotherapy. Following the interim 
analysis, a number of actions could be mandated by the iSRC: the study may continue as 
planned; one or more treatment arms may be dropped; the number of subjects in some or 
all treatment arms may be increased following sample size re-estimation, up to a 
maximum of 120 subjects in the study.
Treatment arms and duration (Section 4.2)
Change from:
Approximately 70 subjects will be recruited into the study initially. At Day 0, subjects 
will be randomized 1:2:2:2 to one of the four treatment arms below
Change to:
Approximately 70 subjects will be recruited into the study initially. Withdrawals may 
be replaced. At Day 0, subjects will be randomized 1:2:2:2 to one of the four treatment 
arms below
 
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Type and number of subjects (Section 4.4)
Change from: 
If subjects prematurely discontinue the study, additional subjects may be randomized and 
assigned to the next treatment in the randomization schedule at the discretion of the 
Sponsor in consultation with the investigator. 
Change to:
In addition, if subjects prematurely discontinue the study, additional subjects may be 
randomized and assigned to the next treatment in the randomization schedule at the 
discretion of the Sponsor in consultation with the investigator. 
SELECTION OF STUDY POPULATIONS AND WITHDRAWAL CRITERIA 
(Section 5)
Exclusion Criteria (Section 5.2)
Change from:
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
32. Have an IgA deficiency (IgA level <10 mg/dL). 
33. Any of the following screening laboratory values:

White blood cells (WBC) <2 x 109/L

Neutrophils <1.5 x 109/L

Circulating IgG < 550 mg / dL 

Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

Bilirubin >1.5 times the upper limit of normal (unless direct bilirubin fraction is 
< 35%)

CD19+ B-lymphocyte counts <0.1 x 109/L (applies only to subjects previously 
exposed to B cell depleting therapies)
34. For FRANCE ONLY, subjects with legal or administrative guardianship (“tutelle” 
or “curatelle”), or subjects deprived of liberty, or subjects receiving psychiatric care, 
or subjects hospitalized in an Health and Social Establishment for purposes other 
than participation in this study.
Change to:
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
35. Have an IgA deficiency (IgA level <10 mg/dL). 
36. Any of the following screening laboratory values:
 
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
White blood cells (WBC) <2 x 109/L

Neutrophils <1.5 x 109/L

Circulating IgG < 550 mg / dL 

Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

Bilirubin >1.5 times the upper limit of normal (unless direct bilirubin fraction is 
< 35%)

CD19+ B-lymphocyte counts <0.1 x 109/L (<100 per CMM) (applies only to 
subjects previously exposed to B cell depleting therapies)
37. For FRANCE ONLY, subjects with legal or administrative guardianship (“tutelle” 
or “curatelle”), or subjects deprived of liberty, or subjects receiving psychiatric care, 
or subjects hospitalized in an Health and Social Establishment for purposes other 
than participation in this study.
Withdrawal/Stopping Criteria (Section 5.4)
General Criteria
Change from:
Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before Week 46 
Subject discontinues 
treatment at or after Week 
46 
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period.
An additional telephone 
call for urine pregnancy 
results at approximately 
52 weeks after the last 
rituximab/placebo dose
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general 
follow-up period.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
 
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Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before Week 46 
Subject discontinues 
treatment at or after Week 
46 
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
Change to:
Subject discontinues 
treatment before the Week 8 
Visit
Subject discontinues 
treatment after the Week 8 
Visit and before Week 46 
Subject discontinues 
treatment at or after Week 
46 
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general follow-
up period.
maintenance of 
contraception and 
monthly telephone calls 
for urine pregnancy test 
results will be required 
until approximately 52 
weeks after the last 
dose of rituximab/pbo 
was administered.
An additional telephone 
call for urine pregnancy 
results at approximately 
52 weeks after the last 
rituximab/placebo dose
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
General follow-up visit 
16 weeks after last dose 
of IP
Monthly telephone calls 
for urine pregnancy test 
results, neurological 
questionnaire, AEs, 
SAEs, and concomitant 
medications during the 
16-week general 
follow-up period.
Individualized safety 
follow-up visits every 
12 weeks subsequent to 
the general follow up 
period (if applicable)
 
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STUDY TREATMNT (Section 6)
Investigation Product and other Study Treatment (Section 6.1)
Rituximab
Change from:
Rituximab/placebo will be administered intravenously by an experienced healthcare 
professional under physician supervision, and in an environment where full resuscitation 
facilities are immediately available. Premedication consisting of an oral anti-pyretic and 
an oral antihistamine, e.g., paracetamol and diphenhydramine (60 minutes prior to 
rituximab) and intravenous methylprednisolone (100 mg) (30 minutes prior to rituximab), 
will be given before each administration of rituximab/placebo.
Change to:
Rituximab/placebo will be administered intravenously by an experienced healthcare 
professional under physician supervision, and in an environment where full resuscitation 
facilities are immediately available. Premedication consisting of an oral anti-pyretic and 
an oral antihistamine, e.g., paracetamol and diphenhydramine (approximately 60 
minutes prior to rituximab) and intravenous methylprednisolone (100 mg) (at least
30 minutes prior to rituximab), will be given before each administration of 
rituximab/placebo.
Blinding (Section 6.3)
Change from:

Sponsor open refers only to those members of the iSRC and the TA DAC who are 
unblinded for the interim analysis, as outlined in the iSRC charter. The GSK study 
team will be blinded except for team members required for monitoring the pharmacy 
e.g., unblinded monitor etc.
Change to:

Sponsor open refers only to those members of the iSRC and the TA DAC who are 
unblinded for the interim analysis, as outlined in the iSRC charter. The GSK study 
team will be blinded except for those team members required for monitoring the 
pharmacy e.g., unblinded monitor etc, as well as a restricted number of team 
members required for interpretation of data at the interim analysis, as specified 
in the iSRC Charter.
Treatment of study overdose (6.7)
Change from:
For this study, any dose of subcutaneous belimumab in excess of 200 mg per week will 
be considered an overdose. GSK does not recommend specific treatment for an overdose. 
 
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Change to:
For this study, any dose of subcutaneous belimumab in excess of 200 mg per week (7 ± 2 
days) will be considered an overdose. GSK does not recommend specific treatment for an 
overdose. 
Treatment after the end of the study (Section 6.8)
Permitted medications and non-drug therapy
Change from:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd for 30 days prior to Day 0 and continues this dose for the duration of the 
study).
Change to:

Hydroxychloroquine (provided subject is on a stable regimen no greater than 400 mg 
po qd (ie daily) for 30 days prior to Day 0 and continues this dose for the duration of 
the study).
STUDY ASSESSMENTS AND PROCEDURES (Section 7)
Time and events table (Section 7.1)
Footnotes:
Change from: 
8. Both doses of rituximab/placebo will be administered in the clinic. 60 minutes prior to rituximab/placebo, subjects will 
receive orally an antipyretic and an antihistamine. 30-60 minutes prior to administration of rituximab/placebo, 
subjects will receive IV 100mg methylprednisilone .The 2nd rituximab/placebo administration at the Week10 visit 
must be given 14 after the first administration (given at the Week 8 visit). A patient alert card should be sent home 
with the subject following each dose of rituximab/placebo.
Change to:
8. Both doses of rituximab/placebo will be administered in the clinic. Approximately 60 minutes prior to 
rituximab/placebo, subjects will receive orally an antipyretic and an antihistamine. At least 30-60 minutes prior to 
administration of rituximab/placebo, subjects will receive IV 100mg methylprednisilone .The 2nd rituximab/placebo 
administration at the Week10 visit must be given 14 days (13-18 days, see SRM) after the first administration (given 
at the Week 8 visit). A patient alert card should be sent home with the subject following each dose of 
rituximab/placebo.
Screening and Critical Baseline Assessments (Section 7.2)
Change from: 
Tuberculosis: Assessment of TB in the screening period is to be done via evaluation of 
the subject’s history, physical examination of the subject and, if judged necessary by the 
Investigator, local  laboratory (screening and confirmatory) testing. 
 
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Change to:
Tuberculosis: Assessment of TB in the screening period is to be done via evaluation of 
the subject’s history, physical examination of the subject and, if judged necessary by the 
Investigator, local  laboratory (screening and confirmatory) testing. For subjects in 
Argentina only, the central lab will perform Quantiferon Gold testing.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES (Section 9)
Hypotheses and Treatment Comparisons (Section 9.1)
Change from: 
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI, stimulated salivary flow, oral dryness numeric response scale and salivary 
gland B cell quantification.  
Change to:
If deemed appropriate, these exploratory comparisons will be made investigating 
ESSDAI, stimulated salivary flow, oral dryness numeric response scale and a subset of
salivary gland and plasma B cell parameters quantification.  Full details will be 
included in the RAP.
Sample Size Considerations (Section 9.2)
Sample Size Re-estimation 
Change from:
At the interim analysis, the sample size will be re-estimated based on the emerging data 
from the study. The sample size may need to be re-estimated if higher variability or 
differing placebo means are observed with any of the four key secondary endpoints 
(ESSDAI score, stimulated salivary flow, oral dryness NRS or the B cell quantification 
within salivary gland biopsy); also if treatment arms are dropped from the study.  
Therefore, any significant deviation from the assumptions used to design the study may 
result in changes to the number of subjects to be randomized. Further details will be 
included in the RAP. A maximum of 120 subjects will be recruited into the study.
Change to:
At the interim analysis, the sample size will may be re-estimated based on the emerging 
data from the study. The sample size may need to be re-estimated if higher variability or 
differing placebo means are observed for the with any of the four ESSDAI, a key 
secondary endpoint (ESSDAI score, stimulated salivary flow, oral dryness NRS or the B 
cell quantification within salivary gland biopsy); also if treatment arms are dropped from 
the study.  Therefore, any significant deviation from the assumptions used to design the 
study may result in changes to the number of subjects to be randomized. Further details
 
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will be included in the RAP and guidance document for interim decision making. A 
maximum of 120 subjects will be recruited into the study.
Secondary Analysis
Change from:
All data will be descriptively summarized, graphically presented and listed appropriately.
Each endpoint will be considered individually and at the treatment level where 
comparisons between treatment groups would be made on any changes observed. 
The relationship between the mechanistic (e.g., salivary gland B cell quantification) and 
clinical effects (e.g., ESSDAI score) will be graphically presented and analyzed using an 
appropriate statistical model identifying any trends. The model will determine whether 
the mechanistic effect significantly explains or predicts the effect on the clinical 
endpoints (e.g., ESSDAI score). This may be conducted through comparing statistical 
models; incorporating different explanatory terms (i.e., mechanistic endpoints) with the 
‘null’ model (no mechanistic endpoints); or, if deemed appropriate, multivariate
statistical methods may also be applied to determine the relationship between the key 
endpoints. The consistency in the changes over time between the endpoints will also be 
assessed.
The ESSDAI, stimulated salivary flow, oral dryness numeric response scale and salivary 
gland B cell quantification change from baseline scores will be statistically analyzed 
using a mixed model repeated measures approach when comparing the belimumab 
monotherapy, rituximab monotherapy and belimumab / rituximab combination therapy 
with placebo at each time point.  Point estimates and corresponding 95% confidence 
intervals will be estimated for the comparisons of interest. Distributional assumptions 
underlying the analyses will be assessed. Additional models may be investigated.
In addition, based on the data that we observe in the study, probabilities of success of the 
co-administration therapy and belimumab monotherapy will be determined. For example, 
what is the probability that we would observe a certain change in the ESSDAI score (i.e., 
comparator rate), based on the data that we have observed in the study?
Further details regarding the statistical analysis will be outlined in the RAP.
Change to:
All data will be descriptively summarized, graphically presented and listed appropriately.
Each endpoint will be considered individually and at the treatment level where 
comparisons between treatment groups would be made on any changes observed. 
The relationship between the mechanistic (e.g., salivary gland B cell quantification) and 
clinical effects (e.g., ESSDAI score) will be graphically presented and analyzed using an 
appropriate statistical model identifying any trends. The model will determine whether 
the mechanistic effect significantly explains or predicts the effect on the clinical 
 
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endpoints (e.g., ESSDAI score). This may be conducted through comparing statistical 
models; incorporating different explanatory terms (i.e., mechanistic endpoints) with the 
‘null’ model (no mechanistic endpoints); or, if deemed appropriate, multivariate 
statistical methods may also be applied to determine the relationship between the key 
endpoints. The consistency in the changes over time between the endpoints will also be 
assessed and further exploratory analyses to characterise relationships between 
endpoints may be conducted.
The ESSDAI, stimulated salivary flow and oral dryness numeric response scale and 
salivary gland B cell quantification change from baseline scores will be statistically 
analyzed using a mixed model repeated measures approach when comparing the 
belimumab monotherapy, rituximab monotherapy and belimumab / rituximab 
combination therapy with placebo at each time point.  Point estimates and corresponding 
95% confidence intervals will be estimated for all the comparisons of interest (see 
Section 9.1) at weeks 24 and 52. Distributional assumptions underlying the analyses will 
be assessed. Additional models may be investigated.
Non-parametric statistical analyses will also be conducted to assess the comparisons 
of interest for a subset of salivary gland histology assessments, and B cell 
quantification in plasma. These analyses will be described in the RAP.    
In addition, based on the data that we observe in the study, probabilities of success of the 
co-administration therapy and belimumab monotherapy may will be determined. For 
example, what is the probability that we would observe a certain change in the ESSDAI 
score (i.e., comparator rate), based on the data that we have observed in the study?
Further details regarding the statistical analysis will be outlined in the RAP.
REFERENCES (Section 11)
Correction made:
Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary 
Sjögren's syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 
20135; 74: 526-31.
Subsequently, the reference has been updated throughout the document.
Removed:
Stohl W, Schwarting A, Okada M, et al. A Randomized, Double-Blind, Placebo-
Controlled, 52-Week Study of the Efficacy and Safety of Belimumab Administered 
Subcutaneously Plus Standard Care to Patients with Systemic Lupus Erythematosus 
(SLE) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).
Added:
Stohl W, Schwarting A, Okada M, Scheinberg M, Doria A, Hammer AE, et al. 
Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a 
 
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fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis 
Rheumatol. 2017;69(5):1016-1027.
Subsequently, the reference has been updated throughout the document.
APPENDICES (Section 12)
Appendix 1 – Abbreviations and Trademarks
Added:
CMM
Cubic Millimeter
 
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12.15.
Appendix 15: Protocol changes in Amendment 6
Amendment 6: global amendment (all sites).
Protocol Amendment 06, 25 June 2019
Summary of Modifications (relative to protocol amendment 5) and Rationale:
1.
Protocol Cover Page

Protocol version and Revision Chronology updated in line with 
amendment 6

Medical Monitor Contact Details updated in line with GSK team changes
2.
Follow up Periods (Section 4.3.2)

Clarification of when a subject is not required to enter the Individualised 
Follow Up period
3.
Blinding (Section 6.3)

Clarification of timing of unblinding for GSK staff and site staff
4.
Statistical Considerations and Data Analyses (Section 9)

Correction of 4 sub-headers
PROTOCOL COVER PAGE
Add:
Protocol Amendment Number: 06
Updated:
 
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Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2014N220285_00
2015-JUN-17
Original
Local
2014N220285_01
2015-OCT-15
Amendment No. 1 for 
Sweden
Protocol amended in response to comments received from Swedish regulatory 
authority.
Local
2014N220285_02
2015-NOV-20
Amendment No. 2 for 
Norway
Protocol amended in response to comments received from Norwegian regulatory 
authority.
Local
2014N220285_03
2016-JAN-04
Amendment No. 3 for Italy
Protocol amended in response to comments received from Italian regulatory authority.
Global
2014N220285_04
2016-JUN-13
Amendment No. 4
The primary reason for this amendment is to modify the subject selection criteria 
(specifically exclusion criterion #30 pertaining to exclusionary laboratory thresholds) 
to better align with the intended population characteristics.
Other amendments include the following:

Greater clarity is provided regarding the committees involved in monitoring 
subject safety and review of study data as well as the governance of the study.

It has been made clear that a single formal interim analysis is planned.

The subject withdrawal and study stopping criteria have been modified.

Greater detail is provided regarding prohibited and permitted medications.

Additional guidance is provided regarding vaccination.

Guidance has been provided for tuberculosis assessment during the screening 
period.

The pregnancy section has been modified to clarify the duration of follow up 
required.
 
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GlaxoSmithKline Document 
Number
Date
Version
This amendment incorporates country-specific changes required by Regulatory 
Authorities during prior review. In addition, changes have been made throughout to 
provide clarity for the conduct of the study and correct typographical errors.
All changes made in Amendment 4 are summarized, rationalized and detailed in 
Appendix 13 (Section 12.13).
Global
2014N220285_05
2018-MAY-11
Amendment No. 5
The primary reason for this amendment is to clarify the definition of “sponsor open” in 
Section 6.3, with respect to study blinding. Additional minor clarifications have been 
made throughout the protocol.
Global
2014N220285_06
2019-JUN-25
Amendment No. 6
The primary reason for this amendment is to clarify the timing of unblinding for GSK 
staff and site staff.  Additional minor updates have been made in several sections of the 
protocol
Updated:
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Numbe
r
Site 
Address
Primary 
Medical 
Monitor *
Mobile:
 
NA
Stevenag
e, 
UNITED 
KINGDO
M
Secondar
y Medical 
Monitor*
Mobile: 
NA
Upper 
Providenc
e
US
SAE 
contact  
informatio
n 
Case 
Management 
Group, Global 
Clinical Safety 
and 
Pharmacovigilan
ce (GCSP)
 
NA
 
 
NA
*Medical monitor name and contact information can also be found in the Study Reference Manual
 
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PPD
PPD
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STUDY DESIGN (Section 4)
Individualised follow up period (Section 4.3.2)
added:
Subjects who prior to the Week 68 visit receive a disease modifying therapy that 
may affect B-cell numbers are not required to enter the IFU.
STUDY TREATMENT (Section 6)
Blinding (Section 6.3)
Change from:
This will be a double blind (sponsor open) study and the following will apply: 

All study staff involved in clinical assessments (which includes the investigator, sub-
investigators, other site staff), and the subject will be blinded to the treatment 
allocated to individual subjects. 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding the 
subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the eCRF.

An unblinded pharmacist will be used at each study site to prepare rituximab and its 
placebo for intravenous administration. Unblinded monitors will be assigned to 
review all pharmacy records, storage and procedures.

An unblinded member of staff at each site will be assigned to use the randomization 
software (RAMOS NG) and to receive all drug shipments and notifications.

Following discussion with GSK medical monitor, a subject may continue in the 
study if that subject’s treatment assignment is unblinded. The primary reason for 
unblinding (the event or condition which led to the unblinding) will be recorded in 
the eCRF.
 
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
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.

During the treatment and 16-week general follow up phase, all study staff (which 
includes the investigator, sub-investigators, other site trial staff, the subject, and 
those managing the conduct of the study) will remain blinded to central laboratory 
data that have the potential to unblind a subject’s treatment assignment. Such data 
may include but is not necessarily limited to:

B-cell lymphocyte counts including results from flow cytometry

IgM and IgA levels
Refer to the central laboratory manual for additional information.

The iSRC will perform safety reviews of laboratory data during the conduct of the 
study, as outlined within the iSRC charter.

Sponsor open refers  to those members of the iSRC and the TA DAC who are 
unblinded, as outlined in the iSRC charter. The GSK study team will be blinded 
except for those monitoring the pharmacy e.g., unblinded monitor etc, as well as a 
restricted number of team members required for interpretation of data at the interim 
analysis, as specified in the iSRC Charter
Change to:
This will be a double blind (sponsor open) study and the following will apply: 

All study staff involved in clinical assessments (which includes the investigator, sub-
investigators, other site staff), and the subject will be blinded to the treatment 
allocated to individual subjects until the primary and follow up analyses have 
been completed (see Section 9.4.1). 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding the 
subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 
 
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
The date and reason for the unblinding must be fully documented in the eCRF.

An unblinded pharmacist will be used at each study site to prepare rituximab and its 
placebo for intravenous administration. Unblinded monitors will be assigned to 
review all pharmacy records, storage and procedures.

An unblinded member of staff at each site will be assigned to use the randomization 
software (RAMOS NG) and to receive all drug shipments and notifications.

Following discussion with GSK medical monitor, a subject may continue in the 
study if that subject’s treatment assignment is unblinded. The primary reason for 
unblinding (the event or condition which led to the unblinding) will be recorded in 
the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.

During the treatment and 16 week general follow up phases (see Sections 4.3.1 and 
4.3.2), all study staff (which includes the investigator, sub-investigators, other site 
trial staff, and the subject and those managing the conduct of the study) will remain 
blinded to central laboratory data that have the potential to unblind a subject’s 
treatment assignment. Such data may include but is not necessarily limited to:

B-cell lymphocyte counts including results from flow cytometry

IgM and IgA levels
Refer to the central laboratory manual for additional information.

The iSRC will perform safety reviews of laboratory data during the conduct of the 
study, as outlined within the iSRC charter.

Sponsor open refers  to those members of the iSRC and the TA DAC who are 
unblinded, as outlined in the iSRC charter. The GSK study team will be remain
blinded until the primary analysis (see Section 9.4.1) except for those monitoring 
the pharmacy in unblinded roles e.g., unblinded monitor for monitoring the 
pharmacy etc, as well as a restricted number of team members required for 
interpretation of data at the interim analysis (Section 9.3.2), as specified in the iSRC 
Charter.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES (Section 9)
Key Elements of Analysis Plan (Section 9.4)
Change from:
9.4.1 Final Analysis
 
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Change to: 
9.4.1 Final Primary Analysis and Follow up Analysis
Change from:
9.4.2 Primary Analyses
Change to: 
9.4.2 Primary Analyses Analysis of Primary Endpoints
Change from:
9.4.3 Secondary Analyses
Change to: 
9.4.3 Secondary Analysis Analysis of Secondary Endpoints
Change from:
9.4.4 - Other Analyses
Change to: 
9.4.4 - Analysis of Other Analyses Endpoints
 
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SAP_001.pdf: 
Statistical Analysis Plan 
Official Title of Study: A randomized, double blind (sponsor open), comparative, multi-center study to 
evaluate the safety and efficacy of subcutaneous belimumab (GSK1550188) and intravenous rituximab 
co-administration in subjects with primary Sjögren’s syndrome. 
 
NCT ID: NCT02631538 
Other Identifiers: 2015-000400-26 
Date of Document: 15Sep2020 
 


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
201842 
1 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for a randomized, double blind 
(sponsor open), comparative, multi-center study to evaluate 
the safety and efficacy of subcutaneous belimumab 
(GSK1550188) and intravenous rituximab co-administration 
in subjects with primary Sjögren’s syndrome. 
Compound Number 
: GSK1550188 
Effective Date 
: 18-AUG-2020 
Description: 
The purpose of this RAP is to describe the planned analyses and outputs to be included in 
the Clinical Study Report for Protocol 201842. 
This RAP is intended to describe the planned safety & tolerability, efficacy, 
biomarker/pharmacodynamic, pharmacokinetic and health outcomes analyses required 
for the study.  
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverables. 
RAP Section 3.3 (Final Analyses) outlined the intended purpose of the RAP was for the 
planned analyses for Primary and End of Study (EoS) SAC deliverables. However, in the 
event that the Primary Analysis reporting does not identify treatment benefit, an abridged 
set of analysis may be conducted for EoS analysis, which will be detailed in a RAP 
amendment or addendum. Therefore, this RAP amendment includes updates to the 
approved version for the Primary Analysis. As the milestone (Last Subject Last Visit) for 
RAP approval as per SOP_54838 has been achieved, agreement and approval steps allow 
confirmation of any planned changes outside the steps outlined in the RAP SOP. 
RAP Author(s) 
Author 
Date 
 
23-OCT-2019
Senior Statistician (Immuno-Inflammation, Biostatistics) 
 
Statistical Leader (Biostatistics, Development, GSK) 
18-AUG-2020
 
Statistical Leader (Biostatistics, Development, GSK) 
14-SEP-2020
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201842 
 
2 
 
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer  
Date 
 
23-OCT-2019 
Clinical Development Director Immuno-Inflammation, GSK  
 
Discovery Medicine Group Leader, GSK  
23-OCT-2019 
 
Programming Manager, Immuno-Inflammation, Biostatistics, 
GSK 
24-OCT-2019 
 
Global Clinical Development Manager, GSK 
23-OCT-2019 
 
Research Manager in Clinical Biomarker Group, GSK 
23-OCT-2019 
 
SERM Physician, Development Global Medical, GSK 
23-OCT-2019 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Pharma TMF eSignature) 
Approver 
Date 
 
25-OCT-2019 
Statistical Leader, Immuno-Inflammation, Biostatistics, GSK 
 
25-OCT-2019 
Director Programming, Immuno-Inflammation, Biostatistics, GSK 
 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201842 
 
3 
 
RAP Team Review Confirmations: RAP Addendum 
(Method: E-mail) 
Reviewer  
Date 
 
14-SEP-20 
Clinical Development Director, Clinical Science Lupus, GSK  
 
Clinical Development Director, Clinical Science (II and Fibrosis), 
GSK 
14-SEP-20 
 
Programming Manager, Biostatistics, Development, GSK 
14-SEP-20 
 
Global Clinical Development Manager, R&D GCSD, GSK 
14-SEP-20 
 
Clinical Biomarker Director, Group, Clinical Biomarkers One, 
GSK 
14-SEP-20 
 
SERM Physician, Development Global Medical, GSK 
14-SEP-20 
Clinical Statistics & Clinical Programming Line Approvals: RAP Addendum 
(Method: Pharma TMF eSignature) 
Approver 
Date 
 
15-SEP-20 
Head - Statistics, Biostatistics (India), Development, GSK 
 
Programming Leader, Biostatistics, Development, GSK 
15-SEP-20 
On behalf of 
 (Line Manager, Director Programming, 
Biostatistics, Development, GSK) 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ......................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ................................................ 10 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan .......................... 10 
2.2. 
Changes to the Final RAP for End of Study Reporting ................................ 10 
2.3. 
Study Objective(s) and Endpoint(s)............................................................. 13 
2.4. 
Study Design .............................................................................................. 14 
2.5. 
Statistical Hypotheses................................................................................. 15 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Regular Data Reviews ................................................................................ 15 
3.2. 
Interim Analyses ......................................................................................... 16 
3.3. 
Final Analyses ............................................................................................ 17 
4. 
ANALYSIS POPULATIONS ................................................................................... 18 
4.1. 
Protocol Deviations ..................................................................................... 19 
4.2. 
Per-Protocol Population .............................................................................. 20 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 20 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 20 
5.2. 
Baseline Definitions .................................................................................... 21 
5.3. 
Multi-center Studies .................................................................................... 23 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 23 
5.4.1. 
Covariates and Other Strata ........................................................ 23 
5.4.2. 
Examination of Subgroups ........................................................... 23 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 23 
5.6. 
Other Considerations for Data Analysis and Data Handling 
Conventions ................................................................................................ 23 
6. 
STUDY POPULATION ANALYSES ....................................................................... 24 
6.1. 
Overview of Planned Analyses ................................................................... 24 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 25 
7.1. 
Safety Analyses .......................................................................................... 25 
7.1.1. 
Overview of Planned Analyses .................................................... 25 
7.1.2. 
Immunogenicity............................................................................ 27 
7.1.3. 
Immunoglobulin ........................................................................... 27 
7.1.4. 
Adverse Events of Special Interest .............................................. 28 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 31 
8.1. 
Efficacy and Biomarker Analyses ................................................................ 31 
8.1.1. 
Overview of Planned Efficacy and Biomarker Analyses ............... 31 
8.1.2. 
Planned Efficacy and Biomarker Statistical Analyses ................... 33 
8.2. 
Pharmacokinetic Analyses .......................................................................... 37 
8.2.1. 
Overview of Planned Pharmacokinetic Analyses ......................... 37 
8.2.2. 
Drug Concentration Measures ..................................................... 37 
8.3. 
Pharmacokinetic / Pharmacodynamic Analyses .......................................... 38 
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9. 
OTHER STATISTICAL ANALYSES ....................................................................... 39 
9.1. 
Exploratory ................................................................................................. 39 
9.1.1. 
Overview of Exploratory Analysis ................................................. 39 
9.1.2. 
Planned Exploratory Analyses ..................................................... 40 
9.2. 
Health Outcomes ........................................................................................ 42 
9.2.1. 
Overview of Health Outcome Analysis ......................................... 42 
9.2.2. 
Planned Health Outcomes Statistical Analyses ............................ 42 
9.2.3. 
Planned Health Outcomes Psychometric Analyses ...................... 45 
10. REFERENCES ....................................................................................................... 46 
11. APPENDICES ........................................................................................................ 47 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 47 
11.1.1. 
Exclusions from Per-Protocol Population ..................................... 47 
11.2. 
Appendix 2: Schedule of Activities .............................................................. 49 
11.2.1. 
Protocol Defined Schedule of Events ........................................... 49 
11.3. 
Appendix 3: Treatment States and Phases ................................................. 53 
11.3.1. 
Treatment Phases ....................................................................... 53 
11.3.2. 
Treatment States ......................................................................... 53 
11.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 54 
11.4.1. 
Reporting Process & Standards ................................................... 54 
11.5. 
Appendix 5: Derived and Transformed Data ............................................... 56 
11.5.1. 
General ........................................................................................ 56 
11.5.2. 
Study Population .......................................................................... 59 
11.5.3. 
Safety .......................................................................................... 60 
11.5.4. 
Efficacy ........................................................................................ 71 
11.5.5. 
Health Outcomes ......................................................................... 74 
11.5.6. 
Biomarkers .................................................................................. 75 
11.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 83 
11.6.1. 
Premature Withdrawals ................................................................ 83 
11.6.2. 
Handling of Missing Data ............................................................. 83 
11.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 85 
11.7.1. 
Laboratory Values ........................................................................ 85 
11.7.2. 
Vital Signs .................................................................................... 86 
11.8. 
Appendix 8: Laboratory Parameters & Toxicity Grading Tables .................. 87 
11.8.1. 
Laboratory Parameters ................................................................ 87 
11.8.2. 
Toxicity Grading Tables ............................................................... 89 
11.9. 
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 92 
11.9.1. 
Statistical Analysis Assumptions .................................................. 92 
11.10. Appendix 10 – Abbreviations & Trade Marks .............................................. 95 
11.11. Appendix 11: Questionnaires ...................................................................... 97 
11.11.1. Columbia Suicide severity rate scale (CSSRS) post 
baseline ....................................................................................... 97 
11.11.2. Columbia Suicide severity rate scale (CSSRS) at baseline ........ 103 
11.11.3. Eular Sjögren’s syndrome disease activity index (ESSDAI) ....... 110 
11.11.4. Neurological Symptoms ............................................................. 115 
11.11.5. Oral and Ocular dryness ............................................................ 116 
11.11.6. Physician global assessment of disease activity (PGA) ............. 116 
11.11.7. Eular Sjögren’s syndrome patient reported index 
(ESSPRI) ................................................................................... 117 
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11.11.8. Profile of fatigue and discomfort - SICCA symptoms 
inventory short form (PROFAD-SSI-SF)..................................... 118 
11.11.9. Patient global assessment of disease activity (PtGA) ................ 121 
11.11.10. Sjogren’s Allowable Medication Categories ............................... 121 
11.11.11. Prednisone Conversion Factors ................................................. 123 
11.11.12. Exit Interview ............................................................................. 125 
11.12. Appendix 12: Headline Results ................................................................. 129 
11.12.1. 
Headline Results Output ............................................................ 129 
11.13. Appendix 13: List of Data Displays............................................................ 130 
11.13.1. Data Display Numbering ............................................................ 130 
11.13.2. Mock Example Shell Referencing .............................................. 131 
11.13.3. Deliverables ............................................................................... 131 
11.13.4. Study Population Tables ............................................................ 132 
11.13.5. Efficacy Tables .......................................................................... 135 
11.13.6. Efficacy Figures ......................................................................... 142 
11.13.7. Safety Tables ............................................................................. 146 
11.13.8. Safety Figures ........................................................................... 156 
11.13.9. Pharmacokinetic Tables ............................................................. 157 
11.13.10. Pharmacokinetic Figures ........................................................... 158 
11.13.11. Pharmacokinetic / Pharmacodynamic Figures ........................... 159 
11.13.12. Health Outcomes Tables ........................................................... 160 
11.13.13. Health Outcomes Figures .......................................................... 164 
11.13.14. Exploratory Tables ..................................................................... 165 
11.13.15. Exploratory Figures .................................................................... 172 
11.13.16. ICH Listings ............................................................................... 175 
11.13.17. Non-ICH Listings ........................................................................ 180 
11.14. Appendix 14: Example Mock Ups ............................................................. 184 
 
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1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP 
Purpose 
This RAP details all planned analyses and outputs required for: 
1. Primary Analyses (post completion of all week 52 assessments)   
2. End of Study (EoS) Analyses (Week 104) 
Protocol 
• This RAP is based on the protocol amendment 06 (Dated 25/Jun/2019) of 
study 201842 (GSK Document Number 2014N220285_06 and eCRF Version 
1.02). 
Primary 
Objective  
• Investigate the safety and tolerability of anti-BLyS / anti-CD20 co-
administration therapy and anti-BLyS and anti-CD20 monotherapies for 
subjects with active primary Sjögren’s syndrome (pSS).  
Primary 
Endpoint 
• Safety and tolerability; including incidence of SAEs and AESIs. 
Study 
Design 
• A randomized, double blind (sponsor open), comparative, multi-national, 
multi-center, placebo-controlled trial in subjects with active pSS.  
• Approximately 70 subjects will be recruited into the study initially. At Day 0, 
subjects will be randomized 1:2:2:2 into one of 4 treatment arms.   
Withdrawals may be replaced.   
• Study 201842 consisted of 3 phases:  
o A 52-week treatment phase during which subjects were randomized to 
one of four arms 
o A 16-week general follow (GFU) up period focused on safety 
assessments 
o An individualized follow (IFU) up period for subjects with persistently 
low B cell counts 
• NOTE: All subjects will enter a 16-week general follow-up period after the 
Week 52 visit or after discontinuation if a subject discontinues IP and 
withdraws from the treatment phase visits prior to Week 52. Assessments to 
be performed are included in protocol Time and Events Table. During the 
general follow up period subjects will remain off of investigational product, 
endeavor not to change concomitant medication regimen, receive monthly 
safety follow up phone calls, and will return to the clinic for asite visit at the 
end of the general follow up period 
• Subjects entering IFU are assessed every 12 wks (± 7 days), with calls every 
4 wks (±7 days) between visits. Subjects exit IFU when: CD19+ B-lymphocyte 
counts are within normal range or 10% of baseline levels (if baseline < LLN), 
OR at investigator’s discretion starts receiving disease modifying therapy that 
may affect B-cell numbers OR for up to a maximum of 2 years (i.e., up to 
Week 104) – whichever comes first. Subjects exiting IFU period will attend a 
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Overview 
Key Elements of the RAP 
final visit (within 28 days of decision) for final assessments (IFU Final Visit).  
• Subjects who withdrew (WD) prematurely from investigational product (IP) 
during treatment phase & refused to attend further visits through wk 52, were 
encouraged to participate in the GFU & IFU for safety purposes. 
Planned 
Analyses 
• Quarterly blinded safety data summaries for SRT. 
• Quarterly un-blinded safety data summaries and secondary efficacy endpoint, 
ESSDAI for iSRC. 
• Interim analyses occurring once approximately 35 subjects have completed 
their Week 24 assessments. 
• Primary Analysis 
o The primary analyses will be conducted following completion of all Week 
52 visits, with inclusion of the FU visit data which is available at this time.  
The analyses will be performed once the data from all visits up to and 
including this Week 52 cutoff have been collected, verified and validated. 
Week 68 data will also be included, if available.  
• End of Study 
• The follow-up (end of study) analyses will include all follow-up data (i.e. 
general follow-up data between Week 52 and Week 68 and individualized 
follow-up data from Week 68 through Week 104/IFU final visit). These 
analyses will be performed once data from Week 52 through Week 
104/IFU final visit has been collected, verified and validated. 
Analysis 
Populations 
• ‘Screened Population’ will be used to evaluate selected study population. 
• ‘Enrolled Population’ will be used to evaluate selected study population.  
• ‘Safety Population’ will be used to evaluate study population, efficacy, safety, 
PD, exploratory and health outcomes data. 
• 
‘PK’ populations will be used to evaluate belimumab and rituximab 
pharmacokinetics. 
• 
‘Per-protocol Population’ may be used to evaluate a subset of Efficacy, PD, 
and biomarker data.  
Hypothesis 
• The study is designed to investigate the safety and tolerability of the co-
administration of belimumab with rituximab and belimumab monotherapy in 
subjects with pSS. 
• No formal hypotheses will be tested.   
• For secondary endpoints, an estimation approach will be adopted with 
derivation of estimates and 95% confidence interval (CI) for the comparisons 
of interest (see Section 2.5)  
Primary 
Endpoint 
Analysis 
• Safety data will be presented in a tabular and graphical format. 
• Clinical interpretation will be based upon review of AEs, laboratory values and 
vital signs. 
• No formal statistical testing will be performed on the safety data. 
Secondary 
• Secondary endpoints will be analysed to provide point estimates and 
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Overview 
Key Elements of the RAP 
Endpoints 
Analysis 
corresponding 95% CIs for the comparisons of interest. 
• In addition, probabilities of success of the co-administration therapy and 
belimumab monotherapy will be conducted.  
 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the planned statistical analysis specified in the 
protocol amendment 06 [(Dated: 25/Jun/2019)]. 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined: 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
Section 9.3.1: Analysis 
Population  
• 
Section 4: Analysis 
Populations 
• 
“Screened” and “Enrolled” populations 
were included to support data disclosure 
displays 
• 
Per Protocol analysis population was also 
defined for sensitivity analysis 
• 
Section 9.4.2 Primary 
Analyses 
• 
Section 8.1.1.1 
ESSDAI 
• 
A corrected ESSDAI score will also be 
calculated. ESSDAI scores disease 
activity in 12 domains. In 5 (renal, PNS, 
CNS, cutaneous and pulmonary) of the 
domains, ESSDAI requires that if activity 
has been present for greater than or 
equal to 12 months then it must be 
treated as irreversible damage and the 
activity should be scored as zero (Seror, 
2015a). This is a problem for clinical trials 
of long duration such as study 201842 
because it can result in misleading 
evidence of reduced activity. 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology. 
2.2. 
Changes to the Final RAP for End of Study Reporting 
This section outlines key (not limited too) updates from the RAP version approved prior 
to the RAP SOP milestone (Last Subject Last Visit). 
Additional updates post EoS Database Release (DBR) have also been included to clarify 
timepoints included for the general follow up period and individualised follow up period. 
Subjects who withdrew (WD) prematurely from investigational product (IP) during the 
treatment phase and refused to attend further visits through week 52, were encouraged to 
participate in the GFU period and the IFU period (if required) for safety purposes. For 
several subjects withdrawing early from IP, this resulted in a temporal misalignment of 
data such that data which were collected during their follow up calls and visits were 
allocated to visits which occurred much later in the study (i.e. in the post W52 general  
and individualized follow up periods). Additional analyses have been included to assess 
the response in the GFU and IFU. 
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RAP Section 
Summary of Change 
4.0 Study Population 
EoS Analysis: A completer population was included to support additional Week 
68/FU / IFU analyses.  
7.1 Safety Analyses 
11.5.3 Safety 
Appendix 13: List of 
Data Displays 
Primary Analysis: Implemented MedDRA V22.0. 
EoS Analysis: Implement MedDRA V23.0 which constitutes a major release and 
relevant sections are updated. 
Primary Analysis: Summarized safety data for all completed visits up to W68 
(where reported by visit) and up to W104 (where not reported by visit), with cut-off 
date of 09/09/19 (W52 LSLV). 
EoS Analysis: Will summarize (Tables, Figures and Listings) AE/AESI safety 
endpoints for all completed visits up to Week 68 only. Other safety endpoints will 
be reported using scheduled visits, unless specified. 
7.1.4. Adverse 
Events of Special 
Interest 
EoS Analysis: Specified additional AESI details for post-administration systemic 
reactions by Rituximab/Placebo Infusion. 
8. Secondary 
Statistical Analyses 
9. Other Statistical 
Analyses 
Appendix 13: List of 
Data Displays 
Primary Analysis: Specified any formal model based statistical analyses included 
visits upto Week 52. 
EoS Analysis: Additional ESSDAI statistical analyses included using the completer 
population. 
8. Secondary 
Statistical Analyses 
Appendix 13: List of 
Data Displays 
Primary Analysis: % change from baseline in No. of B Cells (CD20)/mm2 in 
salivary gland biopsy at Week 24 was reported. 
EoS Analysis:  Change from baseline will be reported instead of % change from 
baseline. 
11.5.3 Appendices: 
Safety   
EoS Analysis: Added Section 11.5.3.2. Coronavirus Disease 2019 (COVID-19) 
Environment Onset Date. 
11.5.6 Biomarker 
Appendix 13: List of 
Data Displays 
11.8.1 Laboratory 
Parameters 
EoS Analysis: Table 11 (Flow Cytometry Parameters) & Table 13 (Minor Salivary 
Gland Parameters) updated to reflect final EoS delivery. Additional details included 
for imputation of Flow Cytometry Parameters.  
11.5.6.1. 
Immunogenicity 
EoS Analysis: Additional details have been included to clarify the reporting of 
Antibodies to Rituximab 
Appendix 13: List of 
Data Displays 
EoS Analysis: Any selected Primary Analysis displays that has been identified for 
generation for EoS has been allocated unique numbering. 
EoS Analysis: All figures will be displayed up to Week 68/FU only and a line break 
after Week 52 will be included, so as to indicate Week 68/FU timepoint is not 
sequential for all subjects. 
EoS Analysis: The following display will not be generated: 
• 
T2.13: ESSDAI and ClinESSDAI Bland-Altman Plot at Week 24 (Corrected) 
• 
T2.14: Scatter Plot of Wk 24 Changes for Total ESSDAI Score vs Salivary 
Gland B Cells  
• 
T2.15: Median Free Blys Vs Median CD19+ B cell by Treatment 
• 
T7.3: Summary Statistics: Lacrimal Gland Function (Schirmer’s Test) 
• 
T7.4: Summary Statistics of Change from Baseline: Lacrimal Gland Function 
(Schirmer’s Test) 
• 
T7.5: Summary Statistics of PGA 
• 
T7.6: Summary Statistics of Change from Baseline: PGA 
• 
T2.1009: Summary of Statistical Analysis Results of Change from Baseline: 
ESSDAI Total Score (Uncorrected) 
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RAP Section 
Summary of Change 
• 
T2.1010: Summary of Statistical Analysis Results of Change from Baseline: 
ESSDAI Total Score (Uncorrected) – Per Protocol Population 
• 
T2.1011: Summary of Statistical Analysis Results of Change from Baseline: 
ESSDAI Total Score (Corrected) 
• 
T2.1012: Summary of Statistical Analysis Results of Change from Baseline: 
ESSDAI Total Score (Corrected) - Per Protocol Population 
• 
T2.1021: Summary of Statistical Analysis of Responder on Total ESSDAI 
Score (Corrected) 
• 
F2.1005: Adjusted Mean (95% CI) Change from Baseline: ESSDAI Total Score 
(Uncorrected) 
• 
F2.1006: Adjusted Mean (95% CI) Change from Baseline: ESSDAI Total Score 
(Corrected) 
• 
T2.1029: Summary of Statistical Analysis Results of Change from Baseline: 
Stimulated Salivary Flow  
• 
T2.1030: Summary of Statistical Analysis Results of Change from Baseline: 
Stimulated Salivary Flow - Per Protocol Population 
• 
T2.1033: Summary of Statistical Analysis Results of Change from Baseline: 
Oral Dryness Numeric Response Scale  
• 
T2.1034: Summary of Statistical Analysis Results of Change from Baseline: 
Oral Dryness Numeric Response Scale - Per Protocol Population 
• 
T6.1006: Summary of Statistical Analysis of Responders on ESSPRI 
EoS Analysis: The following additional displays will be generated: 
• 
Table 1.1006 Summary of Study Populations 
• 
T1.1023: Summary of Overall Subject Status 
• 
T.1.1025: Serious Acute Post-Injection Systemic Reactions per GSK 
Adjudication by PT, in First Six Doses of Belimumab/Placebo 
• 
T.3.63: Post-IV Systemic Reactions per Anaphylactic Reactions CMQ Broad 
search by PT, in First Two 2 Infusions of Rituximab/Placebo 
• 
T2.1040: Summary Statistics of ESSDAI Total Score (Corrected) - Completers 
• 
T2.1041: Summary of Statistical Analysis Results of Change from Baseline: 
ESSDAI Total Score (Corrected) - Completers 
• 
T2.1042: Summary Statistics of Stimulated and Unstimulated Salivary Flow - 
Completers 
• 
T2.1043: Summary Statistics of Oral Dryness Numeric Response Scale - 
Completers 
• 
T6.1015: Summary Statistics of ESSPRI Total Score and Domains - 
Completers 
• 
T7.023: Summary Statistics of Flow Cytometry Flow Parameters- Completers 
• 
L1059: Listing of Overall Subject Status 
• 
L1061: Listing of Protocol Deviations Related to Covid-19 
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2.3. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary 
• Safety and tolerability of anti-BLyS 
/ anti-CD20 co-administration 
therapy and anti-BLyS and anti-
CD20 monotherapies 
• Safety and tolerability; including incidence of SAEs 
and AESIs. 
Secondary 
Clinical efficacy of anti-BLyS / anti-
CD20 co-administration therapy 
and anti-BLyS and anti-CD20 
monotherapies 
• ESSDAI score over time 
• Stimulated salivary flow over time 
• Oral dryness numeric response scale over time 
• Assessment of anti-BLyS / anti-
CD20 co-administration therapy 
and anti-BLyS and anti-CD20 
monotherapies on tissue B-cells. 
• B cell quantification within salivary gland biopsy at 
Week 24 
Exploratory 
Assessment of mechanism and 
durability of effect of anti-BLyS/anti-
CD20 co-administration therapy and 
anti-BLyS and anti-CD20 
monotherapies. 
Clinical efficacy 
• Ocular dryness numeric response scale over time 
• Lacrimal gland function as measured by Schirmer’s 
test 
• Physician’s Global Assessment (PGA) of disease 
activity over time 
Biomarkers 
• Serologic markers over time 
• Change in peripheral blood leukocytes including B 
cell subsets over time 
• BLyS levels in blood 
• Immunogenicity of rituximab and belimumab 
• Pharmacokinetics of rituximab and belimumab 
• Change from baseline in the cellular composition of 
the salivary gland 
• Sustained efficacy of anti-BLyS/anti-CD20 co-
administration at Week 52. Additional exploratory 
biomarkers may be evaluated [1] 
o Transcriptomic analysis of blood and salivary 
gland 
o B and T cell receptor clonal analysis in peripheral 
blood and salivary gland 
o Proteomic assessment of the saliva 
 
Health Outcomes 
Gather preliminary information on 
patient reported outcomes of anti-
BLyS/anti-CD20 co-administration 
• ESSPRI score (and individual scale sub-scores) over 
time 
• Fatigue and Discomfort- SICCA Symptom Inventory 
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Objectives 
Endpoints 
therapy and anti-BLyS and anti-CD20 
monotherapies. 
 
(PROFAD SSI SF) over time 
• Patient Global Assessment (PtGA) of disease activity 
over time. 
• Subject exit interviews. 
NOTE: 
[1] Analysis will be implemented post week 52 primary analysis 
 
2.4. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• Multi-national, multi-center, double-blind (sponsor open), randomized, 
placebo-controlled trial in subjects with active pSS.  
• Disease activity assessment at Week 52 will allow determination of whether 
any clinical effects of co-administration therapy achieved at Week 24 are 
sustained after discontinuation of therapy and/or whether chronic treatment 
with belimumab monotherapy is effective. 
Dosing 
• Belimumab/ Placebo weekly subcutaneous injections  
• Rituximab/Placebo infusions at Weeks 8 and 10. 
Treatment 
Assignment 
• At Day 0, subjects will be randomized 1:2:2:2 to one of 4 treatment arms.   
• Subjects will be stratified based on their baseline disease activity severity 
[ESSDAI total 5-12 (moderate) vs. >12 (severe)]. 
• GSK RandAll NG used to generate randomization schedules. 
• Centralized randomization using GSK RAMOS NG for treatment allocation. 
Safety 
Review 
• Periodic blinded review by SRT, and un-blinded reviews by iSRC, focusing 
on key safety parameters. 
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Overview of Study Design and Key Features 
Interim 
Analysis 
• Formal planned interim analysis was performed once approximately 35 
subjects had completed their Week 24 assessments.   
 
2.5. 
Statistical Hypotheses 
The primary objective of the study is to investigate the safety and tolerability of the co-
administration of belimumab with rituximab and belimumab monotherapy in subjects 
with pSS.  No formal statistical comparisons will be conducted to assess this objective.  
Secondary efficacy and mechanistic endpoints will be investigated. The following 
exploratory comparisons will be conducted: 
1. Co-administration belimumab/rituximab treatment arm vs. Placebo arm 
2. Co-administration belimumab/rituximab treatment arm vs. Rituximab 
monotherapy arm 
3. Co-administration belimumab/rituximab treatment arm vs. Belimumab 
monotherapy arm 
4. Belimumab monotherapy arm vs. Placebo arm 
5. Belimumab monotherapy arm vs. Rituximab monotherapy arm 
3. 
PLANNED ANALYSES 
3.1. 
Regular Data Reviews 
Safety data will be reviewed on a quarterly basis in a blinded fashion by an internal safety 
review team (SRT). Summaries will be produced in order to describe the baseline 
demography and the following safety parameters: 
1. 
Adverse events and serious adverse events including fatalities 
2. 
Adverse events of special interest as defined in the belimumab PSAP 
3. 
Withdrawals and reasons for withdrawal 
4. 
Blood chemistry 
5. 
Hematology  
6. 
CD4 and CD8 as measured by flow cytometry  
7. 
Immunoglobulin levels (IgG) 
The displays for the SRT meetings will not include any laboratory data that could 
potentially un-blind the treatments. IgA, IgM and CD19 assessment are excluded.   
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Additionally, summaries of the above parameters plus IgA, IgM, vital signs and ESSDAI 
will be reviewed in an unblinded manner by the internal Safety Review Committee 
(iSRC) as outlined in protocol and in the iSRC charter.  In order to protect the blinding 
status, these displays will be produced by a third party (Quanticate).   
3.2. 
Interim Analyses 
A formal interim analysis was planned to take place once half of the planned subjects 
(i.e.: approximately 35 subjects) have completed their Week 24 assessments. The interim 
analysis displays included the available data for all visits up to Week 68 as indicated in 
the table below.  The interim analysis reviewed safety outputs produced for iSRC and 
additional summaries for efficacy, biomarkers and health outcomes parameters.  The 
interim analysis summaries were produced by treatment group and reviewed by the TA-
DAC and the iSRC.  At the interim analysis, to aid internal decision making, predictive 
probabilities for ESSDAI effects were computed for comparison of combination 
(belimumab/rituximab) vs placebo at Week 24 and for comparison of belimumab 
monotherapy vs placebo at Week 24.  The predictive probabilities for ESSDAI treatment 
differences greater than 3 and greater than 5, under varying assumptions for target sample 
size were assessed to support potential sample size re-estimation for the study.  Access to 
interim outputs were restricted to individuals specified in the iSRC charter. There were 
no changes made to the sample size/study as a result of the interim analysis. 
Section 
Interim Analysis 
Study Population 
Baseline demography  
Disease History  
Disposition 
Safety 
(Primary study 
objective) 
Adverse events and serious adverse events 
Adverse events of special interest as defined in Belimumab PSAP 
Withdrawals and reasons for withdrawal 
Immunoglobulin (IgG, IgA, IgM) 
Haematology 
Blood chemistry 
Vital Signs 
CD4 and CD8 
Clinical Efficacy 
ESSDAI Total Score and Domains 
Biomarkers 
 
B cells (CD20) count/mm2 in salivary gland biopsy (by histology) 
B cell (CD20) / T cell (CD3) ratio in salivary gland biopsy (by histology) 
Lymphocyte Focus Score (expressed per 4mm2) in salivary gland biopsy (by 
histology) 
Plasma cells (CD138+; both CD20pos and CD20neg) count/mm2 in salivary gland 
tissue (by histology). 
Frequency of B cells1, naïve2, memory3, and plasmablast4 in peripheral blood (by 
flow cytometry) 
Serum SS-A concentration 
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Section 
Interim Analysis 
Health Outcomes 
ESSPRI (total score and the pain, fatigue and dryness domains) 
1. CD19+ B cells (CD3-CD19+) 
2. Naïve B cells (CD19+CD20+CD27-)  
3. Memory B cells (CD19+CD20+CD27+)  
4. Plasmablast All (CD19+CD27+CD38+)  
3.3. 
Final Analyses 
There will be two database freezes for this study, corresponding to the Primary Analyses 
and the End of Study Analyses (Week 104). 
Primary Analysis 
The cut-off date in the Primary Analysis datasets will be 09-Sep-2019 (i.e. the date the 
last subject completed their Week 52 visit). Data after 09-Sep-2019 will be removed from 
the extracted data after DBR based on the algorithms detailed in refer to Appendix 5: 
Derived and Transformed Data for details. The data cut off will be applied on DMDATA 
before generating any analysis datasets and outputs. 
The primary analyses will be performed after the completion of the following sequential 
steps: 
1. All subjects have completed their Week 52 (or early withdrawal assessment for 
subjects withdrawing consent prior to Week 52).  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for un-blinding the randomization codes have been met: 
• 
AESI adjudication through Week 68/FU assessments. 
• 
Protocol deviation review as described in Protocol Deviation Management Plan 
(PDMP) is completed. 
• 
Exclusions from the per protocol population have been agreed and documented. 
4. Randomisation codes have been distributed according to RandAll NG procedures. 
5. Database freeze (DBF) has been declared by Data Management. 
All outputs as described in Section 6 to Section 9 of the RAP and detailed in Appendix 
13 will be reported for the primary analyses: 
• Summary tables reported by visit will include only data collected till Week 68/FU 
• Summary tables not reported by visit will include all date collected based on the 
date-cut date, unless otherwise specified/ required. 
• All collected data from the Individualized Follow Up (IFU) period will be listed. 
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End of Study Analysis 
The end of study (after week 104) analyses will be performed after the completion of the 
following sequential steps: 
1. All subjects have completed the 16-week generalized follow-up visit (Week 68) and 
individualized follow up visit (up to Week 104 or IFU final visit for subjects leaving 
the IFU prior to W104) or Early Withdrawal visit for those subjects who withdraw 
from the study prior to the Week 104 visit. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management as described in 
Steps 2, 3 and 5 above. 
For the End of Study Analysis reporting, selected Primary Analysis displays (Appendix 
13: List of Data Displays) have been identified and will be generated, using the final data.  
The displays will be updated (as required) to capture the additional visits and to reflect 
the final data. If further details are required, a RAP amendment or addendum will be 
generated to specify the changes. 
This RAP details the planned analysis for both database freezes, with the expectation of 
an observed treatment benefit being observed following the Primary Analysis. In the 
event that the Primary Analysis reporting does not identify treatment benefit, an abridged 
set of analysis may be conducted for the end of study analysis, which will be detailed in a 
RAP amendment or addendum. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Selected Study 
Population 
Enrolled 
• 
All participants who passed screening and entered 
the study. Includes Randomized Participants. 
• 
Note: Screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the study. 
• 
Selected Study 
Population 
Safety 
• 
Comprises all subjects who receive at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
subject actually received. 
• 
Study Population 
• 
Efficacy 
• 
Safety/tolerability 
• 
PD/Biomarker 
• 
Exploratory 
• 
Health Outcomes 
Belimumab 
Pharmacokinetic 
(PK-B) 
• 
Subjects in the “Safety” population for whom a post 
treatment belimumab pharmacokinetic sample was 
obtained and analysed. 
• 
Belimumab PK 
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Population 
Definition / Criteria 
Analyses Evaluated 
Rituximab 
Pharmacokinetic 
(PK-R) 
• 
Subjects in the “Safety” population for whom a post 
treatment rituximab pharmacokinetic sample was 
obtained and analysed 
• 
Rituximab PK 
Per-Protocol (PP) 
• 
All participants in the safety population who comply 
with the protocol.  
• 
Protocol deviations that would exclude participants 
from the PP population are defined in Section 4.1 
(Protocol Deviations) and Appendix 1: Protocol 
Deviation Management and Definitions for Per 
Protocol Population. 
• 
The Per-Protocol set will not be analysed if this 
population comprises more than 85% of the safety 
population. 
• 
Subset of 
Efficacy/PD/ 
Biomarker 
Completer 
• 
Subjects who completed the 52 Week treatment 
visits AND general follow up phase of the study 
including the visit at Week 68 
 
NOTE: 
• 
Definition as per protocol Section 5.5 Subject and 
Study Completion 
• 
Does not include any subjects with a study 
treatment discontinuation flag. 
• 
Efficacy 
• 
Health Outcomes 
• 
PD/Biomarkers 
• 
Exploratory 
NOTES:  
• 
Please refer to Appendix 13,  List of Data Displays which details the population to be used for each display 
being generated. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed. 
Separately, important deviations which result in exclusion from the per-protocol analysis 
population will also be summarized and listed.  
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the current Protocol Deviation Management Plan. [Version 007 (18-
Sep-2019 or higher)]. 
• Data related to the Primary Analysis will be reviewed prior to unblinding and 
freezing the database to ensure all important deviations and deviations which lead to 
the exclusion from the analyses are captured and categorized on the protocol 
deviations dataset. 
• This dataset will be the basis for the summaries and listings of the protocol 
deviations. 
All deviations will be discussed and adjudicated as important or not important. 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
 
4.2. 
Per-Protocol Population 
Periodic review of the per-protocol population will be conducted during the course of the 
study, with the final assessment made prior to unblinding the data for Primary Analysis 
reporting.  
The per-protocol population will be primarily based on an assessment of the important 
protocol deviations. However, non-important deviations or other study conduct issues 
may be identified during the study and warrant a subject’s exclusion from the per-
protocol population.  This will be documented in the protocol deviation adjudication 
meeting minutes prior to database freeze.  Only protocol deviations or study conduct 
issues that have the potential to impact a subset of Efficacy/PD/Biomarker evaluations 
will lead to a subject’s exclusion from the per-protocol population. 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Co-administration therapy 
Co-administration 
2 
B 
Belimumab 200 mg SC injection 
Belimumab 
3 
C 
Rituximab 1,000 mg IV infusion 
Rituximab 
4 
P 
Placebo 
Placebo 
1 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
Treatment Descriptors, Colors, Line Style and Symbols for Reporting 
Treatment Descriptor 
Color 
SAS Color 
Line Style 
Symbol 
Co-administration 
Green 
CX228B22 
LongDash 
Circle (filled) 
Belimumab 
Blue 
CX0000FF 
Dash 
Triangle (filled) 
Rituximab 
Purple 
CX800080 
ShortDash 
Diamond (filled) 
Placebo 
Brown 
CXA05000 
Solid 
Square (filled) 
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5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 0 assessments are assumed to be taken prior to first 
dose and used as baseline. 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Screening 
Day 0 (Pre-Dose) 
Week 8 
Safety 
Laboratory [1] 
X 
X 
 
Day 0 (Pre Dose) [3] 
Vital Signs 
X 
X 
 
Day 0 (Pre Dose) [3] 
CSSRS 
 
X 
 
Day 0 (Pre Dose) 
Neurological Assessment 
 
X 
 
Day 0 (Pre Dose) 
Immunogenicity (Rituximab) 
 
 
X 
Week 8 
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Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Screening 
Day 0 (Pre-Dose) 
Week 8 
Efficacy 
ESSDAI/ClinESSDAI 
X 
 
 
Screening 
Salivary Flow 
X 
 
 
Screening 
Oral Dryness 
X 
 
 
Screening 
Salivary Gland B Cell 
Quantification 
X 
 
 
Screening 
Exploratory 
Ocular Dryness 
X 
 
 
Screening 
Lacrimal Gland Function 
X 
 
 
Screening 
PGA 
X 
 
 
Screening 
Unstimulated Salivary Flow 
X 
 
 
Screening 
BLyS  
 
X 
 
Day 0 (Pre Dose) 
Serologic Markers 
X 
X 
 
Day 0 (Pre Dose) [3] 
Flow Cytometry 
X 
X 
 
Day 0 (Pre Dose) [3] 
Minor Salivary Gland 
Histology Assessments [2] 
X 
 
 
Screening 
Health Outcomes 
ESSPRI  
X 
 
 
Screening 
PRO FAD SSI SF 
X 
 
 
Screening 
PtGA 
X 
 
 
Screening 
Notes:  
1. 
Includes Clinical Chemistry, Hematology, Urinalysis and Other Screening Tests 
2. 
Salivary gland biopsy may be conducted at any time during screening up to day 0  
3. 
If day 0 pre dose assessment is missing, the screening assessment will be used as baseline.   
 
• 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.  
• 
Unless otherwise stated, if baseline data are missing no derivation will be performed and baseline will be set to 
missing. 
Changes from baseline will be derived as follows.  
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline] 
NOTES: 
o 
Unless otherwise specified, the baseline definitions specified in Section 5.2 Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on summaries and listings. 
o 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing. 
o 
The baseline definition will be footnoted on all change from baseline displays. 
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5.3. 
Multi-center Studies 
In this multicenter global study, enrolment will be presented by country and site. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
Independent variables to be included in efficacy and exploratory analyses are described in 
Section 8 and Section 9, respectively. 
5.4.2. 
Examination of Subgroups 
Subgroup analysis based on following Randomization Stratum ESSDAI categories may 
be analysed as a post SAC analysis. 
ESSDAI groups: 
• Low (<5) 
• Moderate (>=5 & <=12) 
• Severe (>12) 
• High Activity (>=14) 
 
5.5. 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons are planned.  
5.6. 
Other Considerations for Data Analysis and Data Handling 
Conventions 
Other considerations for Data Analysis are described in the appendices; 
Section  
Component 
11.3 
Appendix 3: Treatment States and Phases 
11.4 
Appendix 4: Data Display Standards and Handling Conventions 
11.5 
Appendix 5: Derived and Transformed Data 
11.6 
Appendix 6: Reporting Standards for Missing Data 
11.7 
Appendix 7: Values of Potential Clinical Importance 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the “Safety” population, unless otherwise 
specified. 
Table 1 provides an overview of the planned study population analyses for the primary 
analyses, and the specific data displays are captured in Appendix 13: List of Data 
Displays. 
Table 1 
Overview of Planned Study Population Analyses 
Display Type 
Data Displays Generated 
Table 
Figure 
Listing 
Randomization 
Randomization and Actual Treatments 
 
 
Y 
Subject Disposition 
Subject Disposition 
Y [1] 
 
 
Reasons for Screening Failures 
Y 
 
Y 
Reasons for Withdrawals 
Y 
 
Y 
Treatment Discontinuations 
 
 
Y 
Important Protocol Deviations 
Y 
 
Y [2] 
Enrolment 
Y 
 
 
Exclusions from Study Populations 
Y 
 
Y  
Demographic and Baseline Characteristics 
Demographic Characteristics 
Y 
 
Y 
Race & Racial Combinations 
Y 
 
Y 
Smoking Use 
Y 
 
 
Family History of Cardiovascular Risk Factors 
Y 
 
 
Physical Examination 
 
 
Y 
Medical Condition & Concomitant Medications 
Medical Conditions (Sjögren specific) 
Y 
 
Y 
Medical Conditions (non-Sjögren specific) 
Y 
 
Y 
Concomitant Medication 
Y 
 
Y 
NOTES: 
Y = Yes display generated. 
[1] For End of Study, a further subject disposition table will be generated to summarize subject’s completion status 
upto Week 52 & W68, subjects withdrawn and who continued or discontinued study visits. 
[2] For End of Study, a further listing will be generated to capture important PDs related to COVID-19. 
Selected Primary Analysis study population displays will also be generated for the End of 
Study Analysis and are identified in Appendix 13: List of Data Displays. Where required, 
programming notes (Appendix 13 or Mock Shell Examples) have been included for any 
specific changes based on the Primary Analysis displays. 
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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Safety Analyses 
7.1.1. 
Overview of Planned Analyses 
The safety analyses will be based on the “Safety” population, unless otherwise specified. 
Table 2 provides an overview of the planned safety Primary Analyses, with further details 
of data displays being presented in Appendix 13: List of Data Displays. 
Table 2 
Overview of Planned Safety Analyses 
Endpoint 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Exposure 
Extent of Exposure 
Y 
 
 
Y 
 
 
 
 
Adverse Events 
All AEs [1]  
Y 
 
 
Y 
 
 
 
 
All Drug-Related AEs  
Y 
 
 
 
 
 
 
 
AEs of Special Interest 
Y 
 
 
Y 
 
 
 
 
Serious AEs 
Y 
 
 
 
 
 
 
 
Withdrawal AEs  
Y 
 
 
Y 
 
 
 
 
Fatal Adverse Events 
Y 
 
 
Y 
 
 
 
 
Common AEs [2] 
Y 
 
 
 
 
 
 
 
Reasons for Considering 
as SAE 
 
 
 
Y 
 
 
 
 
Laboratory Values 
Immunoglobulins 
Y 
Y 
 
Y 
Y 
Y [3] 
 
 
Clinical Chemistry  
Y [4] 
 
 
Y 
Y [4] 
 
 
 
Hematology  
Y [4] 
Y 
 
Y 
Y [4] [5] 
 
 
 
Liver 
Y 
 
 
 
 
 
 
Y 
Urinalysis (Dipstick)  
Y 
 
 
Y 
 
 
 
 
Other Screening Tests [6] [7] 
 
 
 
Y 
 
 
 
 
C-Reactive Protein 
Y 
 
 
 
Y 
 
 
 
CD4 and CD8 
Y 
Y 
 
Y 
 
 
 
 
ECGs 
ECG  
Y 
 
 
 
 
 
 
 
Abnormal ECG 
 
 
 
Y 
 
 
 
 
Vital Signs 
Vital Signs 
Y [8] 
 
 
Y 
Y [8] 
 
 
 
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Endpoint 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Neurological Symptoms 
Neurological Symptoms 
Y 
 
 
Y 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
C-SSRS 
Y 
 
 
Y 
 
 
 
 
Immunogenicity 
Belimumab 
Immunogenicity 
Y 
 
 
Y 
 
 
 
 
Rituximab Immunogenicity9 
Y 
 
 
Y 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
1. 
Listing will include subject’s numbers for individual AE’s & AE system organ classes, preferred terms and verbatim 
text. A separate listing will be generated for Primary & EoS to capture with subjects with post Week 68/FU events. 
2. 
Common AEs are adverse events occurring with a frequency > 5%. 
3. 
IgG, IgA & IgM will be reported 
4. 
Including summaries of Toxicity grading  
5. 
Including evaluation of shifts from baseline.  
6. 
Positive/abnormal findings  
7. 
Other screening tests include HIV, Hepatitis B (HBsAg), HbcAb, Hepatitis C (Hep C antibody), FSH, estradiol and 
serum or urine hCG pregnancy test. 
8. 
Including evaluation of PCI criteria 
9. 
Reported only for End of Study (Baseline is defined as Week 8)  
 
Selected Primary Analysis safety displays will also be generated for the End of Study 
Analysis and are identified in Appendix 13: List of Data Displays. Where required, 
programming notes (Appendix 13 or Mock Shell Examples) have been included for any 
specific changes based on the Primary Analysis displays. 
Primary Analysis:  Summarized safety data for all completed visits up to Week 68 
(where reported by visit) and up to Week 104 (where not reported by visit), with a cut-off 
date of 9 September 2019 (Week 52 LSLV).  
On completion of the Primary Analysis, it was noted that the safety data included 39 AEs 
(out of a total of 49) reported during the IFU phase that were not within the defined scope 
of the protocol for AE collection. The over-reported AEs included 2 SAEs reported by 2 
subjects; both were assessed as unrelated to study treatment. An additional blinded listing 
of the 49 AEs reported during the IFU period was generated. Full details are included in 
the Primary Analysis CSR.  
End of Study Analysis: Summarize AE/AESI safety data for all completed visits up to 
Week 68 only to include AEs collected in the defined protocol AE collection period. An 
unblinded listing of the AEs reported during the IFU period will be generated, which will 
also include information as to whether the AE occurred pre or during the COVID-19 
pandemic. 
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Additional safety analyses may (if required) also be conducted to further assess the 
impact of the over-reported AEs in the FU or COVID-19 pandemic. 
7.1.2. 
Immunogenicity 
Exploratory Analyses: Immunogenicity 
Endpoints 
• 
Immunogenic Response to Belimumab 
• 
Immunogenic response to Rituximab (will not be reported until all subjects have completed the follow-up 
phases of the study) 
Summary Results Presentation 
The method for calculation of belimumab & rituximab immunogenic response is given in Section 11.5.6.1.  
The belimumab and rituximab immunogenicity response will be summarized for the binding antibody assay 
by treatment group and visit. The table will include the number and proportion of subjects in each result 
category for each visit. Binding confirmatory assay results will be categorized as Negative, Positive, or 
Unknown.  Positive samples in the binding assay are further categorized as Transient Positive (i.e. single 
positive response that does not occur at the final assessment) or Persistent Positive (i.e. positive response 
that occurs at least 2 consecutive assessments or a single result at the final assessment)  
Belimumab only:  Presence of neutralizing antibodies and titre for samples confirming positive in the blinding 
assay will be listed. 
Rituximab: Baseline is Week 8. Titre for samples confirming positive in the blinding assay will be listed. 
7.1.3. 
Immunoglobulin 
Exploratory Analyses: Immunoglobulin 
Endpoints 
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) below the LLN at 
each visit will be presented  
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) above the ULN at 
each visit will be presented  
Worst IgG toxicity grade 
The number and percentage of subjects at each toxicity grade will be assessed at baseline and also for 
anytime post baseline.   
IgG toxicity ≥ 2 grade shift post-baseline 
The number and percentage of subjects with at least one ≥ 2 grade shift as well as the specific shift 
categories: Grade 0 to 2, Grade 0 to 3, Grade 0 to 4, Grade 1 to 3, Grade 1 to 4 and Grade 2 to 4 will be 
computed by treatment group. 
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7.1.4. 
Adverse Events of Special Interest 
The AESI definitions from Section 15 and Section 16 of the current belimumab PSAP 
(Note: Version 5 was used for the interim analysis and version 6 for the final analysis) 
will be followed to identify the program level AESI.  Search terms based on the current 
version of MedDRA (Primary Analysis = 22.0 and End of Study = 23.0) at the time of 
database release will be utilized.  The additional study specific AESI are:  
Severe skin reaction: All events identified by Severe Cutaneous Adverse Reactions 
SMQ broad search will be adjudicated (Preferred terms corresponding to broad search 
from SMQ are given in the Section 11.5.3.1)   
Cardiac Disorders: All events identified by applying Cardiac Arrhythmias SMQ, 
Cardiac Failure SMQ, Cardiomyopathy SMQ, and Ischaemic heart disease SMQ will be 
adjudicated (Preferred terms corresponding to broad search from SMQ are given in 
Section 11.5.3.1)   
Posterior Reversible Encephalopathy Syndrome (PRES): Defined as all events 
identified in the preferred term “Posterior Reversible Encephalopathy Syndrome”. 
Progressive Multifocal Leukoencephalopathy (PML): Defined as all events identified 
in the preferred term “Progressive multifocal leukoencephalopathy” 
Adverse events related to the biopsy: Preferred terms corresponding to adverse events 
related to biopsy will be reviewed and adjudicated. 
Malignancies, serious post-administration systemic reactions, potential opportunistic 
infections, suicide/self-injury, fatalities, severe infections and skin reactions will be 
adjudicated at the subject level by the GSK blinded Safety Review Team (SRT). 
Additionally, the study specific AESI’s will be adjudicated at the subject level by the 
study team. Adjudication will be conducted periodically with a final adjudication 
completed prior to the DBF for the primary analysis. Further adjudications (periodically 
and prior to End of Study DBF) will also be performed for the End of Study analysis. 
Only adjudicated study specific AESI’s will be reported.   
An overall summary of AESI will be presented and each specific category of AESI will 
be presented separately by PT.  Infection AESIs will also be presented by PT for all 
infections leading to discontinuation. The number and percentage of subjects with at least 
one occurrence and the number of events for each AESI will be provided.  The AESI 
categories are: 
Malignant Neoplasms 
• 
Malignancies Excluding non-melanoma skin cancer (NMSC) 
• 
Malignancies Including NMSC 
• 
Solid Tumor 
• 
Hematologic 
• 
Skin (All) 
o 
NMSC 
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o 
Excluding NMSC 
• 
Tumors of unspecified malignancy adjudicated as malignant per GSK 
adjudication 
 
Post-Administration Systemic Reactions 
 
• 
Post-Administration Systemic Reactions per Anaphylactic Reaction Customized 
MedDRA Query (CMQ) narrow search 
• 
Post-Administration Systemic Reactions per Anaphylactic Reaction CMQ broad 
search 
• 
Post-Administration Systemic Reactions per Anaphylactic Reaction CMQ 
algorithmic search 
• 
Serious Anaphylaxis per Sampson Criteria 
• 
Serious Acute Post-Administration Systemic Reactions/Hypersensitivity per GSK 
adjudication 
o 
Serious Acute Post-Administration Systemic Reactions Excluding 
Hypersensitivity per GSK adjudication 
o 
Serious Acute Hypersensitivity Reactions per GSK adjudication 
• 
Serious Delayed Acute Hypersensitivity Reactions per GSK adjudication 
• 
Serious Delayed Non-Acute Hypersensitivity Reactions per GSK adjudication 
 
All Infections of Special Interest 
 
• 
All opportunistic infections per GSK adjudication 
• 
Opportunistic infections per GSK adjudication excluding Tuberculosis and 
Herpes Zoster 
o 
Serious opportunistic infections per GSK adjudication excluding 
Tuberculosis and Herpes Zoster 
• 
Active Tuberculosis 
o 
Non-Opportunistic  
o 
Opportunistic 
• 
Herpes Zoster 
o 
Non-Opportunistic  
o 
Opportunistic 
▪ 
Recurrent  
▪ 
Disseminated 
• 
Sepsis 
 
Depression/suicide/self-injury 
• 
Depression (Inc. mood disorders and anxiety) 
• 
Suicide/self-injury 
• 
Serious Suicide/Self-injury per GSK Adjudication 
o 
Suicidal Behaviour per GSK Adjudication 
• 
Completed Suicide per GSK Adjudication 
o 
Suicidal Ideation per GSK Adjudication 
o 
Self-injurious Behaviour Without Suicidal Intent per GSK Adjudication 
 
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Deaths 
 
Study Specific AESI 
 
• 
Severe skin reaction per GSK Adjudication  
• 
Cardiac Disorders 
• 
Posterior Reversible Encephalopathy Syndrome (PRES) 
• 
Progressive multifocal leukoencephalopathy (PML)  
• 
Adverse events related to the biopsy 
 
 
7.1.4.1. 
Post-Administration systemic reactions by Belimumab/Placebo 
Injection  
Summaries of post-injection systemic reactions will be presented by the first six 
injections (belimumab/placebo) in addition to overall injections for the following 
categories: 
• Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ broad search (on 
the day of the injection or within 3 days after the injection) 
• Serious Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ broad 
search (on the day of the injection or within 3 days after the injection) 
• Serious Acute Post-Injection Systemic Reactions/Hypersensitivity per GSK 
adjudication 
• Serious Delayed Acute Post-Injection Systemic Reactions per GSK adjudication 
• Serious Delayed Non-Acute Post-Injection Systemic Reactions per GSK adjudication 
 
7.1.4.2. 
Post-Administration Systemic Reactions by Rituximab/Placebo 
Infusion 
Summaries of post-infusion systemic reactions will be presented by the first two 
infusions (rituximab/placebo): 
• Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ broad search (on 
the day of the infusion or within 3 days after the infusion) 
 
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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Efficacy and Biomarker Analyses 
8.1.1. 
Overview of Planned Efficacy and Biomarker Analyses 
The secondary efficacy analyses will be based on the “Safety” population, unless 
otherwise specified. 
Table 3 provides an overview of the planned efficacy Primary Analyses, with further 
details of data displays being presented in Appendix 13: List of Data Displays. 
Table 3 
Overview of Planned Efficacy and Biomarker Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Clinical Efficacy 
ESSDAI Score 
(Uncorrected & 
Corrected) 
 
 
 
 Y 
Y 
 
Y 
Y 
Y 
[2] 
 
Y 
Y 
 
 
ESSDAI Domains 
(Uncorrected & 
Corrected) 
 
 
 
Y 
Y 
 
Y 
 
 
 
Y 
 
 
 
ESSDAI Responder 
(Corrected) 
Y [2] 
 
 
Y 
Y 
 
 
 
 
 
 
 
 
 
ClinESSDAI 
(Corrected) 
 
 
 
Y 
 
 
Y 
Y [2] 
 
 
Y 
 
 
 
ClinESSDAI 
Responder 
(Corrected) 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
ESSDAI Corrected 
/ClinESSDAI 
Corrected Correlations 
 
 
 
 
 
 
 
 
 
 
 
Y[2] 
 
 
Stimulated Salivary 
Flow 
 
 
 
Y 
 
 
Y 
Y [2] 
 
 
Y 
Y 
 
 
Oral Dryness NRS 
 
 
 
Y 
 
 
Y 
Y [2] 
 
 
Y 
Y 
 
 
Biomarker 
Number of B cells 
(CD20) /mm2 in 
Salivary Gland Biopsy 
 
 
 
Y 
 
 
Y 
Y [1] 
 
 
Y[1] 
Y[1] 
 
Y 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
NRS, Numeric Response Scale 
[1] Based on change from baseline  
[2] Will not be generated for EoS 
 
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Selected Primary Analysis efficacy displays will also be generated for the End of Study 
Analysis and are identified in Appendix 13: List of Data Displays. Where required, 
programming notes (Appendix 13 or Mock Shell Examples) have been included for any 
specific changes based on the Primary Analysis displays. 
8.1.1.1. 
ESSDAI 
ESSDAI scores disease activity in 12 domains. In 5 (renal, PNS, CNS, cutaneous and 
pulmonary) of the domains, ESSDAI requires that if activity has been present for greater 
than or equal to 12 months then it must be treated as irreversible damage and the activity 
should be scored as zero (Seror, 2015a). This is a problem for clinical trials of long 
duration such as study 201842 because it can result in misleading evidence of reduced 
activity. For that reason, a corrected ESSDAI score will be calculated. 
The ESSDAI Corrected score will be calculated as: 
• 
For each damage eligible domain 
o where damage is scored as present for 1st time after screening THEN corrected 
activity score = damage score for that domain for that visit and the activity score 
for all subsequent visits should be changed to equal the corresponding damage 
domain score 
o Except in rare cases where the activity score for the visit concerned is already 
equal to or greater than the damage score, in which case no change should be 
made. 
• If damage is scored as present at screening AND if the damage score increases in 
level of involvement (low to moderate or moderate to high) after the screening visit 
then the activity score for that domain for that visit and all subsequent visits should be 
changed to equal the corresponding damage domain score 
o Except in rare cases where the activity score for the visit concerned is already 
equal to or greater than the damage score, in which case no change should be 
made. 
• If damage is scored at screening and remains constant across visits, then no 
programmed correction can or should be made to the activity scores. 
Further details are included in Section 11.5.4 Efficacy. 
The primary inference will be based on the corrected ESSDAI score, with the uncorrected 
score being used as a supporting sensitivity analysis to assess any impact. 
For the Primary Analysis, the correction could not be applied for 1 subject (ID 
) for 
one domain of ESSDAI. The complexity of disease scoring in the PNS domain for this 
subject prevented the correction algorithm from appropriately recording low activity for 
this domain from Week 24 onwards. Consequently, the total corrected ESSDAI score for 
this subject is underestimated by 5 points for each visit from Week 24 onwards. Only a 
single domain of ESSDAI was affected and there is thought to be no impact on the 
interpretation of the overall corrected ESSDAI data. This subject will subsequently not be 
corrected for the End of Study Analysis. 
 
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8.1.2. 
Planned Efficacy and Biomarker Statistical Analyses 
Secondary Statistical Analyses – Efficacy (MMRM) 
Endpoint(s) 
• 
Change from Baseline in ESSDAI Total Score (Uncorrected & Corrected) 
• 
ESSDAI Domain Scores (Corrected) 
• 
ESSDAI Improvements (At Least 1 Category on Domain Score) (Corrected) 
• 
ESSDAI Worsening (At Least 1 Category on Domain Score) (Corrected) 
• 
Change from Baseline in Stimulated Salivary Flow 
• 
Change from Baseline in Oral Dryness Numeric Response Scale 
Model Specification 
• 
Endpoints will be statistically analyzed using a mixed model repeated measures (MMRM) 
• 
Terms fitted in MMRM models will include: 
       Fixed Categorical 
                       : Treatment, Visit, Treatment * Visit Interaction 
       Fixed Continuous Covariates             : Baseline (see Section 5.2 for baseline definition)  
       Repeated 
                                      : Visit 
• 
For the analysis of salivary flow and oral dryness numeric response, ESSDAI stratification (moderate or 
severe) will also be included as a fixed categorical term.  
Model Checking & Diagnostics 
• 
Refer to Appendix 9: Model Checking and Diagnostics for Statistical analyses. 
Model Results Presentation 
• 
Adjusted means and corresponding standard error of means (SEs) and 95% confidence intervals will be 
presented for changes from baseline on each treatment by Visit. together with estimates and the 
corresponding 95% confidence intervals for the comparisons of interest.  
• 
If the model checking deems the above parametric analysis to be unsuitable, nonparametric rank 
Hodges-Lehmann’s confidence intervals will be provided in order to assess the robustness of the 
parametric analysis. This will be carried out in addition to the parametric analyses  
• 
For ESSDAI Total Score (Uncorrected and Corrected), plots of LS means and SE for changes from 
baseline for each treatment at all visits up to Week 52 as derived from the MMRM model will be 
presented. 
Summary Results Presentation 
• 
Summary statistics (n, mean, median, minimum and maximum), will be presented on the absolute 
values at each visit and the change from baseline at each visit.  
• 
Plots of the mean and corresponding SE on changes from baseline over time for each treatment will 
also be presented. 
Supportive Analyses 
• 
For ESSDAI, additional statistical analysis using MMRM will be conducted for changes from baseline 
for each treatment at all visits up to Week 68/FU, using the completer population.  
• 
The relationship between Scoring of ESSDAI (corrected) and Clinical ESSDAI (corrected) will be 
assessed graphically.  
• 
ESSDAI domain scores (Corrected) will be summarized. The number and proportion of subjects 
reporting no, Low, moderate (and high response where applicable), will be computed for each of the 12 
domains by treatment and visit.     
• 
Improvements in ESSDAI Domain Scores (corrected) will be evaluated.  For each domain, the number 
and proportion of improvers (i.e. higher to lower category) out of the subjects who had an activity score 
on the specific domain at baseline will be computed.  The number and proportion of subjects with 
worsening will be assessed for each ESSDAI Domain (Corrected).  The domain level denominator is 
the subset of subjects who do not have highest level of symptom at baseline.  
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Secondary Statistical Analyses – Efficacy (Bayesian) 
Endpoint(s) 
• 
Change from baseline in Total ESSDAI Score (Corrected) 
Model Specification 
• 
A Bayesian repeated Measures model will be used to fit the change from baseline in Total ESSDAI 
Score (Corrected).  
• 
A multivariate (MVN) normal distribution is assumed for the vector of changes from baseline for each 
subject (i.e. the change from baseline at weeks 12, 24, 36 & 52).  
• 
Markov-Chain-Monte-Carlo (MCMC) method in SAS will be used to derive the posterior distributions of 
the endpoint. 
• 
A linear model for Change from Baseline (CFB) in Total ESSDAI Score at each Week (visit) will be 
constructed to model the within-subject covariance structures: 
 
CFB = Intercept + Treatment + Baseline + Week + Treatment*Week 
Terms fitted in the model will include: 
Fixed Categorical: Week (Week 12 to Week 52), Treatment, Treatment*Week Interaction 
Fixed Continuous: Baseline 
Random: Subject 
 
• 
The prior for the variance covariance matrix will follow an Inverse Wishart Distribution. 
• 
Set seed=123456 with simulation size of 100,000 (i.e. every 10th iteration will be kept which will form the 
final MCMC (thinned) sample of 10,000) & 10,000 burn-in iterations. The simulation size and number of 
burn-in iterations may be updated during the convergence check. 
• 
Vague priors (normal (0, var=1e6)) will be used for regression parameters. 
Model Checking & Diagnostics 
• 
Refer to Appendix 9: Model Checking and Diagnostics for Statistical analyses. 
Summary Results Presentation 
• 
The sample size n, mean, median, standard deviation and highest posterior density (HPD: smallest 
interval width among all credible intervals) interval will be presented from the posterior density function. 
• 
The posterior distribution will be used to produce several probability statements (where θ is the ESSDAI 
change from baseline), such as (but not limited to and maybe refined): 
o Pr (θ Co-administration, 24w – θ Placebo, 24w < 0 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Placebo, 52w < 0 | 201842 data) 
o Pr (θ Co-administration, 24w – θ Placebo, 24w < 3 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Placebo, 52w < 3 | 201842 data) 
 
o Pr (θ Co-administration, 24w – θ Belimumab, 24w < 0 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Belimumab, 52w < 0 | 201842 data) 
 
o Pr (θ Co-administration, 24w – θ Rituximab, 24w < 0 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Rituximab, 52w < 0 | 201842 data) 
 
o Pr (θ Belimumab, 24w – θ Placebo, 24w < 0 | 201842 data) 
o Pr (θ Belimumab, 52w – θ Placebo, 52w < 0 | 201842 data) 
o Pr (θ Belimumab, 24w – θ Placebo, 24w < 3 | 201842 data)  
o Pr (θ Belimumab, 52w – θ Placebo, 52w < 3 | 201842 data)  
 
 
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Secondary Statistical Analyses – Efficacy 
Endpoints 
• 
ESSDAI Responders (Corrected) 
Summary Results Presentation 
• 
The proportion of ESSDAI responders based on corrected total ESSDAI score will be summarized 
descriptively using counts and percentages by treatment and visit. Responders are defined as below 
• Responders 1 - Subjects with a reduction in total ESSDAI of at least 5 points over baseline 
• Responders 2 - Subjects with a reduction in total ESSDAI of at least 3 points over baseline 
• Responders 3 - Subjects with a reduction in total ESSDAI of at least 3 points over baseline, and 
ESSDAI Total Score <5 
• Responders 4 - ESSDAI Total Score < 5 
• 
The proportion of ESSDAI responders will be presented as a bar chart grouped by treatment for each 
visit.  
Model Specification 
• 
Responder endpoints will be statistically analysed using a Generalised Estimating Equations (GEE) 
model 
• 
The model will be fitted using an unstructured covariance structure of the correlated responses. 
• 
Terms fitted in GEE models will include: 
Fixed Categorical                 : Treatment, Visit, Treatment*Visit Interaction 
Fixed Continuous Covariate: Baseline Total ESSDAI Score 
Repeated                             : Visit 
Model Checking & Diagnostics 
• 
Refer to Appendix 9: Model Checking and Diagnostics for Statistical analyses. 
Model Results Presentation 
• 
The Binary endpoints will be summarized using counts and proportions of subjects achieving a 
response by treatment group. 
• 
Differences in the proportions of subjects achieving response between treatment groups will be 
summarized by Visit (up to Week 52). 95% CI for the differences will be constructed using their 
asymptotic standard errors (asymptotic Wald confidence limits) without continuity correction. 
• 
Point estimates and corresponding 95% confidence intervals will be constructed using contrasts for the 
treatment by day interactions. 
 
Secondary Statistical Analyses – Efficacy 
Endpoint(s) 
• 
ClinESSDAI Responders (Corrected) 
Summary Results Presentation 
• 
The proportion of ESSDAI responders based on corrected total ESSDAI score will be summarized 
descriptively using counts and percentages by treatment and visit. Responders are defined as subjects 
with a reduction in total ClinESSDAI of at least 3 points over baseline 
 
Secondary Statistical Analyses – Biomarker 
Endpoint(s) 
• 
Absolute change from baseline in Number of B Cells (CD20)/mm2 in salivary gland biopsy at Week 24  
Model Specification 
• 
The absolute change at Week 24 will be analysed using the Hodges-Lehmann method to provide a 
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Secondary Statistical Analyses – Biomarker 
95% confidence interval for the contrasts of interest specified in Section 2.5 at Week 24 
Model Result Presentation 
• 
Along with the number of subjects (n) and median of absolute change from baseline of each treatment 
group, median difference with 95% Confidence intervals estimated from the H-L method will be 
presented at week 24 for the contrasts of interest. 
Summary Results Presentation 
• 
Summary statistics (n, mean, median, minimum and maximum) will be presented on the absolute 
values and the absolute change from baseline at Week 24.  
 
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8.2. 
Pharmacokinetic Analyses 
8.2.1. 
Overview of Planned Pharmacokinetic Analyses 
The pharmacokinetic (PK) analyses will be based on the Pharmacokinetic (PK-B and PK-
R) populations, unless otherwise specified. 
Table 4 provides an overview of the planned primary analyses, with full details being 
presented in Appendix 13: List of Data Displays.  
Table 4 
Overview of Planned Pharmacokinetic Analyses 
Endpoint 
Untransformed 
Log-Transformed 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Serum Drug 
Concentrations 
 
 
 
Y 
Y 
Y[1] 
 
 
 
 
 
 
 
 
NOTES: 
o 
T = Table, F = Figure, L = Listings, Y = Display generated. 
o 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
o 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
o 
Individual = Represents FL related to any displays of individual subject observed raw data.  
1. 
Linear and Semi-Log plots will be created on the same display. 
 
8.2.2. 
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.1 
Reporting Process & Standards). 
Serum belimumab concentrations will be listed and summarized by visit and nominal 
time.  Standard summary statistics will be calculated (i.e. mean, standard deviation, and 
95% confidence interval of mean, geometric mean, 95% confidence interval for 
geometric mean, % coefficient of variation (CV), median, minimum and maximum). 
Individual subject and median PK concentrations profiles will be graphically presented. 
8.2.2.1. 
Statistical Analysis of Pharmacokinetic Parameters 
No formal statistical analyses will be performed.   
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8.3. 
Pharmacokinetic / Pharmacodynamic Analyses 
The Pharmacokinetic / Pharmacodynamic analyses will be based on the “Safety” and 
“PK-B” populations, unless otherwise specified. 
The primary goal of this analysis is to characterize the 
pharmacokinetic/pharmacodynamic relationship of belimumab administered through 
injection in subjects with Primary Sjogren’s syndrome. 
1. No formal population pharmacokinetic/pharmacodynamics analyses are planned. The 
relationships will be explored using descriptive methods only. 
Table 5 provides an overview of the pharmacokinetic/pharmacodynamics analyses, with 
details being presented in Appendix 13: List of Data Displays. 
Table 5 
Overview of Pharmacokinetic / Pharmacodynamic Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Flow cytometry B 
cells (CD19+) /serum 
Belimumab 
concentration 
Comparison 
 
 
 
 
 
Y 
[1] 
 
 
 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
• 
[1] For Belimumab and Combination Treatment Groups 
 
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9. 
OTHER STATISTICAL ANALYSES 
9.1. 
Exploratory 
9.1.1. 
Overview of Exploratory Analysis 
The exploratory analyses will be based on the “Safety” population, unless otherwise 
specified. 
Table 6 provides an overview of the planned exploratory Primary Analyses, with full 
details of data displays being presented in Appendix 13: List of Data Displays. 
Table 6 
Overview of Exploratory Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Clinical Efficacy 
Ocular Dryness NRS 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
Lacrimal Gland 
Function 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
PGA 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
Unstimulated Salivary 
Flow 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
ESSDAI 
Supplementary 
Damage Assessments 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Biomarkers  
BLyS levels in blood 
     Free BLyS 
     Total BLyS[4] 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
Y[1] Y[1] 
 
 
 
Flow 
CytometryParameters2 
 
 
 
Y 
Y[3] 
 
Y 
Y[1, 
3, 5] 
 
 
Y[1] Y[1,3] 
 
 
Serologic Markers2 
 
 
 
Y 
 
 
Y 
 
 
 
Y[1] 
Y[1] 
 
 
Complement Factors2 
 
 
 
Y 
 
 
Y 
 
 
 
Y[1] 
Y[1] 
 
 
Exploratory Minor 
Salivary Gland 
Histology 
Assessments2 
 
 
 
Y 
Y[3] 
 
Y 
Y[1,3, 
5] 
 
 
Y[1] Y[1,3] 
 
 
Serum Chemokines -
CXCL13 
 
 
 
Y 
 
 
 
 
 
 
Y[1] 
Y[1] 
 
 
ESSDAI/Salivary 
Gland CD20+ B cell 
Evaluation 
 
 
 
 
Y[5] 
 
 
 
 
 
 
 
 
 
Flow cytometry B 
Cells (CD19+) /serum 
BLyS Evaluation 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
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NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
• 
NRS; Numeric Response Scale  
 
1. 
Only Percentage Change from Baseline will be presented 
2. 
See Section 11.5.6 for parameters.  
3. 
Subset of the parameters as defined in Section 9.1.2 
4. 
Total BLyS concentration only for End of Study analyses 
5. 
Will not be reported for End of Study 
 
Selected Primary Analysis exploratory displays will also be generated for the End of 
Study Analysis and are identified in Appendix 13: List of Data Displays. Where required, 
programming notes (Appendix 13 or Mock Shell Examples) have been included for any 
specific changes based on the Primary Analysis displays. 
9.1.2. 
Planned Exploratory Analyses 
Exploratory Analyses: Clinical Efficacy and Biomarkers 
Endpoints 
Salivary Gland Assessments 
• 
Absolute values 
• 
Change from Baseline 
• 
Percentage Change from Baseline 
Refer to Table 13 for parameters to be included in the summary table 
Summary Results Presentation  
• 
Descriptive statistics (N, n, arithmetic mean, standard deviation, median, minimum and maximum) will 
be calculated and summarized by treatment group and visit for the above endpoints.  Absolute values 
and changes from baseline will be assessed.   
Model Results Presentation 
• 
The absolute change from baseline for selected parameters: Lymphocyte Focus Score (in 4mm2), B 
(CD20) / T (CD3) cell ratio and Plasma cell (CD138+; both - CD20pos and CD20neg) count/mm2) at 
Week 24 will be analysed using Hodges-Lehmann method to provide a non-parametric 95% confidence 
interval for the contrasts of interest at Week 24 specified in Section 2.5.   
Endpoints 
• 
Ocular Dryness NRS 
• 
Lacrimal gland function (Schirmers test see Section 11.5.4) 
• 
PGA  
• 
Unstimulated Salivary flow 
• 
Free BLyS 
• 
Total BLyS (NOTE: Total BLyS concentration only for End of Study analysis) 
• 
Serologic Markers: SS-A, SS-B, Rheumatoid factor, Lambda and kappa free light chains 
Beta 2 microglobulins 
• 
Complement Factors (C3, C4, CH50) 
• 
Exploratory Minor Salivary Gland histology assessments (see Section 11.5.6) 
• 
Serum chemokine CXCL13 
Refer to Table 12 for further parameter details 
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Exploratory Analyses: Clinical Efficacy and Biomarkers 
Summary Results Presentation 
• 
Descriptive statistics (N, n, arithmetic mean, standard deviation, median, minimum maximum) will be 
calculated and summarized by treatment group and visit for the above endpoints.   
• 
Absolute values and changes from baseline will be assessed.   
Exploratory Analyses: Damage Scoring  
• 
Damage Scores for Cutaneous, pulmonary, renal, PNS and CNS domains of ESSDAI 
Summary Results Presentation  
• 
The number and percentage of subjects who report damage will be summarized for each of these 5 
domains by treatment and visit.   
• 
For the subset of subjects who report damage, a listing will be produced to display damage scoring 
alongside ESSDAI domain scores. The listing will include only the subject/domain combinations where 
there is damage reported, and in each case assessments from all visits to be presented.    
Exploratory Analyses: Flow Cytometry 
• 
Refer to Table 11 for further details on parameters 
Model Results Presentation  
• 
The absolute  change from baseline in cell count for each parameter at Week 24 will be analysed using 
Hodges-Lehmann method to provide a non-parametric 95% confidence interval for the contrasts of 
interest at Week 24 specified in Section 2.5. Similarly, this analysis will be repeated for the absolute 
changes in cell counts for each parameter at Week 52 
Summary Results Presentation 
• 
The cell counts and percentage change from baseline in cell counts will be summarized (n, mean, 
median, sd, min, max).  Median ( IQR) will be presented by treatment and visit.   
• 
B cells (CD19+) will be summarized by treatment and visit 
• 
In addition, Naïve B Cells, Memory, Plasmablasts (all), Plasmablast (CD20+), Plasmablast (CD20-), 
Transitional and Activated B Cells, will all be additionally expressed as % of CD19+ cells and 
summarized by treatment and visit.   
Sensitivity and Supportive Statistical Analyses 
The relationship between the change in salivary gland B cell quantification from baseline and ESSDAI 
scores will be explored: 
• 
Scatter plots of changes from baseline to Week 24 for Total ESSDAI score vs Change from baseline to 
Week 24 in salivary gland B cells will be produced. 
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9.2. 
Health Outcomes 
9.2.1. 
Overview of Health Outcome Analysis 
Table 7 provides an overview of the planned health outcomes, with full details of data 
displays being presented in Appendix 13 : List of Data Displays 
Table 7 
Overview of Health Outcome Analyses 
Endpoint 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Patient reported health outcomes 
ESSPRI Score 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
ESSPRI Domains - 
Dryness, Fatigue, Pain 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
ESSPRI Responders 
Y 
[1] 
 
 
Y 
Y 
 
 
 
 
 
 
 
 
 
PtGA 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
PROFAD-SSI-SF 
Subscores – PROF, 
PROFAD and SSI 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Will not be generated for EoS 
 
Selected Primary Analysis health outcomes displays will also be generated for the End of 
Study Analysis and are identified in Appendix 13: List of Data Displays. Where required, 
programming notes (Appendix 13 or Mock Shell Examples) have been included for any 
specific changes based on the Primary Analysis displays. 
Exploratory analyses of the EXIT Interview Data will be conducted in a separate report 
under the direction of the VEO/PRO Department after the study is reported and once 
EXIT Interview data has been delivered by ICON. 
 
9.2.2. 
Planned Health Outcomes Statistical Analyses 
Secondary Statistical Analyses  
Endpoint(s) 
• 
Change from Baseline in Total ESSPRI Score 
• 
Change from Baseline in ESSPRI Dryness Domain 
• 
Change from Baseline in ESSPRI Fatigue Domain 
• 
Change from Baseline in ESSPRI Pain Domain 
• 
Change from baseline in PROF Subscore 
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Secondary Statistical Analyses  
• 
Change from baseline in PROFAD Subscore 
• 
Change from baseline in SSI Subscore (assessed for female subjects only) 
Summary Results Presentation 
• 
Summary statistics for observed values and change from baseline (i.e. screening) will be presented by 
treatment group and visit, for the dryness domain, fatigue domain, pain domain, and total ESSPRI 
score  
• 
Summary statistics for observed values and change from baseline will be presented by treatment group 
for the total PROF, PROFAD and SSI Subscore at each time point. 
 
Endpoint(s) 
• 
ESSPRI Responders 
Summary Results Presentation 
• 
The proportion of ESSPRI responders will be summarized descriptively using counts and percentages 
by treatment and visit. The ESSPRI responders are defined as below 
• Responders 1 - Decrease of Total ESSPRI score of at least 1 point or at least 15% relative to 
baseline 
• Responders 2 - Subjects with baseline score of  5 and Total ESSPRI score of < 5 
• 
The proportion of subjects with an ESSPRI response will be presented as bar chart grouped by 
treatment for each visit. 
Model Specification 
• 
Responder endpoints will be statistically analysed using a Generalised Estimating Equations (GEE) 
model using visits up to Week 52  
• 
The model will be fitted using an unstructured covariance structure of the correlated responses. 
• 
Terms fitted in GEE models will include: 
Fixed Categorical                 : Treatment, Visit, Treatment*Visit Interaction 
Fixed Continuous Covariate : Baseline ESSPRI Score 
Repeated                              : Visit 
 Model Checking & Diagnostics 
• 
Refer to Appendix 9: Model Checking and Diagnostics for Statistical analyses. 
Model Results Presentation 
• 
The Binary endpoints will be summarized using counts and proportions of subjects achieving a 
response by treatment group. 
• 
Differences in the proportions of subjects achieving response between treatment groups will be 
summarized by Visit. 95% CI for the differences will be constructed using their asymptotic standard 
errors (asymptotic Wald confidence limits) without continuity correction. 
• 
Point estimates and corresponding 95% confidence intervals will be constructed using contrasts for the 
treatment by day interactions. 
Endpoints 
• 
PtGA 
Summary Results Presentation 
• 
Summary statistics for actual PtGA scores as well as changes from baseline will be presented for 
each time-point by treatment group. 
 
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Secondary Statistical Analyses (Bayesian)   
Endpoint(s) 
• 
Change from Baseline in Total ESSPRI Score 
Model Specification 
• 
A Bayesian repeated Measures model will be used to fit the change from baseline in Total ESSPRI 
Score.  
• 
A multivariate (MVN) normal distribution is assumed for the vector of changes from baseline for each 
subject (i.e. the change from baseline at weeks 12, 24, 36 & 52).  
• 
Markov-Chain-Monte-Carlo (MCMC) method in SAS will be used to derive the posterior distributions of 
the endpoint. 
• 
A linear model for Change from Baseline (CFB) at each Week (visit) will be constructed to model the 
within-subject covariance structures: 
 
CFB = Intercept + Treatment + Baseline + Week + Treatment*Week 
 
Terms fitted in the model will include: 
Fixed Categorical: Week (Week 12 to Week 52), Treatment, Treatment*Week Interaction 
Fixed Continuous: Baseline 
Random: Subject 
 
• 
The prior for the variance covariance matrix will follow an Inverse Wishart Distribution. 
• 
Set seed=123456 with simulation size of 100,000 (i.e. every 10th iteration will be kept which will form the 
final MCMC (thinned) sample of 10,000) & 10,000 burn-in iterations. The simulation size and number of 
burn-in iterations may be updated during the convergence check. 
• 
Vague priors (normal (0, var=1e6)) will be used for regression parameters. 
 
Model Checking & Diagnostics 
• 
Refer to Appendix 9: Model Checking and Diagnostics for Statistical analyses. 
Summary Results Presentation 
• 
The sample size N, mean, standard deviation and highest posterior density (HPD: smallest interval 
width among all credible intervals) interval will be presented from the posterior density function. 
• 
The posterior distribution will be used to produce several probability statements (where θ is the Total 
ESSPRI change from baseline), such as (but not limited to and maybe refined): 
o Pr (θ Co-administration, 24w – θ Placebo, 24w < 0 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Placebo, 52w < 0 | 201842 data) 
o Pr (θ Co-administration, 24w – θ Placebo, 24w < 0.67 | 201842 data)  
o Pr (θ Co-administration, 52w – θ Placebo, 52w < 0.67 | 201842 data) 
 
o Pr (θ Co-administration, 24w – θ Belimumab, 24w < 0 | 201842 data) 
o Pr (θ Co-administration, 52w – θ Belimumab, 52w < 0 | 201842 data) 
 
o Pr (θ Co-administration, 24w – θ Rituximab, 24w < 0 | 201842data) 
Pr (θ Co-administration, 52w – θ Rituximab, 52w < 0 | 201842data) 
o Pr (θ Belimumab, 24w – θ Placebo, 24w < 0 | 201842 data) 
o Pr (θ Belimumab, 52w – θ Placebo, 52w < 0 | 201842 data) 
o Pr (θ Belimumab, 24w – θ Placebo, 24w < 0.67 | 201842 data)  
o Pr (θ Belimumab, 52w – θ Placebo, 52w < 0.67 | 201842 data)  
 
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9.2.3. 
Planned Health Outcomes Psychometric Analyses 
As the original validation of ESSPRI demonstrated a fairly low sensitivity to change, 
validation analyses will be repeated to support interpretation of the data (including the 
ESSPRI responder analysis). The analyses will be conducted by a PRO external vendor, 
following unblinding for the Primary Analyses have been completed. The analysis will be 
done under the direction of the VEO-PCO Department. 
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10. 
REFERENCES 
GlaxoSmithKline Document Number 2014N220285_06 Protocol Amendment 06: A 
randomized, double blind (sponsor open), comparative, multi-center study to evaluate the 
safety and efficacy of subcutaneous belimumab (GSK1550188) and intravenous 
rituximab co-administration in subjects with primary Sjögren’s syndrome. Effective date 
25-JUN-2019. 
Seror R, Bowman SJ, Brito-Zeron P, Theander E, Bootsma H, Tzioufas A, et al. EULAR 
Sjögren’s syndrome disease activity index (ESSDAI): a user guide. RMD Open. 
2015a;1(1):e000022. 
Seror R, Meiners P, Baron G, Bootsma H, Bowman SJ, Vitali C, et al. Development of 
the ClinESSDAI: a clinical score without biological domain. A tool for biological studies. 
Ann Rheum Dis. 2016 Nov;75(11):1945–50. 
Seror R, Theander E, Brun JG, Ramos-Casals M, Valim V, Dörner T, et al. Validation of 
EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes 
(ESSPRI). Ann Rheum Dis. 2015b May;74(5):859–66. 
 
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11. 
APPENDICES 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
11.1.1. 
Exclusions from Per-Protocol Population 
Subjects will be excluded from the per-protocol population if any of the following criteria 
apply. The outputs for the per-protocol population will not be produced if the per-
protocol population comprises >85% of the safety population subjects.  
• Received wrong treatment most of the time (>50% of the time). 
• Did not receive treatment most of the time (>50% of the time). 
• Did not have a clinical diagnosis of Primary Sjögren’s Syndrome according to 
Inclusion Criterion #2. 
• Did not have baseline unstimulated salivary flow >0.0 mL/min or stimulated baseline 
salivary flow >0.05 mL/min) as defined by inclusion criterion #3. 
• Did not have symptomatic oral dryness (≥5/10 on subject completed Numeric 
Response Scale) as defined by inclusion criterion #4. 
• Did not have systemically active disease defined as an ESSDAI score ≥5 at screening 
(Inclusion Criterion 5). 
• Received an excluded systemically administered immunosuppressive or 
immunomodulatory medication prior to screening (see Exclusion Criteria 17-22). 
• Received a prohibited systemically administered immunosuppressive or 
immunomodulatory medication prior to Week 52. 
• Deviation from study blind/unblind procedures:  Investigator/site staff did not remain 
blinded to one or both treatment assignments through Week 52/Early Withdrawal 
Visit. 
• Other, a deviation that does not satisfy the above criteria, however, in the judgment 
of the clinical team, including the medical monitor, constitutes an exclusion from the 
Per-Protocol population. 
 
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A participant meeting any of the following criteria will be excluded from the Per-
Protocol population: 
Exclusion Criteria 
Protocol Deviation 
Category 
Protocol Deviation 
Subcategory 
Received wrong treatment most of the time 
(>50% of the time). 
Wrong study treatment/ 
administration/ dose 
Wrong study treatment or 
assignment administered 
Did not receive treatment most of the time 
(>50% of the time). 
N/A 
N/A 
Did not have a clinical diagnosis of Primary 
Sjögren’s according to Inclusion Criterion #2. 
Eligibility criteria not met 
Documented Primary Sjögren’s 
Syndrome by American 
European Consensus Group 
criteria including: either SS-A or 
SS-B positive. 
Did not have baseline unstimulated salivary 
flow >0.0 mL/min or stimulated baseline 
salivary flow >0.05 mL/min) as defined by 
inclusion criterion #3. 
Eligibility criteria not met 
Baseline unstimulated salivary 
flow >0.0 mL/min or evidence of 
glandular reserve function 
(stimulated baseline salivary 
flow >0.05 mL/min). 
Did not have symptomatic oral dryness 
(≥5/10 on subject completed Numeric 
Response Scale) as defined by inclusion 
criterion #4. 
Eligibility criteria not met 
Symptomatic oral dryness 
(≥5/10 on subject completed 
Numeric Response Scale) 
Did not have systemically active disease 
defined as an ESSDAI score ≥5 at screening 
(Inclusion Criterion 5). 
Eligibility criteria not met 
Systemically active disease, 
ESSDAI ≥5 points OR (for sites 
in ITALY ONLY) Systemically 
active disease, ESSDAI≥5 
points and with at least: a) 1 
extraglandular domain 
moderate, OR b) 2 
extraglandular domains low. 
Received an excluded medication prior to 
screening (per Exclusion Criteria 17-22). 
Eligibility criteria not met 
Check the Protocol Section 5.2 
Received a prohibited medication prior to 
Week 52. 
Excluded medication, 
vaccine or device 
Medication, excluded by the 
protocol, was administered 
Study blind/unblind procedures:  
Investigator/site staff did not remain blinded 
to one or both treatment assignments 
through Week 68/Exit visit efficacy 
evaluation. 
Study Procedures 
Study blinding/unblinding 
procedures 
Other, a deviation that does not satisfy the 
above criteria, however, in the judgment of 
the clinical team, including the medical 
monitor, constitutes an exclusion from the 
Per Protocol population. 
N/A 
N/A 
 
 
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11.2. 
Appendix 2: Schedule of Activities 
11.2.1. 
Protocol Defined Schedule of Events 
Study Day 
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period 
General
follow 
up 
period1 
Individualized
follow up 
period (IFU)6 
IFU 
Final 
Visit 
Day 0 
7 ± 1 days 
28 ± 7days 
56 ± 7days 
70 ± 7 days 
84 ± 7 days 
112 ± 7days 
140 ± 7days 
168 ± 7days 
196± 7days 
224 ± 7days 
252 ± 7days 
280 ± 7days 
308 ± 7days 
336 ± 7days 
364 ± 7days 
Study Week 
W -5 
  
W1 
W4 
W8 W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52 W68 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
 
Inclusion and exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
 
Full physical exam 
X 
X3 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
X 
X 
  
X 
Abbreviated physical exam symptom 
directed 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
X 
 
Past & current medical conditions [including 
AECG criteria & CV medical history]  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
 
Urine pregnancy test (WCBP) in clinic9 
X 
X3 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X10 
X3 
X 
X 
X 
X 
X10 
X 
X 
X10 
X 
X 
X10 
X 
X 
X 
X10 
X10 
X 
X10 
Study Treatments 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
  
 
Belimumab/placebo.(weekly, home, except 
1st & 2nd dose), last dose wk 51 
  
X11 
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  
 
Monitor in clinic after dosing for 3hrs (1st & 
2nd dose of belimumab/pbo) 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
  
 
Rituximab/placebo (at site)  
  
  
  
  
X8 
X8 
  
  
  
  
  
  
  
 
 
 
  
 
  
 
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Study Day 
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period 
General
follow 
up 
period1 
Individualized
follow up 
period (IFU)6 
IFU 
Final 
Visit 
Day 0 
7 ± 1 days 
28 ± 7days 
56 ± 7days 
70 ± 7 days 
84 ± 7 days 
112 ± 7days 
140 ± 7days 
168 ± 7days 
196± 7days 
224 ± 7days 
252 ± 7days 
280 ± 7days 
308 ± 7days 
336 ± 7days 
364 ± 7days 
Study Week 
W -5 
  
W1 
W4 
W8 W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52 W68 
Monitor in clinic after dosing for 1h post 
rituximab/placebo 
  
  
  
  
X 
X 
  
  
  
  
  
  
  
 
 
 
  
 
  
 
Efficacy, pharmacokinetics and pharmacodynamics 
ESSDAI16 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
 
X 
ESSPRI  
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
 
X 
Oral Dryness numerical resp. scale 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
 
X 
Ocular Dryness numerical resp. scale 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
 
X 
Salivary gland biopsy 
X5 
  
  
  
  
  
  
  
  
X12 
  
  
  
 
  
 
X13 
  
  
 
Lacrimal function (Schirmer's) test 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Fatigue- (PROFAD SSI SF) 
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Patient Global Assessment (PtGA)  
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Physicians Global Assessment (PGA)  
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Exit interview 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
X 
 
  
 
Stimulated Salivary Flow 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
  
X 
Unstimulated Salivary Flow  
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
X 
  
X 
Blood: Leukocyte population2 
X 
X3 
X 
X 
X 
  
X 
  
  
X 
X 
  
X 
 
X 
 
X 
X 
X 
X 
Serological biomarkers  
X 
X3 
  
  
X 
  
X 
X 
  
X 
X 
  
X 
 
X 
 
X 
X 
X 
X 
Saliva sample for proteomics 
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Blood: BLyS levels2 
  
X3 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
 
X 
 
X 
X 
 
X 
Blood: Transcriptomics 
  
X3 
  
  
X 
  
  
  
  
X 
  
  
X 
 
  
 
X 
  
  
 
Salivary gland: Transcriptomics 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
 
  
 
X13 
  
  
 
Blood: PBMC exploratory endpoints 
  
X3 
  
  
X 
  
  
  
  
X 
  
  
  
 
  
 
  
  
  
 
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Study Day 
Screening (up 
to 35 days prior 
to Day 0)
Double Blind Treatment Period 
General
follow 
up 
period1 
Individualized
follow up 
period (IFU)6 
IFU 
Final 
Visit 
Day 0 
7 ± 1 days 
28 ± 7days 
56 ± 7days 
70 ± 7 days 
84 ± 7 days 
112 ± 7days 
140 ± 7days 
168 ± 7days 
196± 7days 
224 ± 7days 
252 ± 7days 
280 ± 7days 
308 ± 7days 
336 ± 7days 
364 ± 7days 
Study Week 
W -5 
  
W1 
W4 
W8 W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52 W68 
Blood: Belimumab PK2 
  
 
  
  
 
  
  
 
  
X 
  
  
X 
 
X 
 
X 
  
  
 
Blood: Rituximab PK2 
  
  
  
  
X7 
X7 
X 
  
  
X 
  
  
X 
 
  
 
  
  
  
 
Safety & Laboratory Assessments 
AE/SAE review  
X17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
X 
Vital signs 
X 
X3,4 
X4 
X 
X4 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
 
CSSRS (suicidality assessment)  
  
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Neurological assessment 
  
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X3 
  
  
  
  
X 
  
  
X 
  
  
X 
 
  
 
X 
    X 
 
X 
Blood: Immunoglobulin levels (IgG, IgA2, 
IgM2) 
X 
X3 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood: Cryoglobulins 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
Blood chemistry 
X 
X3 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X3 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hep B and Hep C screen 
X14 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
X 
  
 
Pharmacogenetics blood sample15 
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
 
Blood: Belimumab Immunogenicity2  
  
X3 
  
  
X 
  
  
  
  
X 
  
  
  
 
  
 
X 
X 
  
 
Blood: Rituximab Immunogenicity2  
  
  
  
  
X3 
  
  
  
  
X 
  
  
  
 
  
 
X 
 
  
 
 
1. All subjects, including subjects who are withdrawn from the study and decline to complete the treatment phase visits through Week 52, are required to enter the general follow up 
period. During this 16-week general follow up period, subjects will receive calls every 4 weeks (±7 days) to evaluate AEs, to check concomitant medications and to complete the 
neurological assessment. 
2. In order to maintain the blind, sites will be blinded to these data following screening - including B-cell flow cytometry panels and IgA, IgM levels. 
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3. To be measured or collected pre-dose. 
4. Subjects will be monitored post study treatment as detailed in protocol. 
5. Biopsy can occur on Day 0 or at any time during the screening period provided the subject has met all other entry criteria prior to the biopsy. 
6. Subjects will enter the IFU if, following the general follow up period, their CD19+ B-cell levels remain below the lower limit of normal (or less than 90% of baseline, if baseline 
value was below LLN). During the IFU, subjects will be seen in the clinic every 12 weeks ( 7 days), with calls every 4 weeks (±7 days) between visits to evaluate subjects for AEs 
& concomitant medications. Subjects will exit the IFU when: CD19+ B-lymphocyte counts are within normal range or 10% of baseline levels (if baseline < LLN), OR at the 
investigator’s discretion the subject starts receiving disease modifying therapy that may affect B-cell numbers OR or for up to a maximum of 2 years (i.e., up to Week 104) – 
whichever comes first. Subjects exiting IFU period will attend a final visit (within 28 days of that decision) for final assessments (IFU Final Visit) as detailed in the Table. 
7. Obtain samples post-dose only, within 10 minutes after end of infusion. 
8. Both doses of rituximab/placebo will be administered in the clinic. Approximately 60 minutes prior to rituximab/placebo, subjects will receive orally an antipyretic and an 
antihistamine. At least 30 minutes prior to administration of rituximab/placebo, subjects will receive IV 100mg methylprednisilone .The 2nd rituximab/placebo administration at the 
Week10 visit must be given 14 days (13-18 days, see SRM) after the first administration (given at the Week 8 visit). A patient alert card should be sent home with the subject 
following each dose of rituximab/placebo. 
9. If urine test is positive, confirm with serum test. Pregnancy testing & contraception are required until 16 weeks post last administration of study treatment for those subjects who 
complete Weeks 46- 52 or withdraw from treatment prior to Week 8 dosing. Pregnancy testing and contraception are required for approximately 12 months after the 
administration of the final rituximab/placebo dose for the subset of subjects who discontinue treatment from Week 8 up to Week 46.  
10. Subjects will receive a reminder phone call 48 hours prior to efficacy assessment visits to remind them that they should not be using certain symptomatic therapies prior to visit 
(see Section 4.1 of Study Reference Manual for details); in addition subjects should document their last use of symptomatic therapies in their self injection log book. 
11. First & second dose of belimumab will be administered in clinic by subject or caregiver. A patient alert card will be sent home with the subject each time belimumab is dispensed 
for home administration.  
12. Week 24 biopsy may be taken on a separate day from the other required assessments within the Week 24 study visit window. 
13. Week 52 biopsy is optional. Trancriptomics will only be performed if biopsy is taken. 
14. If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required. 
15. Informed consent for optional substudies e.g.,genetics must be obtained before collecting a sample.  
16. If additional tests (e.g., pulmonary function tests, EMG, MRI) are required to complete ESSDAI assessment, these should be scheduled as close as possible to the stipulated 
study visit window. 
17. From signing of consent until initiation of study treatment, only SAEs related to study participation will be collected. 
18. From the end of general follow-up phase through the last contact (including the individualized safety follow-up phase), only designated AESIs (i.e., infections, malignancies, and 
depression/suicidality/self-injury), fatal SAEs, and SAEs assessed as related to the investigational product or to study participation will be collected. 
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11.3. 
Appendix 3: Treatment States and Phases 
11.3.1. 
Treatment Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment, unless otherwise specified. 
Treatment Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Last Dose + 28  
Post-Treatment 
Date > Last Dose + 28   
 
11.3.2. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
date of first and/or last dose of study treatment. 
11.3.2.1. 
Treatment States for AE Data 
Treatment State 
Definition 
Pre-Treatment 
AE Start Date < Study Treatment Start Date 
On-Treatment 
If AE onset date is on or after treatment start date & up to 28 days after date of last 
dose. 
Study Treatment Start Date ≤ AE Start Date ≤ [ Last Dose Study Treatment + 28]  
Post-Treatment 
If AE onset date is > 28 days after the last dose of study drug. 
AE Start Date >[ Last Dose Study Treatment + 28]  
Onset Time  
Since 1st Dose 
(Days) 
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on Inform/CRF OR value is missing. 
NOTES:  
o 
If the study treatment stop date is missing then the AE will be considered to be On-Treatment. 
 
 
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11.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
11.4.1. 
Reporting Process & Standards  
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Reporting Area (Interim)  
HARP Server 
: US1SALX00259 
HARP Area 
 : \ARPROD\GSK1550188\MID201842\Interim_01 
Reporting Area (Primary Analysis) 
HARP Server 
: US1SALX00259 
HARP Area 
 : \ARPROD\GSK1550188\MID201842\Primary_02 
NOTE: 
• Primary_01 has been taken for previous CDISC reporting and hence not available 
Reporting Area (End of Study Analysis) 
HARP Server 
: US1SALX00259 
HARP Area 
: \ARPROD\GSK1550188\MID201842\Final_02 
Analysis Datasets  
• Analysis datasets will be created according to IDSL standards  
Generation of RTF Files 
• RTF files will be generated at primary and end of study analysis 
• XML files in the format expected by DORS (Disclosure Obligation Reporting System) for 
relevant displays 
 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
Formats 
• All data will be reported according to the actual treatment the subject received unless 
otherwise stated. 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected with a maximum of 4 DP presented. 
• Numeric data will be reported at the precision collected on the eCRF. 
The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
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Reporting Standards 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
o Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate. 
• Reporting for Data Listings:  
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the subject’s listings.  
o Data will be incorporated in figures, summaries and statistical analyses using the visit 
recorded in eCRF.  No visit slotting is planned.  
Unscheduled Visits 
• Unscheduled visits will not be presented in summary tables or figures, with the exception of 
any time post baseline/worst toxicities where all data including unscheduled visits are used in 
derivations.   
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Reporting of Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
• Include ref line (i.e. y=0) for figures having negative values 
 
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11.5. 
Appendix 5: Derived and Transformed Data 
11.5.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented. 
• If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target, then the mean will be taken. 
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from randomization date: 
o Ref Date = Missing                       → Study Day = Missing  
o Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date     
o Ref Data ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) + 1     
Data Cutt-off 
• The study data cut-off date of the primary analysis is September 9th, 2019. Data after 
September 9th will be removed from the extracted data after October 30th based on the 
algorithms detailed below.  
• The data cut off will be applied on DMDATA before the generating of any analysis datasets 
and outputs.  
 
Datasets 
Label 
Algorithm 
AE 
ADVERSE EVENT 
AESTDT <= CUTOFF DATE 
BIOLINK 
BIOMARKER SAMPLE 
BIDT <= CUTOFF DATE 
BIOMARK 
BIOMARKER 
BIDT <= CUTOFF DATE 
BLIND 
BLIND 
BLDT <= CUTOFF DATE 
CC 
EULAR SJOGRENS SYNDROME 
DISEASE ACTIVITY INDEX  
CCDT <= CUTOFF DATE 
CE 
CV CLINICAL EVENTS 
CESTDT <= CUTOFF DATE 
CHDPOT 
PREGNANCY INFORMATION 
IMPUTED CHDMNFD_, THEN THE IMPUTED DATE <= 
CUTOFF DATE 
CONMEDS 
CONCOMITANT MEDICATIONS  
IMPUTED CMSTD_, THEN THE IMPUTED DATE <= 
CUTOFF DATE 
CONV 
LAB CONVERSION FACTOR 
NOT CUT 
CSSRSV4 
COLUMBIA SUICIDE SEVERITY 
RATING SCALE  
ACTDT <= CUTOFF DATE 
CVDXTEST 
CEREBROVASCULAR EVENTS   
DXDT <= CUTOFF DATE 
DEMO 
DEMOGRAPH 
NOT CUT 
DS 
STUDY CONCLUSION  
DSSTDT <= CUTOFF DATE 
DTH 
DEATH 
DDDT <= CUTOFF DATE 
DV1 
PROTOCOL DEVIATION  
DVSTDT <= CUTOFF DATE 
ECG 
12-LEAD ECG 
EGDT <= CUTOFF DATE 
EGCRIT 
ECG REFERENCE DATA 
NOT CUT 
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Datasets 
Label 
Algorithm 
ELIG 
ELIGIBILIT 
NOT CUT 
ENROL 
INFORM ENROLLMENT  
NOT CUT 
ESSPRI 
EULAR SJOGRENS SYNDROME 
PATIENT REPORTED INDEX  
ACTDT <= CUTOFF DATE 
EVIDENCE 
DEEP VEIN THROMBOSIS (DVT) 
/PULMONARY EMBOLISM (PE)  
NOT CUT 
EXPOSURE 
STUDY TREATMENT  
FIRST GET THE LARGEST VISITNUM FROM VISIT 
DATA WHERE VISITDT <= CUTOFF DATE; LEFT JOIN 
EXPOSURE WITH THE VISIT DATA BY SUBJID; 
VISITNUM FROM STATUS < =   THE LARGEST 
VISITNUM FROM VISIT DATA WHERE EXSTDT IS 
MISSING OR EXSTDT < = CUTOFF DATE WHERE SSDT 
IS NOT MISSING. 
FACE 
 NEUROLOGICAL SYMPTOMS 
QUESTIONNAIRE  
FCEDT <= CUTOFF DATE 
FACV 
FINDING ABOUT CLINICAL 
EVENTS 
NOT CUT 
FADE 
 INVESTIGATIONAL PRODUCT 
DEVICE MALFUNCTION (DEV 
MALFUNCTION)  
FDEDT <= CUTOFF DATE 
FADTH 
FINDINGS ABOUT DEATH 
DDORRSDT <= CUTOFF DATE 
FAMH 
FINDING ABOUT METICAL 
HISTORY 
NOT CUT 
FAMHIST 
FAMILY HISTORY 
NOT CUT 
FAPR 
 UNSTIMULATED AND 
STIMULATED SALIVARY FLOW  
FPRDT <= CUTOFF DATE 
GENPRO 
PHARMACOGENETIC (PGx) 
RESEARCH CONSENT  
GPSMPDT <= CUTOFF DATE 
HRU 
HOSPITALISATION 
HUHOSTDT <= CUTOFF DATE 
IMGEN 
IMMUNOGENICITY  
IGDT <= CUTOFF DATE 
IMGLINK 
IMMUNOGENICITY SAMPLING  
IGDT <= CUTOFF DATE 
INVESTIG 
INVESTIGATOR SIGNATUR 
NOT CUT 
IPDISC 
STUDY TREATMENT 
DISCONTINUATION  
SDENDT <= CUTOFF DATE 
LAB 
LABORATORY TEST 
LBDT < = CUTOFF DATE 
LABCRIT 
LAB REFERENCE DATA 
NOT CUT 
LBIOPSY 
LIVER BIOPSY (BIOPSY)  
LPDT < = CUTOFF DATE 
LBTESTCD 
LAB TEST CODES 
NOT CUT 
LEREPORT 
LIVER MONITORING/STOPPING 
EVENT REPORTING (LEREPORT)  
LERSTDT < = CUTOFF DATE 
LIMAGING 
LIVER IMAGING (IMAGING)  
LIDT < = CUTOFF DATE 
MEDHIST 
SJOGRENS SYNDROME SPECIFIC 
MEDICAL HISTORY  
NOT CUT 
MI 
MICROSCOPIC FINDINGS 
GET THE LARGEST VISITNUM FROM VISIT DATA 
WHERE VISITDT <= CUTOFF DATE; LEFT JOIN MI WITH 
THE VISIT DATA BY SUBJID; VISITNUM FROM MI < =   
THE LARGEST VISITNUM FROM VISIT DATA 
MO 
MORPHOLOGY 
MODT < = CUTOFF DATE 
NYHASCR 
NYHA SCORE 
NOT CUT 
OCULAR 
LACRIMAL FUNCTION 
(SCHIRMERS) TEST 
XGDT < = CUTOFF DATE 
OROCNRS 
ORAL AND OCULAR DRYNESS 
NUMERIC RATING SCAL 
ACTDT < = CUTOFF DATE 
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Datasets 
Label 
Algorithm 
PFDSSISF 
PROFILE OF FATIGUE AND 
DISCOMFORT - SICCA SYMPTOMS 
INVENTORY  
ACTDT < = CUTOFF DATE 
PHGA 
PHYSICIAN GLOBAL ASSESSMENT 
OF DISEASE ACTIVITY 
ACTDT < = CUTOFF DATE 
PK 
PK BLOOD SAMPLE COLLECTION; 
PHARMACOKINETICS  
PKSTDT < = CUTOFF DATE 
PR 
SCHIRMERS TEST SATURATION 
PROCEDURE 
PRSTDT < = CUTOFF DATE 
PSRAE 
POSSIBLE SUICIDE RELATED 
ADVERSE EVENT QUESTION  
AESTDT < = CUTOFF DATE 
PSRAECO
M 
POSSIBLE SUICIDE RELATED 
ADVERSE EVENT QUESTION 
COMMENT 
NOT CUT 
PTGA 
PATIENT GLOBAL ASSESSMENT 
OF DISEASE ACTIVITY 
ACTDT < = CUTOFF DATE 
RACE 
COLLECTED RACE 
NOT CUT 
RAND 
RANDOMISATION  
NOT CUT 
RANDALL 
RANDOMISED TREATMENT 
NOT CUT 
RISK 
MEDICAL DEVICE  
NOT CUT 
RUCAM 
LIVER EVENTS (LIVER EVENTS)  
RUDT < = CUTOFF DATE 
SS 
SYMPTOMATIC THERAPY US 
FIRST GET THE LARGEST VISITNUM FROM VISIT 
DATA WHERE VISITDT <= CUTOFF DATE; LEFT JOIN 
SS WITH THE VISIT DATA BY SUBJID; VISITNUM FROM 
STATUS < =   THE LARGEST VIISTNUM FROM VISIT 
DATA WHERE SSDT IS MISSING OR SSDT < = CUTOFF 
DATE WHERE SSDT IS NOT MISSING. 
STATUS 
VISIT STATUS  
GET THE LARGEST VISITNUM FROM VISIT DATA 
WHERE VISITDT <= CUTOFF DATE; LEFT JOIN STATUS 
WITH THE VISIT DATA BY SUBJID; VISITNUM FROM 
STATUS < =   THE LARGEST VISiTNUM FROM VISIT 
DATA 
SUBUSE 
HISTORY OF TOBACCO USE 
NOT CUT 
SURGERY 
 CEREBROVASCULAR SURGERY 
SPDT < = CUTOFF DATE 
TMSLICE 
VISIT AND PERIOD 
NOT CUT 
VISIT 
VISIT 
VISITDT < = CUTOFF DATE 
VITALS 
VITAL SIGNS 
VSDT < = CUTOFF DATE 
VSCRIT 
VITAL SIGNS REFERENCE DATA 
NOT CUT 
VIRAL  
VIRAL LABORATORY RESULTS 
LABDT < = CUTOFF DATE 
 
 
 
 
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11.5.2. 
Study Population 
Subject Disposition Status – Primary Analysis  
Study Completion Status at Week 68 
• A subject is considered Completed at Week 68 if BOTH of the following conditions are met: 
• The study treatment is not stopped permanently before the scheduled end of the treatment 
period  
• Subject completed Week 68 visit 
 
• A subject is considered Ongoing at Week 68 if ALL of the following conditions are met: 
• The study treatment is not stopped permanently before the scheduled end of the treatment 
period subject has not completed Week 68 visit 
• Date of subject completion or withdrawal is missing 
 
• A subject is considered Withdrawn at Week 68 if EITHER of the following conditions is met: 
• The study treatment is stopped permanently before the scheduled end of the treatment 
period 
• The study treatment is not stopped permanently before the scheduled end of the treatment 
period, but subject was withdrawn prior to Week 68 
 
 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
1. Any subject with a missing day will have this imputed as day ‘15’.  
2. Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)]2 
 
Extent of Exposure to Belimumab 
• Number of days of exposure to belimumab will be calculated as:   
Duration of Exposure in Days = Date of Last Belimumab Injection – Date of First 
Belimumab Injection + 7 
• Subjects who were randomized but did not report a treatment start date will be categorized as 
having zero days of exposure.  
Baseline Characteristics 
Autoantibodies 
• SS-A positive subjects are defined as those who have screening SS-A ≥ 7 KU/L.     
• SS-B positive subjects are defined as those who have screening SS-B ≥ 7 KU/L 
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Extent of Exposure to Belimumab 
Time Since Diagnosis 
Time since diagnosis of Primary Sjogren Syndrome is defined as:  
• 
If treatment start date >= diagnosis date and then treatment start date - diagnosis date  
Treatment Start date - diagnosis date + 1 
365.25 
• If the day and month of diagnosis is missing, this will be imputed as ‘30th June’ 
• If the year of diagnosis is missing, time since diagnosis will be set to missing 
Average Daily Prednisone Dose 
• At baseline, the average daily dose of prednisone is the sum of doses over 7 consecutive days 
up to, but not including Day 0 divided by 7: Days on which a subject does not have prednisone 
use recorded will be considered as 0 mg for the day in the calculation of average daily 
prednisone dose. 
11.5.3. 
Safety 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, unless otherwise specified the number of significant digits in the 
observed values will be used to determine how much to add or subtract in order to impute the 
corresponding numeric value.  
1. Example 1: 2 Significant Digits =  ‘< x‘ becomes x – 0.01 
2. Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
3. Example 3: 0 Significant Digits = ‘< x’ becomes x – 1  
Details of rules to apply for biomarker endpoints are covered in Section 11.5.6.  
 
Neurological Symptoms 
• Neurological systems are assessed based upon a questionnaire consisting of 7 questions with 
response of either yes or no. 
• See Appendix 11 for further information. 
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Suicidal Risk Monitoring 
Columbia Suicidality Severity Rating Scale (C-SSRS) 
• The C-SSRS is a measure of suicidal ideation and behavior.   
• The following outcomes are C-SSRS categories and have binary responses (yes/no).  The 
categories have been re-ordered from the actual scale in an increasing order of severity from 1 
to 10 to facilitate the definitions of the comparative endpoints.   
o Category 1 –
o Category 2 –
o Category 3 –
o Category 4 –
o Category 5 –
o Category 6 –
o Category 7 –
o Category 8 –
o Category 9 –
o Category 10 
• The following outcomes are numerical scores derived from the C-SSRS categories.  The scores 
are created at each assessment for each patient. 
o Suicidal Ideation Score:  The maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment.  Assign a score of 0 if no ideation is present. 
o Suicidal Behavior Score:  The maximum suicidal behavior category (6-10 on the C-
SSRS) present at the assessment.  Assign a score of 0 if no behavior is present. 
o Suicidal Ideation or Behavior Score:  The maximum suicidal ideation or behavior 
category (1-10 on the C-SSRS) present at the assessment.  Assign a score of 0 if no 
ideation or behavior is present. 
o See Appendix 11 for further details. 
11.5.3.1. 
Adverse Events of Special Interest 
Handling Study specific AESI: 
• GSK study statistician will generate cumulative spreadsheets in .csv format which is 
created by merging DMDATA.AE with MedDRA dictionary by preferred terms 
corresponding to study specific AESI SMQ’s extracted from latest version of 
MedDRA, as specified in the below table. 
• GSK study statistician will distribute spreadsheets via e-mail to the study team for 
clinical review. 
• GSK study statistician will receive returned spreadsheets. A manual review will be 
performed so that any noted quality issues can be followed up.  
GSK study statistician will create csv versions in the “Adjudicated” folder on arwork 
(\\us1salx00259.corpnet2.com\arenv\arwork\gsk1550188\refdata\aesi\Adjudication 
Results\MID201842\Adjudicated). 
 
 
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Study Specific Primary Analysis AESI specification to be capture in the process. For the 
End of Study Analyses, PTs related the MedDRA version at the time of database release 
will be used. If a new version of MedDRA is used, then a RAP amendment or addendum 
will be created to capture updated PTs.  
End of Study Reporting 
MedDRA 23.0 PTs will be used. This is a major version release that includes changes to 
any level of the hierarchy and additionally includes COVID-19 related terminology. On 
this basis the RAP will not be updated, instead MedDRA V23.0 will be implemented. 
Same search Strategy will be applied to MedDRA V23.0.  
Category: Severe skin reaction per GSK Adjudication (Ten and Steven’s Johnson Syndrome) 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Broad Search: Severe Cutaneous 
Adverse Reactions SMQ.   
Acquired epidermolysis bullosa 
Blister 
Blister rupture 
Bullous impetigo 
Conjunctivitis 
Corneal exfoliation 
Drug eruption 
Epidermolysis 
Epidermolysis bullosa 
Fixed eruption 
Genital ulceration 
HLA-B*1502 assay positive 
HLA-B*5801 assay positive 
Hypopharyngeal synechiae 
Lip exfoliation 
Mouth ulceration 
Mucocutaneous ulceration 
Mucosa vesicle 
Mucosal erosion 
Mucosal exfoliation 
Mucosal necrosis 
Mucosal ulceration 
Nasal mucosal blistering 
Nikolsky's sign 
Noninfective conjunctivitis 
Oral mucosal blistering 
Oral mucosal exfoliation 
Oral papule 
Oropharyngeal blistering 
Pemphigoid 
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Category: Severe skin reaction per GSK Adjudication (Ten and Steven’s Johnson Syndrome) 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Pemphigus 
Penile exfoliation 
Skin erosion 
Skin exfoliation 
Staphylococcal scalded skin syndrome 
Stomatitis 
Symmetrical drug-related intertriginous and flexural exanthema 
Tongue exfoliation 
Vaginal exfoliation 
Vaginal ulceration 
Vulval ulceration 
Vulvovaginal rash 
Vulvovaginal ulceration 
 
Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Broad Search:  Cardiac Arrhythmias 
SMQ 
  
Sub-Category: Arrhythmia related investigations, signs and 
symptoms (SMQ) 
Bezold-Jarisch reflex 
Bradycardia 
Cardiac arrest 
Cardiac death 
Cardiac telemetry abnormal 
Cardio-respiratory arrest 
Central bradycardia 
Electrocardiogram abnormal 
Electrocardiogram ambulatory abnormal 
Electrocardiogram change 
Heart rate abnormal 
Heart rate decreased 
Heart rate increased 
Loss of consciousness 
Palpitations 
Rebound tachycardia 
Respiratory sinus arrhythmia magnitude abnormal 
Respiratory sinus arrhythmia magnitude decreased 
Respiratory sinus arrhythmia magnitude increased 
Sudden death 
Syncope 
Tachycardia 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Tachycardia paroxysmal 
Sub-Category: Cardiac arrhythmia terms (incl bradyarrhythmias 
and tachyarrhythmias) (SMQ) 
-NIL- 
Sub-Category: Tachyarrhythmias (incl supraventricular and 
ventricular tachyarrhythmias) (SMQ) 
-NIL- 
Sub-Category: Supraventricular tachyarrhythmias (SMQ) 
ECG P wave inverted 
Electrocardiogram P wave abnormal 
Retrograde p-waves 
Broad Search:  Congenital and 
neonatal arrhythmias (SMQ) 
  
Baseline foetal heart rate variability disorder 
Bradycardia foetal 
Bradycardia neonatal 
Cardiac arrest neonatal 
Cardio-respiratory arrest neonatal 
Foetal heart rate acceleration abnormality 
Foetal heart rate deceleration abnormality 
Neonatal sinus bradycardia 
Neonatal sinus tachycardia 
Neonatal tachycardia 
Nonreassuring foetal heart rate pattern 
Tachycardia foetal 
Nonreassuring foetal heart rate pattern 
Tachycardia foetal 
Broad Search: Cardiac Failure SMQ 
  
Artificial heart implant 
Atrial natriuretic peptide abnormal 
Atrial natriuretic peptide increased 
Bendopnoea 
Brain natriuretic peptide abnormal 
Brain natriuretic peptide increased 
Cardiac cirrhosis 
Cardiac contractility modulation therapy 
Cardiac device reprogramming 
Cardiac dysfunction 
Cardiac index decreased 
Cardiac output decreased 
Cardiac resynchronisation therapy 
Cardiac ventriculogram abnormal 
Cardiac ventriculogram left abnormal 
Cardiac ventriculogram right abnormal 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Cardiomegaly 
Cardio-respiratory distress 
Cardiothoracic ratio increased 
Central venous pressure increased 
Diastolic dysfunction 
Dilatation ventricular 
Dyspnoea paroxysmal nocturnal 
Heart transplant 
Hepatic vein dilatation 
Implantable cardiac monitor replacement 
Intracardiac pressure increased 
Jugular vein distension 
Left ventricular diastolic collapse 
Left ventricular dilatation 
Left ventricular dysfunction 
Left ventricular enlargement 
Lower respiratory tract congestion 
Myocardial depression 
Nocturnal dyspnoea 
N-terminal prohormone brain natriuretic peptide abnormal 
N-terminal prohormone brain natriuretic peptide increased 
Oedema 
Oedema blister 
Oedema due to cardiac disease 
Oedema neonatal 
Oedema peripheral 
Orthopnoea 
Peripheral oedema neonatal 
Peripheral swelling 
Post cardiac arrest syndrome 
Prohormone brain natriuretic peptide abnormal 
Prohormone brain natriuretic peptide increased 
Pulmonary congestion 
Right ventricular diastolic collapse 
Right ventricular dilatation 
Right ventricular dysfunction 
Right ventricular enlargement 
Scan myocardial perfusion abnormal 
Stroke volume decreased 
Surgical ventricular restoration 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Systolic dysfunction 
Venous pressure increased 
Venous pressure jugular abnormal 
Venous pressure jugular increased 
Ventricular assist device insertion 
Ventricular compliance decreased 
Ventricular dysfunction 
Ventricular dyssynchrony 
Wall motion score index abnormal 
Broad Search: Cardiomyopathy 
SMQ 
  
Abnormal precordial movement 
Acquired cardiac septal defect 
Acute left ventricular failure 
Alcohol septal ablation 
Arrhythmia 
Arrhythmia supraventricular 
Artificial heart implant 
Ascites 
Atrial enlargement 
Atrial hypertrophy 
Atrial pressure increased 
Autoimmune myocarditis 
Bendopnoea 
Blood pressure diastolic abnormal 
Blood pressure diastolic decreased 
Blood pressure diastolic increased 
Blood pressure fluctuation 
Blood pressure inadequately controlled 
Blood pressure systolic abnormal 
Blood pressure systolic decreased 
Blood pressure systolic increased 
Cardiac aneurysm 
Cardiac arrest 
Cardiac contractility modulation therapy 
Cardiac device reprogramming 
Cardiac dysfunction 
Cardiac electrophysiologic study abnormal 
Cardiac failure 
Cardiac failure acute 
Cardiac failure chronic 
Cardiac failure congestive 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Cardiac function test abnormal 
Cardiac imaging procedure abnormal 
Cardiac index abnormal 
Cardiac index decreased 
Cardiac index increased 
Cardiac monitoring abnormal 
Cardiac operation 
Cardiac output decreased 
Cardiac pseudoaneurysm 
Cardiac resynchronisation therapy 
Cardiac ventricular scarring 
Cardiac ventriculogram abnormal 
Cardiac ventriculogram left abnormal 
Cardiac ventriculogram right abnormal 
Cardiomegaly 
Cardiothoracic ratio increased 
Cardiovascular disorder 
Cardiovascular function test abnormal 
Chest pain 
Chest X-ray abnormal 
Computerised tomogram thorax abnormal 
Coxsackie carditis 
Coxsackie myocarditis 
Cytomegalovirus myocarditis 
Decreased ventricular preload 
Diastolic dysfunction 
Dilatation atrial 
Dilatation ventricular 
Directional Doppler flow tests abnormal 
Dyspnoea 
ECG signs of ventricular hypertrophy 
Echocardiogram abnormal 
Electrocardiogram abnormal 
Electrocardiogram change 
Electrocardiogram PR segment depression 
Electrocardiogram U wave inversion 
Endocardial fibroelastosis 
External counterpulsation 
Gonococcal heart disease 
Heart and lung transplant 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Heart transplant 
Hepatomegaly 
Hyperdynamic left ventricle 
Hypersensitivity myocarditis 
Implantable cardiac monitor replacement 
Increased ventricular preload 
Intracardiac pressure increased 
Irregular breathing 
Labile blood pressure 
Left atrial dilatation 
Left atrial enlargement 
Left atrial volume abnormal 
Left atrial volume decreased 
Left atrial volume increased 
Left ventricular dilatation 
Left ventricular dysfunction 
Left ventricular end-diastolic pressure decreased 
Left ventricular enlargement 
Left ventricular failure 
Left ventricular heave 
Lupus myocarditis 
Lyme carditis 
Malarial myocarditis 
Mental status changes 
Multiple gated acquisition scan abnormal 
Myocardiac abscess 
Myocardial necrosis marker increased 
Myocarditis 
Myocarditis bacterial 
Myocarditis helminthic 
Myocarditis infectious 
Myocarditis meningococcal 
Myocarditis mycotic 
Myocarditis post infection 
Myocarditis septic 
Myocarditis syphilitic 
Myocarditis toxoplasmal 
Myoglobinaemia 
Myoglobinuria 
Nocturia 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Nuclear magnetic resonance imaging thoracic abnormal 
Oedema 
Orthostatic hypotension 
Palpitations 
Papillary muscle disorder 
Papillary muscle haemorrhage 
Radiation myocarditis 
Right atrial dilatation 
Right atrial enlargement 
Right atrial pressure increased 
Right ventricle outflow tract obstruction 
Right ventricular dilatation 
Right ventricular enlargement 
Right ventricular heave 
Right ventricular systolic pressure decreased 
Scan myocardial perfusion abnormal 
Sudden cardiac death 
Sudden death 
Surgical ventricular restoration 
Syncope 
Systolic anterior motion of mitral valve 
Systolic dysfunction 
Ultrasound Doppler abnormal 
Vascular resistance pulmonary increased 
Ventricular arrhythmia 
Ventricular assist device insertion 
Ventricular dysfunction 
Ventricular dyskinesia 
Ventricular dyssynchrony 
Ventricular enlargement 
Ventricular hyperkinesia 
Ventricular hypertrophy 
Ventricular hypokinesia 
Ventricular remodelling 
Viral myocarditis 
Wall motion score index abnormal 
Wall motion score index abnormal 
Broad Search:  Ischaemic heart 
disease SMQ 
 
Sub-Category: Myocardial infarction (SMQ) 
Blood creatine phosphokinase abnormal 
Blood creatine phosphokinase increased 
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Category: Cardiac Disorders 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Cardiac ventricular scarring 
ECG electrically inactive area 
ECG signs of myocardial infarction 
Electrocardiogram Q wave abnormal 
Electrocardiogram ST segment abnormal 
Electrocardiogram ST segment elevation 
Electrocardiogram ST-T segment elevation 
Electrocardiogram U wave inversion 
Infarction 
Myocardial necrosis marker increased 
Scan myocardial perfusion abnormal 
Vascular graft occlusion 
Vascular stent occlusion 
Vascular stent thrombosis 
Sub-Category: Other ischaemic heart disease (SMQ) 
Arteriogram coronary abnormal 
Cardiac stress test abnormal 
Cardiopulmonary exercise test abnormal 
Cardiovascular event prophylaxis 
Computerised tomogram coronary artery abnormal 
Elastic vessel recoil complication 
Electrocardiogram PR segment depression 
Electrocardiogram ST segment depression 
Electrocardiogram ST-T segment abnormal 
Electrocardiogram ST-T segment depression 
Electrocardiogram T wave abnormal 
Electrocardiogram T wave inversion 
Electrocardiogram U wave inversion 
Exercise electrocardiogram abnormal 
Exercise test abnormal 
Post angioplasty restenosis 
Restenosis 
Stress echocardiogram abnormal 
Vascular stent stenosis 
Wall motion score index abnormal 
 
Category: Posterior Reversible Encephalopathy Syndrome (PRES) 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Search using Preferred Term 
Posterior Reversible Encephalopathy Syndrome 
 
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Category: PML 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Search using Preferred Term 
Progressive Multifocal Leukoencephalopathy 
 
Category: Biopsy Procedure 
Search Strategy 
MedDRA 22.0 PTs Included in SMQ 
Review all AE Preferred Term for 
biopsy related AESI  
All AE terms will be included 
 
11.5.3.2. 
Coronavirus Disease 2019 (COVID-19) Environment Onset Date 
A COVID-19 environment onset date has been defined by GlaxoSmithKline for each Country as: 
Country 
COVID-19) Environment Onset Date 
Argentina 
10 FEB 2020 
Canada 
10 MAR 2020 
France 
25 FEB 2020 
Germany 
10 FEB 2020 
Italy 
10 FEB 2020 
Netherlands 
10 FEB 2020 
Norway 
10 FEB 2020 
Spain 
10 FEB 2020 
Sweden 
10 FEB 2020 
United Kingdom 
24 FEB 2020 
This represents the best estimate of the outbreak of COVID-19 within each country at this time. 
 
11.5.4. 
Efficacy 
+++Efficacy+++ 
Calculation of ESSDAI/ClinESSDAI score 
• The ESSDAI includes 12 domains (ie, organ systems: cutaneous, respiratory, renal, articular, 
muscular, peripheral nervous system, central nervous system, hematological, glandular, 
constitutional, lymphadenopathy and biological). Each domain has 3 or 4 possible activity 
levels (Table 8). 
 
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+++Efficacy+++ 
Corrected ESSDAI score:  
• For each damage eligible domain 
o where damage is scored as present for 1st time after screening THEN corrected activity 
score = damage score for that domain for that visit and the activity score for all 
subsequent visits should be changed to equal the corresponding damage domain score 
o Except in rare cases where the activity score for the visit concerned is already equal to or 
greater than the damage score, in which case no change should be made. 
• If damage is scored as present at screening AND if the damage score increases in level of 
involvement (low to moderate or moderate to high) after the screening visit then the activity 
score for that domain for that visit and all subsequent visits should be changed to equal the 
corresponding damage domain score 
o Except in rare cases where the activity score for the visit concerned is already equal to or 
greater than the damage score, in which case no change should be made. 
• If damage is scored at screening and remains constant across visits, then no programmed 
correction can or should be made to the activity scores. 
• The ClinESSDAI includes 11 of the 12 ESSDAI domains (biological domain is excluded).  
 
Table 8 
ESSDAI Domains 
Activity level 
Response 
*Refer to Appendix 11 for details of the domains which incorporate High Response 
  
The Total ESSDAI and Total ClinESSDAI  Scores are obtained by multiplying the level of 
activity(Table 8)  by the domain weights (Table 9).  There are differing weightings for the ESSDAI 
and ClinESSDAI, and the biological domain is excluded from the calculation of the ClinESSDAI.  
The ESSDAI total score can range between 0 and 123.  The ClinESSDAI total score can range 
between 0 and 135. 
•  Missing domains: 
o If there are missing responses for ≥ 3 domains, the Total ESSDAI and Total 
ClinESSDAI scores will be set to missing.   
o If <3 domains are missing, imputation of missing domain responses will be applied to 
enable derivation of total scores. The individual domain scores from the nearest prior 
assessment which is up to 28 days earlier (and post baseline) will be carried forward 
and used for computation of total score.   If there is no prior assessment meeting this 
criteria, the total scores will be set to missing.  
 
 
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+++Efficacy+++ 
Table 9 
Weighting for Computation of ESSDAI and ClinESSDAI 
Domain 
Weight 
 
ESSDAI 
ClinESSDAI 
Constitutional 
Lymphadenopathy and lymphoma 
Glandular 
Articular 
Cutaneous 
Pulmonary 
Renal 
Muscular 
Peripheral nervous system 
Central nervous system 
Haematological 
Biological 
    
Calculation of ESSDAI Response (Corrected) 
• Three ESSDAI response variables will be computed. Definitions for responders is specified 
below: 
• 
Responders 1 - Subjects with a reduction in total ESSDAI of at least 5 points over baseline 
• 
Responders 2 - Subjects with a reduction in total ESSDAI of at least 3 points over baseline 
• 
Responders 3 - Subjects with a reduction in total ESSDAI of at least 3 points over baseline, and 
ESSDAI Total Score <5 
• 
Responders 4 - ESSDAI Total Score < 5 
Lacrimal Gland Function 
• Stirp length wet (mm/min) is calculated as length (mm) paper wet divided by time taken to wet 
(min) for the left and right eyes. The length of Schirmer’s strip is 35mm so wet/min can be 
calculated accordingly if the entire paper was wet and the time was recorded. 
• If duration is given as 0 or Not Applicable it will be considered as 5 mins. 
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11.5.5. 
Health Outcomes 
+++Patient Reported Outcomes+++ 
Calculation of ESSPRI Total Score 
• 
The ESSPRI has 3 domains (dryness, fatigue and pain)  
• 
The ESSPRI total score is the mean of the 3 domain scores, with each domain score being the response 
between
 and 
which is provided in response to the below questions. 
- 
- 
- 
• 
If there are missing responses for >1 domain, the ESSPRI total is set to missing.  If 1 domain is missing, 
the nearest prior assessment up to 28 days earlier (and post baseline) for this domain will be carried 
forward and used for computation of total ESSPRI score.   If there is no prior assessment meeting this 
criteria, the total score will be set to missing.  
Calculation of ESSPRI Response 
• 
Two ESSPRI Response will be calculated.  
• 
Definition 1 - An ESSPRI response is defined as a decrease in the ESSPRI total score of at least one 
point or at least 15% compared to baseline. 
• 
Definition 2 - An ESSPRI response is defined as a patient with baseline of ≥ 5 and ESSPRI score < 5. 
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Calculation of PROFAD-SSI-SF 
• 
Each of the 19 questions of the short form PROFAD-SSI-SF has a severity scores ranging from 0 to 
7 indicating increasing severity.  
• 
Eight domain scores are derived from the 19-item PROFAD-SSI-SF questionnaire by taking 
averages of available responses to the relevant questions.  Where responses are available for less 
than 50% of the required questions at the specific visit, the domain score for that visit will be set to 
missing.    
 
Domain 
Questions 
Domain Score Set to Missing 
Somatic fatigue 
Mental fatigue 
Arthralgia 
Vascular 
Cutaneous dryness 
Vaginal dryness 
Ocular dryness 
Oral dryness 
 
PROF, PROFAD and SSI subscores are derived by summing the domain scores listed in Table 10. The SSI 
subscores will be derived for females only. 
 
Table 10 
PROFADSSI Domains 
PROF 
PROFAD 
SSI 
Somatic fatigue 
Somatic fatigue 
Cutaneous dryness 
Mental fatigue 
Mental fatigue 
Vaginal dryness 
 
Arthralgia 
Ocular dryness 
 
Vascular 
Oral dryness 
 
 
11.5.6. 
Biomarkers  
A list of Flow Cytometry Parameters and associated variable names in the Biomarker 
dataset (BIOMARK) which will be summarized are provided in Table 11. 
If BIMETHCD=FLWTBNK AND IF BICATCD = CD19 AND BITESTCD=CONC 
AND BIORRES = ‘<5 ‘then BIORRESN (i.e. Table 11 Column = Low B cell Imputation 
= Yes) will be imputed by S&P to result of subset parameter in % * 2.5.  
 
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Example calculation for subset parameter: 
Panel 
[BIMETH
CD] 
Parame
ter 
[BICAT
CD] 
Unit 
[BITEST
CD] 
Unit 
[BIORRE
SU] 
Result (Numerical) 
[BIORRESN] 
 
Result 
[BIORR
ES] 
FLWTBN
K 
CD19 
CONC 
CELLS/C
UMM 
 
< 5 
FLWPLS
M 
CDX136 
CONC 
CELLS/C
UMM 
Imputation = 96/100 * 2.5 = 2.4 
 
FLWPLS
M 
CDX136 
PERCEN
T 
% 
96 
 
 
IF BIORRES=”UNABLE TO CALCULATE” THEN the standard values (BISTRESC and 
BISTRESN) will be the same as in original values (BIORRES, BIORRESU), do not apply any 
imputation (i.e. DO NOT set 0). 
Any other parameter reported as < x will be imputed to ½*x  
Table 11 
Flow Cytometry Parameters 
Biomarker 
Testing 
Method 
Code 
(BIMETHC
D) 
BICATC
D 
Parameter 
BITEST
CD 
Source 
Data Units 
of 
Measureme
nt 
(BIORRES
U) 
Conversi
on of 
source 
data to 
Cells/mL 
for 
reporting 
Low B 
cell 
Imputati
on 
Label [1] 
FLWTBNK 
CDX03 
CD3+ CD4+ 
CONC 
CELLS/CU
MM 
N 
N 
CD4+ T cells 
FLWTBNK 
CDX02 
CD3+ CD8+ 
CONC 
CELLS/CU
MM 
N 
N 
CD8+ T cells 
FLWTBNK 
CD19 
CD19+ B Cell 
CONC 
CELLS/CU
MM 
N 
Imputed 
CD19+ Total B 
cells 
FLWPLSM 
CDX136 
Naïve CD20+ 
CD27- (% of 
CD19+ cells) 
PERCEN
T 
% 
N 
N 
Naïve B cell 
CD20+ CD27- (% 
of CD19 cells) 
FLWPLSM 
CDX136 
Naïve CD20+ 
CD27- 
CONC 
CELLS/CU
MM 
N 
Y 
Naïve B cell 
CD20+ CD27- 
FLWPLSM 
CDX137 
Memory CD20+ 
CD27+ 
CONC 
CELLS/CU
MM 
N 
Y 
Memory B cell 
CD20+ CD27+ 
FLWPLSM 
CDX137 
Memory CD20+ 
CD27+  
(% of CD19+ 
cells) 
PERCEN
T 
% 
N 
N 
Memory B cell 
CD20+ CD27+ 
(% of CD19+ 
cells) 
FLWPLSM 
CDX143 
CD20- CD138+ 
CONC 
CELLS/CU
MM 
Y 
Y 
Plasmacell 
CD20- CD138+ 
FLWPLSM 
CDX141  Activated B Cell 
CD20+ CD69+ 
 (% of CD19+ 
cells) 
 
PERCEN
T 
% 
 
N 
Activated Total B 
Cells CD20+ 
CD69+ (% of 
CD19+ cells) 
FLWPLSM 
CDX141
Activated B Cell 
CONC 
CELLS/CU
Y 
Y 
Activated Total B 
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Biomarker 
Testing 
Method 
Code 
(BIMETHC
D) 
BICATC
D 
Parameter 
BITEST
CD 
Source 
Data Units 
of 
Measureme
nt 
(BIORRES
U) 
Conversi
on of 
source 
data to 
Cells/mL 
for 
reporting 
Low B 
cell 
Imputati
on 
Label [1] 
a 
CD20+ CD69+ 
MM 
Cells CD20+ 
CD69+ 
FLWPLSM 
CDX156 
Plasmablast All  
CD27+CD38+CD
19+  
(% of CD19+ 
cells) 
PERCEN
T 
% 
N 
N 
Plasmablast All  
CD27+CD38+CD
19+  
(% of CD19+ 
cells) 
FLWPLSM 
CDX156 
Plasmablast All  
CD27+CD38+CD
19+ 
CONC 
CELLS/CU
MM 
Y 
Y 
Plasmablast All  
CD27+CD38+CD
19+ 
FLWPLSM 
CDX493 
Plasmablast 
CD20+ 
CONC 
CELLS/ML 
NA 
Y 
Plasmablast 
CD20+ 
FLWPLSM 
CDX494 
Plasmablast 
CD20- 
CONC 
CELLS/ML 
NA 
Y 
Plasmablast 
CD20- 
FLWPLSM 
CDX145 
CD20+ CD138+ 
CONC 
CELLS/CU
MM 
Y 
Y 
Plasmacells 
CD20+CD138+ 
FLWPLSM 
CD20 
B cells CD20+ 
CONC 
CELLS/CU
MM 
N 
Y 
B cells CD20+ 
FLWTBNK 
CDX04 
Natural Killer 
CD16+ CD56+ 
CONC 
CELLS/CU
MM 
N 
N 
Natural Killer 
CD16+ CD56+ 
FLWTRAN
S 
CDX198 
Transitional T2 
CD19+ CD24Int+ 
CD38Int+ CD27- 
CONC 
CELLS/CU
MM 
Y 
Y 
Transitional T2 
CD24Int+ 
CD38Int+ CD27- 
FLWTRAN
S 
CDX199 
Transitional 
CD19+ CD24b+ 
CD38b+ CD27-  
(% of CD19+ 
cells) 
%CD19+ 
% 
N 
N 
Transitional 
CD24b+ CD38b+ 
CD27-  
(% of CD19+ 
cells) 
FLWTRAN
S 
CDX199 
Transitional 
CD19+ CD24b+ 
CD38b+ CD27- 
CONC 
CELLS/CU
MM 
Y 
Y 
Transitional 
CD24b+ CD38b+ 
CD27- 
FLWTRAN
S 
CDX202 
Memory Breg 
Phenotype  
CD19+ CD24b+ 
CD27+ 
CONC 
CELLS/CU
MM 
Y 
Y 
Memory B cells 
CD24b CD27+ 
FLWTRAN
S 
CDX203 
Naïve IgD+             
CD19+ CD27- 
IgD+ 
CONC 
CELLS/CU
MM 
N 
Y 
Naïve B cell IgD+ 
FLWTRAN
S 
CDX84 
Non-Switched 
Memory  
CD19+ CD27+ 
IgD+ 
CONC 
CELLS/CU
MM 
N 
Y 
Non-Switched 
Memory  
CD27+ IgD+ 
FLWTRAN
S 
CDX86 
Switched Memory  
CD19+ CD27+ 
IgD- 
CONC 
CELLS/CU
MM 
N 
Y 
Switched Memory  
CD27+ IgD- 
FLWTRAN
S 
CDX87 
Plasmablast 
CD38br CD27br 
CD19+ 
CONC 
CELLS/CU
MM 
Y 
Y 
Plasmablast 
CD38br CD27br 
CD19+ 
FLWPLSM 
CDX154 
Short-lived 
Plasma CD20- 
CONC 
CELLS/CU
MM 
Y 
Y 
Short-lived 
Plasma CD20- 
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Biomarker 
Testing 
Method 
Code 
(BIMETHC
D) 
BICATC
D 
Parameter 
BITEST
CD 
Source 
Data Units 
of 
Measureme
nt 
(BIORRES
U) 
Conversi
on of 
source 
data to 
Cells/mL 
for 
reporting 
Low B 
cell 
Imputati
on 
Label [1] 
CD27br 
CD27br 
FLWTRAN
S 
CDX197 
Transitional 
CD24+ CD27-
CD19+ 
CONC 
CELLS/CU
MM 
N 
Y 
Transitional 
CD24+ CD27-
CD19+ 
FLWTRAN
S 
CDX205 
Naïve B cells 
CD24- CD38br 
CD19+ 
CONC 
CELLS/CU
MM 
N 
Y 
Naïve B cell 
CD24- CD38br 
CD19+ 
[1] Label included for reference only 
The cells/mL records will be derived from source data as required.  Cells/mL =1000 * 
Cells/CUMM. 
The reporting units and database information for serologic biomarkers, complement and 
serum chemokines are detailed in Table 12. 
 
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Table 12 
Additional Biomarkers 
Biomarker 
Category 
Biomarker 
Dataset 
Dataset Codes 
Reporting 
Unit 
Notes 
Serologic 
Markers 
SS-A 
LAB 
LBTESTCD = 
ASSARO_PLQ 
KU/L 
 
Categories for summary: 
<7 
7 – 10 
>10 – 120 
>120 – 240 
>240 
SS-B 
 
LAB 
LBTESTCD = 
ASSBLA_PLQ 
KU/L 
 
  
 
Categories for summary: 
<10 
10 – 80 
>80 – 160 
>160 – 320 
>320  
Rheumatoid 
Factor 
 
LAB 
LBTESTCD = 
RF_PLC 
KU/L 
Impute values <10 to 5 
Lambda light 
chain protein  
 
LAB 
LBTESTCD = 
LLCPRO_PLC 
mg/L 
 
Kappa light 
chain protein 
LAB 
LBTESTCD = 
KLCPRO_PLC 
mg/L 
 
kappa/lambda 
ratio* 
LAB 
LABTESTCD = 
LKLC_PLQ 
mg/L 
Derived 
Beta 2 
microglobulin 
LAB 
LBTESTCD = 
B2M_PLC 
NMOL/L=SI 
or 
original=mg/L 
 
Complement CH50 
 
LAB 
LBTESTCD = 
CH50_PLC 
U/ml 
=original unit 
 
Categories for summary: 
<10 
10-30 
>30-60 
>60 
C3 
BIOMARK 
BICATCD=C3 
G/L 
 
C4 
BIOMARK 
BICATD=C4 
G/L 
 
Serum 
cytokine 
CXCL13 
BIOMARK 
BICATCD=BLC = 
BICCAT= B-
lymphocyte 
chemokine 
NG/L  
 
* The parameter is derived as a ratio of Kappa light chain protein to Lambda light chain 
protein 
A list of Minor Salivary Gland Parameters and associated variable names in the MI 
dataset which will be summarized are provided in Table 13. 
Only baseline and Week 24 data will be reported for Primary Analysis reporting. Any 
parameter reported as ‘No B-cells (CD20)’ will be excluded from summary.  
 
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Table 13 
Minor Salivary Gland Parameters 
Parameter 
Units 
MITESTCD 
Replicate Results 
Databased defined by 
MIREFID2 (biopsy 
slices) [3] 
[1] Lymphoma Risk 
Negative/P
ositive 
AG001 
N 
[2] Lymphocyte Focus Score 
 per 4 mm2 
AG006 
Y 
[2] B cell (CD20) 
count/mm2 
AG007 
N 
[2] B (CD20) / T (CD3) cell ratio 
 
AG008 
N 
[2] Plasma cell (CD138+; both - CD20pos and 
CD20neg) 
count/mm2 
AG012 
N 
T cell (CD3)  
count/mm2 
AE005 
N 
Total aggregate area/total glandular area  
ratio 
AG004 
Y 
Average Focus size 
mm2 
AG005 
Y 
Percent Foci displaying Germinal centres* 
% 
AG010 
Y 
Percent Foci displaying follicular dendritic cells 
(CD21) 
% 
AG011 
Y 
Percent Foci displaying CD3/CD20 segregation 
% 
AG009 
Y 
Plasma cell (CD138; both CD20+ and CD20-)/ 
B cell (CD20)  
ratio 
AG018 
N 
Plasma cell (CD138+, CD20+)  
count /mm2 
AG020 
N 
Plasma cell (CD138+, CD20-) 
count /mm2 
AG021 
N 
Memory B Cell (CD20+CD27+) 
count /mm2 
AG022 
N 
Follicular B cell (IgD+, CD20+) 
count /mm2 
AG017 
N 
Non-switched Memory B cell (IgD+, CD20+, 
CD27+) 
count /mm2 
AG023 
N 
Switched Memory B cell (IgD-, CD20+, CD27+) 
count /mm2 
AG024 
N 
[1] Lymphoma risk assessed at screening only and presented in baseline characteristics summary. 
[2] Parameters reported at interim analysis 
[3] For some assessments, sections from two different cutting levels are planned, and an additional section 
may be taken for analysis if discrepant results across cutting levels (difference >2 in focus score). 
For the histology parameters where replicate results (i.e. from two different cutting 
levels) are provided (as indicated by ‘Y’), average across all the replicates will be derived 
for analysis. If no replicate, then available value will be used for summary.  
11.5.6.1. 
Immunogenicity 
Anti-drug antibody (ADA) assays (Belimumab and Rituximab):  
1. 
Binding assay: Tiered assay (Screening, confirmation, and titer) to assess the 
presence of ADA 
o 
Screening assessment is performed producing a result that is positive or 
negative.  Negative samples in the screening assay are negative for the 
binding assay. 
o 
For samples with a positive screening assessment, a confirmation assay is 
carried out which produces a positive or negative result. A subject is 
confirmed as positive for the assessment at this step.  Samples testing 
positive in the screening assay, but negative in the confirmation assay are 
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negative; samples testing positive in both the binding assay and the 
confirmation assay are positive for the binding assay 
o 
For samples with a positive binding assay (positive in the screening and 
confirmation) result, a titer value is obtained to quantify the degree of 
binding in a titration assay step.  The titer result is the inverse of the 
dilution at which the sample no longer tests positive in the screening 
assay. 
2. 
Neutralizing assay (NAb) (only for Belimumab): Assay to determine if ADA 
present in a sample is neutralizing to the activity of the drug. Subjects who test 
positive for the binding assay may be further characterized by testing confirmed 
positive samples from the binding assay in the neutralizing assay, which produces 
a positive or negative result. 
 
If a subject has a positive screening assessment from the binding assay, but the 
confirmatory assessment is missing, the immunogenicity response will be reported as 
“Unknown”. 
• NOTE: For subjects WD IP and immediately entering Week 68/FU, assess any 
impact if visits are not in chronological order, when categorizing Persistent Positive. 
Adjust if required.    
Reporting of Rituximab  
The following definitions will be applied when summarizing the data. 
Persistent Positive (PP) 
Baseline (Week 8): 
1. Baseline (Week 8) is the first-time immunogenicity is being tested and therefore 
cannot be PP 
2. One exception is IF confirming = positive @ Baseline (Week 8) & subject WD from 
study prior to Week 24 THEN PP 
Post Baseline (Week 8): 
Positive response that occurs at least 2 consecutive assessments or a single result at the 
final assessment (i.e. point 2 above) 
Transient Positive (TP) 
• 
Single positive response that does not occur at the final assessment 
NOTE: Both the screening and confirming test for the time point in question must be 
positive 
Additional Programming Notes: 
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• IF your Positive @ Week 8 = TP AND IF the same subject @ Week 24 = Positive 
then will be classified as PP at Week 24 ONLY BUT cannot be retrospectively 
applied (i.e. being PP) to the same subject at Week 8 
• IF the same subject @ Week 52 was negative then classified as negative at this 
timepoint (i.e. PP classification cannot be carried forward from previous timepoint) 
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11.6. 
Appendix 6: Reporting Standards for Missing Data 
11.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
o Subject study completion (i.e. as specified in the protocol) was defined as a 
subject who has completed the treatment and general follow up phase of the 
study including the Week 68 visit. 
o Subjects may discontinue treatment and continue to complete remaining 
scheduled visits whilst off treatment or withdraw from study prior to Week 68.   
o All available data from subjects who discontinue treatment or are withdrawn 
from the study will be included in analysis, summary tables and figures, unless 
otherwise specified. 
11.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
o Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
• These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
• Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such. 
Outliers 
o Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
11.6.2.1. 
Handling of Missing Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Adverse Events o The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the 
month may be missing. In such a case, the following conventions will be 
applied for calculating the time to onset and the duration of the event: 
• Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
3 : Treatment States and Phases. 
• Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used. 
o Completely missing start or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such 
events will be missing. 
 
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11.6.2.2. 
Handling of Partial Dates 
Element 
Reporting Detail 
Concomitant 
Medications 
o Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
• If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month 
• If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
o The recorded partial date will be displayed in listings. 
Adverse 
Events 
o Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made: 
• If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month.  
• However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date.  
• The AE will then be considered to start on-treatment (worst case). 
• If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
o The recorded partial date will be displayed in listings. 
11.6.2.3. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
General 
o Appendix 5 details imputations that will applied to obtain total scores for 
ESSDAI, ClinESSDAI and ESSPRI where sufficient partial data are collected.   
An MMRM approach is planned for the key efficacy readouts. 
 
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11.7. 
Appendix 7: Values of Potential Clinical Importance  
11.7.1. 
Laboratory Values 
Hematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Lymphocytes  
GI/L 
 
0.8 
 
Neutrophil Count  
GI/L 
 
1.5 
 
Platelet Count  
GI/L 
 
100 
550 
While Blood Cell Count (WBC) 
GI/L 
 
3 
20 
Monocytes 
GI/L 
 
1.8 
8 
Eosinophils 
GI/L 
 
0.05 
0.55 
Basophils 
GI/L 
 
0 
0.2 
Red Blood Cell Count (RBC) 
TI/L 
 
3.6 
5.1 
Hemoglobin 
G/L 
 
71 
199 
Hematocrit 
I 
 
0.201 
0.599 
 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
G/L 
 
32 
50 
Creatinine 
umol/L 
 
53 
104.3 
Glucose 
mmol/L 
 
3.9 
6.9 
Potassium 
mmol/L 
 
3.5 
5.3 
Sodium 
mmol/L 
 
135 
146 
Chloride 
mmol/L 
 
95 
108 
Urea/BUN 
mmol/L 
 
2.5 
9 
Creatinine Kinase 
IU/L 
 
0 
190 
Uric Acid 
umol/L 
 
150 
450 
 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
 2x ULN 
AST/SGOT  
U/L 
High 
 2x ULN 
AlkPhos  
U/L 
High 
 2x ULN 
T Bilirubin  
µmol/L 
High 
 1.5xULN 
 
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Laboratory Parameter 
Units 
Normal Ranges 
Low Flag (< x) 
High Flag (>x) 
IgG 
G/L 
6.94 
16.18 
IgM 
G/L 
0.48 
2.71 
IgA 
G/L 
0.81 
4.63 
 
11.7.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern Range 
Decrease 
Increase 
Systolic Blood Pressure 
mmHg 
≥ 30 
≥ 30 
Diastolic Blood Pressure 
mmHg 
≥ 20 
≥ 20 
Heart Rate 
bpm 
≥ 30 
≥ 30 
 
 
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11.8. 
Appendix 8: Laboratory Parameters & Toxicity Grading 
Tables 
11.8.1. 
Laboratory Parameters 
Hematology 
Urinalysis 
Other 
Screening Tests 
CBC: 
• 
WBC Count 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet Count 
 
RBC Indices: 
• 
RBC Count 
• 
MCV 
• 
MCH 
 
WBC Differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Specific gravity 
 
pH, glucose, protein, 
blood and ketones by 
dipstick 
 
HIV, Hepatitis B 
(HBsAg) and HbcAb 
Hepatitis C (Hep C 
antibody) 
FSH and estradiol  
Serum or urine hCG 
Pregnancy 
 
Biological Markers  
Immunogenicity 
PK 
TBNK panel: 
• 
CD16+CD56+ (Natural Killer Cell) Count (counts/ml) 
• 
% CD16+CD56+ (Natural Killer Cell) (as a proportion of tot 
lymphocytes) 
• 
CD3+CD4+ (Helper T Cell) Count 
• 
CD3+CD8+ (Cytotoxic T Cell) Count 
 
Serologic Markers 
• 
Concentration SS-A and SS-B 
• 
Concentration Rheumatoid factor 
• 
Concentration Lambda and kappa free light chains 
• 
Concentration Beta 2 microglobulins 
 
Complement Factors: 
• 
Concentration C3 
• 
Concentration C4 
• 
Concentration CH50 
 
Immunoglobulins 
• 
IgG, IgA, IgM 
 
Core 6-colour B cell assay (‘plasma B cell panel’): 
• 
B cell (CD19+) 
• 
Naïve B cell (CD19+CD20+CD27-) (absolute count) 
Rituximab 
immunogenicity  
 
Belimumab 
immunogenicity  
Rituximab PK 
 
Belimumab PK 
 
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• 
Naïve B cell (CD19+CD20+CD27-) (percentage of CD19+) 
• 
Memory B cell (CD19+CD20+CD27+) (absolute count) 
• 
Memory B cell (CD19+CD20+CD27+) (percentage of CD19+) 
• 
Plasmablast All (CD19+CD27+CD38+) (absolute count) 
• 
Plasmablast All (CD19+CD27+CD38+) (percentage of 
CD19+) 
• 
Plasmablast CD20+ (CD19+CD20+CD27br+CD38br+) 
(absolute count) 
• 
Plasmablast CD20- (CD19+CD20-CD27br+CD38br+) 
(absolute count) 
 
Exploratory 6-colour B cell assay (‘plasma B cell panel’): 
 
• 
Activated B cells (CD19+CD20+CD69+) (absolute count) 
• 
Activated B cells (CD19+CD20+CD69+) (percentage of 
CD19+) 
• 
Plasmacell (CD20- CD138+) (absolute count) 
 
Listings only 6-colour B cell assay (‘plasma B cell panel’): 
• 
Plasmacells CD20+ (CD20+CD138+) (absolute count) 
• 
B cells CD20+ (CD19+CD20+)(absolute count) 
 
Core CD24w/Plasma B cell assay (‘Transitional B cell Panel’): 
• 
Transitional T2 (CD19+ CD24Int+CD38Int+CD27-) (absolute 
count) 
• 
Transitional (CD19+CD24br+CD38br+CD27-) (percentage of 
CD19+)  
• 
Transitional (CD19+CD24br+CD38br+CD27-) (absolute 
count) 
• 
Non-switched memory (CD19+CD27+IgD+) (absolute counts) 
• 
Switched memory (CD19+CD27+IgD-) (absolute counts) 
 
Exploratory CD24w/Plasma B cell assay (‘Translational B cell 
Panel’): 
• 
Memory ‘Breg phenotype’ (CD19+CD24br+CD27+) (absolute 
count) 
• 
Naïve IgD+ (CD19+CD27-IgD+) (absolute count) 
 
Listings only CD24w/Plasma B cell assay (‘Transitional B cell 
Panel’) 
• 
Plasmablasts (CD38br CD27br CD20+) (absolute count) 
• 
Short-lived Plasma (CD20- CD27br) (absolute count) 
• 
Transitional (CD24+ CD27-) (absolute count) 
• 
Naïve B cells (CD24-CD38br+) (absolute count) 
 
Concentration C-Reactive Protein 
 
Concentration free BLyS * 
Core Minor Salivary Gland histology assessments: 
• 
Lymphocyte Focus Score (in 4mm2) 
• 
B cell (CD20) count/mm2 
• 
B (CD20) / T (CD3) cell ratio 
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• 
Plasma cell (CD138+; both - CD20pos and CD20neg) 
count/mm2 
• 
Memory B Cell (CD20+CD27+) count/mm2†  
 
Exploratory Minor Salivary Gland Histology Assessments  
• 
T (CD3) cell /mm2 
• 
Total aggregate area/total glandular area (ratio) 
• 
Average Focus size (mm2) 
• 
% Foci displaying Germinal centres 
• 
% Foci displaying follicular dendritic cells (CD21) 
• 
% Foci displaying CD3/CD20 segregation 
• 
Plasma cell (CD138; both CD20+ and CD20-)/ B cell (CD20) 
ratio 
• 
Plasma cell (CD138+, CD20+) count /mm2 
• 
Plasma cell (CD138+, CD20-) count /mm2 
• 
Lymphoma risk - Assessed as Yes or No 
 
End of Study: Additional parameters maybe reported, if available: 
 
• 
Follicular B cell (IgD+, CD20+)  
• 
Non-switched Memory B cells (IgD+, CD20+, CD27+)  
• 
Switched Memory B cells (IgD-, CD20+, CD27+)  
 
Serum cytokines and chemokines: 
• 
Concentration CXCL13 
 
† Will be reported for End of Study 
*Total BLyS concentrations only for End of Study analysis 
 
11.8.2. 
Toxicity Grading Tables 
Modified version of DMID is used for the toxicity grading with the exception of IgG (values taken 
from scientific literature) and lymphocytes (values taken from CTCAE V4). 
 
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Lymphopenia 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Lymphocyte count 
<LLN - 800/mm3; 
<LLN - 0.8 
x 10e9 /L 
<800 - 500/mm3; 
<0.8 - 0.5 x 
10e9 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 
10e9 /L 
<200/mm3; <0.2 x 10e9 
/L 
 
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11.9. 
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses 
11.9.1. 
Statistical Analysis Assumptions 
11.9.1.1. 
Continuous Endpoints 
Endpoint(s) • Change from Baseline in ESSDAI Score 
• Change from Baseline in ClinESSDAI Score 
• Change from Baseline in Stimulated salivary Flow 
• Change from Baseline in Oral Dryness Numeric Response Scale 
Analysis 
• MMRM 
• Model assumptions will be applied, but appropriate adjustments may be made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line. 
• Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure. 
• In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS.  
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.  
• If there are any serious departures from the distributional assumptions, nonparametric rank 
Hodges-Lehmann’s confidence intervals will be provided in order to assess the robustness of 
the parametric analysis.  This will be carried out in addition to the parametric analyses. 
 
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Endpoint(s) • Change from Baseline in ESSDAI Score 
• Change from Baseline in ESSPRI Score 
Analysis 
• Bayesian 
General Considerations for Bayesian Analysis: 
• Convergence for all the parameters in the model will be verified 
Initial Values: 
• Unless otherwise specified, initial parameter values of 0.5 will be used for the fixed effect 
parameters.  
• If convergence of the Markov chain Monte Carlo (MCMC) algorithm is problematic, then 
alternative estimates may be used (for example, these could be based on maximum likelihood 
estimates). 
Convergence Diagnostics: 
• To be able to perform Bayesian inference using MCMC simulations the samples for all the 
parameters in the model need to be obtained from the corresponding target posterior 
distribution. To ensure that this is the case the following is a list of convergence diagnostics 
that can be applied for each parameter: 
Comparing MCSE vs posterior standard deviation: 
• The Monte Carlo Standard Errors (MCSE) should be compared with the standard deviation of 
the posterior distribution (SD) to ensure that only a fraction of the posterior variability is due to 
the simulation, i.e., the ratio MCSE/SD should be as small as possible, typically close to 0.01. 
• Adequate values for the number of MCMC samples / thinning / number of burn-in samples 
should be chosen to ensure that the ratio MCSE/SD for all the parameters in the model is 
approximately 0.01. 
• In addition, if possible, the number of tuning units and maximum number of tuning iterations 
may be increased to find a better proposal distribution for the model parameters, which in turn 
may reduce the MCSE/SD ratio. 
• Where possible the code should be written to allow the SAS compiler to identify and make use 
of conjugacy, since this can greatly reduce the corresponding MCSE/SD ratio 
Diagnostic plots and visual inspection: 
• Trace plots of samples versus the simulation index can used to assess some aspects of 
convergence. The centre of the chain should appear stable with very small fluctuations, i.e., 
the distribution of points should not change as the chain progresses and the posterior mean 
and variance are relatively constant. 
• Autocorrelation plots can be used to assess degree of autocorrelation (should decline rapidly 
and show no oscillation patterns). 
• The posterior density should look reasonable for each parameter (e.g. for posterior parameters 
expected to follow a normal distribution, the density plot should not appear bi-modal, but for 
parameters acting as binary flags, then bi-modal is acceptable). 
• Examination of correlation structures between relevant posterior parameters should be used to 
provide information about what potential issues may be and also what corrective action(s) may 
be worthwhile attempting. 
 
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11.9.1.2. 
Binary Endpoints 
Endpoint(s) • Binary Endpoints as described in Section 8.1.2 
Analysis 
• Generalised Estimating Equations (GEE) 
• For the GEE analyses, model assumptions will be applied, but appropriate adjustments may be 
made based on the data. 
• An unstructured working correlation structure will be assumed and standard errors will be 
calculated based on the empirical sandwich covariance estimate (default setting for PROC 
GENMOD in SAS) 
• An unstructured correlation structure will be used by specifying ‘type=UN’ on the REPEATED 
line. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as Independent, CS or AR(1).  
o Quasilikelihood under the Independence Model Criteria (QIC) will be used to assist with 
the selection of covariance structure. 
 
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11.10. 
Appendix 10 – Abbreviations & Trade Marks 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modeling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DMID 
Division of Microbiology and Infectious Diseases 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EoS 
End of Study 
ESSDAI 
Eular Sjögren’s Syndrome Disease Activity Index 
ClinESSDAI 
Clinical Eular Sjögren’s Syndrome Disease Activity Index 
ESSPRI 
Eular Sjögren’s Syndrome Patient Reported Index 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IFU 
Individualized Follow Up 
IMMS 
International Modules Management System 
IP 
Investigational Product 
iSRC 
Safety Review Committee 
ITT 
Intent-To-Treat 
LOC 
Last Observation Carries Forward 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PGA 
Physicians Global Assessment 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PSAP 
Program Safety Analysis Plan 
pSS 
Primary Sjogren’s Syndrome 
PtGA 
Patient Global Assessment 
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Abbreviation 
Description 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SE 
Standard Error 
SD 
Standard Deviation 
SOP 
Standard Operation Procedure 
SRDP 
Study Results Dissemination Plan 
SRT 
Safety Review Team 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
VEO-PCO 
Value, Evidence and Outcomes, Patient Centred Outcomes. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
BENLYSTA 
 
MabThera 
 
 
MedDRA 
 
 
Rituxan 
 
 
SAS 
 
 
WinNonlin 
 
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11.11. 
Appendix 11: Questionnaires 
 
11.11.1. 
Columbia Suicide severity rate scale (CSSRS) post baseline 
 
 
 
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11.11.2. 
Columbia Suicide severity rate scale (CSSRS) at baseline 
 
 
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11.11.3. 
Eular Sjögren’s syndrome disease activity index (ESSDAI) 
 
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11.11.4. 
Neurological Symptoms 
 
YES 
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If any of the above are answered “Yes” at any visit, the investigator will contact the medical 
monitor. 
Any neurological symptom that cannot be attributed to a concurrent medical condition or 
concomitant medication must be referred to a neurologist. 
 
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11.11.5. 
Oral and Ocular dryness 
 
 
11.11.6. 
Physician global assessment of disease activity (PGA) 
 
 
 
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11.11.7. 
Eular Sjögren’s syndrome patient reported index (ESSPRI) 
 
 
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11.11.8. 
Profile of fatigue and discomfort - SICCA symptoms inventory 
short form (PROFAD-SSI-SF) 
 
 
 
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11.11.9. 
Patient global assessment of disease activity (PtGA) 
 
 
11.11.10. Sjogren’s Allowable Medication Categories 
Medication Category 
Rule 
Anti-malarials 
Set to "ANTIMALARIALS" if the preferred term begins with 
"QUINACRINE", "QUININE", "HYDROXYCHLOROQUINE", 
"MEPACRINE", or "CHLOROQUINE", “NOVOCHLOROQUINE” 
AND  
the route of administration is “ORAL” 
Steroids 
Set to ‘STEROIDS’ if at least one associated ATC code (ATCCD1 – 
ATCCD6) begins with ‘H02’  
AND  
Route of administration is “ORAL” 
Muscarinic agonists 
Refer to Table 14 
 
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Table 14 
Muscarinic agonists terms  
Term Name 
Term Code 
CARBACHOL + HYPROMELLOSE 
01175401 
PHENYLEPHRINE + PILOCARPINE 
00906001 
ACETYLCHOLINE 
00611301 
METIPRANOLOL HYDROCHLORIDE + PILOCARPINE HYDROCHLORIDE 
01482401 
PHENYLEPHRINE + PILOCARPINE NITRATE 
01309901 
PHENYLEPHRINE HYDROCHLORIDE + PILOCARPINE HYDROCHLORIDE 
00597501 
BORIC ACID + PILOCARPINE HYDROCHLORIDE + THIAMINE 
HYDROCHLORIDE 
00937701 
XANOMELINE 
01302901 
CARTEOLOL HYDROCHLORIDE + PILOCARPINE HYDROCHLORIDE 
40521001 
XANOMELINE TARTRATE 
01302902 
PILOCARPINE BORATE 
00043504 
METHACHOLINE 
00978001 
METHACHOLINE CHLORIDE 
00978002 
PILOCARPINE HYDROCHLORIDE + TIMOLOL MALEATE 
00971201 
CARBACHOL 
00060901 
EUPHRASIA EXTRACT + PILOCARPINE HYDROCHLORIDE + POTASSIUM 
IODIDE 
01200001 
ACECLIDINE HYDROCHLORIDE 
00189502 
ACETYLCHOLINE CHLORIDE 
00611302 
NAPHAZOLINE HYDROCHLORIDE + PILOCARPINE BORATE 
00981301 
NAPHAZOLINE HYDROCHLORIDE + NEOSTIGMINE BROMIDE + PILOCARPINE 
HYDROCHLORIDE 
00280001 
BETHANECHOL HYDROCHLORIDE 
00115903 
PILOCARPINE 
00043501 
PILOCARPINE HYDROCHLORIDE 
00043503 
EPINEPHRINE BITARTRATE + PILOCARPINE HYDROCHLORIDE 
00458001 
ACECLIDINE 
00189501 
NAPHAZOLINE HYDROCHLORIDE + PILOCARPINE BORATE + PILOCARPINE 
HYDROCHLORIDE 
00981401 
PHYSOSTIGMINE SALICYLATE + PILOCARPINE HYDROCHLORIDE 
00578301 
PILOCARPINE NITRATE 
00043502 
BETHANECHOL CHLORIDE 
00115902 
BETHANECHOL HYDROCHLORIDE 
54486501 
BENZALKONIUM CHLORIDE + HYPROMELLOSE + PHENYLMERCURIC 
NITRATE + PILOCARPINE HYDROCHLORIDE 
00221601 
PHYSOSTIGMINE + PILOCARPINE 
01017301 
BETHANECHOL 
00115901 
DIPIVEFRINE HYDROCHLORIDE + PILOCARPINE HYDROCHLORIDE 
53176901 
CEVIMELINE 
01435201 
BENZALKONIUM CHLORIDE + DIPIVEFRINE HYDROCHLORIDE + 
01318101 
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Term Name 
Term Code 
PILOCARPINE HYDROCHLORIDE 
CEVIMELINE HYDROCHLORIDE 
52131601 
 
11.11.11. Prednisone Conversion Factors 
A concomitant medication is identified as a steroid if at least one associated ATC code 
(ATCCD1 – ATCCD6) begins with ‘H02.’  
The following routes are considered to provide systemic exposure: oral, subcutaneous, 
intramuscular, intradermal, and intravenous.  Topical routes of administration are 
excluded (e.g., topical, conjunctival, intranasal).   
At data base release all preferred terms identified with an ATC code beginning with 
‘H02’ will be reviewed to ensure a conversion factor and dosing frequency exist for all 
terms with a systemic route of administration.  
Similarly, all routes of administration for preferred terms with an ATC code beginning 
with ‘H02’will be reviewed to ensure all systemic routes have been identified in the list 
above.   
In order to be converted, the frequency and dose of the steroid must be present with the 
unit dose in milligrams (mg). 
Reported dose for systemic steroid is converted to prednisone equivalent dose using 
conversion factor for each particular medication (refer to online calculator 
http://www.globalrph.com/corticocalc.htm). 
 
Daily Prednisone Equivalent Dose (mg) = Collected Dose (mg) x Conversion Factor x 
Frequency Factor 
Preferred term 
Conversion factor for converting to a 
prednisone-equivalent dose 
BETAMETHASONE 
8.333 
BETAMETHASONE DIPROPIONATE 
8.333 
BETAMETHASONE SODIUM PHOSPHATE 
8.333 
BETAMETHASONE VAL 
8.333 
BETROSPAM 
8.333 
BUDESONIDE 
0.333 
CELESTONA BIFAS 
8.333 
CORTISONE 
0.2 
CORTISONE ACETATE 
0.2 
CRONOLEVEL 
8.333 
DEFLAZACORT 
0.8333 
DEPO-MEDROL MED LIDOKAIN 
1.25 
DEXAMETHASONE 
6.667 
DEXAMETHASONE ACETATE 
6.667 
DEXAMETHASONE SODIUM PHOSPHATE 
6.667 
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Frequency Factors 
Frequency 
Factor 
BID 
2 
BIW 
2/7 
OAM 
1/30 
Once 
1 
One 
1 
OD 
1 
PRN 
null 
Q2H 
12 
Q2W 
1/14 
Q3H 
8 
Q3MO 
1/84 
Q3w 
1/21 
Q4H 
6 
Q4W 
1/28 
Q6H 
4 
Q8H 
3 
Q12H 
2 
QAM 
1 
QD 
1 
QH 
24 
QHS 
1 
FLUOCORTOLONE 
3 
HYDROCORTISONE 
0.25 
Preferred term 
Conversion factor for converting to a 
prednisone-equivalent dose 
HYDROCORTISONE ACETATE 
0.25 
HYDROCORTISONE SODIUM SUCCINATE 
0.25 
MEPREDNISONE 
1.25 
METHYLPREDNISOLONE 
1.25 
METHYLPREDNISOLONE ACEP 
1.25 
METHYLPREDNISOLONE ACETATE 
1.25 
METHYLPREDNISOLONE SODIUM SUCCINATE 
1.25 
PARAMETHASONE 
2.5 
PREDNISOLONE 
1 
PREDNISOLONE SODIUM PHOSPHATE 
1 
PREDNISOLONE SODIUM SUCCINATE 
1 
PREDNISONE 
1 
PREDNISONE ACETATE 
1 
TRIAMCINOLONE 
1.25 
TRIAMCINOLONE ACETATE 
1.25 
TRIAMCINOLONE ACETONIDE 
1.25 
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Frequency Factors 
QID 
4 
QM 
1 
QOD 
½ 
QPM 
1 
QW 
1/7 
QWK 
1/7 
TID 
3 
TIW 
3/7 
UNK 
Null 
2 TIMES PER WEEK 
2/7 
3 TIMES PER WEEK 
3/7 
4 TIMES PER WEEK 
4/7 
5 TIMES PER WEEK 
5/7 
5XWK 
5/7 
5 TIMES PER DAY 
5 
EVERY 2 WEEKS 
1/14 
EVERY 3 WEEKS 
1/21 
EVERY 4 WEEKS  
1/28 
EVERY WEEK 
1/7 
 
11.11.12. Exit Interview 
Instructions for Interviewer:   
• 
At the beginning of the interview, please confirm the patient’s study number. 
• 
Text written in bold is to be read verbatim to each subject.  
• 
Text written in [italics] is an instruction to the interviewer.   
• 
Probes are to be used as needed to encourage the subject to provide full responses to each of the 
questions.  They should be used if the subject gives an incomplete or unclear response or 
explanation with the initial question. 
• 
Actively listen during the interview and take notes as necessary.  
INTRODUCTION: 
Hello, my name is [state first name] and I will be asking you some questions about your experience 
with medications in this study. The interview will be recorded and a transcript will be developed. In 
order to protect your confidentiality, only your study number will be included in the transcript. You 
are free to stop the interview at any time if you decide you no longer wish to participate. 
The following questions have been developed to provide information on patient experiences with 
medications.  It is important that you give your best answers, so please listen carefully to each 
question before you respond.   
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11.12. 
Appendix 12: Headline Results 
11.12.1. 
Headline Results Output 
The following tables will be included as headline results: 
Table 15 
Headline Results Output 
Table 
Title 
1.1 
Summary of Subject Status and Reason for Study Withdrawal 
1.8 
Summary of Demographic Characteristics 
1.20 
Summary of Baseline Disease Activity 
2.11 
Summary of Statistical Analysis Results of Change from Baseline: ESSDAI Total Score 
(Corrected) 
2.19 
Summary of Responders on Total ESSDAI 
2.29 
Summary of Statistical Analysis Results of Change from Baseline: Stimulated Salivary Flow 
2.33 
Summary of Statistical Analysis Results of Change from Baseline: Oral Dryness Numeric 
Response Scale  
2.37 
Summary of Statistical Analysis Results of Percentage Change from Baseline in Core Salivary 
Gland Histology at Week 24 [1] 
2.38 
Summary of Bayesian Posterior Probabilities: ESSDAI Total Score (Corrected) [2] 
3.2 
Summary of All Adverse Events by System Organ Class and Preferred Term 
3.9 
Adverse Events of Special Interest by Category 
3.29 
Summary of Serious Adverse Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
6.2 
Summary Statistics of Change from Baseline: ESSPRI Total Score and Domains 
6.4  
Summary of ESSPRI Responders 
6.11 
Summary of Bayesian Posterior Probabilities: ESSPRI Total Score [2] 
7.10 
Summary Statistics of Percentage Change from Baseline: Flow Cytometry Parameters [1] 
NOTE: 
[1] Only summarize B cell (CD20)/mm2 in Salivary Gland  
[2] If time permits (generated by GSK) 
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11.13. 
Appendix 13: List of Data Displays 
11.13.1. 
Data Display Numbering  
The following numbering will be applied for RAP generated displays:  
Section 
Tables 
Figures 
Study Population 
1.1 to 1.22(EOS: 1.1001 to 
1.1023) 
N/A 
Efficacy 
2.1 to 2.39  
2.2 (EOS: 2.1001 to 2.1043) 
to 2.12 
(EOS: 2.1001 to 2.1011) 
Safety 
3.1 to 3.62 
 (EOS: 3.1002 to 3.1062) 
3.1 to 3.4 
 (EOS: 3.1001 to 3.1004) 
Pharmacokinetic 
4.1 to 4.4 
4.1 to 4.5 
 (EOS: 4.1001 to 4.1002) 
Pharmacokinetic/ 
Pharmacodynamic 
N/A 
5.1 
Health Outcomes 
6.1 to 6.14  
(EOS: 6.1001 to 6.1015) 
6.1 to 6.3  
(EOS: 6.1001 to 6.1002) 
Exploratory/Biomarker 
7.1 to 7.22 
 (EOS: 7.1001 to 7.1023) 
7.1 to 7.9 
 (EOS: 7.1001 to 7.1009) 
Section 
Listings 
ICH Listings 
1 to 31 (EOS: 1002 to 1030) 
Other Listings 
32 to 58 (EOS: 1032 to 1061) 
 
NOTE: For the End of Study Analysis reporting, selected Primary Analysis displays have 
been identified and will be generated. All displays generated for the End of Study 
Analysis will have unique numbering, and their display numbers have been indicated in 
parentheses in the list of displays. 
 
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11.13.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and mock up displays are 
presented separately. 
Section 
Figure 
Table 
Listing 
Study Population 
N/A 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
N/A 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic/Pharmacodynamic 
PKPD_Fn 
N/A 
N/A 
Exploratory/Biomarker 
PD_Fn 
 
 
 
11.13.3. 
Deliverables 
Delivery [Priority] 
Description 
HL [1] 
Primary Analyses (Week 52) Headline Results 
SAC_WK52 [2] 
Primary Analysis (Week 52) SAC 
SAC_EOS [3] 
End of Study (Week 104) SAC 
NOTES: 
• Unless otherwise specified in the Programming Notes, displays will be generated by 
Quanticate. 
For the End of Study Analysis reporting, selected Primary Analysis displays have been 
identified and will be generated, using the final data. The displays will be updated (as 
required) to capture the additional visits and to reflect the final data. If further details are 
required, a RAP amendment or addendum will be generated to specify the changes. If’ 
Per Protocol Population” not run, then no data will be reported”. 
This RAP details the planned analysis for both database freezes (Primary Analysis and 
End of Study Analysis), with the expectation of an observed treatment benefit being 
observed following the Primary Analysis.  
In the event that the Primary Analysis reporting does not identify treatment benefit an 
abridged set of analysis may be conducted for the end of study analysis, which will be 
detailed in a RAP amendment or addendum. 
 
 
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11.13.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. (1.1001) 
Safety 
POP_T1 
Summary of Subject Status and Reason for Study 
Withdrawal 
ICH E3, FDAAA, EudraCT 
EoS : Refer to mock shell POP_T1.1  
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
1.2. (1.1002) 
Safety 
SD1 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment 
ICH E3 
Add Total column (if feasible) 
NOTE: Align with eCRF 
Footnote:  
Note: Treatment status with respective to 
Week 52 
[1] Subjects may have only one primary 
reason. 
SAC_WK52 [2] 
SAC_EOS [3] 
1.3. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Journal Requirements 
NOTE: Align with eCRF 
SAC_WK52 [2] 
1.4. 
Enrolled 
NS1 
Summary of Number of Subjects Enrolled by Country and 
Site ID 
EudraCT/Clinical Operations 
SAC_WK52 [2] 
Protocol Deviation 
1.5. (1.1005) 
Safety 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC_WK52 [2] 
SAC_EOS [3] 
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Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Population Analysed 
1.6. (1.006) 
Safety 
SP1 
Summary of Study Populations 
IDSL 
SAC_WK52 [2] 
SAC_EoS [3] 
1.7. 
Safety 
SP2 
Summary of Exclusions from Per Protocol Population 
 
SAC_WK52 [2] 
Demographics 
1.8. 
Safety 
DM1 
Summary of Demographic Characteristics  
ICH E3, FDAAA, EudraCT 
HL [1] 
SAC_WK52 [2] 
1.9. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
SAC_WK52 [2] 
1.10. 
Safety 
DM5 
Summary of Race and Racial Combinations  
 
SAC_WK52 [2] 
1.11. 
Safety 
FH1 
Summary of Family History of Cardiovascular Risk 
Factors 
Footnote: Women <65 years or men < 55 
years. Half siblings are considered first 
degree relatives 
SAC_WK52 [2] 
1.12. 
Safety 
SU1 
Summary of Substance Use 
 
SAC_WK52 [2] 
Medical Condition & Con Meds 
1.13. 
Safety 
MH4 
Summary of Medical Conditions (Sjögren Specific) 
ISRC version with all medical conditions 
Ref eCRF and align 
SAC_WK52 [2] 
1.14. 
Safety 
MH4 
Summary of Medical Conditions (non-Sjögren Specific) 
 
SAC_WK52 [2] 
1.15. (1.1015) 
Safety 
CM1 
Summary of Concomitant Medications 
ICH E3 
Add Total column (if feasible) 
SAC_WK52 [2] 
SAC_EOS [3] 
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Study Population Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.16. (1.1016) 
Safety 
CM1 
Summary of Most Frequently used Concomitant 
Medications by Generic Term 
Footnote: Includes concomitant medications 
taken by >= 5% subjects 
Add Total column (if feasible) 
SAC_WK52 [2] 
SAC_EOS [3] 
1.17. 
Safety 
POP_T2 
Summary of Permitted pSS Medication Usage at Baseline 
Add Total column (if feasible) 
SAC_WK52 [2] 
1.18. 
Safety 
POP_T3 
Summary of Steroids, Anti-malarial and Muscarinic 
Agonists Use at Baseline 
Add Total column (if feasible) 
SAC_WK52 [2] 
Disease History 
1.19. 
Safety 
POP_T4 
Summary of AECG Classification Criteria Reported for 
Subjects at Baseline 
 Add Total column (if feasible) 
 
SAC_WK52 [2] 
1.20. 
Safety 
POP_T5 
Summary of Baseline Disease Activity 
Add Total column (if feasible) 
HL [1] 
SAC_WK52 [2] 
1.21. 
Safety 
POP_T6 
Summary of Autoantibody, Immunoglobulin, Complement, 
and Other Biomarker Measurements at Baseline 
Add Total column (if feasible) 
SAC_WK52 [2] 
Other 
1.22. (1.1022) 
Safety 
POP_T7 
Cumulative Study Withdrawal by Study Week 
 
SAC_WK52 [2] 
SAC_EOS [3] 
1.1023. 
Safety 
POP_T8 
Summary of Overall Subject Status 
 
SAC_EOS [3] 
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11.13.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ESSDAI Score 
2.1. (2.1001) 
Safety 
EFF_T1 
Summary Statistics of ESSDAI Total Score 
(Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.2. (2.1002) 
Per 
Protocol 
EFF_T1 
Summary Statistics of ESSDAI Total Score 
(Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.3. (2.1003) 
Safety 
EFF_T1 
Summary Statistics of ESSDAI Total Score (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.4. (2.1004) 
Per 
Protocol 
EFF_T1 
Summary Statistics of ESSDAI Total Score (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits  
SAC_WK52 [2] 
SAC_EOS [3] 
2.5. (2.1005) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: ESSDAI 
Total Score (Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.6. (2.1006) 
Per 
Protocol 
EFF_T1 
Summary Statistics of Change from Baseline: ESSDAI 
Total Score (Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.7. (2.1007) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: ESSDAI 
Total Score (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.8. (2.1008) 
Per 
Protocol 
EFF_T1 
Summary Statistics of Change from Baseline: ESSDAI 
Total Score (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.9. 
Safety 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ESSDAI Total Score (Uncorrected) 
All visits to wk 52 entered to MMRM model.   
Note: Add the final model parameters 
SAC_WK52 [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.10. 
Per 
Protocol 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ESSDAI Total Score (Uncorrected) 
All visits to wk 52 entered to MMRM model. 
Note: Add the final model parameters 
SAC_WK52 [2] 
 
2.11. 
Safety 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ESSDAI Total Score (Corrected) 
All visits to wk 52 entered to MMRM model.   
Note: Add the final model parameters 
HL [1] 
SAC_WK52 [2] 
 
2.12. 
Per 
Protocol 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ESSDAI Total Score (Corrected) 
All visits to wk 52 entered to MMRM model. 
Note: Add the final model parameters 
SAC_WK52 [2] 
 
2.13. (2.1013) 
Safety 
EFF_T3 
Summary of ESSDAI Domain Activity (Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.14. (2.1014) 
Per 
Protocol 
EFF_T3 
Summary of ESSDAI Domain Activity (Uncorrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
2.15. (2.1015) 
Safety 
EFF_T3 
Summary of ESSDAI Domain Activity (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.16. (2.1016) 
Per 
Protocol 
EFF_T3 
Summary of ESSDAI Domain Activity (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.17. (2.1017) 
Safety 
EFF_T4 
ESSDAI Improvement (At Least 1 Category on Domain 
Score) by Domain Among Subjects with Domain 
Involvement at Baseline (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.18. (2.1018) 
Safety 
EFF_T5 
ESSDAI Worsening (At Least 1 Category on Domain 
Score) by Domain (Corrected) 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.19. (2.1019) 
Safety 
EFF_T6 
Summary of Responders on Total ESSDAI Score 
(Corrected) 
Corrected ESSDAI score will be used. 
Include all visits up to Week 68 
HL [1] 
SAC_WK52 [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
EoS: Include all scheduled visits 
Footnote: 
Responders are defined as below: 
Responder 1: ≥5 point reduction in ESSDAI 
Total vs baseline 
Responder 2: ≥3 point reduction in ESSDAI 
Total vs baseline 
Responder 3: ≥3 point reduction in ESSDAI 
Total vs baseline and Total Score < 5 
Responder 4: Total score <5 
SAC_EOS [3] 
2.20. (2.1020) 
Per 
Protocol 
EFF_T6 
Summary of Responders on Total ESSDAI Score 
(Corrected) 
Corrected ESSDAI score will be used. 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
Footnote: 
Responders are defined as below: 
Responder 1: ≥5 point reduction in ESSDAI 
Total vs baseline 
Responder 2: ≥3 point reduction in ESSDAI 
Total vs baseline 
Responder 3: ≥3 point reduction in ESSDAI 
Total vs baseline and Total Score < 5 
Responder 4: Total Score <5 
Footnote to include model parameter as per 
mock table 
SAC_WK52 [2] 
SAC_EOS [3] 
2.21. 
Safety 
EFF_T7 
Summary of Statistical Analysis of Responder on Total 
ESSDAI Score (Corrected) 
Footnote: Responder definition and include 
footnotes as per EFF_T7 
Note: Add the final model parameters 
SAC_WK52 [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.22. (2.1022) 
Safety 
EFF_T8 
Proportion of Subjects with Damage by Domain 
Additional Supplementary to ESSDAI for 5 
domains  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
ClinESSDAI Score 
2.23. (2.1023) 
Safety 
EFF_T1 
Summary Statistics: ClinESSDAI Total Score 
(Corrected) 
Corrected ESSDAI score will be used. 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.24. (2.1024) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
ClinESSDAI Total Score (Corrected) 
Corrected ESSDAI score will be used. 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.25. (2.1025) 
Safety 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ClinESSDAI Total Score (Corrected) 
Corrected ESSDAI score will be used.  
All visits to wk 52 entered to MMRM model.   
Note: Add the final model parameters 
SAC_WK52 [2] 
2.26. (2.1026) 
Safety 
EFF_T6 
Summary of ClinESSDAI Responders (Corrected) 
Corrected ESSDAI score will be used. 
Including just one section with Responder 
Criteria: Reduction from baseline ≥3 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
Stimulated and Unstimulated Salivary Flow 
2.27. (2.1027) 
Safety 
EFF_T1 
Summary Statistics of Stimulated and Unstimulated 
Salivary Flow 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
Page by parameter – stimulated and 
unstimulated flow 
SAC_WK52 [2] 
SAC_EOS [3] 
2.28. (2.1028) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
Stimulated and Unstimulated Salivary Flow 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
by parameter 
SAC_WK52 [2] 
SAC_EOS [3] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Page by parameter – stimulated and 
unstimulated flow 
2.29. 
Safety 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: Stimulated Salivary Flow  
All visits to wk 52 entered to MMRM model. 
Note: Add the final model parameters 
HL [1] 
SAC_WK52 [2] 
 
2.30. 
Per 
Protocol 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: Stimulated Salivary Flow  
All visits to wk 52 entered to MMRM model. 
Note: Add the final model parameters 
SAC_WK52 [2] 
Oral Dryness 
2.31. (2.1031) 
Safety 
EFF_T1 
Summary Statistics of Oral Dryness Numeric Response 
Scale 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.32. (2.1032) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: Oral 
Dryness Numeric Response Scale 
Include all visits up to Week 68 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
2.33. 
Safety 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: Oral Dryness Numeric Response Scale  
All visits to wk 52 entered to MMRM model  
Note: Add the final model parameters 
HL [1] 
SAC_WK52 [2] 
2.34. 
Per 
Protocol 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: Oral Dryness Numeric Response Scale  
All visits to wk 52 entered to MMRM model. 
Note: Add the final model parameters 
SAC_WK52 [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Salivary Gland Histology 
2.35. (2.1035) 
Safety 
EFF_T9 
Summary Statistics for Salivary Gland Histology 
Assessments 
Includes baseline and Week 24 only 
Include all parameters as specified in RAP 
Table 13 
Note: Include Week 52 for EoS reporting 
SAC_WK52 [2] 
SAC_EOS [3] 
2.36. (2.1036) 
Safety 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Salivary Gland Histology Assessments 
 
EOS: 
Summary Statistics of Change from Baseline: Salivary 
Gland Histology Assessments 
Includes only Week 24 data 
Include all parameters as specified in RAP 
Table 13 
Note: Include Week 52 for EoS reporting 
SAC_WK52 [2] 
SAC_EOS [3] 
2.37. (2.1037) 
Safety 
EFF_T10 
Summary of Statistical Analysis Results of Percentage 
Change from Baseline in Core Salivary Gland Histology 
at Week 24 
 
EOS: 
Summary of Statistical Analysis Results of Change 
from Baseline in Core Salivary Gland Histology at 
Week 24 
Parameters to be included in the analysis 
are 
• 
B cell (CD20) count/mm2 
• 
Lymphocyte Focus Score (per 4mm2) 
• 
B (CD20) / T (CD3) cell ratio 
• 
Plasma cell (CD138+; both - CD20pos 
and CD20neg) count/mm2 
Note: Exclude Week 52 for EoS reporting 
(i.e. only n=6 samples).  
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
Further Efficacy Evaluation 
2.38. 
Safety 
EFF_T11 
Summary of Bayesian Posterior Probabilities: ESSDAI 
Total Score (Corrected) 
Add appropriate footnotes based on final 
out 
To be generated by GSK 
HL [1] 
SAC_WK52 [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Further Evaluation  
2.39. (2.1039) 
Safety 
N/A 
Summary of Responders on Total ESSDAI Score  
EoS: Include all scheduled visits 
% responders calculated using n for each 
visit 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
(2.1040) 
Completer 
EFF_T1 
Summary Statistics of ESSDAI Total Score (Corrected) 
– Completer 
Include all scheduled visits 
Add footnote: 
Note: Completer is defined as “Subjects 
who completed the 52 Week treatment 
visits AND general follow up phase of the 
study including the visit at Week 68” 
SAC_EOS [3] 
(2.1041) 
Completer 
EFF_T2 
Summary of Statistical Analysis Results of Change 
from Baseline: ESSDAI Total Score (Corrected) - 
Completer 
Include visits upto and including Week 
68/FU 
Add footnote: As T2.1040 
SAC_EOS [3] 
(2.1042) 
Completer 
EFF_T1 
Summary Statistics of Stimulated and Unstimulated 
Salivary Flow - Completer 
Include all scheduled visits 
Page by parameter – stimulated and 
unstimulated flow 
Add footnote: As T2.1040 
SAC_EOS [3] 
(2.1043) 
Completer 
EFF_T1 
Summary Statistics of Oral Dryness Numeric Response 
Scale - Completer 
Include all scheduled visits 
Add footnote: As T2.1040 
SAC_EOS [3] 
 
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11.13.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ESSDAI 
2.1. (2.1001) 
Safety 
EFF_F1 
Mean ( SE) of ESSDAI Total Score (Uncorrected) 
All scheduled visits 
Legend: Treatment 
EoS: Include all visits up to Week 68/FU. X-
axis: Add line break between Week 52 and 
Week 68/FU with no joining lines. 
 
SAC_WK52 [2] 
SAC_EOS [3] 
2.2. (2.1002) 
Safety 
EFF_F1 
Mean ( SE) of ESSDAI Total Score (Corrected) 
All scheduled visits 
Legend: Treatment 
EoS: As F2.1001 
SAC_WK52 [2] 
SAC_EOS [3] 
2.3. (2.1003) 
Safety 
EFF_F1 
Mean ( SE) of Change from Baseline in ESSDAI Total 
Score (Uncorrected) 
All scheduled visits 
Legend: Treatment 
EoS: As F2.1001 
SAC_WK52 [2] 
SAC_EOS [3] 
2.4. (2.1004) 
Safety 
EFF_F1 
Mean ( SE) of Change from Baseline in ESSDAI Total 
Score (Corrected) 
All scheduled visits 
Legend: Treatment 
EoS: As F2.1001 
SAC_WK52 [2] 
SAC_EOS [3] 
2.5. 
Safety 
EFF_F1 
Adjusted Mean (95% CI) Change from Baseline: ESSDAI 
Total Score (Uncorrected) 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Visit: Continuous Scale 
Y-Axis: ESSDAI total Score and scaled 
accordingly  
Legend: Treatment 
Include all visits to Week 52 
Note: Add the final model parameters 
SAC_WK52 [2] 
2.6. 
Safety 
EFF_F1 
Adjusted Mean (95% CI) Change from Baseline: ESSDAI 
Total Score (Corrected) 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Visit: Continuous Scale 
Y-Axis: ESSDAI total Score and scaled 
SAC_WK52 [2] 
SAC_EOS [3] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
accordingly  
Legend: Treatment 
Include all visits to Week 52 
Note: Add the final model parameters 
2.7. (2.1007) 
Safety 
EFF_F2 
ESSDAI Activity by Domain 
Page By: Domain 
Panel: Visit (Include only Baseline, Week 
24 and Week 52) 
EoS: Panel: Visit (Include only Baseline, 
Week 24 & Week 52) 
X-Axis = Treatment 
Y-Axis = Percentage of Subjects 
Stacked bar chart 
SAS colors for the categories are 
    No Activity - CXDCDCDC  
    Low Activity - CX9370DB  
    Moderate Activity - CX7FFF00  
    High Activity - CXFF8C00 
SAC_WK52 [2] 
SAC_EOS [3] 
2.8. (2.1008) 
Safety 
EFF_F3 
ESSDAI Responders Bar Chart by Treatment and Visit 
(Corrected) 
EoS: Include all scheduled visits except 
IFU, EW & W68/FU 
Footnote: 
Responders are defined as below: 
Responder 1: ≥5 point reduction in ESSDAI 
Total vs baseline 
Responder 2: ≥3 point reduction in ESSDAI 
Total vs baseline 
Responder 3: ≥3 point reduction in ESSDAI 
Total vs baseline and Total Score < 5 
Responder 4: Total Score <5  
SAC_WK52 [2] 
SAC_EOS [3] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Stimulated & Unstimulated Salivary Flow 
2.9. (2.1009) 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in Stimulated 
Salivary Flow   
EoS:  As F2.1001 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Visit: Continuous Scale 
Legend: Treatment 
SAC_WK52 [2] 
SAC_EOS [3] 
2.10. (2.1010) 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in Unstimulated 
Salivary Flow 
As F2.1001 
Legend: Treatment 
SAC_WK52 [2] 
SAC_EOS [3] 
Oral Dryness 
2.11. (2.1011) 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in Oral Dryness 
Numeric Response  
EoS:  As F2.1001 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Visit: Continuous Scale 
Y-Axis: Oral dryness numeric response and 
scaled accordingly  
Legend: Treatment 
SAC_WK52 [2] 
SAC_EOS [3] 
Salivary Gland Histology 
2.12. 
(2.1012) 
Safety 
EFF_F4 
Median (+/- IQR) of Percentage Change from Baseline in 
Salivary Gland Core Parameters 
 
EoS: 
Median (+/- IQR) of Change from Baseline in Salivary 
Gland Core Parameters 
Percentage change (Primary) and change 
(EoS) to wk 24 for 
• 
B cell (CD20) count/mm2 
• 
Lymphocyte Focus Score (in 4mm2) 
• 
B (CD20) / T (CD3) cell ratio 
• 
Plasma cell (CD138+; both - CD20pos 
and CD20neg) count/mm2 
X-Axis: Week 24 visit only  
Legend: Treatment 
NOTE: Limited sample at WK52 (i.e. n=6), 
hence Week 52 not required for EoS. 
SAC_WK52 [2] 
SAC_EOS [3] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 Exploratory Correlation Evaluation 
2.13. 
Safety 
PD_F1 
ESSDAI and ClinESSDAI Bland-Altman Plot at Week 24 
(Corrected) 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Average of Change from baseline 
to Wk24 Total ClinESSDAI and Change 
from baseline to wk 24 Total ESSDAI  
Y-Axis: Difference of Change from baseline 
to Wk24 Total ESSDAI and Change from 
baseline to wk 24 Clin ESSDAI  
Legend: Treatment 
Note: Add footnotes as required 
Note: For SAC_EOS [3]: Include other 
timepoints and add identifies 
SAC_WK52 [2] 
2.14. 
Safety 
PD_F2 
Scatter Plot of Wk 24 Changes for Total ESSDAI Score vs 
Salivary Gland B Cells 
Panel: Rows = 1 by Cols = 1 for parameter 
X-Axis: Percentage Change from baseline 
to Wk24 Salivary Gland B Cells  
Y-Axis: Change from baseline to Wk24 
Total ESSDAI 
 Legend: Treatment 
SAC_WK52 [2] 
2.15. 
Safety 
PD_F3 
Median Free Blys Vs Median CD19+ B cell by Treatment 
Panel per Treatment.  Legend: Visit  
X-axis: CD19+ B cells  
Y-axis: Free Blys 
B Cell measured by flow cytometry 
SAC_WK52 [2] 
 
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11.13.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1.  
Safety 
SAFE_T15 
Summary of Extent of Exposure   
 
SAC_WK52 [2] 
Adverse Events (AEs) 
3.2. (3.1002) 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term  
ICH E3 
Footnote: 
Note: Subjects are counted only once per 
SOC/PT 
EoS: Include visits upto W68/FU 
 
EoS Footnote: 
Note: Includes Treatment & General Follow 
Up periods only. 
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
3.3. (3.1003) 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class  
Excludes Preferred Term breakdown 
Footnote: 
Note: Subjects are counted only once per 
SOC 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.4. (3.1004) 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency 
ICH E3 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.5. (3.1005) 
Safety 
AE3 
Summary of Common (>=5%) Grade 2-4 Adverse Events 
ICH E3 
SAC_WK52 [2] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
by Overall Frequency 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.6. (3.1006) 
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term 
ICH E3 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.7. (3.1007) 
Safety 
AE15 
Summary of Common (>=5%) Non Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Participant and Occurrences) 
FDAAA 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.8. (3.1008) 
Safety 
AE3 
Summary of Common (>=5%) Drug-Related Grade 2-4 
Adverse Events by Overall Frequency 
ICH E3 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.9. (3.1009) 
Safety 
SAFE_T7 
Adverse Events of Special Interest by Category 
Includes events defined in Belimumab 
PSAP and study specific special interest 
events 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
3.10. (3.1010) 
Safety 
SAFE_T8 
Malignant Neoplasm Adverse Events of Special Interest 
by Category and PT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.11. (3.1011) 
Safety 
SAFE_T9 
Post-Administration Systemic Reaction Adverse Events 
of Special Interest by Category and PT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.12. (3.1012) 
Safety 
SAFE_T9 
Serious Post-Administration Systemic Reaction Adverse 
Events of Special Interest by Category and PT 
Change title and content so only Serious 
PASR’s are summarized 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.13.  
Safety 
SAFE_T10 
Post-Injection Systemic Reactions per Anaphylactic 
Reactions CMQ Broad search by PT, in First Six Doses 
of Belimumab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_WK52 [2] 
3.14.  
Safety 
SAFE_T10 
Serious Post-Injection Systemic Reactions per 
Anaphylactic Reactions CMQ Broad search by PT, in 
First Six Doses of Belimumab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_WK52 [2] 
3.15.  
Safety 
SAFE_T10 
Serious Acute Post-Injection Systemic Reactions per 
GSK Adjudication by PT, in First Six Doses of 
Belimumab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_WK52 [2] 
3.16.  
Safety 
SAFE_T10 
Serious Delayed Acute Post-Injection Systemic 
Reactions per GSK Adjudication by PT, in First Six Doses 
of Belimumab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_WK52 [2] 
3.17.  
Safety 
SAFE_T10 
Serious Delayed Non-Acute Post-Injection Systemic 
Reactions per GSK Adjudication by PT, in First Six Doses 
of Belimumab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_WK52 [2] 
3.18. (3.1018) 
Safety 
SAFE_T11 
Infection Adverse Events of Special Interest by Category 
and PT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.19. (3.1019) 
Safety 
SAFE_T11 
Infection Adverse Events of Special Interest Leading to 
Study Agent Discontinuation by Category and PT by 
Category and PT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.20. (3.1020) 
Safety 
SAFE_T12 
Depression/Suicide/Self-injury Adverse Events of Special 
Interest by Category and PT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.21. (3.1021) 
Safety 
SAFE_T13 
Severe Skin Reactions Adverse Events of Special 
Interest by Preferred Term 
Study specific AESI 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.22. (3.1022) 
Safety 
SAFE_T13 
Cardiac Disorders Adverse Events of Special Interest by 
Preferred Term 
Study specific AESI 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.23. (3.1023) 
Safety 
SAFE_T13 
Posterior Reversible Encephalopathy Syndrome (PRES) 
Adverse Events of Special Interest by Preferred Term 
Study specific AESI 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.24. (3.1024) 
Safety 
SAFE_T13 
Progressive Multifocal Leukocephalopathy (PML) 
Adverse Events of Special Interest by Preferred Term 
Study specific AESI 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.25. (3.1025) 
Safety 
SAFE_T13 
Biopsy Adverse Events of Special Interest by Preferred 
Term 
Study specific AESI 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.26. (3.1026) 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.27. (3.1027) 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class 
No preferred term breakdown 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.28. (3.1028) 
Safety 
AE1 
Summary of Adverse Events Leading to Discontinuation 
of Study Treatment or Withdrawal from Study by System 
Organ Class and Preferred Term 
EACTRCD and AEWD 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.29. (3.1029) 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) 
FDAAA, EudraCT 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
3.30. (3.1030) 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
3.31. (3.1031) 
Safety 
AE1 
Summary of Fatal Adverse Events by System Organ 
Class and Preferred Term 
EoS: Include visits upto W68/FU 
EoS Footnote: Add as T3.1002 
SAC_WK52 [2] 
SAC_EOS [3] 
Labs 
3.32. (3.1032) 
Safety 
LB1 
Summary of Hematology Laboratory Values 
EoS: Include all scheduled visits 
Add footnote:  
Basophils% = % of leukocytes; 
Eosinophils% = % of leukocytes 
SAC_WK52 [2] 
SAC_EOS [3] 
3.33. (3.1033) 
Safety 
LB1 
Summary of Hematology Changes from Baseline  
EoS: Include all scheduled visits 
ICH E3 
Includes baseline values. 
Add footnote:  
Basophils% = % of leukocytes; 
Eosinophils% = % of leukocytes 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.34. (3.1034) 
Safety 
SAFE_T5 
Laboratory Reference Range Shifts from Baseline: 
Hematology 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.35. (3.1035) 
Safety 
SAFE_T1 
Worst Laboratory Toxicity Grade: Hematology 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.36. (3.1036) 
Safety 
SAFE_T2 
Laboratory Toxicity Grade Worsening of at Least 2 
Grades from Baseline: Hematology 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.37. (3.1037) 
Safety 
LB1 
Summary of Clinical Chemistry Laboratory Values 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.38. (3.1038) 
Safety 
LB1 
Summary of Changes from Baseline: Clinical Chemistry 
Laboratory Values 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.39. (3.1039) 
Safety 
SAFE_T1 
Worst Laboratory Toxicity Grade: Clinical Chemistry 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.40. (3.1040) 
Safety 
SAFE_T2 
Laboratory Toxicity Grade Worsening of at Least 2 
Grades from Baseline: Clinical Chemistry 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.41. (3.1041) 
Safety 
SAFE_T6 
Summary of Liver Assessments  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.42. (3.1042) 
Safety 
UR3 
Summary of Urinalysis Dipstick Results 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.43. (3.1043) 
Safety 
LB1 
Summary of Protein/Creatinine Ratio 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.44. (3.1044) 
Safety 
LB1 
Summary of Immunoglobulins by Visit 
EoS: Include all scheduled visits 
Page by parameter: IgG, IgA, IgM,  
SAC_WK52 [2] 
SAC_EOS [3] 
3.45. (3.1045) 
Safety 
LB1 
Summary of Change from Baseline in Immunoglobulins 
by Visit 
EoS: Include all scheduled visits 
Page by parameter: IgG, IgA, IgM, 
SAC_WK52 [2] 
SAC_EOS [3] 
3.46. (3.1046) 
Safety 
SAFE_T1 
Worst Laboratory Toxicity Grade: Immunoglobulin 
EoS: Include all scheduled visits 
Includes IgG only 
Include footnote for baseline 
SAC_WK52 [2] 
SAC_EOS [3] 
3.47. (3.1047) 
Safety 
SAFE_T2 
Laboratory Toxicity Grade Worsening of at Least 2 
Grades from Baseline: Immunoglobulin 
EoS: Include all scheduled visits 
Includes IgG only 
Include footnote for baseline 
SAC_WK52 [2] 
SAC_EOS [3] 
3.48. (3.1048) 
Safety 
SAFE_T4 
Immunoglobulins below LLN 
EoS: Include all scheduled visits 
Page by parameter: IgG, IgA, IgM, 
SAC_WK52 [2] 
SAC_EOS [3] 
3.49. (3.1049) 
Safety 
SAFE_T4 
Immunoglobulins above ULN 
EoS: Include all scheduled visits 
Page by parameter: IgG, IgA, IgM, 
SAC_WK52 [2] 
SAC_EOS [3] 
3.50. (3.1050) 
Safety 
LB1 
Summary of C-Reactive Protein  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.51. (3.1051) 
Safety 
LB1 
Summary of Changes from Baseline in C-Reactive 
Protein  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
3.52. (3.1052) 
Safety 
VS1 
Summary of Vital Signs 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.53. (3.1053) 
Safety 
VS1 
Summary of Change from Baseline for Vital Signs 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
ECG 
3.54.  
Safety 
EG1 
Summary of ECG Findings 
Screening Visit Only 
SAC_WK52 [2] 
3.55.  
Safety 
EG2 
Summary of Screening ECG 
Include all intervals  
SAC_WK52 [2] 
TBNK 
3.56. (3.1056) 
Safety 
LB1 
Summary of CD4 and CD8  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.57. (3.1057) 
Safety 
LB1 
Summary of Changes from Baseline in CD4 and CD8  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
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Safety: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Neurological Symptoms 
3.58. (3.1058) 
Safety 
SAFE_T3 
Summary of Neurological Symptoms 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
Columbia-Suicide Severity Rating Scale 
3.59. (3.1059) 
Safety 
ECSSRS1 
Summary of C-SSRS Suicidal Ideation or Behaviour 
During Treatment 
EoS: Include all scheduled visits 
Include summaries for both lifetime and 
current state. 
SAC_WK52 [2] 
SAC_EOS [3] 
3.60. (3.1060) 
Safety 
ECSSRS2 
Summary of Treatment-Emergent C-SSRS Suicidal 
Ideation or Behaviour Relative to Pre-treatment 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
3.61. (3.1061) 
Safety 
ECSSRS3 
Shift Table of Changes in C-SSRS Categories from Pre-
Treatment to On-Treatment 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
Immunogenicity 
3.62. (3.1062) 
Safety 
SAFE_T14 
Summary of Immunogenic Response by Visit 
EoS: Include all scheduled visits 
Belimumab antibodies 
Rituximab antibodies 
EoS Footnote: 
For anti-Rituximab, baseline is Week 8 
SAC_WK52 [2] 
SAC_EOS [3] 
Further Analyses 
3.1063 
Safety 
SAFE_10 
Post-IV Systemic Reactions per Anaphylactic Reactions 
CMQ Broad search by PT, in First Two 2 Infusions of 
Rituximab/Placebo 
All infusion column would include the 
overall study treatment 
SAC_EOS [3] 
 
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11.13.8. 
Safety Figures 
Safety: Figures 
No.  
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Lab 
3.1 (3.1001) 
Safety 
EFF_F1 
Mean (+/- SE) of Hematology 
EoS: As F2.1001 
Parameters for SAC:  
WBC count, Neutrophil counts, 
Haemoglobin, Platelets, Lymphocytes, 
Hematocrit, Monocytes, Eosinophils, 
Basophils 
All visits contained with the summary 
source table, with Day 0 being included as 
part of the plot 
SAC_WK52 [2] 
SAC_EOS [3] 
3.2 (3.1002) 
Safety 
EFF_F4 
Median (+/- IQR) of Immunoglobulins 
EoS: As F2.1001 
x-axis is visit, line per treatment group. 
SAC_WK52 [2] 
SAC_EOS [3] 
3.3 (3.1003) 
Safety 
EFF_F4 
Median (+/- IQR) of Change from baseline of 
Immunoglobulins 
EoS: As F2.1001 
x-axis is visit, panel per treatment group. 
Include IgG, IgA and IgM. 
SAC_WK52 [2] 
SAC_EOS [3] 
3.4 (3.1004) 
Safety 
EFF_F1 
Median (+/- IQR) of Absolute Values of CD4 and CD8 
EoS: As F2.1001 
x-axis is visit, line per treatment group. 
SAC_WK52 [2] 
SAC_EOS [3] 
 
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11.13.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
4.1. 
PK-B 
PK01 
Summary of Plasma Belimumab Pharmacokinetic 
Concentration-Time Data (ng/mL)  
Include 3 columns:  
Combination, Belimumab, Total 
SAC_WK52 [2] 
4.2. 
PK-B 
PK01 
Summary of Plasma Belimumab Pharmacokinetic 
Concentration-Time Data (g/mL) by Baseline Body Weight 
Quartiles 
Include 3 columns:  
Combination, Belimumab, Total 
SAC_WK52 [2] 
4.3. 
PK-R 
PK01 
Summary of Plasma Rituximab Pharmacokinetic 
Concentration-Time Data (ng/mL) 
Include 3 columns: 
Combination, Rituximab, Total 
SAC_WK52 [2] 
4.4. 
PK-B 
PK01 
Summary of Plasma Belimumab Pharmacokinetic 
Concentration-Time Data (g/mL) by Belimumab 
Immunogenicity Status  
Include 3 columns:  
Combination, Belimumab, Total Produce if 
≥6 subjects in total have positive 
belimumab immunogenicity.  
SAC_WK52 [2] 
 
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11.13.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Plots 
4.1. (4.1001) 
PK-B 
PKCF1P 
Individual Belimumab Plasma Concentration-Time Plot by 
Treatment (Linear and Semi-Log) 
Paginate by Treatment 
Combo and Bel Arms 
NOTE: Ensure treatment legends can be 
differentiated 
SAC_EOS [3] 
4.2. (4.1002) 
PK-R 
PKCF1P 
Individual Rituximab Plasma Concentration-Time Plot by 
Treatment (Linear and Semi-Log) 
Paginate by Treatment 
Combo and Ritux Arms 
NOTE: Ensure treatment legends can be 
differentiated  
SAC_EOS [3] 
Median Plots 
4.3.  
PK-B 
PKCF3 
Median Plasma Belimumab Concentration-Time Plots by 
Treatment (Linear and Semi-log) 
Combo and Bel Arms 
SAC_WK52 [2] 
4.4.  
PK-B 
PKCF3 
Median Plasma Belimumab Concentration-Time Plots by 
Body Weight Quartile (Linear and Semi-log) 
Combo and Bel Arms 
SAC_WK52 [2] 
4.5.  
PK-R 
PKCF3 
Median Plasma Rituximab Concentration-Time Plots by 
Treatment (Linear and Semi-log) 
Combo and Ritux Arms 
SAC_WK52 [2] 
 
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11.13.11. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic: Figures 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 
5.1. 
Safety 
PKPD_F1 
Scatterplot of CD19+ B cells Versus Belimumab 
Concentration 
2 panels: combo and bel 
Individual subject data  
y-axis=CD19+ B cells (from TBNK panel 
CONC record) 
x-axis=Belimumab concentration 
SAC_WK52 [2] 
 
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11.13.12. Health Outcomes Tables 
Health Outcomes: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ESSPRI Score 
6.1. (6.1001) 
Safety 
EFF_T1 
Summary Statistics of ESSPRI Total Score and 
Domains 
EoS: Include all scheduled visits 
Summarize for both the overall score and 3 
domains (dryness, fatigue and pain) 
SAC_WK52 [2] 
SAC_EOS [3] 
6.2. (6.1002) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
ESSPRI Total Score and Domains 
EoS: Include all scheduled visits 
Summarized for both the overall score and 
3 domains (dryness, fatigue and pain) 
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
6.3. (6.1003) 
Per 
Protocol 
EFF_T1 
Summary Statistics of Change from Baseline: 
ESSPRI Total Score and Domains 
EoS: Include all scheduled visits 
Summarized for both the overall score and 
3 domains (dryness, fatigue and pain) 
SAC_WK52 [2] 
SAC_EOS [3] 
6.4. (6.1004) 
Safety 
EFF_T4 
Summary of ESSPRI Responders 
EoS: Include all scheduled visits 
Footnote: 
Responder 1: Decrease in the ESSPRI total 
score of at least one point or at least 15% 
compared to baseline 
HL [1] 
SAC_WK52 [2] 
SAC_EOS [3] 
6.5. (6.1005) 
Per 
Protocol 
EFF_T4 
Summary of ESSPRI Responders 
EoS: Include all scheduled visits 
Footnote: 
Responder 1: Decrease in the ESSPRI total 
score of at least one point or at least 15% 
compared to baseline 
SAC_WK52 [2] 
SAC_EOS [3] 
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Health Outcomes: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.6.  
Safety 
EFF_T7 
Summary of Statistical Analysis of Responders on 
ESSPRI 
Footnote: 
Responder 1: Decrease in the ESSPRI total 
score of at least one point or at least 15% 
compared to baseline 
Responder 2: Subjects with baseline score 
of >= 5 and Total ESSPRI score of < 5. The 
denominator for percentages at each visit 
are the subjects who had a score >= 5 at 
baseline. 
Note: Add the final model parameters 
SAC_WK52 [2] 
PROFAD SSI SF 
6.7. 
Safety 
EFF_T1 
Summary Statistics of PROFAD SSI SF Subscores 
Summarize for the 3 subscores (PROF, 
PROFAD, SSI) 
Footnote (if feasible):  
1. PROF is calculated as the sum of 
domains Somatic fatigue and Mental 
fatigue 
2. PROFAD is calculated as the sum of 
domains Somatic fatigue, Mental fatigue, 
Arthralgia and Vascular 
3. SSI is calculated as the sum of domains 
Cutaneous dryness, Vaginal dryness, 
Ocular dryness and Oral dryness. The SSI 
subscore is derived for females only. 
SAC_WK52 [2] 
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Health Outcomes: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.8. 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline in 
PROFAD SSI SF Subscores 
Summarize for the 3 subscores (PROF, 
PROFAD, SSI) 
Footnote (if feasible):  
1. PROF is calculated as the sum of 
domains Somatic fatigue and Mental 
fatigue 
2. PROFAD is calculated as the sum of 
domains Somatic fatigue, Mental fatigue, 
Arthralgia and Vascular 
3. SSI is calculated as the sum of domains 
Cutaneous dryness, Vaginal dryness, 
Ocular dryness and Oral dryness. The SSI 
subscore is derived for females only. 
SAC_WK52 [2] 
PtGA 
6.9. 
Safety 
EFF_T1 
Summary Statistics of PtGA 
 
SAC_WK52 [2] 
6.10. 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: PtGA 
 
SAC_WK52 [2] 
Further Health Outcomes Analyses 
6.11. 
Safety 
EFF_T11 
Summary of Bayesian Posterior Probabilities: ESSPRI 
Total Score 
To be generated by GSK 
Add appropriate footnotes based on final 
output 
SAC_WK52 [2] 
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Health Outcomes: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.14. (6.1014) 
Safety 
EFF_T4 
Summary of ESSPRI Responders 
EoS: Include all scheduled visits 
Footnote: 
Responder 1: Decrease in the ESSPRI total 
score of at least one point or at least 15% 
compared to baseline 
Responder 2: Subjects with baseline score 
of >= 5 and Total ESSPRI score of < 5. The 
denominator for percentages at each visit 
are the subjects who had a score >= 5 at 
baseline. 
SAC_WK52 [2] 
SAC_EOS [3] 
(6.1015) 
Completer 
EFF_T1 
Summary Statistics of ESSPRI Total Score and 
Domains – Completer 
Include all scheduled visits 
Summarize for both the overall score and 3 
domains (dryness, fatigue and pain) 
Add footnote: 
Note: Completer is defined as “Subjects 
who completed the 52 Week treatment 
visits AND general follow up phase of the 
study including the visit at Week 68” 
SAC_EOS [3] 
 
 
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11.13.13. Health Outcomes Figures 
Health Outcomes: Figures 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ESSPRI Score 
6.1. (6.1001) 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline of ESSPRI 
Total Score and Domains 
EoS: As F2.1 
Intervals with compose of arithmetic mean 
 SE. All visits. Legend: Treatment 
SAC_WK52 [2] 
SAC_EOS [3] 
6.2. (6.1002) 
Safety 
EFF_F3 
Proportion of Subjects with an ESSPRI Response 
EoS: Include all scheduled visits 
Footnote: Responder 1: Decrease in the 
ESSPRI total score of at least one point or 
at least 15% compared to baseline 
Responder 2: Subjects with baseline score 
of ≥ 5 and Total ESSPRI score of < 5 at 
each visit. The denominator for 
percentages are the subjects who had a 
score >=5 at baseline at each visit. 
SAC_WK52 [2] 
SAC_EOS [3] 
PROFAD SSI SF 
6.3. 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline PROFAD 
SSI SF Subscores 
Parameter by: Subscores 
Intervals with compose of arithmetic mean 
 SE. All visits. Legend: Treatment 
SAC_WK52 [2] 
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11.13.14. Exploratory Tables 
Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
Ocular Dryness 
7.1. (7.1001) 
Safety 
EFF_T1 
Summary Statistics of Ocular Dryness Score 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
7.2. (7.1002) 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
Ocular Dryness Score 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
Lacrimal Gland Function 
7.3. 
Safety 
EFF_T1 
Summary Statistics: Lacrimal Gland Function 
(Schirmer’s test) 
Page by: Laterality 
Parameter: Strip length wet (mm/min) 
Footnote:  
Note: Unit = mm/min 
SAC_WK52 [2] 
7.4. 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
Lacrimal Gland Function (Schirmer’s test) 
Page by: Laterality 
Parameter: Strip length wet (mm/min) 
Footnote:  
Note: Unit = mm/min 
SAC_WK52 [2] 
PGA 
7.5. 
Safety 
EFF_T1 
Summary Statistics of PGA 
 
SAC_WK52 [2] 
7.6. 
Safety 
EFF_T1 
Summary Statistics of Change from Baseline: 
PGA 
 
SAC_WK52 [2] 
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Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
Serologic Markers 
7.7. (7.1007) 
Safety 
EFF_T1 
Summary Statistics of Serologic Markers 
Page by marker  
Include all visits up to Week 68 
EoS: Include all scheduled visits 
Lambda and Kappa Light Chains 
Ratio of Kappa / Lambda 
Beta 2 Microglobulin 
Rheumatoid Factor 
SAC_WK52 [2] 
SAC_EOS [3] 
7.8. (7.1008) 
Safety 
EFF_T9 
Summary Statistics Percentage Change from 
Baseline: Serologic Markers 
Page by marker  
Include all visits up to Week 68 
EoS: Include all scheduled visits 
Ratio of Kappa /Lambda Light Chains 
Beta 2 Microglobulin 
Rheumatoid Factor 
SAC_WK52 [2] 
SAC_EOS [3] 
Flow Cytometry Parameters 
7.9. (7.1009) 
Safety 
EFF_T9 
Summary Statistics of Flow Cytometry Flow 
Parameters 
Include all parameters specified in RAP 
Table 11 except for: 
• 
Plasmablasts (CD38br CD27br 
CD20+) 
• 
Plasmacells CD20+ (CD20+ 
CD138+) 
• 
Short-lived Plasma (CD20- 
CD27br) 
• 
Transitional (CD24+ CD27-) 
• 
Naïve B cells (CD24-CD38br+) 
• 
B cells CD20+ (CD19+CD20+) 
SAC_WK52 [2] 
SAC_EOS [3] 
7.10. (7.1010) 
Safety 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Flow Cytometry Parameters 
Include all parameters specified in RAP 
Table 11 for the Final Analysis except 
for: 
• 
Plasmablasts (CD38br CD27br 
CD20+) 
HL [1] SAC_WK52 [2] 
SAC_EOS [3] 
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Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
• 
Plasmacells CD20+ (CD20+ 
CD138+) 
• 
Short-lived Plasma (CD20- 
CD27br) 
• 
Transitional (CD24+ CD27-) 
• 
Naïve B cells (CD24-CD38br+) 
• 
B cells CD20+ (CD19+CD20+) 
7.11. (7.1011) 
Safety 
EFF_T10 
Summary of Statistical Analysis Results of 
Percentage Change from Baseline in: Flow 
Cytometry Parameters at Week 24 
 
EOS: 
Summary of Statistical Analysis Results of 
Change from Baseline in: Flow Cytometry 
Parameters at Week 24 
Include only the below parameters for 
analysis 
• 
CD19+ B cell (CD3-CD19+)  
• 
Naïve B cell (CD19+CD20+CD27-)  
• 
Memory B cell 
(CD19+CD20+CD27+) 
• 
Activated B Cell (CD20+ CD69+) 
• 
Plasmablast All 
(CD19+CD27+CD38+)  
• 
Plasmablast (CD20+) 
• 
Plasmablast (CD20-) 
• 
Transitional B cells 
(CD19+CD24bCD38+CD27-) 
Footnote: Analysis performed using 
Hodges-Lehmann estimator based on 
Wilcoxon rank test for 2 sample 
populations. 
SAC_WK52 [2] 
SAC_EOS [3] 
7.12. 
 
Per 
Protocol 
EFF_T10 
Summary of Statistical Analysis Results of 
Percentage Change from Baseline in: Flow 
Cytometry Parameters at Week 24 
Include only the below parameters for 
analysis 
• 
CD19+ B cell (CD3-CD19+)  
• 
Naïve B cell (CD19+CD20+CD27-)  
• 
Memory B cell 
(CD19+CD20+CD27+) 
• 
Activated B Cell (CD20+CD69+) 
• 
Plasmablast All 
SAC_WK52 [2] 
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No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
(CD19+CD27+CD38+)  
• 
Plasmablast (CD20+) 
• 
Plasmablast (CD20-) 
• 
Transitional B cells 
(CD19+CD24bCD38+CD27-) 
Footnote: Analysis performed using 
Hodges-Lehmann estimator based on 
Wilcoxon rank test for 2 sample 
populations. 
7.13. 
 
(7.1013) 
Safety 
EFF_T10 
Summary of Statistical Analysis Results of 
Percentage Change from Baseline in: Flow 
Cytometry Parameters at Week 52 
 
EoS 
Summary of Statistical Analysis Results of 
Change from Baseline in: Flow Cytometry 
Parameters at Week 52 
Include only the below parameters for 
analysis 
CD19+ B cell (CD3-CD19+)  
Naïve B cell (CD19+CD20+CD27-)  
Memory B cell (CD19+CD20+CD27+)  
Activated B Cell (CD20+CD69+) 
Plasmablast All (CD19+CD27+CD38+)  
Transitional B cells 
(CD19+CD24bCD38+CD27-) 
Plasmablast (CD20+) 
Plasmablast (CD20-) 
Footnote: Analysis performed using 
Hodges-Lehmann estimator based on 
Wilcoxon rank test for 2 sample 
populations. 
SAC_WK52 [2] 
SAC_EOS [3] 
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Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
BLyS 
7.14. (7.1014) 
Safety 
EFF_T9 
Summary Statistics of Free BLyS Levels in 
Blood 
EoS: 
Summary Statistics of Free and Total BLyS 
Levels in Blood 
EoS: Include all scheduled visits 
Subset BICATCD = ”TNF13BPF”  
SAC_WK52 [2] 
SAC_EOS [3] 
7.15. (7.1015) 
Safety 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Free BLyS Levels in Blood 
EoS: 
Summary Statistics of Free and Total BLyS 
Levels in Blood 
EoS: Include all scheduled visits 
Subset BICATCD = ”TNF13BPF” 
SAC_WK52 [2] 
SAC_EOS [3] 
7.16. (7.1016) 
Per 
Protocol 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Free BLyS Levels in Blood 
EoS 
Summary Statistics of Free and Total BLyS 
Levels in Blood 
EoS: Include all scheduled visits 
Subset BICATCD = ”TNF13BPF” 
SAC_WK52 [2] 
SAC_EOS [3] 
Complement Factors 
7.17. (7.1017) 
Safety 
EFF_T9 
Summary Statistics of Complement Factors 
EoS: Include all scheduled visits 
To be run on C3, C4 
SAC_WK52 [2] 
SAC_EOS [3] 
7.18. (7.1018) 
Safety 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Complement Factors 
EoS: Include all scheduled visits 
To be run on C3, C4 
Note: For SAC_EOS [3] - Include 
protocol defined Serological biomarkers 
SAC_WK52 [2] 
SAC_EOS [3] 
7.19. (7.1019) 
Safety 
PD_T1 
Summary of CH50 by Visit 
Frequency count 
SAC_WK52 [2] 
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Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
SAC_EOS [3] 
Serum Cytokines and Chemokines 
7.20. (7.1020) 
Safety 
EFF_T9 
Summary Statistics of Serum Cytokines and 
Chemokines 
EoS: Include all scheduled visits 
CXCL13 
NOTE: BICATCD=BLC = BICAT = B-
lymphocyte chemokine 
 
Add footnote: 
Note: B-lymphocyte Chemokine = 
CXCL13 
SAC_WK52 [2] 
SAC_EOS [3] 
7.21. (7.1021) 
Safety 
EFF_T9 
Summary Statistics of Percentage Change from 
Baseline: Serum Cytokines and Chemokines 
EoS: Include all scheduled visits 
CXCL13 
NOTE: BICATCD=BLC = BICAT = B-
lymphocyte chemokine 
 
Add footnote: 
Note: B-lymphocyte Chemokine = 
CXCL13 
SAC_WK52 [2] 
SAC_EOS [3] 
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Exploratory: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
SS-A and SS-B 
7.22. (7.1022) 
Safety 
PD_T2 
Summary of Autoantibodies by Visit 
EoS: Include all scheduled visits 
Frequency count of SS-A and SS-B at 
final 
SAC_WK52 [2] 
SAC_EOS [3] 
Further Evaluation 
(7.1023) 
Completer 
EFF_T9 
Summary Statistics of Flow Cytometry Flow 
Parameters – Completer 
Include all parameters specified in RAP 
Table 11 except for: 
• 
Plasmablasts (CD38br CD27br 
CD20+) 
• 
Plasmacells CD20+ (CD20+ 
CD138+) 
• 
Short-lived Plasma (CD20- 
CD27br) 
• 
Transitional (CD24+ CD27-) 
• 
Naïve B cells (CD24-CD38br+) 
B cells CD20+ (CD19+CD20+) 
 
Add footnote: 
Note: Completer is defined as “Subjects 
who completed the 52 Week treatment 
visits AND general follow up phase of 
the study including the visit at Week 68” 
SAC_EOS [3] 
 
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11.13.15. Exploratory Figures 
Exploratory: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Ocular Dryness NRS 
7.1. (7.1001) 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in 
Ocular Dryness NRS 
All scheduled visits 
Legend: Treatment 
EoS: As F2.1001 
SAC_WK52 [2] 
SAC_EOS [3] 
Lacrimal Gland Function 
7.2. 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in 
Lacrimal Gland Function (Schirmers Test) 
All scheduled visits 
Legend: Treatment 
EoS: As F2.1001 
SAC_WK52 [2] 
PGA 
7.3. 
Safety 
EFF_F1 
Mean (+/- SE) of Change from Baseline in PGA 
All scheduled visits 
Legend: Treatment 
SAC_WK52 [2] 
Flow Cytometry 
7.4. (7.1004) 
Safety 
EFF_F4 
Median (+/- IQR) of Absolute Values of Flow 
Cytometry 
EoS:  As F2.1001 
Include only the following parameters (Page 
by) 
• 
CD19+ B cell (CD3-CD19+)  
• 
Naïve B cell (CD19+CD20+CD27-)  
• 
Memory B cell (CD19+CD20+CD27+)  
• 
Activated B Cell (CD20+CD69+) 
• 
Plasmablast All (CD19+CD27+CD38+)  
• 
Transitional B cells 
(CD19+CD24bCD38+CD27-) 
• 
Plasmablast CD20+ 
• 
Plasmablast CD20- 
x-axis is visit, y-axis in absolute values of the 
parameters. Panel per treatment group. 
SAC_WK52 [2] 
SAC_EOS [3] 
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Exploratory: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
7.5. (7.1005) 
Safety 
EFF_F4 
Median (+/- IQR) for Percentage Change from 
Baseline in Flow Cytometry  
EoS: As F2.1001 
• 
CD19+ B cell (CD3-CD19+)  
• 
Naïve B cell (CD19+CD20+CD27-)  
• 
Memory B cell (CD19+CD20+CD27+)  
• 
Activated B Cell (CD20+CD69+) 
• 
Plasmablast All (CD19+CD27+CD38+)  
• 
Transitional B cells 
(CD19+CD24bCD38+CD27-) 
• 
Plasmablast CD20+ 
• 
Plasmablast CD20- 
x-axis is visit, y-axis in percentage change 
from baseline of the parameters. Panel per 
treatment group. 
SAC_WK52 [2] 
SAC_EOS [3] 
Blys 
7.6. (7.1006) 
Safety 
EFF_F4 
Median (+/- IQR) for Percentage Change from 
Baseline in Free Blys 
EoS 
Median (+/- IQR) for Percentage Change from 
Baseline in Free and Total Blys 
EoS: EoS: As F2.1001 
x-axis is visit, panel by parameter (Free & 
Total BLyS). 
SAC_WK52 [2] 
SAC_EOS [3] 
Serologic Biomarkers 
7.7. (7.1007) 
Safety 
EFF_F4 
Median (+/- IQR) for Percentage Change from 
Baseline in Serological Biomarkers 
EoS: EoS: As F2.1001 
Include Rheumatoid Factor, Lambda light 
chain protein, Kappa light chain protein, 
Kappa/Lambda ratio, Beta 2 microglobulin 
SAC_WK52 [2] 
SAC_EOS [3] 
Complement Factors 
7.8. (7.1008) 
Safety 
EFF_F4 
Median (+/- IQR) for Percentage Change from 
Baseline in Complement Factors 
EoS: EoS: As F2.1001 
Include C3 and C4 
SAC_WK52 [2] 
SAC_EOS [3] 
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Exploratory: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Serum Chemokines 
7.9. (7.1009) 
Safety 
EFF_F4 
Median (+/- IQR) for Percentage Change from 
Baseline in CXCL13 
EoS: EoS: As F2.1001 
NOTE: BICATCD=BLC = BICAT = B-
lymphocyte chemokine 
SAC_WK52 [2] 
SAC_EOS [3] 
 
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11.13.16. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Study Population 
1.  
Safety 
TA1 
Listing of Randomized and Actual Treatments 
 
SAC_WK52 [2] 
2. (1002) 
Safety 
ES2 
Listing of Reasons for Study Withdrawal 
 
SAC_WK52 [2] 
SAC_EOS [3] 
3.  
Safety 
POP_L1 
Listing of Reasons for Permanent Study Treatment 
Discontinuation 
 
SAC_WK52 [2] 
4.  
Screened 
ES7 
Listing of Reasons for Screening Failure 
 
SAC_WK52 [2] 
5. (1005) 
Safety 
SP3 
Listing of Subjects Excluded from Any Populations 
 
SAC_WK52 [2] 
SAC_EOS [3] 
6. (1006) 
Safety 
DV2 
Listing of Important Protocol Deviations 
 
SAC_WK52 [2] 
SAC_EOS [3] 
7.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
 
SAC_WK52 [2] 
Demographics 
8.  
Safety 
DM2 
Listing of Demographic Characteristics 
 
SAC_WK52 [2] 
9.  
Safety 
DM9 
Listing of Race 
 
SAC_WK52 [2] 
10. (1010) 
Safety 
POP_L2 
Listing of Physical Exam 
 
SAC_WK52 [2] 
SAC_EOS [3] 
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ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Medical Condition & Concomitant Medications 
11.  
Safety 
MH2 
Listing of Medical Conditions (Sjögren specific) 
iSRC version has all medical conditions 
SAC_WK52 [2] 
12.  
Safety 
MH2 
Listing of Medical Conditions (non-Sjögren specific) 
 
SAC_WK52 [2] 
13. (1013) 
Safety 
CP_CM3 
Listing of Concomitant Medications 
 
SAC_WK52 [2] 
SAC_EOS [3] 
Disease History 
14.  
Safety 
POP_L3 
Listing of Disease Characteristics (AECG Criteria) 
 
SAC_WK52 [2] 
Exposure 
15.  
Safety 
OEX3a 
Listing of Exposure 
 
SAC_WK52 [2] 
Adverse Events 
16. (1016) 
Safety 
AE7 
Listings of Subject Numbers for Individual Adverse 
Events 
EoS: Include visits upto W68/FU 
EoS Footnote: 
Note: Includes Treatment & General 
Follow Up periods only. 
SAC_WK52 [2] 
SAC_EOS [3] 
17. (1017) 
Safety 
AE8 
Listing of All Adverse Events 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
18. (1018) 
Safety 
AE8 
Listing of Post Treatment Adverse Events 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
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ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
19. (1019) 
Safety 
SAFE_L3 
Listing of Adverse Events of Special Interest 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
Include all AESI, including study 
specific  
SAC_WK52 [2] 
SAC_EOS [3] 
20. (1020) 
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
21. (1021) 
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
22. (1022) 
Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
23. (1023) 
Safety 
AE8 
Listing of Adverse Events Leading to 
Discontinuation of Treatment or Withdrawal from 
Study  
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
24. (1024) 
Safety 
AE2 
Listing of Relationship between System Organ 
Class and Verbatim Text 
EoS: Include visits upto W68/FU 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
 SAC_EOS [3] 
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ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
25. (1025) 
Safety 
LB5 
Listing of Hematology Laboratory Data  
EoS: Include all scheduled visits 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
26. (1026) 
Safety 
LB5 
Listing of Clinical Chemistry Laboratory Data  
EoS: Include all scheduled visits 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
27. (1027) 
Safety 
LB5 
Listing of Liver Function Laboratory Data 
EoS: Include all scheduled visits 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
28. (1028) 
Safety 
UR2a 
Listing of Urinalysis Data  
EoS: Include all scheduled visits 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
29. (1029) 
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
EoS: Include all scheduled visits 
EoS Footnote: As Listing 1016 
SAC_WK52 [2] 
SAC_EOS [3] 
Vital Signs 
30. (1030) 
Safety 
VS4 
Listing of Vital Signs  
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
ECGs 
31.  
Safety 
EG5 
Listing of Abnormal ECG Findings 
 
SAC_WK52 [2] 
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ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Other 
(1061) 
Safety 
DV2 
Listing of Protocol Deviations Related to Covid-19 
Include only subjects with related 
Covid-19 PD’s. 
Subset standard text ‘COVID-19’.   
SAC_EOS [3] 
 
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11.13.17. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Safety 
32. (1032) 
Safety 
SAFE_L1 
Listing of Neurological Symptoms 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
33. (1033) 
Safety 
ECSSRS4 
Listing of C-SSRS Suicidal Ideation and Behavior 
Data 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
34. (1034) 
Safety 
ECSSRS5 
Listing of C-SSRS Suicidal Behavior Details 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
35. (1035) 
Safety 
SAFE_L2 
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Hematology 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
36. (1036) 
Safety 
SAFE_L2 
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Clinical Chemistry 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
37. (1037) 
Safety 
SAFE_L2 
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Immunoglobulin 
EoS: Include all scheduled visits 
IgG only 
SAC_WK52 [2] 
SAC_EOS [3] 
38.  
Safety 
SAFE_L4 
Listing of Positive Results for Other Screening 
Tests 
Include HIV, Hepatitis B (HBsAg), 
HbcAb, Hepatitis C (Hep C antibody), 
FSH, estradiol and serum or urine hCG 
pregnancy test. 
SAC_WK52 [2] 
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Non-ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
39. (1039) 
Safety 
IMM2 
Listing of Positive Immunogenicity Results 
Primary 
Belimumab 
 
EoS  
Belimumab & Rituximab Results 
All antibody and assay data 
 
Footnote: 
For anti-Rituximab, baseline is Week 8 
SAC_WK52 [2] 
SAC_EOS [3] 
40. (1040) 
Safety 
LB5 
Listing of Immunoglobulins 
Define flags "I" "N" "U" etc… in the 
footnotes 
SAC_WK52 [2] 
SAC_EOS [3] 
41. (1041) 
Safety 
LB5 
Listing of CD4 and CD8 
EoS: Include all scheduled visits 
SAC_WK52 [2] 
SAC_EOS [3] 
Efficacy 
42. (1042) 
Safety 
EFF_L1 
Listing of ESSDAI Responses 
EoS: Include all scheduled visits 
At SAC Include Total ESSDAI, 
ClinESSDAI and individual domains 
SAC_WK52 [2]  
SAC_EOS [3] 
43. (1043) 
Safety 
EFF_L2 
Listing of Damage Scoring for Subjects with 
Damage 
EoS: Include all scheduled visits 
For each subject with damage.  All 
timepoints, but only in domain which 
has any damage reported.  
SAC_WK52 [2] 
SAC_EOS [3] 
44. (1044) 
Safety 
EFF_L3 
Listing of Change from Baseline of Clinical Efficacy 
Endpoints and Number of B cells (CD20/mm2) in 
salivary gland. 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
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Non-ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
45. (1045) 
Safety 
EFF_L4 
Listing of Stimulated and Unstimulated Salivary 
Flow 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
46. (1046) 
Safety 
EFF_L5 
Listing of Oral and Ocular Dryness NRS 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
47.  
Safety 
EFF_L6 
Listing of Lacrimal Function (Schirmer’s) Test 
To be generated by GSK 
SAC_WK52 [2] 
48.  
Safety 
EFF_L7 
Listing of PROFAD-SSI-SF Subscores 
To be generated by GSK 
SAC_WK52 [2] 
49.  
Safety 
EFF_L8 
Listing of Patient Global Assessment (PtGA) 
To be generated by GSK 
SAC_WK52 [2] 
50.  
Safety 
EFF_L9 
Listing of Physicians Global Assessment (PGA) 
To be generated by GSK 
SAC_WK52 [2] 
51. (1051) 
Safety 
EFF_L10 
Listing of Free and Total BLyS Levels 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
52. (1052) 
Safety 
EFF_L11 
Listing of Flow Cytometry Parameters 
EoS: Include all scheduled visits 
Include all parameters 
Page by: Parameters 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
53. (1053) 
Safety 
EFF_L11 
Listing of Serologic Markers 
EoS: Include all scheduled visits 
Include all parameters 
Page by: Parameters 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
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Non-ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
54.  
Safety 
EFF_L11 
Listing of Salivary Gland Assessment 
Include all parameters 
Page by: Parameters 
To be generated by GSK 
SAC_WK52 [2] 
55. (1056) 
Safety 
EFF_L12 
Listing of ESSPRI Score 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
541 (1057) 
Safety 
EFF_L11 
Listing of Complement Factors (CH50) 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
542 (1058) 
Safety 
EFF_L11 
Listing of Complement Factors (Biomarkers) 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
1059. 
Safety 
POP_L4 
Listing of Overall Subject Status 
EoS: Include all scheduled visits 
To be generated by GSK 
SAC_EOS [3] 
411 (1411) 
Safety 
SAFE_L4 
Listing of All Adverse Events Post Week 68 during 
the Individualized Follow Up Period 
Primary: Blinded listing 
EoS: Unblinded listing 
To be generated by GSK 
SAC_WK52 [2] 
SAC_EOS [3] 
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11.14. 
Appendix 14: Example Mock Ups 
Data Display Specification are presented in a separate document. 
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