Conditions: Systemic Lupus Erythematosus
Keywords: treatment holiday PGA belimumab Lymphostat-B rebound SELENA SLEDAI Systemic Lupus Erythematosus immunogenicity
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This study will assess the effect of a 24-week withdrawal followed by a 28-week reintroduction of belimumab 10 mg/kg plus standard of care medications in subjects with stable low systemic lupus erythematosus (SLE) disease activity. Rebound phenomenon will be assessed for subjects who have permanently withdrawn from further belimumab treatment.

Detailed description:
This study will assess the effect of a 24-week withdrawal of belimumab followed by a 28-week reintroduction of belimumab 10 mg/kg plus standard of care medications on immunogenicity, markers of biological activity, efficacy, and safety in subjects with stable low systemic lupus erythematosus (SLE) disease activity. Additionally, this study will assess rebound phenomenon in subjects with any disease level of SLE who have permanently withdrawn from further belimumab treatment

Arms:
arm 1: Subjects in the Treatment Holiday Group will undergo a 6 month belimumab treatment holiday while remaining on standard of care SLE therapy, then re-start belimumab therapy for 6 months while receiving standard of care SLE therapy. arm 2: Subjects in the Control Group will continue to receive monthly belimumab therapy, in addition to standard of care SLE therapy for 52 weeks. arm 3: Subjects in the Long-Term Discontinuation Group have elected to discontinue further belimumab therapy and will remain on standard of care SLE therapy as directed by the investigator, and agree to return for monthly visits for 52 weeks.

Interventions: intervention 1: Belimumab
Intervention descriptions: intervention 1: Monthly intravenous infusions dosed as 10 mg/kg body weight

Protocol document:
Prot_001.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An Open-label, Non-randomized, 52-Week Study to Evaluate 
Treatment Holidays and Rebound Phenomenon After Treatment 
With Belimumab 10 mg/kg in Systemic Lupus Erythematosus 
Subjects
Compound Number:
GSK1550188
Development Phase:
IIIB
Effective Date:
12-SEP-2017
Protocol Amendment Number:  6
Author (s):
(GlaxoSmithKline); 
(Parexel 
International)
Copyright 2017 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
2012N154810_00
2013-AUG-22
Original
2012N154810_01
2013-OCT-04
Amendment No. 1
China Specific Protocol Amendment.
Addition of description to title page to clarify amendment 01 is China specific.
Modification of Protocol Summary study design paragraph to clarify China subject 
recruitment.
Modification of Section 3.1 Investigational Plan, Study Design, Study Schematic to 
clarify China subjects from the open-label period of BEL113750 can be recruited.
Modification of Section 3.1 Investigational Plan, Study Design, description of three 
subject groups.
Modification of Section 3.2 Discussion of Design to include recruitment of China 
subjects from open-label BEL113750.
Modification of Section 4.2 Inclusion Criteria for China subjects in the open-label period 
of BEL113750.
Modification of Section 4.3 Exclusion Criteria for China subjects in the open-label period 
of BEL113750.
Modification of Section 5.1 Investigational Product and Other Study Treatment for China 
subjects in the open-label period of BEL113750.
Modification of Section 6, Time and Events Table footnotes for China subjects in the 
open-label period of BEL113750.
Modification of Section 6.1.2 Secondary Endpoints for China subjects in the open-label 
period of BEL113750.
Modification of Section 6.2 Critical Baseline Assessments for China subjects in the open-
label period of BEL113750.
Modification of Section 6.3.1.1 SELENA SLEDAI Score for China subjects in the open-
label period of BEL113750.
Addition of Section 6.4.1.1 for Additional Hepatitis B Monitoring for consistency with 
the parent/feeder China specific BEL113750 protocol amendment 04 hepatitis B changes. 
Modification of Section 6.7 Pharmacogenetic Research clarifying PGx sampling not 
needed from China subjects from the BEL113750 study.
Modification of Appendix 11.5 Clinical Laboratory Tests for consistency with the 
parent/feeder China specific BEL113750 protocol amendment 04.
Appendix 8 added, providing detailed changes to the protocol.
 
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2012N154810_02
2014-JAN-14
Amendment No. 2
Updating of Progressive Multifocal Leuko-encephalopathy (PML) wording to reflect new 
information received by the Sponsor; global administrative changes regarding study 
phase mentioned in the protocol.
Modification of title regarding the study phase.
Addition of description to title page to clarify that protocol amendment 02 is a global 
protocol amendment.
Modification of the Protocol Summary of the Study Design section for sponsor 
administrative change of study phase.
Modification of Section 3.1 for sponsor administrative change of study phase.
Updating of Section 6.4.13.1 Progressive Multifocal Leukoencephalopahthy (PML).
Updating of Appendix 5 Clinical Laboratory Tests.
Updating of Appendix 7 Country Specific Requirements to include China Specific 
Protocol Amendment 01 changes in this protocol amendment 02.
Updating of Appendix 8 Protocol Changes.
2012N154810_03
2014-APR-01
Amendment No. 3
Sponsor administrative change affecting the Interactive Voice Response System (IVRS).
Update sponsor serious adverse event (SAE) contact information on the Sponsor 
Information Page.
Correction of typographical error in Section 5.1 Investigational Product and Reference 
Therapy regarding the 1 hour infusion time.
Modification of Section 5.2 Treatment Assignment regarding the Interactive Voice 
Response System (IVRS) due to a sponsor administrative change.
Clarification of Section 5.5.1 Permitted Medications and Non-Drug Therapies regarding 
subjects receiving live vaccines.
Clarification of Section 6 Study Assessments and Procedures, Time and Events Table 
(Year 1) for informed consent signing footnote 4.
Clarification of Section 6 Study Assessments and Procedures, Time and Events Table 
(Year 1) for PK sampling footnote 12 for Long-term discontinuation subjects 
withdrawing from the study.
Clarification of Section 6.2 Critical Baseline Assessments for signing the informed 
consent form.
Clarification of Section 6.6 Pharmacokinetics for PK sampling for Long-term 
discontinuation subjects withdrawing from the study. 
Clarification of Section 9.2 Regulatory and Ethical Considerations, Including the 
Informed Consent Process, for signing the informed consent form.
 
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2012N154810_04
2015-AUG-31
Amendment No. 4
Updates to SPONSOR INFORMATION PAGE for the Primary Medical Monitor and 
Backup Medical Monitor telephone numbers, and Case Management Group email 
address and fax number.  The Regulatory Agency Identifying Number was also added as 
United States clinical sites joined this study.
Modification of Section 3.1 Study Design describing when the maintenance phase of 
BEL116027 may end.
Modification of Section 5.6 Treatment after the End of the Study describing when the 
maintenance phase of BEL116027 may end.
Modification of Section 6 Study Assessments and Procedures, Table 2, Time and Events 
Table (Year 1), footnote 3 to correct typographical error, as no switching between the 
three groups is allowed.
Modification of Section 6.4.1 Liver chemistry stopping and follow up criteria.
Addition of Section 6.4.1.1 Study Treatment Restart, as relating to liver stopping criteria.
Modification of Section 8.1.6 Interim Analysis to correct typographical errors.
Modification of Section 9.5 Study and Site Closure describing when the maintenance 
phase of BEL116027 may end.
Addition of Le Gal 2005 reference to Section 10 References, as Le Gal 2005 reference 
added to liver chemistry stopping and follow up criteria section updates.
Modification of Section 11.7 Appendix 7:  Country Specific Requirements describing 
when the maintenance phase of BEL116027 may end.
Updated Phase III-IV Liver Safety Algorithms in Section 11.3, Appendix 3.
2012N154810_05
2015-DEC-03
Amendment No. 5
Modification of Section 6, Study Assessments and Procedures, Table 2, Time and Events 
Table (Year 1) to clarify that the PK assay is needed as part of immunogenicity testing.
Modification of Section 6.4.7 Time Period and Frequency of Detecting AEs and SAEs to 
clarify SAE reporting for China sites.
Modification of Section 6.4.16 Immunogenicity to clarify that an attempt will be made to 
determine the amount of belimumab (PK) present in immunogenicity samples with 
confirmed anti-drug binding antibodies (ADA). 
Modification of Section 6.4.16 Immunogenicity as neutralizing antibody testing will not 
be performed in China.
Modification of Section 6.6 Pharmacokinetics to clarify that the PK assay is needed as 
 
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part of immunogenicity testing.
Modification of Section 11.5, Appendix 5:  Clinical Laboratory Tests updated to include 
the additional labs mentioned in Section 6.4.1 liver Chemistry stopping and follow up 
criteria which was updated in the previous amendment.
2012N154810_06
2017-SEP-12
Amendment No. 6
Updates to Sponsor Information Page for Backup Medical Monitor.
Modification of Section 3.1 Study Design, Section 3.2 Discussion of Design, Section 4, 
Number of Subjects, and Section 8 Data Analysis and Statistical Considerations updated 
for change in sample size as agreed upon with the European Medicines Agency (EMA). 
Modification of Section 3.1 Study Design to provide clarification.
Modification of Protocol Summary, Section 3.1 Study Design, and Section 3.2 
Discussion of Design to provide clarification on Appendix 11.7, recruitment of China 
subjects from open-label BEL113750.
Modification of Section 4.4 Withdrawal Criteria to provide clarification.
Modification of Section 6 Study Assessments and Procedures to provide clarification.
Modification of Section 6.1.4. Definitions of SLE Flares Used in This Study to update 
definition of renal flare by removing hematuria criteria.
Updates to Appendix 7 Country Specific Requirements to include corresponding updates 
from protocol amendment 06 to the China Specific Protocol Amendment 01.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
BEL116027
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406
Telephone number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information:  
Primary Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
 
Mobile: 
 
Backup Medical Monitor
See Study Reference Manual for Contact Information
Sponsor Serious Adverse Events (SAE) Contact Information: 
Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP) 
Email: 
 
Fax: 
Regulatory Agency Identifying Number(s): 9970
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BEL116027
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................12
PROTOCOL SUMMARY...............................................................................................14
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.2.
Rationale ....................................................................................................16
2.
OBJECTIVE(S) ......................................................................................................17
2.1.
Primary Objective .......................................................................................17
2.2.
Secondary Objectives.................................................................................17
3.
INVESTIGATIONAL PLAN.....................................................................................17
3.1.
Study Design ..............................................................................................17
3.2.
Discussion of Design ..................................................................................20
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................21
4.1.
Number of Subjects ....................................................................................21
4.2.
Inclusion Criteria.........................................................................................21
4.3.
Exclusion Criteria........................................................................................24
4.4.
Withdrawal Criteria .....................................................................................24
5.
STUDY TREATMENTS..........................................................................................26
5.1.
Investigational Product and Other Study Treatment....................................26
5.2.
Treatment Assignment................................................................................27
5.3.
Product Accountability ................................................................................27
5.4.
Treatment Compliance................................................................................28
5.5.
Concomitant Medications and Non-Drug Therapies....................................28
5.5.1.
Permitted Medications and Non-Drug Therapies..........................28
5.5.2.
Prohibited Medications and Non-Drug Therapies.........................28
5.6.
Treatment after the End of the Study ..........................................................29
5.7.
Treatment of Study Treatment Overdose....................................................29
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30
6.1.
Endpoints....................................................................................................36
6.1.1.
Primary Endpoints .......................................................................36
6.1.2.
Secondary Endpoints...................................................................36
6.1.3.
Other Endpoints...........................................................................36
6.1.4.
Definitions of SLE Flares Used in This Study...............................37
6.2.
Critical Baseline Assessments....................................................................37
6.3.
Efficacy.......................................................................................................38
6.3.1.
SELENA SLEDAI.........................................................................38
6.3.1.1.
SELENA SLEDAI Score .............................................38
6.3.1.2.
Laboratory tests for SELENA SLEDAI ........................40
6.3.1.3.
SLE Flare Index..........................................................40
6.3.1.4.
Physician’s Global Assessment (PGA) .......................40
6.3.2.
SLICC/ACR Damage Index .........................................................41
6.4.
Safety .........................................................................................................41
 
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6.4.1.
Liver chemistry stopping and follow up criteria.............................41
6.4.1.1.
Study Treatment Restart ............................................45
6.4.2.
Adverse Events............................................................................46
6.4.2.1.
Definition of an AE......................................................46
6.4.2.2.
Definition of a SAE .....................................................47
6.4.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................48
6.4.4.
Death Events...............................................................................49
6.4.5.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................49
6.4.6.
Pregnancy ...................................................................................50
6.4.7.
Time Period and Frequency of Detecting AEs and SAEs.............50
6.4.8.
Method of Detecting AEs and SAEs.............................................51
6.4.9.
Investigator Evaluation of Adverse Events...................................51
6.4.10.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................51
6.4.10.1.
Regulatory reporting requirements for SAEs ..............53
6.4.11.
Laboratory Evaluations ................................................................54
6.4.12.
Infusion-related Reactions and Hypersensitivity Reactions ..........54
6.4.13.
Other Immunosuppression Related Considerations.....................55
6.4.13.1.
Progressive Multifocal Leukoencephalopathy.............55
6.4.14.
Vital Signs and Weight.................................................................55
6.4.15.
Physical examination ...................................................................55
6.4.16.
Immunogenicity............................................................................55
6.5.
Biomarkers .................................................................................................56
6.6.
Pharmacokinetics .......................................................................................57
6.7.
Pharmacogenetic Research........................................................................57
7.
DATA MANAGEMENT ...........................................................................................57
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................58
8.1.
Data Analysis Considerations .....................................................................58
8.1.1.
Analysis Populations....................................................................58
8.1.2.
Primary Efficacy Analysis.............................................................58
8.1.3.
Analysis of Additional Efficacy Endpoints.....................................59
8.1.4.
Safety Analysis ............................................................................59
8.1.5.
Pharmacokinetic Analysis............................................................59
8.1.6.
Interim Analysis ...........................................................................59
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................60
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
9.3.
Quality Control (Study Monitoring) ..............................................................60
9.4.
Quality Assurance.......................................................................................61
9.5.
Study and Site Closure ...............................................................................61
9.6.
Records Retention......................................................................................62
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................62
10. REFERENCES.......................................................................................................64
 
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11. APPENDICES........................................................................................................68
11.1.
Appendix 1: SELENA SLEDAI Disease Assessment Scales.......................68
11.2.
Appendix 2: SLICC/ACR Damage Index.....................................................71
11.3.
Appendix 3: Liver Chemistry Stopping and Followup Criteria......................73
11.4.
Appendix 4: Adverse Event and Laboratory Value Severity Grade 
Tables.........................................................................................................75
11.5.
Appendix 5: Clinical Laboratory Tests.........................................................83
11.6.
Appendix 6: Pharmacogenetic Research ....................................................84
11.7.
Appendix 7: Country Specific Requirements...............................................89
11.8.
Appendix 8: Protocol Changes..................................................................108
 
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LIST OF ABBREVIATIONS
mol
Micromoles
aCL
Anticardiolipin
ACR
American College of Rheumatology
ADA
Anti-drug Antibodies
AE
Adverse Event
ALT
Alanine Aminotransferase
ANA
Anti-nuclear Antibody
Anti-IL-6
Anti-Interleukin-6
Anti-TNF
Anti–Tumour Necrosis Factor
AST
Aspartate Aminotransferase
BLyS
B Lymphocyte Stimulator
CBC
Complete Blood Count
CNS
Central Nervous System
CPK
Creatinine Phosphokinase
CrCL
Creatinine Clearance
DAS
Disease Activity Scales
dL
Decilitre
DMID
Division of Microbiology and Infectious Diseases
DNA
Deoxyribonucleic Acid
dsDNA
Double Stranded Deoxyribonucleic Acid
ECL
Electrochemiluminescence
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
g
Gram
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
HBV
Hepatitis B Virus Quantitative DNA PCR
HGS
Human Genome Sciences, Inc
hpf
High Power Field
HPLC
High Pressure Liquid Chromatography
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine Device
IUS
Intrauterine System
IV
Intravenous
IVIG
Intravenous Immunoglobulins
IVRS
Interactive voice response system
kg
Kilograms
L
Litre
 
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LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Affairs
mg
Milligrams
mL
Millilitre
MMF
Mycophenolate
MSD
Meso Scale Discovery
MSDS
Materials Safety Data Sheet
NSAIDs
Non-steroidal Anti-inflammatory Drugs
NWHIC
National Women’s Health Information Center
OL
Open-label
OMHRC
Office of Minority Health Resource Center
PCR
Polymerase Chain Reaction
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PML
Progressive Multifocal Leukoencephalopathy
PT
Prothrombin Time
PTT
Partial thromboplastin Time
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SELENA
Safety of Estrogen in Lupus National Assessment
SFI
SLE Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SOC
Standard of Care
SPM
Study Procedures Manual
SS
SELENA SLEDAI Score
SWFI
Sterile Water for Injection
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
VAS
Visual Analogue Scale
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the
GlaxoSmithKline group of companies
NONE
Benlysta
BLyS
Lymphostat-B
PASS 2005
RIBA
 
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PROTOCOL SUMMARY
Rationale
Belimumab is currently approved as a treatment for SLE but there is no current efficacy 
or safety data on the effects of temporary discontinuation of belimumab therapy in 
subjects with stable low disease activity and subsequent reintroduction of belimumab 
therapy (so-called ‘treatment holidays’) or data on rebound phenomenon. This study is 
intended to provide data on treatment holidays and rebound phenomenon of belimumab 
therapy in SLE and to fulfil a post-marketing commitment made to the European 
Medicines Agency (EMA).
This study will assess the effect of a 24-week withdrawal followed by a 28-week 
reintroduction of belimumab 10 mg/kg plus standard of care on immunogenicity, markers 
of biological activity, efficacy, and safety in subjects with stable low SLE disease 
activity. In addition, this study will assess rebound phenomenon in subjects with any 
disease level of SLE who have permanently withdrawn from further belimumab 
treatment.
Objectives
Primary Objective
Characterize the efficacy of a 24-week withdrawal followed by a 28-week reintroduction 
of intravenous belimumab therapy compared with uninterrupted intravenous belimumab 
therapy for 52 weeks in subjects with low SLE disease activity receiving belimumab 10 
mg/kg plus standard of care, as measured by time to first flare.
Secondary Objectives

Evaluate the rate of any flare.

Assess safety, SLE disease activity, immunogenicity, markers of autoimmune 
response (e.g., immunoglobulins, complement), and changes in corticosteroid use.
Study Design
A phase IIIB, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:

the effect of temporary discontinuation of belimumab 10 mg/kg therapy for 24 weeks 
and reintroduction of belimumab 10 mg/kg therapy for 28 weeks plus standard of 
care (referred to as ‘treatment holiday’) in subjects with low SLE disease activity.

rebound phenomenon in subjects who have discontinued belimumab therapy 
(stratified by SLE disease activity, SELENA SLEDAI score 3 or SELENA 
SLEDAI score >3).
 
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The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase.  The study consists of a treatment holiday group, a control group, and a long-term 
discontinuation group. All 3 subject groups will be recruited from the BEL114333 
continuation study of belimumab in SLE and as described in Appendix 11.7, from the 
open-label (OL) period BEL113750 for China subjects. Additionally, subjects in the 
long-term discontinuation group will also be recruited from the HGS1006-C1066 and 
LBSL99 continuation studies of belimumab in SLE. All subjects will be assessed every 4 
weeks for 52 weeks. After 52 weeks, eligible subjects in the treatment holiday and 
control groups have the option to continue receiving belimumab therapy in the 
maintenance phase of this study. Two follow-up visits are scheduled for subjects in the 
treatment holiday and control groups who are prematurely withdrawn from the study. 
Subject completion for subjects in the treatment holiday group is defined as completion 
of the 24-week treatment holiday period plus the belimumab re-introduction treatment 
period to Week 52.  Subject completion for subjects in the control and long-term 
discontinuation groups is defined as completion of all visits to Week 52.
Study Endpoints/Assessments
Efficacy will be assessed from, SELENA SLEDAI (SS) score, SLE flare index 
Physician’s Global Assessment (PGA) and SLICC/ACR damage index. The primary 
efficacy endpoint is time to any SLE Flare Index flare.
The safety assessments are adverse events (AEs) (including infusion-related and 
hypersensitivity reactions, infections and malignancies), haematological and clinical 
chemistry parameters, urinalysis, B cell markers, immunogenicity, vital signs (including 
weight), and physical examinations.
 
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1.
INTRODUCTION
1.1.
Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterised by 
autoantibody production and abnormal B lymphocyte function [Pisetsky, 2001].  This 
disease is more common in women (~90% of patients) than men [NWHIC, 2003] and 
prevalence varies with race [OMHRC, 2001; NWHIC, 2003].  SLE can lead to arthritis, 
kidney failure, heart and lung inflammation, and central nervous system (CNS) changes. 
Patients with SLE have about a 3-fold greater risk of mortality than the general 
population.  Approximately 70% of SLE patients survive 20 years from time of diagnosis
A clinical diagnosis of SLE includes features that are thought to involve dysregulation of 
B lymphocytes [Liossis, 1996; Lipsky, 2001].  The B lymphocyte stimulator (BLyS) 
protein is a potent co-stimulator of B lymphocytes and elevated levels of BLyS are 
observed in autoimmune diseases in humans and animal models [Cheema, 2001; 
Gross, 2001; Khare, 1999; Mackay, 1999; Moore, 1999; Zhang, 2001; Carter, 2003].  In 
SLE, the elevation of BLyS may contribute to the persistence of B cell subsets that 
produce pathogenic autoantibodies or promote inflammation that would otherwise be 
subject to down regulation.  Thus a therapeutic strategy which involves an antagonist to 
BLyS, to reduce B lymphocyte stimulation, reducing autoantibody production, may have 
therapeutic benefit in SLE.
Belimumab is currently approved in the United States, Canada and Europe for the 
treatment of SLE. Belimumab is a B lymphocyte stimulator (BLyS)-specific inhibitor that 
blocks the binding of soluble BLyS, a B-cell survival factor, to its receptor on B cells.  
Belimumab does not bind B-cells directly, but by binding BLyS, belimumab inhibits the 
survival of B cells, including autoreactive B cells, and reduces the differentiation of B 
cells into immunoglobulin-producing plasma cells.  Further information on the risk 
benefit of belimumab is provided in the Investigator Brochure (IB) and in the belimumab 
product label.
1.2.
Rationale
Belimumab is currently approved as a treatment for SLE but there is no current efficacy 
or safety data on the effects of temporary discontinuation of belimumab therapy in 
subjects with stable low disease activity and subsequent reintroduction of belimumab 
therapy (so-called ‘treatment holidays’) or data on rebound phenomenon. This study is 
intended to provide data on treatment holidays and potential rebound phenomenon of 
belimumab therapy in SLE and to fulfil a post-marketing commitment made to the 
European Medicines Agency (EMA).
This study will assess the effect of a 24-week withdrawal followed by a 28-week 
reintroduction of belimumab 10 mg/kg plus standard of care on immunogenicity, markers 
of biological activity, efficacy, and safety in subjects with stable low SLE disease 
activity. In addition, this study will assess rebound phenomenon in subjects with any 
disease level of SLE who have permanently withdrawn from further belimumab 
treatment.
 
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2.
OBJECTIVE(S)
2.1.
Primary Objective
Characterize the efficacy of a 24-week withdrawal followed by a 28-week reintroduction 
of intravenous belimumab therapy compared with uninterrupted intravenous belimumab 
therapy for 52 weeks in subjects with low SLE disease activity receiving belimumab 10 
mg/kg plus standard of care, as measured by time to first flare.
2.2.
Secondary Objectives

Evaluate the rate of any flare.

Assess safety, SLE disease activity, immunogenicity, markers of autoimmune 
response (e.g., immunoglobulins, complement), and changes in corticosteroid use.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
A phase IIIB, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:

the effect of temporary discontinuation of belimumab 10 mg/kg therapy for 24 weeks 
and reintroduction of belimumab 10 mg/kg therapy for 28 weeks plus standard of 
care (referred to as ‘treatment holiday’) in subjects with low SLE disease activity 
(Figure 1).

rebound phenomenon in subjects who have discontinued belimumab therapy (Figure 
1).
 
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Figure 1
Study Schematic
Subjects will be recruited from 3 open-label continuation studies of belimumab in SLE. 
See Appendix 11.7 for recruitment from the open-label (OL) period BEL113750 for 
China subjects. This study will comprise 3 distinct groups of subjects as outlined below:

Treatment Holiday group: This group will be used to assess the effect of temporary 
discontinuation (including rebound phenomenon) and re-introduction of belimumab 
10 mg/kg therapy. These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE. Subjects will have been treated with 
belimumab for at least 6 months and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal. The target enrolment for this group is at least 10 subjects.

Treatment Control group: This group will serve as a control to the treatment 
holiday group.  These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE. Subjects will have been treated with 
belimumab for at least 6 months and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal but will continue their current treatment with belimumab 10 mg/kg. The 
target enrolment for this group is at least 26 subjects.

Long-term Discontinuation group: This group will also be used to assess rebound 
phenomenon in SLE subjects who have discontinued therapy with belimumab 10 
mg/kg and are expected to remain off belimumab therapy for at least 12 months but 
remain on standard of care therapy. These subjects will be recruited from 3 
 
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belimumab open-label continuation studies in subjects with SLE (BEL114333; 
HGS1006-C1066; LBSL99). Subjects will have been treated with belimumab for at 
least 6 months in one of these continuation studies but will have withdrawn from 
belimumab therapy for no longer than 8 weeks prior to entry into this study. These 
subjects may have any level of SLE disease activity. The target enrolment for this 
group is 35 subjects.
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor discontinues the maintenance phase of the study 
for China subjects with the provision for China subjects to elect to participate in a 
different protocol to continue to receive belimumab, or the Sponsor decides to terminate 
the study.  Safety reporting will be as specified in the protocol the subject participates in.
A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups after the withdrawal visit or the last dose of belimumab as appropriate. 
Additionally, a 6 month follow-up visit is required for those subjects in the treatment 
holiday or control groups.
Subjects in the treatment holiday group may re-start belimumab therapy prior to Week 24 
in the event of a severe SLE flare as per the SLE flare index (Appendix 1). These subjects 
will then enter the maintenance part of this study by the escape option for ongoing 
belimumab treatment.
Subject completion for subjects in the treatment holiday group is defined as completion 
of the 24-week treatment holiday period plus the belimumab re-introduction treatment 
period to Week 52.  Subject completion for subjects in the control and long-term 
discontinuation groups is defined as completion of all visits to Week 52.
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. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
 
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3.2.
Discussion of Design
This study proposes to recruit subjects from ongoing open-label continuation studies of 
belimumab in SLE subjects in order to obtain an eligible population in the shortest 
timeframe. There are 3 continuation studies of belimumab suitable for recruitment of 
subjects required for this study:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan, South Korea and China (for 
China see Appendix 11.7 for country-specific requirements regarding recruitment 
from the open-label period of BEL113750).

HGS1006-C1066: An ongoing Phase III, open-label continuation study of parent 
study HGS1006-C1056 (BLISS 76), which enrolled and treated 268 SLE subjects 
with belimumab conducted in the United States

LBSL99: An ongoing Phase II, open-label continuation study of parent study 
LBSL02, which enrolled and treated 296 SLE subjects with belimumab conducted 
in the United States and Canada.
Subjects eligible for inclusion in the treatment holiday group will have been treated with 
belimumab for at least 6 months in BEL114333 and have a SELENA SLEDAI score 3 
and complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal.
Subjects eligible for inclusion in the control group will have been treated with belimumab 
for at least 6 months in BEL114333 and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of normal 
but elect to continue their current treatment with belimumab 10 mg/kg.
Subjects eligible for inclusion in the long-term discontinuation group may have any level 
of SLE disease activity; will have been treated with belimumab for at least 6 months in 
any of the 3 continuation studies mentioned above; have discontinued belimumab therapy 
for no longer than 8 weeks prior to entry into this study and intend to remain off 
belimumab treatment for the 12 months of this study but to remain on standard of care 
therapy.
Subjects eligible for inclusion in the treatment holiday group will not be recruited from 
the long-term continuation studies LBSL99 or HGS1006-C1066, due to regulatory 
commitments for completing 10 years and 5 years on treatment, respectively. However, 
subjects who discontinue belimumab treatment in studies LBSL99 or HGS1006-C1066 
can be recruited into the long-term discontinuation group in the present study.
For subjects entering the study, a minimum of 6 months previous participation in an 
open-label continuation study will provide subjects initially randomized to placebo in 
parent studies with the opportunity to reach sufficient biological activity to achieve a 
belimumab pharmacological and/or clinical response.
 
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The target sample size of at least 10 subjects in the treatment holiday group and at least 
26 subjects in the control group is based on estimates of subject eligibility and number of 
subjects from continuation study BEL114333  anticipated to provide consent to 
participate in this study.  The target sample size of 35 subjects for the long-term 
discontinuation group is based on practical considerations of numbers of subjects 
anticipated to drop-out and not on statistical considerations.
Enrolment of subjects from the 3 belimumab continuation studies into the long-term 
discontinuation group will remain open while recruitment to the treatment holiday and 
control groups is ongoing or until 36 months have elapsed since study start. A target 
sample size of 35 subjects in the long-term discontinuation group is anticipated.
Because this study is non-randomized, subjects and investigators from study BEL114333 
will jointly decide upon which of the three groups to enrol into.  Subjects recruited from 
the HGS1006-C1066 and the LBSL99 studies may only choose to enter the long-term 
discontinuation group, as they elect to no longer receive further belimumab therapy.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
The target sample size for subjects in the treatment holiday group is at least 10 subjects 
and in the control group, at least 26 subjects.  Each group will end recruitment when their 
target sample size is reached.  Enrolment in this study will close when the target number 
of subjects in the treatment holiday and control groups has been achieved or 36 months 
after study start, whichever comes first.  As many subjects as possible will be enrolled in 
the long-term discontinuation group while recruitment to the treatment holiday and 
control groups is ongoing and will cease when recruitment to the treatment holiday and 
control groups is closed or until 36 months have elapsed since study start.  A target 
sample size of 35 subjects in the long-term discontinuation group is anticipated.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the belimumab IB/IB 
supplement(s) and belimumab product label.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in all 3 subject groups in the study must meet all of the 
following criteria:
1.
Belimumab therapy: Received a minimum of 6 months therapy with belimumab 10 
mg/kg in the continuation study BEL114333. Subjects in the long-term 
discontinuation group may additionally be recruited from continuation studies 
HGS1006-C1066 or LBSL99.
 
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2.
Age: 18 years of age at the Day 0 visit.
3.
Females: A non-pregnant, non-lactating female subject is eligible to enter the study 
if at least one of the following conditions apply:

Of non-childbearing potential (i.e., women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented female sterilization procedure); 
or 

Of childbearing potential (i.e., women with functional ovaries and no 
documented impairment of oviductal or uterine function that would cause 
sterility).  This category includes women with oligomenorrhoea (even severe), 
women who are perimenopausal or have just begun to menstruate.  These 
women must have a negative urine pregnancy test at Day 0, and agree to one of 
the following:

Complete abstinence from penile-vaginal intercourse, when this is the 
female’s preferred and usual lifestyle, for the duration of the study for 
subjects in the long-term discontinuation group or until 16 weeks after the 
last dose of belimumab for subjects in the treatment holiday and control 
groups; or

Consistent and correct use of one of the following acceptable methods of 
birth control for the duration of the study for subjects in the long-term 
discontinuation group or until 16 weeks after the last dose of belimumab for 
subjects in the treatment holiday and control groups:

Implants of etonogestrel or levonorgestrel;

Estrogenic vaginal ring 

Injectable progesterone; 

Any intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year;

Oral contraceptives (either combined or progesterone only); 

Double barrier method with vaginal spermicidal agent: Condom and an 
occlusive cap (cervical cap/vault or diaphragm) with a vaginal 
spermicidal agent (foam/gel/film/cream/suppository); 

Percutaneous contraceptive patch; 

Male partner who is sterile prior to the female subject’s entry into the 
study and is the sole sexual partner for the female subject.
Note: MMF and other forms of mycophenolate affect the metabolism of 
oral contraceptives and may reduce their effectiveness. As such, women 
receiving mycophenalate who are using oral contraceptives for birth control 
should employ an additional method (e.g., barrier method).
4.
Informed consent: Able to provide written informed consent to participate.
 
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Additional eligibility criteria for subject enrolment in the treatment holiday and control 
groups in the study:
1. SLE: achieve the required minimal disease activity criteria defined as SELENA 
SLEDAI score 3 after a minimum of 6 months of belimumab therapy (see Appendix 
1 for SELENA SLEDAI).
2. SLE Treatment:  Are on a stable SLE treatment regimen consisting of any of the 
following medications (alone or in combination) during the 30 day screening period 
prior to Day 0:

Corticosteroids  (prednisone or prednisone equivalent)

Other 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, oral 
cyclophosphamide, 6-mercaptopurine, or thalidomide.

Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine).

Non-steroidal anti-inflammatory drugs (NSAIDs), including sulfasalazine.
3. Complement: C3 and C4 complement levels at or above the lower limit of normal of 
the central laboratory reference range.
Additional eligibility criteria for subject enrolment in the control group in the study:
1. Belimumab therapy: Agree to continue receiving 10mg/kg belimumab intravenous 
infusions every 4 weeks.  Subjects must be able to receive the first dose of belimumab 
in this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose 
in their previous continuation study.
Additional eligibility criteria for subject enrolment in the long-term discontinuation 
group in the study:
1. Continuation studies: Voluntarily withdrawn from continuation studies BEL114333, 
HGS1006-C1066, or LBSL99 and have withdrawn from belimumab therapy for no 
longer than 8 weeks prior to entry into this study.
Note:  investigators may stop, start, and/or change SLE medications and dosages as 
deemed necessary; yet long-term discontinuation subjects will remain on local 
standard of care SLE treatment therapy as determined by the physician during the 
study, or will need to be withdrawn.
 
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4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in any of the 3 
subject groups in the study:
1. Undue risk: Have developed clinical evidence of significant, unstable or 
uncontrolled, acute or chronic diseases not due to SLE (i.e., cardiovascular, 
pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or 
infectious diseases), or experienced an adverse event (AE) in the belimumab 
continuation studies BEL114333, HGS1006-C1066, or LBSL99 studies that could, in 
the opinion of the principal investigator, put the subject at undue risk.
2. Subject suitability: Have developed any other medical diseases (e.g., 
cardiopulmonary), laboratory abnormalities, or conditions (e.g., poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
Subjects meeting any of the following additional criteria must not be enrolled in the 
control or treatment holiday groups in the study:
1. SLE: New mild-moderate or severe flare as defined by the SLE Flare Index during 
the 30 day screening period prior to Day 0.
2. Steroids: Prednisone (or prednisone equivalent) greater than 20mg/day within the 30 
day screening period.
3. New agents: Any new immunosuppressive/immunomodulatory agent, anti-malarial, 
or NSAID within the 30 day screening period prior to Day 0.  However, any NSAID 
use for < 1 week is allowed.
4.4.
Withdrawal Criteria
A subject may voluntarily discontinue participation in this study at any time or may be 
withdrawn at the discretion of the investigator. Record the primary reason for withdrawal 
in the electronic case report form (eCRF).
Subjects in the treatment holiday and control groups will be withdrawn from the study 
for:

Pregnancy: positive urine pregnancy test.

Clinically significant, potentially life-threatening (Grade 4) AE that in the clinical 
judgement of the investigator is possibly, probably or definitely related to 
belimumab.

Liver chemistry abnormalities.  Refer to details regarding liver chemistry 
abnormalities and withdrawal as specified in Section 6.4.1.
 
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
Laboratory parameters: Demonstrate clinically important changes in laboratory 
parameters.

Prohibited concurrent medication or therapy.
These subjects will complete the Week 52 Exit visit (except for dosing with belimumab) 
at the time of discontinuation and the16-week follow-up visit assessments at least 16 
weeks after the withdrawal visit or last dose of belimumab as appropriate (see Section 6). 
The 6 month follow-up visit is scheduled only for those subjects in the treatment holiday 
or control groups.
Subjects in the long-term discontinuation group will be withdrawn from the study for:

Pregnancy: positive urine pregnancy test.

Laboratory parameters: Demonstrate clinically important changes in laboratory 
parameters.

Have developed clinical evidence of significant, unstable or uncontrolled, acute or 
chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, 
gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases), or 
experienced an adverse event (AE) that could, in the opinion of the principal 
investigator, put the subject at undue risk.

Have developed any other medical diseases (e.g., cardiopulmonary), laboratory 
abnormalities, or conditions (e.g., poor venous access) that, in the opinion of the 
principal investigator, makes the subject unsuitable for the study.
These subjects will complete the Week 52 visit assessments (see Section 6).
Subjects in the treatment holiday group are anticipated to be temporarily withdrawn from 
belimumab treatment for the initial 24 week holiday period of this study but therapy with 
belimumab 10 mg/kg can be reintroduced before the Week 24 visit if the subject’s 
condition worsens or meets the definition of a severe flare as per the SLE flare index 
(Appendix 1). Subjects in the treatment holiday group who re-start belimumab treatment 
before the end of the 24-week holiday period will escape to the maintenance part of this 
study to receive further belimumab therapy.
The investigator must make every reasonable attempt to re-start belimumab therapy at the 
Week 24 visit. Any subject in the treatment holiday group who remains off-therapy with 
belimumab at the Week 24 visit can still be treated with belimumab from Week 28 
onwards.
 
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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Belimumab for intravenous (IV) infusion will be supplied in glass vials by GSK. The 
contents of the label will be in accordance with all applicable regulatory requirements. 
Detailed instructions on the preparation, administration and storage of belimumab are 
provided in the Pharmacy Manual.  Belimumab IV solution should be prepared by a 
pharmacist. Reconstitute the 400 mg single use vial of belimumab with 4.8 mL sterile 
water for injection to yield a final concentration of belimumab 80 mg/mL. Remove an 
amount of normal saline from the infusion bag equivalent to the amount of belimumab to 
be added, add the reconstituted belimumab, and gently invert the infusion bag to mix the 
solution. After reconstitution and dilution in normal saline, the material is stable for up to 
8 hours at 2-8C or at room temperature. The characteristics of belimumab are 
summarized in Table 1.
Table 1
Belimumab Characteristics
Property
Belimumab
Formulation
Belimumab 400 mg per vial plus excipients (citric 
acid/sodium citrate/sucrose/polysorbate)
Dosage Form
Reconstituted solution
Unit dose strength
400 mg per vial (to contain 80 mg/mL when reconstituted 
with 4.8mL sterile water for injection [SWFI])
Physical description
White uniform lyophilised cake in a 20 mL vial
Manufacturer
Human Genome Sciences, Inc.
Route of administration
Intravenous
Subjects enrolled in the treatment holiday group will receive treatment with belimumab 
10 mg/kg from Week 24 onwards after the initial 24-week treatment holiday period of 
the study has elapsed (see Section 3.1). At the start of the belimumab reintroduction 
period, subjects in the treatment holiday group will receive belimumab 10 mg/kg IV 
infused for over 1 hour every 28 days.
Subjects in the control group will receive belimumab 10 mg/kg IV infused for over 1 
hour every 28 days from Day 0 onwards. Subjects in this group must be able to receive 
their first dose of belimumab on Day 0 of this study 4 weeks (minimum of 2 weeks, 
maximum of 8 weeks) after the last dose in the BEL114333 open-label continuation 
study.
Subjects in the long-term discontinuation group will not receive belimumab at any point 
in this study.
The dose of belimumab administered may not be altered but the rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or 
infusion-associated symptoms. Do not increase the rate of infusion above the 
recommended rate.
 
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Monitor the subject during and after each infusion according to study sites’ guidelines or 
standard operating procedure for IV infusions. This may include, but is not limited to, 
monitoring vital signs and observing for any untoward reactions. Trained rescue 
personnel and rescue medications/equipment should be available for a minimum of the 
first dose.
Consider administering premedication for prophylaxis against infusion reactions and 
hypersensitivity reactions for subjects who have previously received intravenous 
immunoglobulins (IVIG) or subjects with a history of allergies (allergic responses to 
food, drugs, insects, or a history of urticaria). The dose of belimumab may be delayed by 
up to 2 weeks or the dose may be withheld if the subject experiences a clinically 
significant AE that, in the clinical judgement of the investigator, is possibly, probably or 
definitely related to belimumab, and this AE continues at the next scheduled dose, or 
could potentially be exacerbated by the next dose. If a similar concern is present at the 
time of the next scheduled dose, the investigator and Medical Monitor will discuss 
whether to discontinue treatment with belimumab.
Under normal conditions of handling and administration, investigational product 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. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. Belimumab should be diluted to 250 mL normal saline after reconstitution, 
using a typical approved plastic intravenous administration set for the infusion.
Belimumab must be stored in a secure area under the appropriate physical conditions for 
the product, which includes storage in a refrigerator at a temperature of 2-8C.  
Maintenance of a temperature log (manual or automated) is required. Access to and 
administration of belimumab will be limited to the investigator and authorized site staff.  
Belimumab must be dispensed or administered only to subjects enrolled in the study and 
in accordance with the protocol.
Destroy all used belimumab vials according to site guidelines for the destruction of 
investigational products, after the monitor has conducted a check of the product 
accountability log during the study. At the end of the study, unused belimumab vials will 
be destroyed on site at the study closeout visit, after the monitor has conducted final 
belimumab accountability and given the site approval to destroy all remaining supplies.
5.2.
Treatment Assignment
This is an open-label, non-randomized study.  Site personnel will access the interactive 
voice response system (IVRS) to enrol the subject in the study and to log subject visits.   
Supplementary information is provided in the Study Procedures Manual (SPM).
5.3.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
 
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investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.
5.4.
Treatment Compliance
All doses administered within the study unit will be administered under the supervision 
of the investigator, designee or study nurses and the data entered into the electronic case 
report form (eCRF).
Drug dispensing /accountability logs will be maintained by the separate pharmacist or 
pharmacy designee.
5.5.
Concomitant Medications and Non-Drug Therapies
Record all concomitant medications taken during the study in the eCRF.  
5.5.1.
Permitted Medications and Non-Drug Therapies
Subjects in the treatment holiday and control groups must be on a stable SLE treatment 
regimen during the 30 day screening period prior to Day 0.
After Day 0, the investigator may adjust concurrent medications (add, eliminate, change 
dose level/frequency) as clinically required in response to improving or worsening 
conditions for the treatment holiday and control groups.
Note:  Live vaccines are permitted for subjects in the long-term discontinuation group.  
Subjects in the control and treatment holiday groups are prohibited from receiving live 
vaccines.
5.5.2.
Prohibited Medications and Non-Drug Therapies
Subjects in the treatment holiday and control groups who start prohibited medications 
or therapies at any time during the study must be withdrawn from the study. These 
subjects will return for the EXIT visit, and the follow-up visits 16 weeks and 6 months 
after receiving their last dose of belimumab as described in Section 4.4.  
The following medications and therapies are prohibited at any time during the study:

Other investigational agents (biologic or non-biologic). Investigational applies to any 
drug not approved for sale in the country in which it is being used.

Co-enrolment into another study of an investigational agent or non-drug therapy that 
may interfere with the conduct of this protocol.

Anti-TNF or anti-IL-6 therapy (e.g., adalimumab, etanercept, infliximab, 
tocilizumab).

Other biologics (e.g., rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra]).
 
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
Intravenous immunoglobulin (IVIG).

IV cyclophosphamide.

Plasmapheresis, leukapheresis.
5.6.
Treatment after the End of the Study
Eligible subjects in the treatment holiday and control groups may continue to receive 
belimumab therapy every 4 weeks under the maintenance phase of this protocol until the 
subject withdraws from the study, or the subject elects to participate in another 
belimumab continuation study for SLE, or the Sponsor discontinues the maintenance 
phase of the study for China subjects with the provision for China subjects to elect to 
participate in a different protocol to continue to receive belimumab, or belimumab 
becomes commercially available in a subject’s country of participation, or upon the 
decision by the sponsor to discontinue the study. Safety reporting will be as specified in 
the protocol the subject participates in.  Subjects in the treatment holiday and control 
groups who complete Week 52 of this study are not eligible to receive further treatment 
with belimumab in the maintenance phase of this study if belimumab is commercially 
available in the subject’s country of participation.
No treatment with belimumab at end of this study is anticipated for subjects in the long-
term discontinuation group since they did not receive belimumab therapy in this study.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
5.7.
Treatment of Study Treatment Overdose
The dose of belimumab considered to be an overdose has not been defined. There are no 
known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. The investigators will use clinical judgement in treating the 
symptoms of a suspected overdose.
The approved product label for belimumab states for overdosage “There is no clinical 
experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been 
given by intravenous infusion to humans with no increase in incidence or severity of 
adverse reactions compared with doses of 1, 4, or 10 mg/kg”.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
All subjects will attend clinic visits for efficacy and safety assessments every 4weeks for 
52 weeks (see Table 2). 
Subjects in the treatment holiday and control groups will be dosed with belimumab at the 
Week 52 visit in Table 2 only if they are continuing belimumab therapy in the 
maintenance phase of this study. Subjects in the treatment holiday and control groups 
who wish to continue belimumab therapy after the Week 52 visit, will proceed to the 
Week 4 visit in Table 3 (Time and Events Table for additional years) and continue to 
cycle through clinic visits from Week 4 through Week 48 in Table 3 on an annual basis 
(see Section 3.1). Subjects in the treatment holiday and control groups who do not wish 
to continue belimumab therapy after Week 48 will proceed to the Week 52 (Exit) visit 
but will not be dosed with belimumab.
Subjects in the treatment holiday and control groups who meet the protocol-defined 
withdrawal criteria specified in Section 4.4 at any time during Year 1 or the additional 
years will undergo assessments scheduled at the Exit visit (Week 52) in Table 2 except
for dosing with belimumab. At approximately 16 weeks after the withdrawal visit or the 
last dose of belimumab as appropriate, these subjects will also undergo the assessments 
scheduled at the 16-week follow-up visit; the 6 month follow-up visit is scheduled only 
for these discontinued subjects in the treatment holiday or control groups.
Subjects in the long-term discontinuation group will attend for clinic visits from Day 0 
through Week 52 in Table 2 only. The 16-week and 6-month follow-up visits do not 
apply to this group. Subjects in the long-term discontinuation group who meet the 
protocol-defined withdrawal criteria specified in Section 4.4 at any time during Year 1 
will undergo assessments scheduled at the Exit visit (Week 52) in Table 2.
 
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Table 2
Time and Events Table (Year 1)
Screen
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up to 
-30 1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
140
7d
168 
7d
196
7d
224 
7d
252 
7d
280
7d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
Written Informed Consent 4
X
Demography
X
Medical History
X
SLE History
X
Therapy History
X
Physical Examination
X
Inclusion/Exclusion
X
Efficacy Assessments
DAS: SS, SLE Flare Index, 
PGA 5
X 1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR Damage Index
X
X
X
Safety Assessments
Vital Signs 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, height 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom-driven Physical 
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology & Modified 
Chem 20 (non-fasting) 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spot urine (protein to 
creatinine ratio) 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 6, 9
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Pharmacogenetic Sampling 10
X
aCL Autoantibody
X
X
C3/C4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Screen
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up to 
-30 1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
140
7d
168 
7d
196
7d
224 
7d
252 
7d
280
7d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
Anti-dsDNA Autoantibodies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA Autoantibodies 
X
X
X
IgG, IgA & IgM 11
X
X
X
X
X
X
X
X
PT/ PTT
X
Exploratory Lab Assessments
Pharmacokinetic Sampling 12
X
X
X
X 12
X
X 12
Immunogenicity 6, 13
X
X
X 13
X
X
X
X
X 13
BLyS Protein 14
X
X
X
B cell Markers 15
X
X
X
X
X
X
X
X
Investigational Product (IP)
IP Administration 16
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
DAS = disease activity scales; SS = SELENA SLEDAI; SLE = systemic Lupus Erythematosus; PGA = Physician’s Global Assessment; SLICC/ACR = Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; PT/PTT = prothrombin time/partial thromboplastin 
time; BlyS = B Lymphocyte Stimulator; IP = investigational product; aCL = anticardiolipin
1.
A screening visit of up to 30 days prior to the Day 0 visit will be scheduled for subjects in the treatment holiday and control groups for assessment of SELENA SLEDAI score to 
assess eligibility.
2.
The EXIT Visit in the respective feeder continuation studies will serve as the Day 0 visit for all 3 subject groups in this study. Assessments covered for both this study at Day 0 
and the Exit visit of the feeder continuation studies need only be performed once and recorded in the appropriate case report forms for each study. Subjects in the control group 
must be able to receive the 1st dose of belimumab on Day 0 of this study on average 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the feeder 
continuation study.
3.
The 16 week follow-up visit will occur at approximately 16 weeks after last dose of investigational product for subjects in the control group who withdraw at any time during the 
study, or for subjects in the treatment holiday group who withdraw from the study from Week 24 onwards (Visit 7) during the belimumab re-introduction period. The 16-week and 6 
month follow-up visits do not apply to subjects in the long-term discontinuation group. 
4.
Obtain written informed consent to participate in this study at the Screening visit.
5.
Guidelines for scoring proteinuria for SELENA SLEDAI are provided in Section 6.3.1.1.
6.
Complete assessment prior to belimumab dosing for subjects in the control group (to Week 48) and for subjects in the treatment holiday group (during Weeks 24 to 48 or earlier in 
the event of a flare).  Immunogenicity testing includes quantifying the amount of belimumab present in the samples using the belimumab PK assay.
7.
For any subject whose weight changes by more than 5% from that recorded at Day 0, use the weight at the current visit for calculating the belimumab dose to be administered. 
Height measured only at Day 0.
 
 
 
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8.
A 24-hour urine may be done as an additional assessment if clinically indicated (e.g., renal flare).
9.
Urine pregnancy test results for women of child-bearing potential must be available prior to dosing (during Weeks 0 to 48 in the control group and during Weeks 24 to 48 or earlier 
in the event of a flare in the treatment holiday group).Can be performed at any time during the visit for females of child-bearing potential in the long-term discontinuation group.
10. PGx sampling from consenting subjects recruited from all studies except from study BEL114333. PGx informed consent must be obtained prior to sampling.
11. Serum immunoglobulin isotypes: IgG, IgM, IgA.
12. Pharmacokinetic sampling at select sites for subjects in the control and treatment holiday groups; subjects in the treatment holiday group can have PK sampling performed at any 
time during the visit between Weeks 0 and 16.  Otherwise, if on a dosing day, sampling must be performed prior to dosing. Collect blood samples pre-dose and post-dose at the 
end of the infusion at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the event of a severe flare by using the escape option).   Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before Week 24 will have one PK sampling performed at any time during the EXIT visit.   PK sampling 
for long-term discontinuation subjects withdrawing after Week 24 is not performed at the EXIT visit.
13. Blood sample for immunogenicity will be taken at Weeks 12, 24, 36 and 52 for all three groups.  In addition, a blood sample for immunogenicity will also be taken 4 weeks prior
to the reintroduction of belimumab (at Week 20 since belimumab will be reintroduced at Week 24) in the treatment holiday group. A blood sample for immunogenicity must be 
taken at least 6 months after the final dose of investigational product for any subjects in the control group or treatment holiday group who had an anti-belimumab antibody 
response at the 16-week follow-up visit (or at the last immunogenicity assessment if 16-week follow-up is not available). Note that serum samples for immunogenicity must be 
collected pre-dose at the time of dosing from subjects in the treatment holiday group who experience a severe flare prior to Week 24 and consequently receive open-label 
belimumab as rescue.  Immunogenicity blood sample will not be collected at the 6-month follow up visit for subjects in the long-term discontinuation group as this visit does not 
apply to this subject group.
14. Measured in treatment holiday group at Weeks 16 and pre-dose at Week 24. Measured in long-term discontinuation group at Weeks 16, 24 and 32. Not measured in control 
group.
15. Biological Markers include FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells). Note: B cell markers will not be collected at the 6-month follow up visit for subjects in the long-term 
discontinuation group as this visit does not apply to this subject group.
16. Only subjects in the control group will receive belimumab 10 mg/kg during Weeks 0 through 20 inclusive;  subjects in the control group must be able to receive the first dose of 
belimumab in this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in their previous open-label continuation study  Subjects in the control group 
and treatment holiday groups will receive belimumab from Weeks 24 through 48 although subjects in the treatment holiday group may be treated with belimumab prior to Week 
24 as determined by the investigator in the event of increased SLE activity. When belimumab therapy is re-started, subjects in the treatment holiday group will remain under 
clinical supervision for 3 hours after completion of the first 2 infusions. At the Week 52 visit, only subjects in the treatment holiday and control groups who are continuing 
belimumab therapy beyond this time will be dosed.
 
 
 
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Table 3
Time and Events Table (Additional Years)
Study Visit (Weeks) 1
4
8
12
16
20
24
28
32
36
40
44
48
Study Day
28   
7d
56   
7d
84   
7d
112 
7d
140 
7d
168 
7d
196 
7d
224 
7d
252 
7d
280 
7d
308 
7d
336 
7d
Efficacy Assessments
Disease Activity Scales: SELENA SLEDAI, 
SLE Flare Index, and PGA 2
X
X
SLICC/ACR Damage Index
X
Safety Assessments
Symptom-driven Physical Exam
X
X
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs 3, 4
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology & Modified Chem 20 (non-
fasting) 3, 5
X
X
Urinalysis 5, 6
X
X
Spot urine (protein to creatinine ratio) 3, 5, 6
X
X
Urine Pregnancy Test 3, 5, 7
X
X
X
X
X
X
X
X
X
X
X
X
C3, C4, Anti-dsDNA Autoantibodies 3, 5
X
X
IgG 3, 5,  8
X
IgA & IgM 3, 5, 8
X
Exploratory Lab Assessments
Immunogenicity 3 ,9
X
X
B cell Markers 10
X
Investigational Product
Belimumab  Administration 4, 11
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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1.
Calendar represents a yearly (48-week) ongoing visit schedule until the subject is terminated from the study.
2.
Guidelines for scoring proteinuria for SELENA SLEDAI are provided in Section 6.3.1.1.
3.
Assessments performed prior to dosing.
4.
For any subject whose weight changes by more than 5% from that recorded at Day 0, use the weight at the current visit for calculating the belimumab dose to be administered.
5.
During “Additional years”, investigators can obtain any of the same laboratory assessments that are mentioned for Year 1 (haematology, modified Chem 20, urinalysis, spot urine 
to creatinine ratio, urine pregnancy, C3, C4, anti-ds DNA autoantibodies, IgG, IgA, and IgM), as unscheduled laboratory tests at any time during Year 2 and beyond, if clinically 
indicated.  Any additional laboratory tests beyond this, if not related to the protocol, will be the responsibility of the investigator and subject.
6.
A 24-hour urine may be done as an additional assessment if clinically indicated (e.g., renal flare). 
7.
Results of urine pregnancy tests in women of child-bearing potential must be available prior to belimumab dosing.
8.
Serum immunoglobulin isotypes: IgG, IgM, IgA.
9.
Immunogenicity testing includes quantifying the amount of belimumab present in the samples using the belimumab PK assay.
10. Biological Markers include FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells).
11. After completion of the Week 48 visit during year 1 of the study, subjects in the treatment holiday and control groups can continue to receive belimumab therapy at 4-weekly 
intervals in the maintenance phase of this study. Subjects who withdraw from belimumab therapy during this maintenance phase will complete the Exit and follow-up visits detailed 
in the Year 1 Time and Events Table (Table 2). The Exit visit Schedule should be scheduled 4 weeks after the final belimumab dose and the 16-week follow-up visit 16 weeks after 
the final belimumab dose.
 
 
 
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6.1.
Endpoints
6.1.1.
Primary Endpoints
The primary efficacy endpoint is time to any SLE Flare Index flare.
6.1.2.
Secondary Endpoints
The secondary endpoints are:

Rate of any SLE Flare Index flares.

Time to first severe SLE Flare Index flare.

Number of subjects in the treatment holiday and long-term discontinuation group 
with evidence of rebound (defined as a SELENA SLEDAI score during the first 24 
weeks that exceeds the baseline SELENA SLEDAI score in the original parent study.

Number of subjects with confirmed true positive belimumab anti-drug antibodies 
(ADA) by the end of the study.

Percentage change from baseline in:

Total serum immunoglobulin (IgG, and other isotypes: IgM and IgA)

Autoantibodies (anti-dsDNA, ANA), and complement (C3, C4)

Percent change in absolute B cell subsets (CD20+, CD20+/27+ memory, CD20+/27–
naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells) at Weeks 
0, 8, 16, 24, 32, 40 and 52 and from Weeks 24 to 52.

Absolute change in SELENA SLEDAI score.

Number of days of daily prednisone dose 7.5 mg/day and/or increased by 25% from 
Day 0 of this study to Week 24, from Day 0 of this study to Week 52, and from 
Week 24 to Week 52.

Number of days of daily prednisone dose 7.5 mg/day and/or decreased by 25% 
from Day 0 of this study to Week 24, from Day 0 of this study to Week 52, and from 
Week 24 to Week 52.
Note: baseline is the time before any treatment with belimumab, which was Day 0 of the 
original parent studies that fed into the 3 continuation studies from which subjects were 
recruited into this study. When Day 0 is used in relation to endpoints, this refers to Day 0 
of this study.
6.1.3.
Other Endpoints

Change in SLICC/ACR Damage Index.

Percentage change in PGA.

Percentage change from baseline of prednisone dose at each scheduled visit.
 
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
Percentage of subjects whose average prednisone dose was reduced to 7.5 mg/day 
from >7.5 mg/day at baseline.
6.1.4.
Definitions of SLE Flares Used in This Study
SLE flares are defined as:

SFI Flare: A mild/moderate or severe flare according to the modified SELENA 
SLEDAI SLE Flare Index (modified excludes severe flares from the SELENA 
SLEDAI flare assessment that were triggered only by an increase in SELENA 
SLEDAI score to >12).
A SLE renal flare is defined as the occurrence of 1 or more of the following in 2 or more 
consecutive visits during the study:
1. A reproducible increase in 24-hour urine protein equivalent levels to 

1 g if the Day 0 value was 0.2 g, 

2 g if the Day 0 value was 0.2 to 1 g, or 

More than twice the value at Day 0 if the Day 0 value is 1 g.
2. A reproducible increase in GFR of >20% accompanied by at least one of the 
following: proteinuria (1 g/24 hour equivalent), and/or cellular (RBC or WBC) casts 
[Alarcón-Segovia, 2003] .
6.2.
Critical Baseline Assessments
The screening phase of up to 30 days will allow an assessment of the SELENA SLEDAI 
score as part of the eligibility criteria for subjects in the treatment holiday and control 
groups.
The EXIT visit of the relevant SLE continuation protocol (BEL114333, HGS1006-
C1066, or LBSL99) from which the subject is recruited will serve as the Day 0 visit in 
this study. Subjects in the control group will be dosed with belimumab at the Day 0 visit 
as part of this protocol. These subjects must be able to receive the Day 0 dose in this 
study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the 
previous open-label continuation study.  Any procedures from this protocol or from the 
relevant previous open-label continuation protocols to be performed pre-dose must be 
completed before dosing subjects in the control group. Obtain written informed consent 
from all subjects to participate in this study at the Screening visit.
Procedures necessary for the Day 0 visit of this protocol and for the last visit of the 
relevant SLE open-label continuation protocol from which the subject is recruited need 
only be performed once. Results from Day 0 procedures that are duplicated in the 
relevant SLE continuation study will be recorded in the eCRF for that study and must 
also be transcribed to the relevant eCRFs in this study. Additional Day 0 procedures 
exclusive to this study will be recorded directly in the eCRFs for this study.
 
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6.3.
Efficacy
Efficacy will be assessed from SELENA SLEDAI score, SLE flare index, Physician’s 
Global Assessment (PGA) and SLICC/ACR damage index.
All site staff scoring SELENA SLEDAI assessments are required to pass proficiency tests 
before carrying out assessments to ensure consistency across centres.
6.3.1.
SELENA SLEDAI
6.3.1.1.
SELENA SLEDAI Score
The SELENA SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) used in 
this study is a slightly modified version of the SLEDAI developed for a National 
Institutes of Health sponsored multicentre study of estrogen/progesterone hormone use in 
women with SLE [Buyon, 2005; Petri, 2005]. The descriptions for some of the items are 
slightly modified, but the organ systems and weighted scores are the same as the 
published SLEDAI.
The SLEDAI is a validated index for assessing SLE disease activity [Bombardier, 1992].  
It is a weighted index in which signs and symptoms, laboratory tests, and physician’s 
assessment for each of 9 organ systems are given a weighted score and summed, if 
present at the time of the visit or in the preceding 10 days:

Score of 8 each for CNS and vascular items.

Score of 4 each for renal and musculoskeletal items.

Score of 2 each for serosal, dermal, and immunologic items.

Score of 1 each for constitutional and hematologic items.
The maximum theoretical score for the SELENA SLEDAI is 105 (all 24 descriptors 
present simultaneously) with 0 indicating inactive disease. A copy of the index is 
provided in Appendix 1.
Completion of the index requires collection of a 24-hour urine sample for assessment of 
proteinuria (although spot urine protein:creatinine ratio is commonly substituted in 
practice), measurement of anti-dsDNA, C3, C4, haematology, and urinalysis, and for 
subjects with myosis, CPK. 
However, spot urine protein:creatinine ratio will be used for determining proteinuria for 
the SELENA SLEDAI in this study since there is a strong correlation between the protein 
content of a 24-hour urine collection and the protein:creatinine ratio in a single urine 
sample [Ginsberg, 1983; Ruggenenti, 1998; Clinical Practice Guidelines for Chronic 
Kidney Disease, 2002; Price, 2005].
Scoring for proteinuria in the SELENA SLEDAI disease activity index will be in 
accordance with the following guidelines.
 
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Scoring for Proteinuria at Screening for Eligibility
The proteinuria score for SELENA SLEDAI must be 0 at the most recent assessment 
performed in BEL114333.  If at the screening visit the assessment of 24-hour proteinuria 
(by spot urine protein to creatinine ratio) shows >0.5 g/24 hour equivalent increase above 
the previous value (in BEL114333) or the subject develops new onset of proteinuria >0.5 
g/24 hour equivalent, 4 points will be assigned at the screening assessment.
Scoring for Proteinuria at Day 0 and Subsequent Study Visits
According to the SELENA SLEDAI scoring rules, unless the proteinuria continues to rise 
such that it has increased by > 0.5 g/24 hour equivalent at Day 0 (i.e., baseline), the 
subject, by default, will have an improving SELENA SLEDAI score.  This is problematic 
for data analysis since the percent change in the disease activity scales are calculated 
from the baseline (not screening) SELENA SLEDAI score.  As such, the following 
scoring rules will be applied:

Scoring for a Subject with 0 Points for Proteinuria in SELENA SLEDAI 
If the proteinuria score for SELENA SLEDAI is 0 and at the subsequent visit the 
assessment of 24-hour proteinuria (by spot urine protein to creatinine ratio) shows 
>0.5 g/24 hour equivalent increase above the previous value or the subject develops 
new onset of proteinuria >0.5 g/24 hour equivalent, 4 points will be assigned at this 
current visit.

Scoring for a Subject with Proteinuria and 4 Points Assigned in SELENA 
SLEDAI
If there is an increase from the last visit of >0.5 g/24 hour equivalent, only 4 points 
for proteinuria will continue to be applied (so no subject can get more than 4 points 
for proteinuria at any 1 time point).
If the proteinuria has not improved (i.e., there has not been a decrease in proteinuria 
of >0.5 g/24 hour equivalent) since the previous assessment, then 4 points will 
continue to be assigned on the SELENA SLEDAI index at the current visit.
If proteinuria has improved (decrease of >0.5 g/24 hour equivalent or a decrease to 
≤0.5 g/24 hour equivalent) from the previous visit to the current visit, then 0 points 
will be assigned on the SELENA SLEDAI index at the current visit.
 
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6.3.1.2.
Laboratory tests for SELENA SLEDAI
A strong correlation has been demonstrated between the protein content of a 24-hour 
urine collection and the protein:creatinine ratio in a single urine sample [Ginsberg, 1983; 
Ruggenenti, 1998; Clinical Practice Guidelines for Chronic Kidney Disease, 2002; Price, 
2005].  For this reason, spot urine protein:creatinine ratio will be used for determining 
proteinuria in this study for the SELENA SLEDAI disease activity indices.
Measurement of creatinine clearance (CrCl)/glomerular filtration rate (GFR) using timed 
(for example, 24-hour) urine collections is time consuming and error prone and has 
consistently been shown to be no more, and often less, reliable than serum creatinine 
based equations for the estimation of GFR [Clinical Practice Guidelines for Chronic 
Kidney Disease, 2002].  Therefore, GFR estimated by the Cockroft-Gault formula will be 
used as was done in the Phase II trial of belimumab (LBSL02) and Phase III.
Cockroft-Gault Equation [Cockcroft, 1976]
female
if
x
dL
mg
tinine
xserumcrea
kg
xweight
yrs
age
mL
Clcr
85
.0
)
/
(
72
)
(
))
(
140
(
min)
/
(


Values outside the reference laboratory normal range that require the investigator’s 
assessment of relationship to SLE:
6.3.1.3.
SLE Flare Index
The SLE Flare Index categorizes SLE flare as “mild or moderate” or “severe” based on a 
positive assessment for at least one of 5 variables [Buyon, 2005; Petri, 2001; Petri, 2005].

Change in SELENA SLEDAI score from the most recent assessment to current (not 
used for severe flare).

Change in signs or symptoms of disease activity.

Change in prednisone dosage.

Use of new medications for disease activity or hospitalization.

Change in PGA score.
Hospitalization for SLE activity is an additional category included only for a severe flare.
A copy of the SLE Flare Index is provided in Appendix 1.
6.3.1.4.
Physician’s Global Assessment (PGA)
The PGA is part of the validated SELENA SLEDAI index and is designed for the 
physician to indicate the subject’s overall disease activity at a particular visit [Petri, 
1999]. The PGA is a 0-10 cm visual analogue scale (VAS), anchored at 0 (none) and 3 
(severe), with intermediate lines at 1 (mild), and 2 (moderate). Each PGA measurement 
will be transformed linearly (x 3/10) to obtain a value between 0.00 and 3.00.
 
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The same primary investigator or same subinvestigator will evaluate and score the PGA 
for the subject each time, unless agreed otherwise with the GSK medical monitor.
A copy of the PGA VAS is provided in Appendix 1.
6.3.2.
SLICC/ACR Damage Index
The Systemic Lupus International Collaborative Clinics/American College of 
Rheumatology (SLICC/ACR) Damage Index is a validated instrument developed to 
assess the accumulated damage in patients with SLE, resulting from either the disease 
process or its sequelae.  It can identify changes in damage seen in patients with both 
active and inactive disease and records damage occurring in patients with SLE regardless 
of its cause [Gladman, 1996].  The index is a predictor of severe outcome and an 
indicator of morbidity in different ethnic groups [Stoll, 1996]. SLICC/ACR Damage 
Index was designed to be useful both as a descriptor for patient populations included in 
studies, and as an outcome measure for therapeutic trials and studies of prognosis 
[Gladman, 1996].
The SLICC/ACR Damage Index consists of 39 items in 12 different organ systems.  For a 
feature to represent damage, it must be present for at least 6 months, to enable 
discrimination between active inflammation and tissue damage [Gladman, 1996] 
Scoring is usually 0 or 1, although in 6 items, a score of 2 can be given if there is a repeat 
episode more than 6 months apart.  The exception is end-stage renal disease, which 
scores 3. 
A copy of the SLICC/ACR Damage Index is provided in Appendix 2.
6.4.
Safety
The safety assessments are adverse events (AEs) (including infusion-related and 
hypersensitivity reactions, infections and malignancies), haematological and clinical 
chemistry parameters, urinalysis, B cell markers, immunogenicity, vital signs (including 
weight), and physical examinations.
6.4.1.
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance) [James, 2009; Le Gal, 2005].  For subjects in 
the treatment holiday group having belimumab therapy re-introduced from Week 24 
onwards or escaping to the maintenance phase of the study prior to Week 24, subjects in 
the control group, or any subject entering the maintenance phase of the study, the 
following applies:
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 
3:
 
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1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and
INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw 
belimumab for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.
2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks OR ALT 3xULN but <5 xULN 
persists for 4 weeks
4. ALT 3xULN if associated with symptoms (new or worsening) believed to be related 
to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks OR 
ALT 3xULN but <5 xULN and cannot be monitored weekly for 4 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately discontinue belimumab for that subject

Report the event to GSK within 24 hours

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw 
belimumab for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Do not restart subject with belimumab unless GSK Medical Governance approval is 
granted (refer to Section 6.4.1.1)
Monitoring for liver chemistry stopping criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
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
A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
Monitoring for liver chemistry stopping criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Phase III-IV Liver Chemistry Increased Monitoring Criteria With Continued 
Therapy
Subjects with ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms 
believed to be related to liver injury or hypersensitivity, and who can be monitored 
weekly for 2 weeks OR ALT x3xULN, but <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

Can continue belimumab 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly.

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Follow-up Assessments For Liver Stopping Criteria 1-5
Make every attempt to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  
 
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
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed, it can 
be replaced with a PCR of hepatitis D RNA virus (where needed) [Le Gal, 2005].  

Blood sample for PK analysis, obtained within approximately one to two weeks after 
the liver event.  Record the date/time of the PK blood sample draw and the date/time 
of the last dose of belimumab 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 SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) or ALT 3xULN and INR>1.5, if INR measured; but are optional for other 
abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and 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 computerized tomography) to 
evaluate liver disease.
For long-term discontinuation group subjects found to have met the liver stopping criteria 
without receiving belimumab, investigators will apply the withdrawal criteria in Section 
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6.4.1.1.
Study Treatment Restart
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 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 drug induced liver injury [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.

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. 
 
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
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 6.4.7.
6.4.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  Subjects will also be issued a paper 
diary to record adverse events and concomitant medications during the study. This will be 
used to assist subject recall in discussions with the investigator, for site staff to then enter 
as appropriate in the eCRF.
6.4.2.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after 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 that do not meet the definition of an AE include:
 
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
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
6.4.2.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or 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, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, 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.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
 
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treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.4.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs, including but not limited to:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization

Hypersensitivity reactions
 
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
Herpes zoster

Malignancies
This information should be recorded within one week of when the AE/SAE(s) are first 
reported.
6.4.4.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.4.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following conditions (preferred terms; MedDRA v. 14.0) are disease-related events 
(DRE) that can occur in the study population regardless of belimumab exposure. 
When these conditions are considered SAEs, they must be reported to the sponsor within 
24 hours of site personnel becoming aware as described in Section 6.4.10. However, 
because these events are typically associated with the disease under study, the sponsor 
will not submit these events as expedited reports to regulatory authorities, investigators, 
or IRBs/IECs (unless considered by the sponsor to be related to study agent). 
Butterfly rash
Cutaneous lupus erythematosus
Glomerulonephritis membranoproliferative 
Glomerulonephritis membranous 
Glomerulonephritis proliferative 
Lupus encephalitis
Lupus endocarditis
Lupus enteritis
Lupus hepatitis
Lupus myocarditis
Lupus nephritis  
Lupus pancreatitis
Lupus pneumonitis
Lupus vasculitis
Nephritic syndrome
Nephritis
Neuropsychiatric lupus
Pericarditis lupus
Peritonitis lupus
SLE arthritis
Systemic lupus erythematosus rash
Systemic lupus erythematosus
 
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6.4.6.
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
Female subjects who become pregnant during the study, should not be treated with 
belimumab and must be withdrawn from the study (see Section 4.4).  Female subjects in 
the long-term discontinuation group who become pregnant during the study must still be 
withdrawn from the study despite not being treated with belimumab during the initial 52 
weeks of the study (see Section 4.4).
6.4.7.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of the study (Day 0) and until the 16-week follow up 
contact for subjects in the treatment holiday and control groups or until the Week 52 visit 
for subjects in the long-term discontinuation group.
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.4.10. Note:  for China sites, serious AEs should be 
recorded from the time the consent form is signed until the 16-week follow up contact for 
subjects in the treatment holiday and control groups, or until the Week 52 visit for 
subjects in the long-term discontinuation group.  GSK’s pharmacovigilance safety 
database will contain all SAEs occurring after the first dose of investigational product 
plus any SAEs related to study participation occurring after the subject signs the 
informed consent form.  SAEs that occur after signing the informed consent form but 
before the first dose of investigational product that are not considered to be related to 
study participation will not be entered into the GSK pharmacovigilance safety database, 
and will be summarized separately in the clinical study report.
 
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6.4.8.
Method of Detecting AEs and SAEs
Care must 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?” or for paediatric studies, “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or for 
paediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for paediatric studies, ”Has your child needed to take any 
medicines, other than those provided in this study, since his/her last visit/contact?”
6.4.9.
Investigator Evaluation of Adverse Events
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
serious are listed in Section 6.4.2.2), severity (intensity) and causality (relationship to 
belimumab).  The investigator will make an assessment of intensity for each AE and SAE 
based on the Division of Microbiology and Infectious Diseases (DMID) Adverse Event 
Severity Grade Tables (see Appendix 4), where possible:
SEVERITY:
Mild
- An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities (Grade 1 DMID)
Moderate - An event that is sufficiently discomforting to interfere with normal everyday 
activities (Grade 2 DMID)
Severe - An event that prevents normal everyday activities (Grade 3 or 4 DMID)
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.
6.4.10.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition for that event.
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
“CV events” 
and/or “death”
data collection 
tool(s) if 
applicable
24 hours
Updated “SAE” 
data collection tool
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse 
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
DRE
2 weeks4
DRE CRF
2 weeks4
Updated DRE CRF
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 
weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
4.
The SRT (or Study Team, if there is no SRT) should determine the appropriate time frame, if one is needed, for 
completion of DRE CRF pages.
Liver chemistry stopping and follow-up criteria are provided in Section 6.4.1.
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM.  Procedures for post-study AEs/SAEs are provided in the SPM.
6.4.10.1.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
 
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6.4.11.
Laboratory Evaluations
Collect samples (blood and urine) for clinical laboratory tests as specified in the 
appropriate Time and Events schedule (Table 2 or Table 3). Additional samples may be 
taken for safety reasons at the discretion of the Investigator. Clinical laboratory tests will 
consist of a complete blood count (CBC) with differential, Chem-20, magnesium, and 
urinalysis as listed in Appendix 5.
All protocol required laboratory assessments, as defined in Appendix 5, must be 
performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the central laboratory.
Reference ranges for all safety parameters will be provided to the site by the central 
laboratory.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the subject’s eCRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.
6.4.12.
Infusion-related Reactions and Hypersensitivity Reactions
Infusion-related reactions on the day of an infusion occurred in approximately 17% of 
patients treated with belimumab 1mg/kg or 10mg/kg during the double-blind portion of 
the Phase 2 and 3 SLE studies, but at rates similar to placebo (15%). Most infusion-
related/hypersensitivity events have been mild-moderate in nature; however, severe and 
or serious events have been reported infrequently (<2% of patients). These events have 
included reports of rash, urticaria, angioedema, hypotension and anaphylaxis. As has 
been done in recent protocols, this protocol recommends that administering 
premedication for prophylaxis against infusion reactions and hypersensitivity reactions 
should be considered for subjects with a history of allergies or urticaria.  
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity 
reactions has been observed. Subjects in the treatment holiday group should remain 
under clinical supervision for 3 hours after completion of the first 2 infusions when re-
starting belimumab, whether upon receiving as ‘rescue’ after a severe flare or upon 
returning for the Week 24 visit and re-introduction of belimumab. Should symptoms of 
acute hypersensitivity occur, an extended period of monitoring may be appropriate, based 
on clinical judgment.  Subjects should be made aware of the potential risk, including the 
risk of delayed reactions, the signs and symptoms of such reactions, and the importance 
of immediately seeking medical attention.
In addition, delayed-type, non-acute hypersensitivity reaction have also been observed 
and included symptom s such as rash, nausea, fatigue, myalgia, headache, and facial 
oedema. 
 
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6.4.13.
Other Immunosuppression Related Considerations
Although there is no evidence to date for an increased risk with belimumab treatment, the 
possibility of immunosuppression resulting in an increase in the frequency and/or 
severity of infection and/or an increased risk of malignancy cannot be excluded.  During 
the trial, subjects will be questioned at all study visits about adverse events and results 
recorded in the eCRF.  Examinations and laboratory evaluations will be performed 
routinely and the results, including markers of potential immunosuppression, will be 
reported to the investigators.
6.4.13.1.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab.  A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and symptoms.  
The subject should be referred to a neurologist or other appropriate specialist for 
evaluation.  If PML is confirmed, study agent should be discontinued and consideration 
should be given to stopping immunosuppressant therapy.
If PML is suspected, this should be immediately reported to the Medical Monitor. 
The appropriateness of continuing study agent, while the case is being assessed, should 
be discussed.
6.4.14.
Vital Signs and Weight
Measure systolic and diastolic blood pressure (sitting), heart rate, temperature and 
weight.  Oral or tympanic temperatures are acceptable, but the method for each subject 
should remain consistent.  Axillary temperatures are not permitted.  Vital sign and weight 
measurements must be taken pre-dose at all dosing visits.  For non-dosing visits, vitals 
and weight assessment can be performed at any time during the subject’s visit.  For any 
subject whose weight changes by more than 5% from that recorded at the Day 0 visit, the 
weight at the current visit will be used to calculate the belimumab dose to be 
administered at this dosing visit. At the discretion of the investigator, vital signs may be 
assessed at unscheduled visits.
6.4.15.
Physical examination
As a minimum, brief physical examination will include assessment of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). At the discretion of the 
investigator, physical examinations may be assessed at unscheduled visits.
6.4.16.
Immunogenicity
Serum samples will be collected for immunogenicity assessment.  All samples should be 
collected prior to dosing (where appropriate) as specified in the appropriate Time and 
Events schedule (Table 2 or Table 3).  Note that serum samples for immunogenicity must 
be collected pre-dose at the time of dosing from subjects in the treatment holiday group 
who experience a severe flare prior to Week 24 and consequently receive open-label 
 
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belimumab as rescue.  For non-dosing visits, assessment can be performed at any time 
during the visit.  An attempt will be made to determine the amount of belimumab (PK) 
present in immunogenicity samples with confirmed anti-drug binding antibodies (ADA). 
The belimumab level in these samples will be used in the interpretation of ADA results 
and will be included in the immunogenicity section in the CSR.
An attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 
6 months after the last dose of belimumab for any subject who had an anti-belimumab 
antibody response at the 16-week follow-up visit or if the 16-week follow-up 
immunogenicity sample is not available.
All immunogenicity testing will be carried out according to the multi-tier assay testing 
scheme including the detection of anti-drug binding antibodies (ADA, including 3-steps 
of screening, confirmation/specificity and titration) and the detection of anti-drug 
neutralizing antibodies (Nab).  Note:  Nab testing will not be performed in China.
All samples will be tested in ADA screening step.  Any samples tested positive in the 
screening step will then be tested using an ADA confirmation step.  Any confirmed 
positive samples in the confirmation will be further tested in the titration to obtain ADA 
titer values and in the Nab assay to evaluate the presence of neutralizing antibodies. The 
incidence of subjects with confirmed positive ADA responses with titers and positive 
Nab will be reported, respectively at the end of the study.  However, Nab results will not 
be available for China subjects.
Details for sample processing and analysis are provided in the SPM.
6.5.
Biomarkers
As yet, no clear surrogate endpoints have been widely accepted that clearly define 
clinical outcomes for the multi-organ system manifestations of SLE.  However 
autoantibodies have been shown to be important early markers of specific disease 
processes or severity in SLE [Hahn, 1998; Leslie, 2001; Ravirajan, 2001] and are 
associated with disease activity [Villarreal, 1997]. Therefore autoantibody levels will be 
included as endpoints.
Collect blood samples as specified in the appropriate Time and Events schedule (Table 2
or Table 3), in order to assess the following endpoints:

Percent change from baseline:
-Total serum immunoglobulin (IgG and other isotypes: IgM and IgA).
-Autoantibodies (anti-dsDNA) and complement (C3, C4).

Percent change in absolute B cell subsets (CD20+, CD20+/27+ memory, CD20+/27–
naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT 
SLE subset and CD20-/138+ plasma cells).
All biomarker samples will be analysed centrally.
 
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6.6.
Pharmacokinetics
Collect blood samples for measurement of serum belimumab concentrations from 
subjects in the treatment holiday and control groups at selected sites at the times specified 
in the Time and Events Table (Table 2). Only one PK sampling for the treatment holiday 
group between Weeks 0 and 16 can be performed at any time during the visit.  Otherwise, 
sampling must be performed prior to dosing (pre-dose sample) at Day 0 and Weeks 8 and 
16. Sampling must be performed pre-dose and post-dose (at the end of the belimumab 
infusion) at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the 
event of a severe flare by using the escape option).  For non-dosing visits, assessment can 
be performed once at any time during the subject’s visit.  Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit 
between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before Week 
24 will have one PK sampling performed at any time during the EXIT visit.  PK sampling 
for long-term discontinuation subjects withdrawing after Week 24 is not performed at the 
EXIT visit.  Samples will be analysed at a central laboratory.   PK assessment will also be 
used to determine belimumab concentration in confirmed positive immunogenicity 
samples.        
6.7.
Pharmacogenetic Research
Collect a blood sample for pharmacogenetics (PGx) from consenting subjects except 
those recruited from Study BEL114333 (who have already provided a sample as part of 
that study). Samples for PGx must be drawn prior to dosing as appropriate.
Information regarding PGx research is included in Appendix 6.
7.
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 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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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
Originally a total of approximately 135 subjects (50 in the treatment holiday group, 50 in 
the control group, and 35 in the long term discontinuation group) were planned to be
enrolled in this study.  After 36 months had elapsed since study start, a reduction in 
sample size was agreed to with regulatory authorities, and a total of at least 71 patients (at 
least 10 in treatment holiday, at least 26 in the control group and 35 in the long term 
discontinuation group) will be the target sample size to be enrolled in this study. The total 
sample size is based on practical considerations on the availability of subjects from other 
ongoing belimumab studies, rather than on statistical considerations. Since this is a non-
randomized study, results will be descriptive only, and not intended to be inferential.  No 
power calculations were made in the determination of sample size for this study.  
However, the total of subjects is expected to provide adequate information to characterize 
time to SLE flare.  Table 4 shows the flare rates for the pooled BLISS studies.
Table 4
Flare Rates from Pooled BLISS Studies
ISE Table
Analysis
Placebo
1 mg/kg
10 mg/kg
T57
Percentage of Subjects 
with Flare Over  52 
Weeks
81.5%
74.6%
74.6%
TAC411
Percentage of Subjects 
with Flare Over 52 
Weeks Post Week 24
68.5%
54.7%
57.5%
TAC613
Percentage of Subjects 
with Flare Over 52 
Weeks Among SRI Wk 
52 Responders
73.4%
69.8%
67.4%
8.1.
Data Analysis Considerations
8.1.1.
Analysis Populations
The primary analysis population will be the Intent-to-treat (ITT) population.  The ITT 
population will consist of all subjects enrolled in the study.
8.1.2.
Primary Efficacy Analysis
Time to first SLE flare will be analyzed using a time-to-event analysis.  Time to first SLE 
flare is defined as the number of days from Day 0 of the BEL116027 study to the first 
occurrence of a SLE flare.  If a subject withdraws from the study or completes week 52 
without a SLE flare, time to the first SLE flare will be censored at the time of the last 
observation (last visit measuring flare). However, if a subject receives prohibited 
medication during the study, the subject will be considered as having a SLE flare at the 
time the medication is started.  Data observed at or prior to the Day 0 visit will not be 
included in this analysis.
 
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8.1.3.
Analysis of Additional Efficacy Endpoints
For the primary analysis of the additional efficacy and biomarkers, the baseline will be 
defined as study Day 0 of the original parent study.  Additionally, for some of the 
endpoints, a secondary analysis will be performed by defining the baseline as Day 0 of 
the BEL116027 study.
The major analysis of the additional efficacy and biomarkers will include descriptive 
tabulation of secondary endpoints by treatment group according to the treatment group 
they are assigned to in the BEL116027 study.
8.1.4.
Safety Analysis
AEs will be graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 6) or the grades in Section 6.4.8, as appropriate. The frequency of AEs 
will be tabulated by MedDRA system organ class and preferred term and by treatment 
groups, according to the treatment group that the subjects were assigned to in the 
BEL116027 study. Additional analysis may be performed based on event rates adjusting 
for subject-years on study agent. The number of subjects with AEs and the incidence rate 
of AEs will be summarised in each 6-month time interval. AEs will also be summarised 
by MedDRA SOCs and preferred terms for those that are considered to be at least 
possibly related to study agent and those that are considered to be severe (Grade 3 and 
Grade 4). Discontinuations due to AEs will be summarised.
The frequency of laboratory abnormalities will be tabulated by treatment group. 
Laboratory values will be assessed for significant changes from baseline. Laboratory 
toxicity will be graded using Adverse Event Severity Grading Tables when possible. 
Shift tables will be used to determine if subjects move from normal to abnormal during 
the course of the study. Shifts of ≥2 grades and Grade 3 or Grade 4 laboratory 
abnormalities will be summarised.
Immunogenicity (anti-belimumab antibodies) will be summarized at baseline and during 
treatment and follow-up.
8.1.5.
Pharmacokinetic Analysis
Serum belimumab concentration will be determined by an ECL-based immunoassay. 
Results for this study will be presented using appropriate graphic and tabular summaries.
8.1.6.
Interim Analysis
An interim analysis of the data in this trial may be performed to support a submission to 
regulatory authorities relating to marketing authorization (e.g., to summarize and submit 
this long term safety data to regulatory authorities in the initial BLA and other marketing 
authorization submissions). Additional interim analyses may be required to support 
subsequent safety updates to regulatory authorities. 
 
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9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.  Obtain written informed consent from all subjects to participate in this study at the 
Screening visit.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 6, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
 
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identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance 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.
9.5.
Study and Site Closure
Subjects recruited into this study will continue to receive treatment with belimumab until 
such time as belimumab becomes commercially available in Northeast Asia, or the 
subject elects to participate in another belimumab continuation study for SLE, or the 
Sponsor discontinues the maintenance phase of the study for China subjects with the 
provision for China subjects to elect to participate in a different protocol to continue to 
receive belimumab, or until either the subject's physician withdraws the subject from the 
study, or upon the decision by the sponsor to discontinue the study.  Safety reporting will 
be as specified in the protocol the subject participates in.  Upon completion of treatment, 
every effort should be made to evaluate subjects for Week 16 post-treatment follow-up 
visit and the 6-month post-treatment visit.  Once all reasonable efforts have been made, 
the study will be considered complete/terminated.
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
 
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If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting 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.
 
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GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 
 
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Viner N, Zoma A. The BILAG index: a reliable and valid instrument for measuring 
clinical disease activity in systemic lupus erythematosus. Q J Med. 1993;86(7):447-58.
Isenberg DA, Gordon C. From BILAG to BLIPS--disease activity assessment in lupus 
past, present and future. Lupus. 2000;9(9):651-4.
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Chang D, Van G, Ross L, Delaney J, Wang L, Lacey D, Boyle WJ, Hsu H. Severe B-cell 
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serum by consensus real-time PCR indicates different patterns of virological response to 
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Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell 
hyperactivity. Nature Immunology. 2001;2(9):764-6.
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Browning JL. Mice transgenic for BAFF develop lymphocytic disorders along with 
autoimmune manifestations. J Exp Med. 1999;190:1697-1710.
 
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Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, 
Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, 
Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM. BLyS: 
member of the tumor necrosis family and B lymphocyte stimulator. Science. 
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trials. Lupus. 1999;8:685-91.
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Merrill JT, Belmont HM, Askanase AD, McCune WJ, Hearth-Holmes M, Dooley MA, 
Von Feldt J, Friedman A, Tan M, Davis J, Cronin M, Diamond B, Mackay M, Sigler L, 
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systemic lupus erythematosus. N Engl J Med. 2005;353:2550-8.
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following cardiac transplantation: a link between rejection and infection. J Heart Lung 
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11.
APPENDICES
11.1.
Appendix 1: SELENA SLEDAI Disease Assessment Scales
 
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SELENA SLEDAI Disease Assessment Scales (continued)
SELENA SLEDAI Disease Assessment Scales (continued)
Physician’s Global Disease Assessment
 
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References
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the 
SLEDAI: a disease activity index for lupus patients. The Committee on Prognosis Studies 
in SLE. Arthritis Rheum. 1992;35(6):630-640. 
Buyon JP, Petri MA, Kim MY,Kalunian KC, Grossman J, Hahn BH, Merrill JT, 
Sammaritano L, Lockshin M, Alarcón GS, Manzi S, Belmont HM, Askanase AD, Sigler 
L, Dooley MA, Von Feldt J, McCune WJ, Friedman A, Wachs J, Cronin M, Hearth-
Holmes M, Tan M, Licciardi F. The Effect of Combined Estrogen and Progesterone 
Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: 
A Randomised Trial. Ann Internal Med. 2005;142(12 Pt 1):953-62. 
Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical 
trials. Lupus. 1999;8:685-91.
Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR, Lockshin M, 
Merrill JT, Belmont HM, Askanase AD, McCune WJ, Hearth-Holmes M, Dooley MA, 
Von Feldt J, Friedman A, Tan M, Davis J, Cronin M, Diamond B, Mackay M, Sigler L, 
Fillius M, Rupel A, Licciardi F, Buyon JP. Combined oral contraceptives in women with 
systemic lupus erythematosus. N Engl J Med. 2005;353:2550-8.
 
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11.2.
Appendix 2: SLICC/ACR Damage Index
 
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SLICC/ACR Damage Index (continued)
References
From the Systemic Lupus International Collaborating Clinics (SLICC) and the American 
College of Rheumatology Diagnostic and Therapeutic Criteria Committee, 1996
Gladman EM, Ginzler E, Goldsmith C, Fortin P, Liang M, Sanchez-Guerrero J, Urowitz 
M, Bacon P, Bombardieri S, Hanly J, Jones J, Hay E, Symmons D, Isenberg D, Kalunion 
K, Maddison P, Nived O, Sturfelt G, Petri M, Richter M, Snaith M, Zoma A. The 
development and initial validation of the systemic lupus international collaborating 
clinics/American college of rheumatology damage index for systemic lupus 
erythematosus. Arthritis Rheum. 1996;39(3):363-9.
 
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11.3.
Appendix 3: Liver Chemistry Stopping and Followup Criteria
Phase III-IV 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
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
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*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.4.1.
 
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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
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*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.4.1.
 
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11.4.
Appendix 4: Adverse Event and Laboratory Value Severity 
Grade Tables
HEMATOLOGY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-
THREATENING
Hemoglobin
> 9.5 - 11.0 
g/dL
> 8.0 – 9.5 
g/dL
6.5 - 8.0 g/dL
< 6.5 g/dL
Leukocytes
3000-
3999/mm3
2000-
2999/mm3
1000-
1999/mm3
< 1000/mm3
Absolute Neutrophil Count 1500-
1999/mm3
1000-
1499/mm3
500-999/mm3 < 500/mm3
Platelets
75,000 -
99,999/mm3
50,000 –
74,999/mm3
25,000 -
49,999/mm3
< 25,000/mm3
Prothrombin Time (PT)
> 1.0-1.25 x 
ULN*
> 1.25-1.5 x 
ULN
> 1.5-3.0 x 
ULN
> 3.0 x ULN
Partial Thromboplastin 
Time (PTT)
> 1.0-1.66 x 
ULN
> 1.66-2.33 x 
ULN
> 2.33-3.0 x 
ULN
> 3.0 x ULN
Methemoglobin
5.0-10.0 %
10.1-15.0 %
15.1-20.0 %
> 20%
(continued)
*ULN = Upper Limit of Normal                                                        Modified from DMID Adult Toxicity Tables, 2001
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
CARDIOVASCULAR
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cardiac Arrhythmia
-
Asymptomatic/transient; 
dysrhythmia; no treatment req
Recurrent/persistent 
dysrhythmia. Symptomatic; 
treatment req
Unstable dysrhythmia hospitalization
and treatment required
Hypotension
Transient orthostatic 
hypotension, no treatment
Symptoms correctable 
with oral fluid treatment
IV fluid req,
no hospitalization req
Hospitalization req
Hypertension
Transient, increase
> 20 mm/Hg; no treatment
Recurrent; chronic increase
> 20 mm/Hg, treatment req
Acute treatment req; out patient 
hospitalization possible
Hospitalization req
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion,
pain, ECG changes
Tamponade OR pericardiocentesis 
OR surgery req
Hemorrhage, Blood Loss
-
Mildly symptomatic; 
no treatment required
Gross blood loss OR
1-2 units transfused
Massive blood loss OR
> 2 units transfused
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
CHEMISTRIES
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Sodium
  Hyponatremia
130-135 meq/L
123-129 meq/L
116-122 meq/L
< 116 meq/L
  Hypernatremia
146-150 meq/L
151-157 meq/L
158-165 meq/L
> 165 meq/L
Potassium
  Hypokalemia
3.0-3.4 meq/L
2.5-2.9 meq/L
2.0-2.4 meq/L
< 2.0 meq/L
  Hyperkalemia
5.6-6.0 meq/L
6.1-6.5 meq/L
6.6-7.0 meq/L
> 7.0 meq/L
Phosphate
  Hypophosphatemia
2.0-2.4 mg/dL
1.5-1.9 mg/dL
1.0-1.4 mg/dL
< 1.0 mg/dL
Calcium- (Corrected For Albumin)
  Hypocalcemia
7.8-8.4 mg/dL
7.0-7.7 mg/dL
6.1-6.9 mg/dL
< 6.1 mg/dL
  Hypercalcemia
10.6-11.5 mg/dL
11.6-12.5 mg/dL
12.6-13.5 mg/dL
>13.5 mg/dL
Magnesium
  Hypomagnesemia
1.2-1.4 meq/L
0.9-1.1 meq/L
0.6-0.8 meq/L
< 0.6 meq/L
Albumin
  Hypoalbuminemia
3.00-3.49 g/dL
2.50-2.99 g/dL
2.00-2.49 g/dL
< 2.00 g/dL
Bilirubin (Total)
  Hyperbilirubinemia (Total)
> 1.0-1.5 x ULN
> 1.5-2.5 x ULN
> 2.5-5 x ULN
> 5 x ULN
Glucose
  Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
< 30 mg/dL
  Hyperglycemia 
116-160 mg/dL
161-250 mg/dL
251-500 mg/dL
> 500 mg/dL
  (nonfasting & no prior diabetes)
  Triglycerides
151-399 mg/dL
400-750 mg/dL
751-1200 mg/dL
> 1200 mg/dL
Creatinine
> 1.0-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0-6.0 x ULN
> 6.0 x ULN
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
CHEMISTRIES (continued)
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Uric Acid
  Hyperuricemia
7.5-10.0 mg/dL
10.1-12.0 mg/dL
12.1-15.0 mg/dL
> 15.0 mg/dL
Liver Transferases  (AST, ALT, and 
GGT)
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Alkaline Phosphatase
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Pancreatic Enzymes
Amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Pancreatic amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Lipase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Hypoglobulinemia (IgG)*
550-700 mg/dL
400-549 mg/dL
250-399 mg/dL
< 250 mg/dL
(continued)
*[Eibl, 1995; Goldfarb, 2001; Yamini, 2001].                                                                                                                                      Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
GASTROINTESTINAL
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Nausea
Mild OR transient; 
reasonable intake 
maintained
Mod discomfort 
OR intake decreased 
for < 3 days
Severe discomfort OR 
minimal intake 
for 3 days
Hospitalization required
Vomiting
Mild OR transient; 
2-3 episodes/day OR 
mild vomiting lasting 
< 1 week
Mod OR persistent; 
4-5 episodes per day; 
OR vomiting lasting 
1 week
Severe vomiting of all 
foods/fluids in 24 hours 
OR orthostatic hypotension
OR IV treatment req
Hypotensive shock OR hospitalization 
required for IV treatment req
Diarrhea
Mild or transient; 
3-4 loose stools per day 
OR mild diarrhea lasting 
< 1 week
Mod OR persistent; 
5-7 loose stools per day 
or diarrhea lasting 
1 week
Bloody diarrhea; 
OR orthostatic hypotension 
OR > 7 loose stools/day 
OR IV treatment req
Hypotensive shock 
OR hospitalization req
Oral Discomfort/Dysphagia
Mild discomfort, no difficulty 
swallowing
Difficulty swallowing but able 
to eat and drink
Unable to swallow solids
Unable to drink fluids; 
IV fluids req
Constipation
Mild
Moderate
Severe
Distention with vomiting
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
RESPIRATORY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cough 
(for aerosol studies) 
Transient; no treatment
Treatment associated 
cough; inhaled bronchodilator
Uncontrolled cough; 
systemic treatment req
Bronchospasm Acute
Transient; no treatment; 
FEV1 70% to 
< 80% 
(or peak flow)
treatment req; normalizes with 
bronchodilator; 
FEV1 50% to < 70% 
(or peak flow)
No Normalization 
with bronchodilator; 
FEV 25% to < 50% 
(or peak flow), retractions
Cyanosis; FEV1 < 25% 
(or peak flow) OR intubated
Dyspnea
Dyspnea on exertion
Dyspnea with 
normal activity
Dyspnea at rest
Dyspnea requiring O2 therapy
URINALYSIS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Proteinuria
Dispstick
Protein
1 +
2-3 +
4 +
Nephrotic syndrome
Spot Urine:    
Protein:Creatinine 
Ratio mg/mg
0.2-1.0
> 1.0-2.0
> 2.0-3.5
> 3.5
24 Hour Urine:
Protein
200 mg - 1g loss/day
> 1-2 g loss/day
> 2-3.5 g loss/day
Nephrotic syndrome
OR > 3.5 g loss/day
Hematuria
Microscopic only
> 3 to < 10 RBC/hpf
Gross, No clots
10 RBC/hpf
Gross plus clots OR 
RBC casts
Obstructive OR transfusion required
(continued)
RBC = red blood cell; hpf = high power field.
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
MISCELLANEOUS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Fever (oral > 12 hours)
37.7-38.5C or
100.0-101.5F
38.6-39.5C OR
101.6-102.9F
39.6-40.5C OR
103-105F
> 40.5C OR > 105F
Headache
Mild; No treatment req
Mod; or non-narcotic analgesia 
treatment
Severe; OR responds to initial 
narcotic treatment
Intractable; OR requiring 
repeated narcotic treatment
Allergic Reaction
Pruritus without rash
Localized urticaria
Generalized urticaria 
angioedema
Anaphylaxis
Cutaneous/Rash/ Dermatitis
Erythema, pruritus rash 
OR dry desquamation
Diffuse maculopapular 
OR dry desquamation
Vesiculation OR moist 
desquamation ulceration
ANY ONE: mucous membrane involvement, 
suspected 
Stevens-Johnson (TEN), erythema multiforme, 
necrosis req surgery, exfoliative dermatitis
Local Reaction (secondary 
to parenteral treatment- not 
vaccination or skin test)
Erythema
Induration < 10 mm 
OR inflammation 
OR phlebitis
Induration > 10 mm 
OR ulceration
Necrosis of skin
Fatigue
Normal activity 
Reduced < 25%
Normal activity 
Reduced 25-50%
Normal activity 
reduced > 50%; 
cannot work
Unable to care for self
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Appendix 4: Adverse Event and Laboratory Value Severity Grade Tables (continued)
NEUROLOGIC
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Neuro-cerebellar
Slight incoordination OR 
dysdiadochokinesia
Intention tremor OR 
dysmetria OR slurred speech 
OR nystagmus
Ataxia requiring assistance to walk 
or arm incoordination interfering 
with ADLs
Unable to stand
Neuro-psych/ mood
none
Severe mood changes requires 
medical intervention
Acute psychosis requiring 
hospitalization
Paresthesia 
(burning, tingling, etc)
Mild discomfort; 
no treatment needed
Mod discomfort 
non-narcotic analgesia req
Severe discomfort; OR narcotic 
analgesia req with symptomatic 
improvement
Incapacitating; OR not responsive 
to narcotic analgesia
Neuro-motor
Mild weakness in muscle 
of feet but 
able to walk and/or mild
increase or decrease in 
reflexes
Mod weakness in feet (unable to walk on 
heels and/or toes), mild weakness in 
hands, still able to do most hand tasks 
and/or loss of previously present reflex 
or development of hyperreflexia 
and/or unable to do deep knee 
bends due to weakness
Marked distal weakness (unable to 
dorsiflex toes or foot drop), and 
mod proximal weakness ie, in 
hands interfering with ADLs and/or 
requiring assistance to walk and/or 
unable to rise from chair 
unassisted
Confined to bed or wheelchair 
because of muscle weakness
Neuro-sensory
Mild impairment 
sensations, 
(ie, vibratory, pinprick, 
hot/cold in great toes) in 
focal area or symmetrical 
distribution
Mod impairment mod de-sensation, 
(ie, of vibratory, pinprick, hot/cold to 
ankles) and/or joint position or mild 
impairment that is not symmetrical.
Severe impairment (dec or loss of 
sensation to knees or wrists) or 
loss of sensation of at least mod 
degree in multiple different body 
areas (ie, upper and lower 
extremities)
Sensory loss involves limbs 
and trunk
(concluded)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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11.5.
Appendix 5: Clinical Laboratory Tests
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)
Partial thromboplastin time (PTT)
  
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Dysmorphic RBC
Casts (specified by 
type e.g., RBC, WBC)
Spot Urine (protein : creatinine 
ratio)
Urine Pregnancy
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutanyl transpeptidase (GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
        Hepatitis B Viral DNA PCR
            Quantitative (HBV DNA)
Estimated Creatinine Clearance/ GFR 
(Cockroft-Gault)
Liver event follow-up assessments:
       Hepatitis A IgM antibody
       HBsAg and hep B Core antibody (IgM)
       Hepatitis C RNA
       Hepatitis delta antibody
       Cytomegalovirus IgM antibody
       Epstein-Barr viral capsid antigen IgM
            antibody
       Hepatitis E IgM antibody
       CPK
       Anti-smooth muscle antibody
       Type 1 anti-liver kidney microsomal
             antibodies
       PK
       IgG
       Fractionated bilirubin
       Serum acetaminophen
Biological Markers
BLyS protein
Serum complement (C3 and C4) 
B-cell subtypes
Immunoglobulins
Serum immunoglobulin isotypes:  IgG, IgM, IgA
Immunogenicity
Autoantibodies
ANA
Anti-dsDNA
aCL
 
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11.6.
Appendix 6: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 20
02; Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia Chung, 
2010; Ferrell, 
2008
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
 
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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to belimumab. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
belimumab.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with belimumab, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
 
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Study Assessments and Procedures
Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6 ml) will be collected for the PGx research using a tube 
containing EDTA.  It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomized and provided informed consent for PGx 
research, but may be taken at any time while the subject is participating in the clinical 
study.

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
belimumab has been completed and the clinical study data reviewed.  In some cases, the 
samples may not be studied. e.g., no questions are raised about how people respond to 
belimumab.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx 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 PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx 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. The investigator should forward the Pharmacogenetic Sample 
 
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Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx 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.
Pharmacogenetics Analyses
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to belimumab.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood being taken for 
PGx research.
 
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Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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 PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.
 
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11.7.
Appendix 7: Country Specific Requirements
The following sections were changed in country-specific Protocol Amendment 01 for 
China and all China sites and these changes continue to apply only to China and all 
China sites. Appendix 8 provides the list of changes made in Protocol Amendment 01.
TABLE OF CONTENTS
Page
PROTOCOL SUMMARY, Study Design ....................................................................90
Investigational Plan, Study Design...............................................................................90
Discussion of Design ....................................................................................................93
Inclusion Criteria ..........................................................................................................94
Exclusion Criteria .........................................................................................................97
Investigational Product and Other Study Treatment.....................................................97
Time and Events Table (Year 1).................................................................................100
Secondary Endpoints ..................................................................................................103
Critical Baseline Assessments ....................................................................................103
SELENA SLEDAI Score............................................................................................104
Laboratory tests for SELENA SLEDAI .....................................................................106
Liver Chemistry Stopping and Follow up Criteria, Additional Hepatitis B Monitoring 106
Pharmacogenetic Research .........................................................................................107
Clinical Laboratory Tests............................................................................................107
 
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Amendment 01, PROTOCOL SUMMARY, Study Design
A phase IV, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:

the effect of temporary discontinuation of belimumab 10 mg/kg therapy for 24 weeks 
and reintroduction of belimumab 10 mg/kg therapy for 28 weeks plus standard of 
care (referred to as ‘treatment holiday’) in subjects with low SLE disease activity.

rebound phenomenon in subjects who have discontinued belimumab therapy 
(stratified by SLE disease activity, SELENA SLEDAI score 3 or SELENA 
SLEDAI score >3).
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase.  The study consists of a treatment holiday group, a control group, and a long-term 
discontinuation group. All 3 subject groups will be recruited from the BEL114333 
continuation study of belimumab in SLE, and from the open-label (OL) period 
BEL113750 for China subjects.  Additionally, subjects in the long-term discontinuation 
group will also be recruited from the HGS1006-C1066 and LBSL99 continuation studies 
of belimumab in SLE. All subjects will be assessed every 4 weeks for 52 weeks. After 52 
weeks, eligible subjects in the treatment holiday and control groups have the option to 
continue receiving belimumab therapy in the maintenance phase of this study. Two 
follow-up visits are scheduled for subjects in the treatment holiday and control groups 
who are prematurely withdrawn from the study. Subject completion for subjects in the 
treatment holiday group is defined as completion of the 24-week treatment holiday period 
plus the belimumab re-introduction treatment period to Week 52.  Subject completion for 
subjects in the control and long-term discontinuation groups is defined as completion of 
all visits to Week 52.
Amendment 01, Section 3.1 Investigational Plan, Study Design
A phase IV, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:

the effect of temporary discontinuation of belimumab 10 mg/kg therapy for 24 weeks 
and reintroduction of belimumab 10 mg/kg therapy for 28 weeks plus standard of 
care (referred to as ‘treatment holiday’) in subjects with low SLE disease activity 
(Figure 1).

rebound phenomenon in subjects who have discontinued belimumab therapy (Figure 
1).
 
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Amendment 01, Figure 1
Study Schematic
Subjects will be recruited from 3 open-label continuation studies of belimumab in SLE, 
and from the open-label (OL) period of BEL113750 for China subjects. This study will 
comprise 3 distinct groups of subjects as outlined below:

Treatment Holiday group: This group will be used to assess the effect of temporary 
discontinuation (including rebound phenomenon) and re-introduction of belimumab 
10 mg/kg therapy. These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE, and from the open-label period of 
BEL113750 for China subjects.  Subjects will have been treated with belimumab for 
at least 6 months and have a SELENA SLEDAI score 3 and complement (C3 and 
C4) levels at or above the central laboratory lower limit of normal. The target 
enrolment for this group is at least 10 subjects.

Treatment Control group: This group will serve as a control to the treatment 
holiday group.  These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE, and from the open-label period of 
BEL113750 for China subjects.  Subjects will have been treated with belimumab for 
at least 6 months and have a SELENA SLEDAI score 3 and complement (C3 and 
C4) levels at or above the central laboratory lower limit of normal but will continue 
their current treatment with belimumab 10 mg/kg. The target enrolment for this 
group is at least 26 subjects.
 
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
Long-term Discontinuation group: This group will also be used to assess rebound 
phenomenon in SLE subjects who have discontinued therapy with belimumab 10 
mg/kg and are expected to remain off belimumab therapy for at least 12 months but 
remain on standard of care therapy. These subjects will be recruited from 3 
belimumab open-label continuation studies in subjects with SLE (BEL114333; 
HGS1006-C1066; LBSL99), and from the open-label period of BEL113750 for 
China subjects.  Subjects will have been treated with belimumab for at least 6 
months in one of these continuation studies and from the open-label period of 
BEL113750 for China subjects for at least 6 months, but will have withdrawn from 
belimumab therapy for no longer than 8 weeks prior to entry into this study. These 
subjects may have any level of SLE disease activity. The target enrolment for this 
group is 35 subjects.
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor discontinues the maintenance phase of the study 
for China subjects with the provision for China subjects to elect to participate in a 
different protocol to continue to receive belimumab, or the Sponsor decides to terminate 
the study.  Safety reporting will be as specified in the protocol the subject participates in.  
A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups after the withdrawal visit or the last dose of belimumab as appropriate. 
Additionally, a 6 month follow-up visit is required for those subjects in the treatment 
holiday or control groups.
Subjects in the treatment holiday group may re-start belimumab therapy prior to Week 24 
in the event of a severe SLE flare as per the SLE flare index (Appendix 1). These subjects 
will then enter the maintenance part of this study by the escape option for ongoing 
belimumab treatment.
Subject completion for subjects in the treatment holiday group is defined as completion 
of the 24-week treatment holiday period plus the belimumab re-introduction treatment 
period to Week 52.  Subject completion for subjects in the control and long-term 
discontinuation groups is defined as completion of all visits to Week 52.
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. 
 
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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
Amendment 01, Section 3.2 Discussion of Design
This study proposes to recruit subjects from 3 ongoing open-label continuation studies of 
belimumab in SLE subjects as well as from the open-label period of BEL113750 for 
China subjects in order to obtain an eligible population in the shortest timeframe:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan and South Korea.

BEL113750:  Only China subjects from the open-label portion of this Phase III, 
randomized, parallel group, double-blind study to evaluate the efficacy and safety 
of 10mg/kg belimumab intravenously at Weeks 0, 2, and 4, and then every 4 
weeks, compared with placebo over a 52-week treatment period in subjects with 
active systemic lupus erythematosus (SELENA SLEDAI score 8) in Northeast 
Asia. 

HGS1006-C1066: An ongoing Phase III, open-label continuation study of parent 
study HGS1006-C1056 (BLISS 76), which enrolled and treated 268 SLE subjects 
with belimumab conducted in the United States

LBSL99: An ongoing Phase II, open-label continuation study of parent study 
LBSL02, which enrolled and treated 296 SLE subjects with belimumab conducted 
in the United States and Canada.
Subjects eligible for inclusion in the treatment holiday group will have been treated with 
belimumab for at least 6 months in BEL114333 or for at least 6 months in the 
BEL113750 open-label period for China subjects, and have a SELENA SLEDAI score 
3 and complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal.
Subjects eligible for inclusion in the control group will have been treated with belimumab 
for at least 6 months in BEL114333 or for at least 6 months in the BEL113750 open-label 
period for China subjects, and have a SELENA SLEDAI score 3 and complement (C3 
and C4) levels at or above the central laboratory lower limit of normal but elect to 
continue their current treatment with belimumab 10 mg/kg.
Subjects eligible for inclusion in the long-term discontinuation group may have any level 
of SLE disease activity; will have been treated with belimumab for at least 6 months in 
any of the 3 continuation studies mentioned above, or for at least 6 months in the 
BEL113750 open-label period for China subjects; have discontinued belimumab therapy 
for no longer than 8 weeks prior to entry into this study and intend to remain off 
 
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belimumab treatment for the 12 months of this study but to remain on standard of care 
therapy.
Subjects eligible for inclusion in the treatment holiday group will not be recruited from 
the long-term continuation studies LBSL99 or HGS1006-C1066, due to regulatory 
commitments for completing 10 years and 5 years on treatment, respectively. However, 
subjects who discontinue belimumab treatment in studies LBSL99 or HGS1006-C1066 
can be recruited into the long-term discontinuation group in the present study.
For subjects entering the study, a minimum of 6 months previous participation in an 
open-label continuation studies or China subjects in BEL113750 receiving open-label 
belimumab for at least 6 months, will provide subjects initially randomized to placebo in 
parent studies with the opportunity to reach sufficient biological activity to achieve a 
belimumab pharmacological and/or clinical response.
The target sample size of at least 10 subjects in the treatment holiday group and at least 
26 subjects in the control group is based on estimates of subject eligibility and number of 
subjects from continuation study BEL114333 and China subjects in BEL113750 
receiving open-label belimumab for at least 6 months, is anticipated to provide consent to 
participate in this study.  The target sample size of 35 subjects for the long-term 
discontinuation group is based on practical considerations of numbers of subjects 
anticipated to drop-out and not on statistical considerations.
Enrolment of subjects from the 3 belimumab continuation studies or from the open-label 
period of BEL113750 for China subjects into the long-term discontinuation group will 
remain open while recruitment to the treatment holiday and control groups is ongoing or 
until 36 months have elapsed since study start. A target sample size of 35 subjects in the 
long-term discontinuation group is anticipated.
Because this study is non-randomized, subjects and investigators from study BEL114333 
and China subjects and China investigators from study BEL113750 will jointly decide 
upon which of the three groups to enrol into.  Subjects recruited from the HGS1006-
C1066 and the LBSL99 studies may only choose to enter the long-term discontinuation 
group, as they elect to no longer receive further belimumab therapy.
Amendment 01, Section 4.2 Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the belimumab IB/IB 
supplement(s) and belimumab product label.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
 
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Subjects eligible for enrolment in all 3 subject groups in the study must meet all of the 
following criteria:
1.
Belimumab therapy: Received a minimum of 6 months therapy with belimumab 10 
mg/kg in the continuation study BEL114333 or from China subjects in BEL113750 
who received open-label belimumab for at least 6 months. Subjects in the long-term 
discontinuation group may additionally be recruited from continuation studies 
HGS1006-C1066 or LBSL99.
2.
Age: 18 years of age at the Day 0 visit.
3.
Females: A non-pregnant, non-lactating female subject is eligible to enter the study 
if at least one of the following conditions apply:

Of non-childbearing potential (i.e., women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented female sterilization procedure); 
or 

Of childbearing potential (i.e., women with functional ovaries and no 
documented impairment of oviductal or uterine function that would cause 
sterility).  This category includes women with oligomenorrhoea (even severe), 
women who are perimenopausal or have just begun to menstruate.  These 
women must have a negative urine pregnancy test at Day 0, and agree to one of 
the following:

Complete abstinence from penile-vaginal intercourse, when this is the 
female’s preferred and usual lifestyle, for the duration of the study for 
subjects in the long-term discontinuation group or until 16 weeks after the 
last dose of belimumab for subjects in the treatment holiday and control 
groups; or

Consistent and correct use of one of the following acceptable methods of 
birth control for the duration of the study for subjects in the long-term 
discontinuation group or until 16 weeks after the last dose of belimumab for 
subjects in the treatment holiday and control groups:

Implants of etonogestrel or levonorgestrel;

Estrogenic vaginal ring 

Injectable progesterone; 

Any intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year;

Oral contraceptives (either combined or progesterone only); 

Double barrier method with vaginal spermicidal agent: Condom and an 
occlusive cap (cervical cap/vault or diaphragm) with a vaginal 
spermicidal agent (foam/gel/film/cream/suppository); 

Percutaneous contraceptive patch; 
 
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
Male partner who is sterile prior to the female subject’s entry into the 
study and is the sole sexual partner for the female subject.
Note: MMF and other forms of mycophenolate affect the metabolism of 
oral contraceptives and may reduce their effectiveness. As such, women 
receiving mycophenalate who are using oral contraceptives for birth control 
should employ an additional method (e.g., barrier method).
4.
Informed consent: Able to provide written informed consent to participate.
Additional eligibility criteria for subject enrolment in the treatment holiday and control 
groups in the study:
1. SLE: achieve the required minimal disease activity criteria defined as SELENA 
SLEDAI score 3 after a minimum of 6 months of belimumab therapy (see Appendix 
1 for SELENA SLEDAI).
2. SLE Treatment:  Are on a stable SLE treatment regimen consisting of any of the 
following medications (alone or in combination) during the 30 day screening period 
prior to Day 0:

Corticosteroids  (prednisone or prednisone equivalent)

Other 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, oral 
cyclophosphamide, 6-mercaptopurine, or thalidomide.

Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine).

Non-steroidal anti-inflammatory drugs (NSAIDs), including sulfasalazine.
3. Complement: C3 and C4 complement levels at or above the lower limit of normal of 
the central laboratory reference range.
Additional eligibility criteria for subject enrolment in the control group in the study:
1. Belimumab therapy: Agree to continue receiving 10mg/kg belimumab intravenous 
infusions every 4 weeks.  Subjects must be able to receive the first dose of belimumab 
in this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose 
in their previous continuation study, or the open-label period of BEL113750 for 
China subjects.
Additional eligibility criteria for subject enrolment in the long-term discontinuation 
group in the study:
1. Continuation studies: Voluntarily withdrawn from continuation studies BEL114333, 
HGS1006-C1066, LBSL99, or the open-label period of BEL113750 for China 
subjects, and have withdrawn from belimumab therapy for no longer than 8 weeks 
prior to entry into this study.
 
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Note:  investigators may stop, start, and/or change SLE medications and dosages as 
deemed necessary; yet long-term discontinuation subjects will remain on local 
standard of care SLE treatment therapy as determined by the physician during the 
study, or will need to be withdrawn.
Amendment 01, Section 4.3 Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in any of the 3 
subject groups in the study:
1. Undue risk: Have developed clinical evidence of significant, unstable or 
uncontrolled, acute or chronic diseases not due to SLE (i.e., cardiovascular, 
pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or 
infectious diseases), or experienced an adverse event (AE) in the belimumab 
continuation studies BEL114333, HGS1006-C1066, LBSL99, or in the BEL113750 
open-label period for China subjects, that could, in the opinion of the principal 
investigator, put the subject at undue risk.
2. Subject suitability: Have developed any other medical diseases (e.g., 
cardiopulmonary), laboratory abnormalities, or conditions (e.g., poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
Subjects meeting any of the following additional criteria must not be enrolled in the 
control or treatment holiday groups in the study:
1. SLE: New mild-moderate or severe flare as defined by the SLE Flare Index during 
the 30 day screening period prior to Day 0.
2. Steroids: Prednisone (or prednisone equivalent) greater than 20mg/day within the 30 
day screening period.
3. New agents: Any new immunosuppressive/immunomodulatory agent, anti-malarial, 
or NSAID within the 30 day screening period prior to Day 0.  However, any NSAID 
use for < 1 week is allowed.
Amendment 01, Section 5,1 Investigational Product and Other Study 
Treatment
Belimumab for intravenous (IV) infusion will be supplied in glass vials by GSK. The 
contents of the label will be in accordance with all applicable regulatory requirements. 
Detailed instructions on the preparation, administration and storage of belimumab are 
provided in the Pharmacy Manual.  Belimumab IV solution should be prepared by a 
 
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pharmacist. Reconstitute the 400 mg single use vial of belimumab with 4.8 mL sterile 
water for injection to yield a final concentration of belimumab 80 mg/mL. Remove an 
amount of normal saline from the infusion bag equivalent to the amount of belimumab to 
be added, add the reconstituted belimumab, and gently invert the infusion bag to mix the 
solution. After reconstitution and dilution in normal saline, the material is stable for up to 
8 hours at 2-8C or at room temperature. The characteristics of belimumab are 
summarized in Table 1.
Table 1
Belimumab Characteristics
Property
Belimumab
Formulation
Belimumab 400 mg per vial plus excipients (citric 
acid/sodium citrate/sucrose/polysorbate)
Dosage Form
Reconstituted solution
Unit dose strength
400 mg per vial (to contain 80 mg/mL when reconstituted 
with 4.8mL sterile water for injection [SWFI])
Physical description
White uniform lyophilised cake in a 20 mL vial
Manufacturer
Human Genome Sciences, Inc.
Route of administration
Intravenous
Subjects enrolled in the treatment holiday group will receive treatment with belimumab 
10 mg/kg from Week 24 onwards after the initial 24-week treatment holiday period of 
the study has elapsed (see Amendment 01, Section 3.1). At the start of the belimumab 
reintroduction period, subjects in the treatment holiday group will receive belimumab 10 
mg/kg IV infused for 1 hour every 28 days.
Subjects in the control group will receive belimumab 10 mg/kg IV infused for 1 hour 
every 28 days from Day 0 onwards. Subjects in this group must be able to receive their 
first dose of belimumab on Day 0 of this study 4 weeks (minimum of 2 weeks, maximum 
of 8 weeks) after the last dose in the BEL114333 open-label continuation study, or after 
the last dose from China subjects in the open-label period of BEL113750.
Subjects in the long-term discontinuation group will not receive belimumab at any point 
in this study.
The dose of belimumab administered may not be altered but the rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or 
infusion-associated symptoms. Do not increase the rate of infusion above the 
recommended rate.
Monitor the subject during and after each infusion according to study sites’ guidelines or 
standard operating procedure for IV infusions. This may include, but is not limited to, 
monitoring vital signs and observing for any untoward reactions. Trained rescue 
personnel and rescue medications/equipment should be available for a minimum of the 
first dose.
 
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Consider administering premedication for prophylaxis against infusion reactions and 
hypersensitivity reactions for subjects who have previously received intravenous 
immunoglobulins (IVIG) or subjects with a history of allergies (allergic responses to 
food, drugs, insects, or a history of urticaria). The dose of belimumab may be delayed by 
up to 2 weeks or the dose may be withheld if the subject experiences a clinically 
significant AE that, in the clinical judgement of the investigator, is possibly, probably or 
definitely related to belimumab, and this AE continues at the next scheduled dose, or 
could potentially be exacerbated by the next dose. If a similar concern is present at the 
time of the next scheduled dose, the investigator and Medical Monitor will discuss 
whether to discontinue treatment with belimumab.
Under normal conditions of handling and administration, investigational product 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. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. Belimumab should be diluted to 250 mL normal saline after reconstitution, 
using a typical approved plastic intravenous administration set for the infusion.
Belimumab must be stored in a secure area under the appropriate physical conditions for 
the product, which includes storage in a refrigerator at a temperature of 2-8C.  
Maintenance of a temperature log (manual or automated) is required. Access to and 
administration of belimumab will be limited to the investigator and authorized site staff.  
Belimumab must be dispensed or administered only to subjects enrolled in the study and 
in accordance with the protocol.
Destroy all used belimumab vials according to site guidelines for the destruction of 
investigational products, after the monitor has conducted a check of the product 
accountability log during the study. At the end of the study, unused belimumab vials will 
be destroyed on site at the study closeout visit, after the monitor has conducted final 
belimumab accountability and given the site approval to destroy all remaining supplies.
 
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Amendment 01, Section 6, Time and Events Table (Year 1)
Scr-
een
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up 
to 
-30 
1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
1407d
168 
7d
1967d
224 
7d
252 
7d
2807d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
Written Informed Consent 4
X
X
Demography
X
Medical History
X
SLE History
X
Therapy History
X
Physical Examination
X
Inclusion/Exclusion
X
Efficacy Assessments
DAS: SS, SLE Flare Index, 
PGA 5
X 1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR Damage Index
X
X
X
Safety Assessments
Vital Signs 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, height 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom-driven Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology & Modified Chem 
20 (non-fasting) 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spot urine (protein to creatinine 
ratio) 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 6, 9
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Pharmacogenetic Sampling 10
X
aCL Autoantibody
X
X
 
 
 
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Scr-
een
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up 
to 
-30 
1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
1407d
168 
7d
1967d
224 
7d
252 
7d
2807d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
C3/C4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-dsDNA Autoantibodies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA Autoantibodies 
X
X
X
IgG, IgA & IgM 11
X
X
X
X
X
X
X
X
PT/ PTT
X
Exploratory Lab Assessments
Pharmacokinetic Sampling 12
X
X
X
X 12
X
X 12
Immunogenicity 6, 13
X
X
X 13
X
X
X
X
X 13
BLyS Protein 14
X
X
X
B cell Markers 15
X
X
X
X
X
X
X
X
Investigational Product (IP)
IP Administration 16
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
DAS = disease activity scales; SS = SELENA SLEDAI; SLE = systemic Lupus Erythematosus; PGA = Physician’s Global Assessment; SLICC/ACR = Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; PT/PTT = prothrombin time/partial thromboplastin 
time; BlyS = B Lymphocyte Stimulator; IP = investigational product; aCL = anticardiolipin
1.
A screening visit of up to 30 days prior to the Day 0 visit will be scheduled for subjects in the treatment holiday and control groups for assessment of SELENA SLEDAI score to 
assess eligibility.
2.
The EXIT Visit in the respective feeder continuation studies and in the open-label period of BEL113750 for China subjects will serve as the Day 0 visit for all 3 subject groups in 
this study. Assessments covered for both this study at Day 0 and the Exit visit of the feeder continuation studies and the open-label period of BEL113750 for China subjects need 
only be performed once and recorded in the appropriate case report forms for each study. Subjects in the control group must be able to receive the 1st dose of belimumab on Day 
0 of this study on average 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the feeder continuation study and in the open-label period of BEL113750 for 
China subjects.
3.
The 16 week follow-up visit will occur at approximately 16 weeks after last dose of investigational product for subjects in the control group who withdraw at any time during the 
study but do not wish to enter the long-term discontinuation group and be followed for a further 12 months or for subjects in the treatment holiday group who withdraw from the 
study from Week 24 onwards (Visit 7) during the belimumab re-introduction period. The 16-week and 6 month follow-up visits do not apply to subjects in the long-term 
discontinuation group. 
4.
For subjects in the control group only, obtain written informed consent to participate in this study at the visit prior to the last visit in the relevant SLE feeder continuation study 
 
 
 
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and the open-label period of BEL113750 for China subjects.
5.
Guidelines for scoring proteinuria for SELENA SLEDAI are provided in Section 6.3.1.1.
6.
Complete assessment prior to belimumab dosing for subjects in the control group (to Week 48) and for subjects in the treatment holiday group (during Weeks 24 to 48 or earlier in 
the event of a flare).
7.
For any subject whose weight changes by more than 5% from that recorded at Day 0, use the weight at the current visit for calculating the belimumab dose to be administered. 
Height measured only at Day 0.
8.
A 24-hour urine may be done as an additional assessment if clinically indicated (e.g., renal flare).
9.
Urine pregnancy test results for women of child-bearing potential must be available prior to dosing (during Weeks 0 to 48 in the control group and during Weeks 24 to 48 or earlier 
in the event of a flare in the treatment holiday group).Can be performed at any time during the visit for females of child-bearing potential in the long-term discontinuation group.
10. PGx sampling from consenting subjects recruited from all studies except from study BEL114333 and except from the open-label period of BEL113750 for China subjects. PGx 
informed consent must be obtained prior to sampling.
11. Serum immunoglobulin isotypes: IgG, IgM, IgA.
12. Pharmacokinetic sampling at select sites for subjects in the control and treatment holiday groups; subjects in the treatment holiday group can have PK sampling performed at any 
time during the visit between Weeks 0 and 16.  Otherwise, if on a dosing day, sampling must be performed prior to dosing. Collect blood samples pre-dose and post-dose at the 
end of the infusion at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the event of a severe flare by using the escape option).   Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.
13. Blood sample for immunogenicity will be taken at Weeks 12, 24, 36 and 52 for all three groups.  In addition, a blood sample for immunogenicity will also be taken 4 weeks prior
to the reintroduction of belimumab (at Week 20 since belimumab will be reintroduced at Week 24) in the treatment holiday group. A blood sample for immunogenicity must be 
taken at least 6 months after the final dose of investigational product for any subjects in the control group or treatment holiday group who had an anti-belimumab antibody 
response at the 16-week follow-up visit (or at the last immunogenicity assessment if 16-week follow-up is not available). Note that serum samples for immunogenicity must be 
collected pre-dose at the time of dosing from subjects in the treatment holiday group who experience a severe flare prior to Week 24 and consequently receive open-label 
belimumab as rescue.  Immunogenicity blood sample will not be collected at the 6-month follow up visit for subjects in the long-term discontinuation group as this visit does not 
apply to this subject group.
14. Measured in treatment holiday group at Weeks 16 and pre-dose at Week 24. Measured in long-term discontinuation group at Weeks 16, 24 and 32. Not measured in control 
group.
15. Biological Markers include FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells). Note: B cell markers will not be collected at the 6-month follow up visit for subjects in the long-term 
discontinuation group as this visit does not apply to this subject group.
16. Only subjects in the control group will receive belimumab 10 mg/kg during Weeks 0 through 20 inclusive;  subjects in the control group must be able to receive the first dose of 
belimumab in this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in their previous open-label continuation study  Subjects in the control group 
and treatment holiday groups will receive belimumab from Weeks 24 through 48 although subjects in the treatment holiday group may be treated with belimumab prior to Week 
24 as determined by the investigator in the event of increased SLE activity. When belimumab therapy is re-started, subjects in the treatment holiday group will remain under 
clinical supervision for 3 hours after completion of the first 2 infusions. At the Week 52 visit, only subjects in the treatment holiday and control groups who are continuing 
belimumab therapy beyond this time will be dosed.
 
 
 
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Amendment 01, Section 6.1.2 Secondary Endpoints
The secondary endpoints are:

Rate of any SLE Flare Index flares.

Time to first severe SLE Flare Index flare.

Number of subjects in the treatment holiday and long-term discontinuation group 
with evidence of rebound (defined as a SELENA SLEDAI score during the first 24 
weeks that exceeds the baseline SELENA SLEDAI score in the original parent study.

Number of subjects with confirmed true positive belimumab anti-drug antibodies 
(ADA) by the end of the study.

Percentage change from baseline in:

Total serum immunoglobulin (IgG, and other isotypes: IgM and IgA)

Autoantibodies (anti-dsDNA, ANA), and complement (C3, C4)

Percent change in absolute B cell subsets (CD20+, CD20+/27+ memory, CD20+/27–
naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells) at Weeks 
0, 8, 16, 24, 32, 40 and 52 and from Weeks 24 to 52.

Absolute change in SELENA SLEDAI score.

Number of days of daily prednisone dose 7.5 mg/day and/or increased by 25% from 
Day 0 of this study to Week 24, from Day 0 of this study to Week 52, and from 
Week 24 to Week 52.

Number of days of daily prednisone dose 7.5 mg/day and/or decreased by 25% 
from Day 0 of this study to Week 24, from Day 0 of this study to Week 52, and from 
Week 24 to Week 52.
Note: baseline is the time before any treatment with belimumab, which was Day 0 of the 
original parent studies that fed into the 3 continuation studies, and Day 0 of the blinded 
period of BEL113750 for China subjects, from which subjects were recruited into this 
study. When Day 0 is used in relation to endpoints, this refers to Day 0 of this study.
Amendment 01, Section 6.2 Critical Baseline Assessments
The screening phase of up to 30 days will allow an assessment of the SELENA SLEDAI 
score as part of the eligibility criteria for subjects in the treatment holiday and control 
groups.
The EXIT visit of the relevant SLE continuation protocol ((BEL114333, HGS1006-
C1066, or LBSL99), or the open-label period of BEL113750 for China subjects, from 
which the subject is recruited will serve as the Day 0 visit in this study. Subjects in the 
control group will be dosed with belimumab at the Day 0 visit as part of this protocol. 
These subjects must be able to receive the Day 0 dose in this study 4 weeks (minimum of 
 
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2 weeks, maximum of 8 weeks) after the last dose in the previous open-label continuation 
study, or the open-label period of BEL113750 for China subjects.  Any procedures from 
this protocol or from the relevant previous open-label continuation protocols, or the open-
label period of BEL113750 for China subjects to be performed pre-dose must be 
completed before dosing subjects in the control group. Subjects in the control group 
should sign the informed consent to participate in this study at the visit immediately prior 
to the EXIT visit to ensure a supply of belimumab for the Day 0 visit in this study.  
Subjects in the treatment holiday and long-term discontinuation groups should sign the 
informed consent at the screening visit and Day 0 visit, respectively of this study.
Procedures necessary for the Day 0 visit of this protocol and for the last visit of the 
relevant SLE open-label continuation protocol, or the open-label period of BEL113750 
for China subjects, from which the subject is recruited need only be performed once. 
Results from Day 0 procedures that are duplicated in the relevant SLE continuation study 
will be recorded in the eCRF for that study and must also be transcribed to the relevant 
eCRFs in this study. Additional Day 0 procedures exclusive to this study will be recorded 
directly in the eCRFs for this study.
Amendment 01, Section 6.3.1.1 SELENA SLEDAI Score
The SELENA SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) used in 
this study is a slightly modified version of the SLEDAI developed for a National 
Institutes of Health sponsored multicentre study of estrogen/progesterone hormone use in 
women with SLE [Buyon, 2005; Petri, 2005]. The descriptions for some of the items are 
slightly modified, but the organ systems and weighted scores are the same as the 
published SLEDAI.
The SLEDAI is a validated index for assessing SLE disease activity [Bombardier, 1992].  
It is a weighted index in which signs and symptoms, laboratory tests, and physician’s 
assessment for each of 9 organ systems are given a weighted score and summed, if 
present at the time of the visit or in the preceding 10 days:

Score of 8 each for CNS and vascular items.

Score of 4 each for renal and musculoskeletal items.

Score of 2 each for serosal, dermal, and immunologic items.

Score of 1 each for constitutional and hematologic items.
The maximum theoretical score for the SELENA SLEDAI is 105 (all 24 descriptors 
present simultaneously) with 0 indicating inactive disease. A copy of the index is 
provided in Appendix 1.
Completion of the index requires collection of a 24-hour urine sample for assessment of 
proteinuria (although spot urine protein:creatinine ratio is commonly substituted in 
 
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practice), measurement of anti-dsDNA, C3, C4, haematology, and urinalysis, and for 
subjects with myosis, CPK. 
However, spot urine protein:creatinine ratio will be used for determining proteinuria for 
the SELENA SLEDAI in this study since there is a strong correlation between the protein 
content of a 24-hour urine collection and the protein:creatinine ratio in a single urine 
sample [Ginsberg, 1983; Ruggenenti, 1998; Clinical Practice Guidelines for Chronic 
Kidney Disease, 2002; Price, 2005].
Scoring for proteinuria in the SELENA SLEDAI disease activity index will be in 
accordance with the following guidelines.
Scoring for Proteinuria at Screening for Eligibility
The proteinuria score for SELENA SLEDAI must be 0 at the most recent assessment 
performed in BEL114333 or in the open-label period of BEL113750 for China subjects.  
If at the screening visit the assessment of 24-hour proteinuria (by spot urine protein to 
creatinine ratio) shows >0.5 g/24 hour equivalent increase above the previous value (in 
BEL114333) or the subject develops new onset of proteinuria >0.5 g/24 hour equivalent, 
4 points will be assigned at the screening assessment.
Scoring for Proteinuria at Day 0 and Subsequent Study Visits
According to the SELENA SLEDAI scoring rules, unless the proteinuria continues to rise
such that it has increased by > 0.5 g/24 hour equivalent at Day 0 (i.e., baseline), the 
subject, by default, will have an improving SELENA SLEDAI score.  This is problematic 
for data analysis since the percent change in the disease activity scales are calculated 
from the baseline (not screening) SELENA SLEDAI score.  As such, the following 
scoring rules will be applied:

Scoring for a Subject with 0 Points for Proteinuria in SELENA SLEDAI 
If the proteinuria score for SELENA SLEDAI is 0 and at the subsequent visit the 
assessment of 24-hour proteinuria (by spot urine protein to creatinine ratio) shows 
>0.5 g/24 hour equivalent increase above the previous value or the subject develops 
new onset of proteinuria >0.5 g/24 hour equivalent, 4 points will be assigned at this 
current visit.

Scoring for a Subject with Proteinuria and 4 Points Assigned in SELENA 
SLEDAI
If there is an increase from the last visit of >0.5 g/24 hour equivalent, only 4 points 
for proteinuria will continue to be applied (so no subject can get more than 4 points 
for proteinuria at any 1 time point).
If the proteinuria has not improved (i.e., there has not been a decrease in proteinuria 
of >0.5 g/24 hour equivalent) since the previous assessment, then 4 points will 
continue to be assigned on the SELENA SLEDAI index at the current visit.
 
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If proteinuria has improved (decrease of >0.5 g/24 hour equivalent or a decrease to 
≤0.5 g/24 hour equivalent) from the previous visit to the current visit, then 0 points 
will be assigned on the SELENA SLEDAI index at the current visit.
Amendment 01, Section 6.3.1.2 Laboratory tests for SELENA SLEDAI
A strong correlation has been demonstrated between the protein content of a 24-hour 
urine collection and the protein:creatinine ratio in a single urine sample [Ginsberg, 1983; 
Ruggenenti, 1998; Clinical Practice Guidelines for Chronic Kidney Disease, 2002; Price, 
2005].  For this reason, spot urine protein:creatinine ratio will be used for determining 
proteinuria in this study for the SELENA SLEDAI disease activity indices.
Measurement of creatinine clearance (CrCl)/glomerular filtration rate (GFR) using timed 
(for example, 24-hour) urine collections is time consuming and error prone and has 
consistently been shown to be no more, and often less, reliable than serum creatinine 
based equations for the estimation of GFR [Clinical Practice Guidelines for Chronic 
Kidney Disease, 2002].  Therefore, GFR estimated by the Cockroft-Gault formula will be 
used as was done in the Phase II trial of belimumab (LBSL02) and Phase III.
Cockroft-Gault Equation [Cockcroft, 1976]
female
if
x
dL
mg
tinine
xserumcrea
kg
xweight
yrs
age
mL
Clcr
85
.0
)
/
(
72
)
(
))
(
140
(
min)
/
(


Values outside the reference laboratory normal range require the investigator’s 
assessment of relationship to SLE.
Amendment 01, Section 6.4.1.1 Liver Chemistry Stopping and Follow 
up Criteria, Additional Hepatitis B Monitoring
Safety assessment for Hepatitis B during the trial will be as follows:

ALT and/or AST elevations of greater than 2.5 x ULN will require:

Sites to review blinded period screening laboratory results for anti-HBc:
o If screening anti-HBc result was reactive, then obtain HBV DNA.
o If HBV DNA returns reactive, withdraw subject from further treatment and enter 
follow up visit schedule.  Investigator will determine the extent of required 
attention for proper follow up of potential hepatitis B re-activation.
o If screening anti-HBc result was negative, then repeating hepatitis B testing is 
optional per investigator upon investigating for other causes.

Refer to the SPM for guidance on documenting the suspected reason for ALT and/or 
AST elevations of greater than 2.5 x ULN.
 
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Amendment 01, Section 6.7 Pharmacogenetic Research
Collect a blood sample for pharmacogenetics (PGx) from consenting subjects except 
those recruited from Study BEL114333 and except from the open-label period of 
BEL113750 for China subjects (who have already provided a sample as part of that 
study). Samples for PGx must be drawn prior to dosing as appropriate.
Information regarding PGx research is included in Appendix 6.
Amendment 01, Appendix 5:  Clinical Laboratory Tests
The changes made to this section during Amendment 01 (i.e., adding Hepatitis B Viral 
DNA PCR Quantitative (HBV DNA), BLyS Protein, ANA, aCL) are now incorporated 
into Appendix 5 as part of Global Amendment 02. See current Appendix 5.
 
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11.8.
Appendix 8: Protocol Changes
Protocol Amendment 06
Protocol amendment 06 applies to all countries and sites.
Description of Changes
Changes are highlighted in bold.
Change 1:  SPONSOR INFORMATION PAGE
Change from:
Backup Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
Mobile: 
To:
Backup Medical Monitor
See Study Reference Manual for Contact Information
Rationale:  Update location of contact information for Backup Medical Monitor.   
Change 2: Protocol Summary Study Design
Change from:
All 3 subject groups will be recruited from the BEL114333 continuation study of 
belimumab in SLE.
To:
All 3 subject groups will be recruited from the BEL114333 continuation study of 
belimumab in SLE and as described in Appendix 11.7, from the open-label (OL) 
period BEL113750 for China subjects.
Rationale:  Provide clarification on Appendix 11.7, recruitment from open-label 
BEL113750 for China subjects.
 
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Change 3: Section 3.1 Study Design
Change from:
Subjects will be recruited from 3 open-label continuation studies of belimumab in SLE. 
This study will comprise 3 distinct groups of subjects as outlined below:
To:
Subjects will be recruited from 3 open-label continuation studies of belimumab in SLE. 
See Appendix 11.7 for recruitment from the open-label (OL) period BEL113750 for 
China subjects. This study will comprise 3 distinct groups of subjects as outlined below:
Rationale:  Provide clarification on Appendix 11.7, recruitment from open-label 
BEL113750 for China subjects.
Change 4: Section 3.1 Study Design, Figure 1
Change from:
To:
 
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Rationale:  Updated figure for changes in target sample size as agreed upon with the 
EMA.
Change 5: Section 3.1 Study Design
Change from:

Treatment Holiday group: The target enrolment for this group is 50 subjects.

Treatment Control group: The target enrolment for this group is 50 subjects.
To:

Treatment Holiday group: The target enrolment for this group is at least 10
subjects.

Treatment Control group: The target enrolment for this group is at least 26
subjects.
Rationale:  Updated text for changes in target sample size as agreed upon with the EMA. 
Change 6: Section 3.1 Study Design
Change from:
 
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A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups who withdraw prior to Week 52. Additionally, a 6 month follow-up visit is 
required for those subjects in the treatment holiday or control groups who have an anti-
belimumab antibody response at the 16-week follow-up visit (or at the last 
immunogenicity assessment if 16-week follow-up is not available).
To:
A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups after the withdrawal visit or the last dose of belimumab as 
appropriate. Additionally, a 6 month follow-up visit is required for those subjects in the 
treatment holiday or control groups.
Rationale:  Provides clarification of protocol wording.  The sentence regarding 6-month 
follow-up should have been truncated prior to protocol amendment 5 publishing.
Change 7: Section 3.2 Discussion of Design
Change from:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan, South Korea and China.
To:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan, South Korea and China (for 
China see Appendix 11.7 for country-specific requirements regarding 
recruitment from the open-label period of BEL113750).
Rationale:  Provide clarification on Appendix 11.7, recruitment from open-label 
BEL113750 for China subjects.
Change 8: Section 3.2 Discussion of Design
Change from:
The target sample size of 50 subjects in each of the treatment holiday and control groups 
is based on estimates of subject eligibility and number of subjects from continuation 
study BEL114333  anticipated to provide consent to participate in this study.  
 
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To:
The target sample size of at least 10 subjects in the treatment holiday group and at least 
26 subjects in the control group is based on estimates of subject eligibility and number 
of subjects from continuation study BEL114333 anticipated to provide consent to 
participate in this study.
Rationale:  Updated text for changes in target sample size as agreed upon with the EMA.
Change 9: Section 4.1 Number of Subjects
Change from:
The target sample size for subjects in the treatment holiday and control groups is 50 
subjects per group.  Each group will end recruitment when their target sample size of 50 
subjects is reached.  Enrolment in this study will close when the target of 50 subjects in 
the treatment holiday and control groups has been achieved or 36 months after study 
start, whichever comes first.  
To:
The target sample size for subjects in the treatment holiday group is at least 10 subjects 
and in the control group, at least 26 subjects.  Each group will end recruitment when 
their target sample size is reached.  Enrolment in this study will close when the target 
number of subjects in the treatment holiday and control groups has been achieved or 36 
months after study start, whichever comes first.
Rationale:  Updated text for changes in target sample size as agreed upon with the EMA.
Change 10:  Section 4.4 Withdrawal Criteria
Change from:
These subjects will complete the Week 52 Exit visit (except for dosing with belimumab) 
at the time of discontinuation and the16-week follow-up visit assessments at least 16 
weeks after the withdrawal visit or last dose of belimumab as appropriate (see Section 6). 
The 6 month follow-up visit is scheduled only for those subjects in the treatment holiday 
or control groups who have an anti-belimumab antibody response at the 16-week 
follow-up visit.
To:
These subjects will complete the Week 52 Exit visit (except for dosing with belimumab) 
at the time of discontinuation and the16-week follow-up visit assessments at least 16 
weeks after the withdrawal visit or last dose of belimumab as appropriate (see Section 6). 
 
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The 6 month follow-up visit is scheduled only for those subjects in the treatment holiday 
or control groups.
Rationale: Provides clarification of protocol wording.  The sentence should have been 
truncated prior to protocol amendment 5 publishing.
Change 11:  Section 6 Study Assessments and Procedures
Change from:
Subjects in the treatment holiday and control groups who meet the protocol-defined 
withdrawal criteria specified in Section 4.4 at any time during Year 1 or the additional 
years will undergo assessments scheduled at the Exit visit (Week 52) in Table 2 except 
for dosing with belimumab. At approximately 16 weeks after the withdrawal visit or the 
last dose of belimumab as appropriate, these subjects will also undergo the assessments 
scheduled at the 16-week follow-up visit; the 6 month follow-up visit is scheduled only 
for these discontinued subjects in the treatment holiday or control groups who have an 
anti-belimumab antibody response at the 16-week follow-up visit (or the last 
immunogenicity assessment if the 16-week follow-up is not available).
To:
Subjects in the treatment holiday and control groups who meet the protocol-defined 
withdrawal criteria specified in Section 4.4 at any time during Year 1 or the additional 
years will undergo assessments scheduled at the Exit visit (Week 52) in Table 2 except 
for dosing with belimumab. At approximately 16 weeks after the withdrawal visit or the 
last dose of belimumab as appropriate, these subjects will also undergo the assessments 
scheduled at the 16-week follow-up visit; the 6 month follow-up visit is scheduled only 
for these discontinued subjects in the treatment holiday or control groups.
Rationale:  Provides clarification of protocol wording.  The sentence should have been 
truncated prior to protocol amendment 5 publishing.
Change 12:  Section 6.1.4 Definitions of SLE Flares Used in This Study
Change from:
2. A reproducible increase in serum creatinine of >20% or at least 0.3 mg/dL,
accompanied by proteinuria (>1 g/24 hour equivalent), haematuria (4 red blood cells 
[RBCs]/high-power field [hpf]), and/or RBC casts.
3. Treatment emergent, reproducible haematuria (11 to 20 RBCs/ hpf) or a reproducible 
increase in haematuria by 2 grades compared with baseline, associated with >25% 
dysmorphic RBCs, glomerular in origin, exclusive of menses, accompanied by either an 
 
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0.8 g increase in 24-hour urinary protein levels (equivalent) or new RBC casts [Alarcón-
Segovia, 2003] .
To:
2. A reproducible increase in GFR of >20% accompanied by at least one of the 
following: proteinuria (>1 g/24 hour equivalent), and/or cellular (RBC or WBC) casts 
[Alarcón-Segovia, 2003].
Rationale:  Remove hematuria criteria from definition of renal flare.
Change 13: Section 8 Data Analysis and Statistical Considerations
Change from:
A total of approximately 135 subjects (50 in the treatment holiday group, 50 in the 
control group, and 35 in the long term discontinuation group) will be enrolled in this 
study.  
To:
Originally a total of approximately 135 subjects (50 in the treatment holiday group, 50 in 
the control group, and 35 in the long term discontinuation group) were planned to be
enrolled in this study.  After 36 months had elapsed since study start, a reduction in 
sample size was agreed to with regulatory authorities, and a total of at least 
71 subjects (at least 10 in the treatment holiday group, at least 26 in the control 
group, and 35 in the long term discontinuation group) will be the target sample size 
to be enrolled in this study.  
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Change 14: Appendix 7, Amendment 01, Section 3.1, Figure 1
Change from:
To:
Rationale:  Updated figure for changes in target sample size as agreed upon with the 
EMA.
 
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Change 15: Appendix 7, Amendment 01, Section 3.1, Investigational Plan, Study 
Design
Change from:

Treatment Holiday group: The target enrolment for this group is 50 subjects.

Treatment Control group: The target enrolment for this group is 50 subjects.
To:

Treatment Holiday group: The target enrolment for this group is at least 10
subjects.

Treatment Control group: The target enrolment for this group is at least 26
subjects.
Rationale:  Updated text for changes in target sample size as agreed upon with the EMA. 
Change 16:  Appendix 7, Amendment 01, Section 3.1, Investigational Plan, Study 
Design
Change from:
A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups who withdraw prior to Week 52. Additionally, a 6 month follow-up visit 
is required for those subjects in the treatment holiday or control groups who have an 
anti-belimumab antibody response at the 16-week follow-up visit (or at the last 
immunogenicity assessment if 16-week follow-up is not available).
To:
A 16-week follow-up visit will be scheduled for subjects in the treatment holiday and 
control groups after the withdrawal visit or the last dose of belimumab as 
appropriate. Additionally, a 6 month follow-up visit is required for those subjects in the 
treatment holiday or control groups.
Rationale:  Provides clarification of protocol wording.  The sentence regarding 6-month 
follow-up should have been truncated prior to protocol amendment 5 publishing. 
Change 17: Appendix 7, Amendment 01, Section 3.2, Discussion of Design
Change from:
The target sample size of 50 subjects in each of the treatment holiday and control groups 
is based on estimates of subject eligibility and number of subjects from continuation 
study BEL114333 and China subjects in BEL113750 receiving open-label belimumab for 
at least 6 months, is anticipated to provide consent to participate in this study.  
 
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To:
The target sample size of at least 10 subjects in the treatment holiday group and at least 
26 subjects in the control group is based on estimates of subject eligibility and number 
of subjects from continuation study BEL114333 and China subjects in BEL113750 
receiving open-label belimumab for at least 6 months, is anticipated to provide consent to 
participate in this study.
Rationale:  Updated text for changes in target sample size as agreed upon with the EMA.
Protocol Amendment 05
Protocol amendment 05 applies to all countries and sites
Description of Changes
Changes are highlighted in bold.
Change 1:  Study Assessments and Procedures, Table 2, Time and Events Table 
(Year 1), footnote 6.
Change from:
6.  Complete assessment prior to belimumab dosing for subjects in the control group (to 
Week 48) and for subjects in the treatment holiday group (during Weeks 24 to 48 or 
earlier in the event of a flare).
To:
6.  Complete assessment prior to belimumab dosing for subjects in the control group (to 
Week 48) and for subjects in the treatment holiday group (during Weeks 24 to 48 or 
earlier in the event of a flare).  Immunogenicity testing includes quantifying the 
amount of belimumab present in the samples using the belimumab PK assay.
Rationale:  Clarifies PK analysis is needed for analysis of confirmed ADA positive 
samples.
Change 2: Time Period and Frequency of Detecting AEs and SAEs
This change affects Section 6.4.7 Time Period and Frequency of Detecting AEs and 
SAEs, last paragraph
Change from:
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
 
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procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.4.10. 
To:
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.4.10.  Note:  for China sites, serious AEs should be 
recorded from the time the consent form is signed until the 16-week follow up 
contact for subjects in the treatment holiday and control groups, or until the Week 
52 visit for subjects in the long-term discontinuation group.  GSK’s 
pharmacovigilance safety database will contain all SAEs occurring after the first 
dose of investigational product plus any SAEs related to study participation 
occurring after the subject signs the informed consent form.  SAEs that occur after 
signing the informed consent form but before the first dose of investigational 
product that are not considered to be related to study participation will not be 
entered into the GSK pharmacovigilance safety database, and will be summarized 
separately in the clinical study report.
Rationale:  This change clarifies China sites are able to record all SAEs from when the 
subject signs the informed consent form, not just reporting SAEs related to study 
participation or a GSK concomitant medication.
Change 3:  Immunogenicity
This change affects Section 6.4.16 Immunogenicity, first paragraph.
Change from:
Serum samples will be collected for immunogenicity assessment.  All samples should be 
collected prior to dosing (where appropriate) as specified in the appropriate Time and 
Events schedule (Table 2 or Table 3).  Note that serum samples for immunogenicity must
be collected pre-dose at the time of dosing from subjects in the treatment holiday group 
who experience a severe flare prior to Week 24 and consequently receive open-label 
belimumab as rescue.  For non-dosing visits, assessment can be performed at any time 
during the visit.  
To:
Serum samples will be collected for immunogenicity assessment.  All samples should be 
collected prior to dosing (where appropriate) as specified in the appropriate Time and 
Events schedule (Table 2 or Table 3).  Note that serum samples for immunogenicity must 
 
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be collected pre-dose at the time of dosing from subjects in the treatment holiday group 
who experience a severe flare prior to Week 24 and consequently receive open-label 
belimumab as rescue.  For non-dosing visits, assessment can be performed at any time 
during the visit.  An attempt will be made to determine the amount of belimumab 
(PK) present in immunogenicity samples with confirmed anti-drug binding 
antibodies (ADA). The belimumab level in these samples will be used in the 
interpretation of ADA results and will be included in the immunogenicity section in 
the CSR.
Rationale:  Clarifies PK analysis is needed for analysis of confirmed ADA positive 
samples.
Change 4:  Immunogenicity
This change affects Section 6.4.16 Immunogenicity, 3rd and 4th paragraphs.
Change from:
All immunogenicity testing will be carried out according to the multi-tier assay testing 
scheme including the detection of anti-drug binding antibodies (ADA, including 3-steps 
of screening, confirmation/specificity and titration) and the detection of anti-drug 
neutralizing antibodies (Nab).
All samples will be tested in ADA screening step.  Any samples tested positive in the 
screening step will then be tested using an ADA confirmation step.  Any confirmed 
positive samples in the confirmation will be further tested in the titration to obtain ADA 
titer values and in the Nab assay to evaluate the presence of neutralizing antibodies. The 
incidence of subjects with confirmed positive ADA responses with titers and positive 
Nab will be reported, respectively at the end of the study.
To:
All immunogenicity testing will be carried out according to the multi-tier assay testing 
scheme including the detection of anti-drug binding antibodies (ADA, including 3-steps 
of screening, confirmation/specificity and titration) and the detection of anti-drug 
neutralizing antibodies (Nab).  Note:  Nab testing will not be performed in China.
All samples will be tested in ADA screening step.  Any samples tested positive in the 
screening step will then be tested using an ADA confirmation step.  Any confirmed 
positive samples in the confirmation will be further tested in the titration to obtain ADA 
titer values and in the Nab assay to evaluate the presence of neutralizing antibodies. The 
incidence of subjects with confirmed positive ADA responses with titers and positive 
Nab will be reported, respectively at the end of the study.  However, Nab results will 
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Rationale:  Clarifies the immunogenicity testing process for China subjects, because the 
Nab test will not be performed in China.
Change 5:  Pharmacokinetics
This change affects Section 6.6 Pharmacokinetics
Change from:
Collect blood samples for measurement of serum belimumab concentrations from 
subjects in the treatment holiday and control groups at selected sites at the times specified 
in the Time and Events Table (Table 2). Only one PK sampling for the treatment holiday 
group between Weeks 0 and 16 can be performed at any time during the visit.  Otherwise, 
sampling must be performed prior to dosing (pre-dose sample) at Day 0 and Weeks 8 and 
16. Sampling must be performed pre-dose and post-dose (at the end of the belimumab 
infusion) at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the 
event of a severe flare by using the escape option).  For non-dosing visits, assessment can 
be performed once at any time during the subject’s visit.  Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit 
between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before Week 
24 will have one PK sampling performed at any time during the EXIT visit.  PK sampling 
for long-term discontinuation subjects withdrawing after Week 24 is not performed at the 
EXIT visit.  Samples will be analysed at a central laboratory. 
To:
Collect blood samples for measurement of serum belimumab concentrations from 
subjects in the treatment holiday and control groups at selected sites at the times specified 
in the Time and Events Table (Table 2). Only one PK sampling for the treatment holiday 
group between Weeks 0 and 16 can be performed at any time during the visit.  Otherwise, 
sampling must be performed prior to dosing (pre-dose sample) at Day 0 and Weeks 8 and 
16. Sampling must be performed pre-dose and post-dose (at the end of the belimumab 
infusion) at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the 
event of a severe flare by using the escape option).  For non-dosing visits, assessment can 
be performed once at any time during the subject’s visit.  Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit 
between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before Week 
24 will have one PK sampling performed at any time during the EXIT visit.  PK sampling 
for long-term discontinuation subjects withdrawing after Week 24 is not performed at the 
EXIT visit.  Samples will be analysed at a central laboratory.   PK assessment will also 
be used to determine belimumab concentration in confirmed positive 
immunogenicity samples.        
Rationale:  Clarifies PK analysis is needed for analysis of confirmed ADA positive 
samples.
 
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Change 6: Appendix 5:  Clinical Laboratory Tests
This change affects Section 11.5, Appendix 5:  Clinical Laboratory Tests, Liver event 
follow-up assessments category.
Add:
IgG, hepatitis delta antibody, fractionated bilirubin, and serum acetaminophen
Rationale:  Addition of laboratory tests mentioned in Section 6.4.1 Liver chemistry 
stopping and follow up criteria.  Note:  ANA is already shown under the Autoantibodies 
sub-heading, hep B viral DNA is already shown under the Modified Chem-20/Other sub-
heading, and the esoinophils are already shown under the Hematology sub-heading.
Protocol Amendment 04
Protocol amendment 04 applies to all countries and sites
Description of Changes
Changes are highlighted in bold.
Change 1:  SPONSOR INFORMATION PAGE
This change affects the SPONSOR INFORMATION PAGE, Sponsor Medical Monitors 
Contact Information and Case Management Group sections.
Change from:
Sponsor Medical Monitor Contact Information:  
Primary Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
Mobile: 
 
Backup Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information: 
 
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Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP) 
Email: 
Fax: 
To:
Sponsor Medical Monitor Contact Information:  
Primary Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
Mobile: 
 
Backup Medical Monitor
 DO (Director, Immuno-Inflammation Medicine Development Center) 
Tel: 
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information: 
Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP) 
Email: 
Fax: 
Regulatory Agency Identifying Number(s): 9970
Rationale:  Update telephone numbers for the Primary and Backup Medical Monitors, 
and the Case Management Group email address and fax number.   The Regulatory 
Agency Identifying Number has been added because United States clinical study sites 
have joined this clinical trial.
Change 2:  Study Design
This change affects Section 3.1, Study Design, 3rd paragraph.
Change from:
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
 
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will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor decides to terminate further development of 
belimumab for SLE.
To:
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor discontinues the maintenance phase of the 
study for China subjects with the provision for China subjects to elect to participate 
in a different protocol to continue to receive belimumab, or the Sponsor decides to 
terminate the study.  Safety reporting will be as specified in the protocol the subject 
participates in.
Rationale:  This change allows the sponsor the option to discontinue the maintenance 
phase of the study for China subjects.  This change also allows the sponsor the option of 
terminating the study while still continuing the development/marketing of belimumab for 
SLE. Provision of intravenous belimumab to China study subjects who participated in 
the maintenance phase this trial may be offered through a separate continuation protocol, 
such as the 200140 protocol, which was submitted to the China FDA in October 2014 and 
approval is anticipated by July 2017. If the 200140 protocol is approved, then 
participation is voluntary.  Japanese subjects who enter the maintenance phase of the 
BEL116027 study will be allowed to continue the maintenance phase because the 
Japanese regulatory framework does not include expanded access or compassionate use 
programs.  Belimumab has been available in Korea since the first quarter of 2015.
Change 3:  Treatment after the End of the Study
This change affects Section5.6 Treatment after the End of the Study, first paragraph.
Change from:
Eligible subjects in the treatment holiday and control groups may continue to receive 
belimumab therapy every 4 weeks under the maintenance phase of this protocol until the 
subject withdraws from the study, or the subject elects to participate in another 
belimumab continuation study for SLE, or belimumab becomes commercially available 
in a subject’s country of participation, or upon the decision by the sponsor to discontinue 
development/marketing of belimumab for SLE. Subjects in the treatment holiday and 
control groups who complete Week 52 of this study are not eligible to receive further 
 
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treatment with belimumab in the maintenance phase of this study if belimumab is 
commercially available in the subject’s country of participation.
To:
Eligible subjects in the treatment holiday and control groups may continue to receive 
belimumab therapy every 4 weeks under the maintenance phase of this protocol until the 
subject withdraws from the study, or the subject elects to participate in another 
belimumab continuation study for SLE, or the Sponsor discontinues the maintenance 
phase of the study for China subjects with the provision for China subjects to elect 
to participate in a different protocol to continue to receive belimumab, or belimumab 
becomes commercially available in a subject’s country of participation, or upon the 
decision by the sponsor to discontinue the study. Safety reporting will be as specified 
in the protocol the subject participates in.  Subjects in the treatment holiday and 
control groups who complete Week 52 of this study are not eligible to receive further 
treatment with belimumab in the maintenance phase of this study if belimumab is 
commercially available in the subject’s country of participation.
Rationale:  This change allows the sponsor the option to discontinue the maintenance 
phase of the study for China subjects.  This change also allows the sponsor the option of 
terminating the study while still continuing the development/marketing of belimumab for 
SLE. Provision of intravenous belimumab to China study subjects who participated in 
the maintenance phase this trial may be offered through a separate continuation protocol, 
such as the 200140 protocol, which was submitted to the China FDA in October 2014 and 
approval is anticipated by July 2017. If the 200140 protocol is approved, then 
participation is voluntary.  Japanese subjects who enter the maintenance phase of the 
BEL116027 study will be allowed to continue the maintenance phase because the 
Japanese regulatory framework does not include expanded access or compassionate use 
programs.  Belimumab has been available in Korea since the first quarter of 2015.
Change 4:  Time and Events Table (Year 1)
This change affects Section 6, Study Assessments and Procedures, Table 2, Time and 
Events Table (Year 1), footnote 3.
Change from:
3.  The 16 week follow-up visit will occur at approximately 16 weeks after last dose of 
investigational product for subjects in the control group who withdraw at any time during 
the study but do not wish to enter the long-term discontinuation group and be 
followed for a further 12 months or for subjects in the treatment holiday group who 
withdraw from the study from Week 24 onwards (Visit 7) during the belimumab re-
introduction period. The 16-week and 6 month follow-up visits do not apply to subjects 
in the long-term discontinuation group. 
To:
 
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3.  The 16 week follow-up visit will occur at approximately 16 weeks after last dose of 
investigational product for subjects in the control group who withdraw at any time during 
the study, or for subjects in the treatment holiday group who withdraw from the study 
from Week 24 onwards (Visit 7) during the belimumab re-introduction period. The 16-
week and 6 month follow-up visits do not apply to subjects in the long-term 
discontinuation group. 
Rationale:  Correction of the typographical error by removing the wording as no 
switching between the three groups is allowed.  This wording should not have appeared 
in the footnote.
Change 5: Liver chemistry stopping and follow up criteria.
This change affects Section 6.4.1.  Updates to the entire section below are in bold.  
Removed text has been shown by strikethroughs.
Updated Section:
6.4.1
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance) [James, 2009; Le Gal, 2005].  For subjects in the treatment 
holiday group having belimumab therapy re-introduced from Week 24 onwards or 
escaping to the maintenance phase of the study prior to Week 24, subjects in the control 
group, or any subject entering the maintenance phase of the study, the following applies:
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 3:
1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and 
INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw 
belimumab for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury.
2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks OR ALT 3xULN but <5 xULN
persists for 4 weeks
4. ALT 3xULN if associated with symptoms (new or worsening) believed to be related 
to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks OR 
ALT 3xULN but <5 xULN and cannot be monitored weekly for 4 weeks
 
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When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw discontinue belimumab for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies 
of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw 
belimumab for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Withdraw the subject from the study after completion of the liver chemistry 
monitoring.

Do not re-challenge with belimumab.Do not restart subject with belimumab unless 
GSK Medical Governance approval is granted (refer to Section 6.4.1.1)
Monitoring for liver chemistry stopping criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
Monitoring for liver chemistry stopping criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Phase III-IV Liver Chemistry Increased Monitoring Criteria With Continued 
Therapy
Subjects with ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms 
believed to be related to liver injury or hypersensitivity, and who can be monitored 
 
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weekly for 2 weeks OR which exhibit a decrease to ALT x3xULN, but <5xULN and 
bilirubin <2xULN without hepatitis symptoms or rash 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

Can continue belimumab 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly.

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Follow-up Assessments For Liver Stopping Criteria 1-5
Make every attempt to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and 
hepatitis delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be 
performed, it can be replaced with a PCR of hepatitis D RNA virus (where 
needed) [LeGal, 2005].

Blood sample for PK analysis, obtained within approximately one to two weeks after 
the liver event.  Record the date/time of the PK blood sample draw and the date/time 
of the last dose of belimumab 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 SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
 
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
Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) or ALT 3xULN and INR>1.5, if INR measured; but are optional for other 
abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and 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. 

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed, it can 
be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
For long-term discontinuation group subjects found to have met the liver stopping criteria 
without receiving belimumab, investigators will apply the withdrawal criteria in Section 
4.4.
Rationale:  Include updates to this section.
Change 6:  Study Treatment Restart
This change affects Section 6.4.1.1.  
Add new section:
6.4.1.1
Study Treatment Restart
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:
 
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
GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart 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 drug induced liver injury [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.

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.
 
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
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 6.4.8.
Rationale:  Add new section for restarting investigational product after a subject has 
experienced a liver event.
 
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Change 7:  Interim Analysis
This change affects Section 8.1.6 Interim Analysis
Change from:
An unblinded interim analysis of the data in this continuation trial may be performed to 
support a submission to regulatory authorities relating to marketing authorization (e.g., to 
summarize and submit this long term safety data to regulatory authorities in the initial 
BLA and other marketing authorization submissions). Additional interim analyses may 
be required to support subsequent safety updates to regulatory authorities. 
To:
An interim analysis of the data in this trial may be performed to support a submission to 
regulatory authorities relating to marketing authorization (e.g., to summarize and submit 
this long term safety data to regulatory authorities in the initial BLA and other marketing 
authorization submissions). Additional interim analyses may be required to support 
subsequent safety updates to regulatory authorities. 
Rationale:  Two of the three subjects groups in this study will receive open-label 
belimumab, and removal of the typographical error of “unblinded” in the sentence is 
appropriate.   Additionally, this study is not a “continuation” trial as the primary and 
secondary objectives state specific objectives, and removing “continuation” corrects this 
typographical error.
Change 8:  Study and Site Closure
This change affects Section 9.5 Study and Site Closure, first paragraph.
Change from:
Subjects recruited into this study will continue to receive treatment with belimumab until 
such time as belimumab becomes commercially available in Northeast Asia, or the 
subject elects to participate in another belimumab continuation study for SLE, or until 
either the subject's physician withdraws the subject from the study or upon the decision 
by the sponsor to discontinue further development of belimumab for SLE.  Upon 
completion of treatment, every effort should be made to evaluate subjects for Week 16 
post-treatment follow-up visit and the 6-month post-treatment visit.  Once all reasonable 
efforts have been made, the study will be considered complete/terminated.
To:
Subjects recruited into this study will continue to receive treatment with belimumab until 
such time as belimumab becomes commercially available in Northeast Asia, or the 
subject elects to participate in another belimumab continuation study for SLE, or the 
Sponsor discontinues the maintenance phase of the study for China subjects with 
the provision for China subjects to elect to participate in a different protocol to 
 
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continue to receive belimumab, or until either the subject's physician withdraws the 
subject from the study, or upon the decision by the sponsor to discontinue the study.  
Safety reporting will be as specified in the protocol the subject participates in.  Upon 
completion of treatment, every effort should be made to evaluate subjects for Week 16 
post-treatment follow-up visit and the 6-month post-treatment visit.  Once all reasonable 
efforts have been made, the study will be considered complete/terminated.
Rationale:  This change allows the sponsor the option to discontinue the maintenance 
phase of the study for China subjects.  This change also allows the sponsor the option of 
terminating the study while still continuing the development/marketing of belimumab for 
SLE. Provision of intravenous belimumab to China study subjects who participated in 
the maintenance phase this trial may be offered through a separate continuation protocol, 
such as the 200140 protocol, which was submitted to the China FDA in October 2014 and 
approval is anticipated by July 2017. If the 200140 protocol is approved, then 
participation is voluntary.  Japanese subjects who enter the maintenance phase of the 
BEL116027 study will be allowed to continue the maintenance phase because the 
Japanese regulatory framework does not include expanded access or compassionate use 
programs.  Belimumab has been available in Korea since the first quarter of 2015.
Change 9:  References
This change affects Section 10, References.
Add:
Le Gal F, Gordien E, Affolabi D, et al. Quantification of hepatitis delta virus RNA in 
serum by consensus real-time PCR indicates different patterns of virological response to 
interferon therapy in chronically infected patients. J Clin Microbiol 2005;43(5):2363–9.
Rationale:  Now referenced in updated Section 6.4.1 Liver chemistry stopping and 
follow up criteria.
Change 10:  Appendix 7: Country Specific Requirements
This change affects Section11.7, Appendix 7:  Country Specific Requirements, 
Amendment 01, Section 3.1 Investigational Plan, Study Design, 3rd paragraph.
Change from:
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
 
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belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor decides to terminate further development of 
belimumab for SLE.
To:
The study consists of a screening phase of up to 30 days, a 52-week 
treatment/observation phase with an escape option, a maintenance phase, and a follow-up 
phase. The screening phase will allow an assessment of the SELENA SLEDAI score and 
complement (C3 and C4) levels as part of the eligibility criteria for subjects in the 
treatment holiday and control groups.  All subjects will attend clinic visits for efficacy 
and safety assessments every 4 weeks for 52 weeks. At the end of the 52 week period, 
subjects in the treatment holiday and control groups will have the option to continue 
belimumab therapy in the maintenance phase of this study only if belimumab is not 
commercially available in a subject’s country of participation. This maintenance phase 
will last until such time as belimumab becomes commercially available in a subject’s 
country of participation, or the Sponsor discontinues the maintenance phase of the 
study for China Subjects with the provision for China subjects to elect to participate 
in a different protocol to continue to receive belimumab, or the Sponsor decides to 
terminate the study.  Safety reporting will be as specified in the protocol the subject
participates in.  
Rationale:  This change allows the sponsor the option to discontinue the maintenance 
phase of the study for China subjects.  This change also allows the sponsor the option of 
terminating the study while still continuing the development/marketing of belimumab for 
SLE. Provision of intravenous belimumab to China study subjects who participated in 
the maintenance phase this trial may be offered through a separate continuation protocol, 
such as the 200140 protocol, which was submitted to the China FDA in October 2014 and 
approval is anticipated by July 2017. If the 200140 protocol is approved, then 
participation is voluntary.  Japanese subjects who enter the maintenance phase of the 
BEL116027 study will be allowed to continue the maintenance phase because the 
Japanese regulatory framework does not include expanded access or compassionate use 
programs.  Belimumab has been available in Korea since the first quarter of 2015.
 
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Change 11:  Appendix 3:  Liver Chemistry Stopping and Follow up Criteria
This change affects section 11.3; Appendix 3, Liver Chemistry Stopping and Follow up 
Criteria.
Change from:
 
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To:
Phase III-IV 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
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
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*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.4.1.
 
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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
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*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.4.1.
Rationale:  Updated Phase III_IV Liver Safety Algorithm.
 
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Protocol Amendment 03
Protocol amendment 03 applies to all countries and sites
Description of Changes
Changes are highlighted in bold.
Change 1:  Sponsor Information Page
This change affects the Sponsor Information Page, Sponsor Serious Adverse Event (SAE) 
Contact Information:
Change from:
Email:  
Fax:  
To:
Email:  
Fax:  
Rationale:  Update sponsor serious adverse event (SAE) contact information
Change 2:  Investigational Product and Reference Therapy
This change affects Section 5.1, Study Treatments, Investigational Product and Reference 
Therapy, second paragraph, second sentence.
Change from:
At the start of the belimumab reintroduction period, subjects in the treatment holiday 
group will receive belimumab 10 mg/kg IV infused for 1 hour every 28 days.
To:
At the start of the belimumab reintroduction period, subjects in the treatment holiday 
group will receive belimumab 10 mg/kg IV infused for over 1 hour every 28 days.
Rationale:  This corrects the typographical error as the word “over” was inadvertently 
omitted from the text.
Change 3:  Investigational Product and Reference Therapy
This change affects Section 5.1, Study Treatments, Investigational Product and Reference 
Therapy, third paragraph, first sentence.
 
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Change from:
Subjects in the control group will receive belimumab 10 mg/kg IV infused for 1 hour 
every 28 days from Day 0 onwards.
To:
Subjects in the control group will receive belimumab 10 mg/kg IV infused for over 1 
hour every 28 days from Day 0 onwards.
Rationale:  This corrects the typographical error as the word “over” was inadvertently 
omitted from the text.
Change 4: Treatment Assignment
This change affects Section 5.2 Treatment Assignment
Change from:
This is an open-label, non-randomized study.  Site personnel will access RAMOS NG, 
the interactive voice response system (IVRS) to enrol the subject in the study and to log 
subject visits. 
To:
This is an open-label, non-randomized study.  Site personnel will access the interactive 
voice response system (IVRS) to enrol the subject in the study and to log subject visits.   
Supplementary information is provided in the Study Procedures Manual (SPM).
Rationale:  A sponsor administrative change has prompted removing RAMOS NG as the 
designated interactive voice response system.  
Change 5:  Permitted Medications and Non-Drug Therapies
This change affects section 5.5.1 Permitted Medications and Non-Drug Therapies, Live 
vaccines.
Change from:
Note:  Live vaccines are permitted in this study and can be given at the investigator’s 
discretion.
 
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To:
Note:  Live vaccines are permitted for subjects in the long-term discontinuation 
group.  Subjects in the control and treatment holiday groups are prohibited from 
receiving live vaccines.
Rationale:  This change clarifies that live vaccines can only be provided to subjects in 
the long-term discontinuation group, since these subjects will not be receiving belimumab 
during the study.
Change 6:  Study Assessments and Procedures
This change affects Section 6, Time and Events Table (Year 1), Footnote 4 and 
corresponding “X” for Written Informed Consent at Visit 2.
Change from:
4   For subjects in the control group only, obtain written informed consent to participate in this 
study at the visit prior to the last visit in the relevant SLE feeder continuation study.
To:
4   Obtain written informed consent to participate in this study at the Screening visit.
Rationale:  Because of the sponsor administrative change removing RAMOS NG as the 
IVRS system, this change clarifies that written informed consent will be obtained for all 
subjects at the screening visit.
Change 7:  Critical Baseline Assessments
This change affects Section 6.2 Critical Baseline Assessments, second paragraph.
Change from:
The EXIT visit of the relevant SLE continuation protocol ((BEL114333, HGS1006-
C1066, or LBSL99) from which the subject is recruited will serve as the Day 0 visit in 
this study. Subjects in the control group will be dosed with belimumab at the Day 0 visit 
as part of this protocol. These subjects must be able to receive the Day 0 dose in this 
study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the 
previous open-label continuation study.  Any procedures from this protocol or from the 
relevant previous open-label continuation protocols to be performed pre-dose must be 
completed before dosing subjects in the control group. Subjects in the control group 
should sign the informed consent to participate in this study at the visit immediately 
prior to the EXIT visit to ensure a supply of belimumab for the Day 0 visit in this 
study.  Subjects in the treatment holiday and long-term discontinuation groups 
 
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should sign the informed consent at the screening visit and Day 0 visit, respectively 
of this study.
To:
The EXIT visit of the relevant SLE continuation protocol (BEL114333, HGS1006-
C1066, or LBSL99) from which the subject is recruited will serve as the Day 0 visit in 
this study. Subjects in the control group will be dosed with belimumab at the Day 0 visit 
as part of this protocol. These subjects must be able to receive the Day 0 dose in this 
study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the 
previous open-label continuation study.  Any procedures from this protocol or from the 
relevant previous open-label continuation protocols to be performed pre-dose must be 
completed before dosing subjects in the control group.  Obtain written informed 
consent from all subjects to participate in this study at the Screening visit.
Rationale:  Because of the sponsor administrative change removing RAMOS NG as the 
IVRS system, this change clarifies that written informed consent will be obtained for all 
subjects at the screening visit.
Change 8:  Study Assessments and Procedures
This change affects Section 6, Time and Events Table (Year 1), Footnote 12.
Change from:
12.  Pharmacokinetic sampling at select sites for subjects in the control and treatment 
holiday groups; subjects in the treatment holiday group can have PK sampling performed 
at any time during the visit between Weeks 0 and 16.  Otherwise, if on a dosing day, 
sampling must be performed prior to dosing. Collect blood samples pre-dose and post-
dose at the end of the infusion at Weeks 24 and 52 (or earlier if belimumab is re-started 
before Week 24 in the event of a severe flare by using the escape option).   Subjects in 
the long-term discontinuation group will have one PK sampling performed at any time 
during the visit between Weeks 0 and 24.  PK sampling for the long-term discontinuation 
group is not performed after Week 24. 
To:
12.  Pharmacokinetic sampling at select sites for subjects in the control and treatment 
holiday groups; subjects in the treatment holiday group can have PK sampling performed
at any time during the visit between Weeks 0 and 16.  Otherwise, if on a dosing day, 
sampling must be performed prior to dosing. Collect blood samples pre-dose and post-
dose at the end of the infusion at Weeks 24 and 52 (or earlier if belimumab is re-started 
before Week 24 in the event of a severe flare by using the escape option).   Subjects in 
the long-term discontinuation group will have one PK sampling performed at any time 
during the visit between Weeks 0 and 24.  PK sampling for the long-term discontinuation 
group is not performed after Week 24.  Long-term discontinuation subjects 
withdrawing before Week 24 will have one PK sampling performed at any time 
 
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during the EXIT visit.   PK sampling for long-term discontinuation subjects 
withdrawing after Week 24 is not performed at the EXIT visit.
Rationale:  Clarifies PK sampling for long-term discontinuation subjects who withdraw 
from the study.
Change 9:  Pharmacokinetics
This change affects Section 6.6, Pharmacokinetics
Change from:
Collect blood samples for measurement of serum belimumab concentrations from 
subjects in the treatment holiday and control groups at selected sites at the times specified 
in the Time and Events Table (Table 2). Only one PK sampling for the treatment holiday 
group between Weeks 0 and 16 can be performed at any time during the visit.  Otherwise, 
sampling must be performed prior to dosing (pre-dose sample) at Day 0 and Weeks 8 and 
16. Sampling must be performed pre-dose and post-dose (at the end of the belimumab 
infusion) at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the 
event of a severe flare by using the escape option).  For non-dosing visits, assessment can 
be performed once at any time during the subject’s visit.  Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit 
between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Samples will be analysed at a central laboratory. 
To:
Collect blood samples for measurement of serum belimumab concentrations from 
subjects in the treatment holiday and control groups at selected sites at the times specified 
in the Time and Events Table (Table 2). Only one PK sampling for the treatment holiday 
group between Weeks 0 and 16 can be performed at any time during the visit.  Otherwise, 
sampling must be performed prior to dosing (pre-dose sample) at Day 0 and Weeks 8 and 
16. Sampling must be performed pre-dose and post-dose (at the end of the belimumab 
infusion) at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the 
event of a severe flare by using the escape option).  For non-dosing visits, assessment can 
be performed once at any time during the subject’s visit.  Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit 
between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before 
Week 24 will have one PK sampling performed at any time during the EXIT visit.  
PK sampling for long-term discontinuation subjects withdrawing after Week 24 is 
not performed at the EXIT visit.  Samples will be analysed at a central laboratory. 
Rationale:  Clarifies PK sampling for long-term discontinuation subjects who withdraw 
from the study.
 
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Change 10:  Regulatory and Ethical Considerations, Including the Informed Consent 
Process.
This change affects Section 9.2 Regulatory and Ethical Considerations, Including the 
Informed Consent Process, next to the last paragraph.
Change from:
Written informed consent must be obtained from each subject prior to participation in the 
study.  Subjects in the control group should sign the informed consent to participate 
in this study at the visit immediately prior to the EXIT visit to ensure a supply of 
belimumab for the Day 0 visit in this study.  Subjects in the treatment holiday and 
long-term discontinuation groups should sign the informed consent at the Day 0 
visit of this study.
To:
Written informed consent must be obtained from each subject prior to participation in the 
study.  Obtain written informed consent from all subjects to participate in this 
study at the Screening visit.
Rationale:  Because of the sponsor administrative change removing RAMOS NG as the 
IVRS system, this change clarifies that written informed consent will be obtained for all 
subjects at the screening visit.
 
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Protocol Amendment 02
Protocol amendment 02 is a global protocol amendment that applies to all involved 
countries and sites.
Description of Changes
Changes are highlighted in bold.
Change 1:  Title page
This change affects the Title page, study title.
Change from:
A Phase IV, Open-label, Non-randomized, 52-Week Study to Evaluate Treatment 
Holidays and Rebound Phenomenon After Treatment With Belimumab 10 mg/kg in 
Systemic Lupus Erythematosus Subjects
To:
An Open-label, Non-randomized, 52-Week Study to Evaluate Treatment Holidays and 
Rebound Phenomenon After Treatment With Belimumab 10 mg/kg in Systemic Lupus 
Erythematosus Subjects
Rationale:  Sponsor administrative change to remove reference to the study phase in the 
title, as study phases are interpreted differently in different participating countries, and 
thus removes any inconsistencies.
Change 2:  Title page
This change affects the Title page.
Add:
Description:  Protocol amendment number 02 is a global protocol amendment
Rationale: Clarifies that protocol amendment 02 is a global protocol amendment that 
applies to all involved countries and sites.
Change 3:  Protocol Summary
This change affects the Protocol Summary Section, Study Design, first sentence.
Change from:
A phase IV, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:
 
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To:
A phase IIIB, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:
Rationale:  Sponsor administrative change of study phase reduces inconsistencies from 
some participating countries in which belimumab has not yet been approved.
Change 4: Study Design
This change affects Section 3.1 Study Design, first sentence.
Change from:
A phase IV, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:
To:
A phase IIIB, multi-centre, open-label, non-randomized, efficacy and safety study 
(including potential rebound) of:
Rationale: Sponsor administrative change of study phase reduces inconsistencies from 
some participating countries in which belimumab has not yet been approved.
Change 5:  Progressive Multifocal Leukoencephalopathy
This change affects Section 6.4.13.1 Progressive Multifocal Leukoencephalopathy.
Change from:
Patients with SLE may be at increased risk for PML secondary to SLE itself, as well as 
the concurrent use of immunosuppressive drugs.  The most common signs and symptoms 
of PML include visual disturbances, ocular movements, ataxia, and mental status changes 
such as disorientation or confusion.  Clinical signs and symptoms of PML and SLE can 
be similar.  The investigator must exercise best judgement in further workup and clinical 
intervention as appropriate.  Cases of suspected PML will be promptly reported to the 
sponsor.
To:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and symptoms. 
The subject should be referred to a neurologist or other appropriate specialist for 
evaluation. If PML is confirmed, study agent should be discontinued and consideration 
should be given to stopping immunosuppressant therapy.
 
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If PML is suspected, this should be immediately reported to the Medical Monitor. 
The appropriateness of continuing study agent, while the case is being assessed, should 
be discussed.
Rationale:
Updated wording addresses new information received by the Sponsor.
Change 6:  Appendix 5
This change affects Appendix 5:  Clinical Laboratory Tests.
Add:
aCL, ANA, BLyS protein, and Hepatitis B Viral DNA PCR Quantitative (HBV DNA)
Rationale:  Corrects inadvertent omission in the Clinical Lab Test Appendix.
 
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Protocol Amendment 01
Protocol amendment 01 for China Specific protocol Amendment applies only to China 
and all China sites.
Description of Changes
Changes are highlighted in bold.
Change 1:  Title page
Add:
Description:  Protocol amendment number 01 is a China specific protocol amendment
Rationale:
Clarifies Protocol Amendment 01 is China specific
Change 2:  Protocol Summary, Study Design
This change affects Section Protocol Summary, study design, first paragraph, third 
sentence.
Change from:
All 3 subject groups will be recruited from the BEL114333 continuation study of 
belimumab in SLE.  
To:
All 3 subject groups will be recruited from the BEL114333 continuation study of 
belimumab in SLE, and from the open-label (OL) period BEL113750 for China 
subjects.  
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 3:  Investigational Plan
This change affects Section 3.1, Investigational Plan, Study Design, Figure 1, Study 
Schematic, 6 Months Minimum Column, and first descriptive sentence below schematic.
 
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Change from:
Subjects will be recruited from 3 continuation studies of belimumab in SLE.
 
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To:
Subjects will be recruited from 3 continuation studies of belimumab in SLE, and from 
the open-label (OL) period of BEL113750 for China subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 4:  Investigational Plan
This change affects Section 3.1, Investigational Plan, Study Design, three different 
groups of subjects, bullet points.
Change from:

Treatment Holiday group: This group will be used to assess the effect of temporary 
discontinuation (including rebound phenomenon) and re-introduction of belimumab 
10 mg/kg therapy. These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE.  Subjects will have been treated with 
belimumab for at least 6 months and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal. The target enrolment for this group is 50 subjects.
 
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
Treatment Continuation control group: This group will serve as a control to the 
treatment holiday arm.  These subjects will be recruited from the BEL114333 
belimumab continuation study in subjects with SLE.  Subjects will have been treated 
with belimumab for at least 6 months and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal but will continue their current treatment with belimumab 10 mg/kg. The 
target enrolment for this group is 50 subjects.

Long-term Discontinuation group: This group will also be used to assess rebound 
phenomenon in SLE subjects who have discontinued therapy with belimumab 10 
mg/kg and are expected to remain off belimumab therapy for at least 12 months but 
remain on standard of care therapy. These subjects will be recruited from 3 
belimumab continuation studies in subjects with SLE (BEL114333; HGS1006-
C1066; LBSL99).   Subjects will have been treated with belimumab for at least 6 
months in one of the continuation studies, but will have withdrawn from belimumab 
therapy for no longer than 8 weeks prior to entry into this study. These subjects may 
have any level of SLE disease activity. The target enrolment for this group is 35 
subjects.
To:

Treatment Holiday group: This group will be used to assess the effect of temporary 
discontinuation (including rebound phenomenon) and re-introduction of belimumab 
10 mg/kg therapy. These subjects will be recruited from the BEL114333 belimumab 
continuation study in subjects with SLE, and from the open-label period of 
BEL113750 for China subjects.  Subjects will have been treated with belimumab 
for at least 6 months and have a SELENA SLEDAI score 3 and complement (C3 
and C4) levels at or above the central laboratory lower limit of normal. The target 
enrolment for this group is 50 subjects.

Treatment Continuation control group: This group will serve as a control to the 
treatment holiday arm.  These subjects will be recruited from the BEL114333 
belimumab continuation study in subjects with SLE, and from the open-label 
period of BEL113750 for China subjects.  Subjects will have been treated with 
belimumab for at least 6 months and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal but will continue their current treatment with belimumab 10 mg/kg. The 
target enrolment for this group is 50 subjects.

Long-term Discontinuation group: This group will also be used to assess rebound 
phenomenon in SLE subjects who have discontinued therapy with belimumab 10 
mg/kg and are expected to remain off belimumab therapy for at least 12 months but 
remain on standard of care therapy. These subjects will be recruited from 3 
belimumab continuation studies in subjects with SLE (BEL114333; HGS1006-
C1066; LBSL99), and from the open-label period of BEL113750 for China 
subjects.   Subjects will have been treated with belimumab for at least 6 months in 
one of the continuation studies, and from the open-label period of BEL113750 for 
China subjects for at least 6 months, but will have withdrawn from belimumab 
therapy for no longer than 8 weeks prior to entry into this study. These subjects may 
 
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have any level of SLE disease activity. The target enrolment for this group is 35 
subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 5:  Discussion of Design
This change affects Section 3.2 Discussion of Design.
Change from:
This study proposes to recruit subjects from ongoing open-label continuation studies of 
belimumab in SLE subjects in order to obtain an eligible population in the shortest 
timeframe. There are 3 continuation studies of belimumab suitable for recruitment 
of subjects required for this study:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan, South Korea and China.

HGS1006-C1066: An ongoing Phase III, open-label continuation study of parent 
study HGS1006-C1056 (BLISS 76), which enrolled and treated 268 SLE subjects 
with belimumab conducted in the United States

LBSL99: An ongoing Phase II, open-label continuation study of parent study 
LBSL02, which enrolled and treated 296 SLE subjects with belimumab conducted 
in the United States and Canada.
Subjects eligible for inclusion in the treatment holiday group will have been treated with 
belimumab for at least 6 months in BEL114333, and have a SELENA SLEDAI score 3 
and complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal.
Subjects eligible for inclusion in the control group will have been treated with belimumab 
for at least 6 months in BEL114333, and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of normal 
but elect to continue their current treatment with belimumab 10 mg/kg.
Subjects eligible for inclusion in the long-term discontinuation group may have any level 
of SLE disease activity; will have been treated with belimumab for at least 6 months in 
any of the 3 continuation studies mentioned above, and have discontinued belimumab 
therapy for no longer than 8 weeks prior to entry into this study and intend to remain off 
belimumab treatment for the 12 months of this study but to remain on standard of care 
therapy.
 
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Subjects eligible for inclusion in the treatment holiday group will not be recruited from 
the long-term continuation studies LBSL99 or HGS1006-C1066, due to regulatory 
commitments for completing 10 years and 5 years on treatment, respectively. However, 
subjects who discontinue belimumab treatment in studies LBSL99 or HGS1006-C1066 
can be recruited into the long-term discontinuation group in the present study.
For subjects entering the study, a minimum of 6 months previous participation in an 
open-label continuation studies will provide subjects initially randomized to placebo in 
parent studies with the opportunity to reach sufficient biological activity to achieve a 
belimumab pharmacological and/or clinical response.
The target sample size of 50 subjects in each of the treatment holiday and control groups 
is based on estimates of subject eligibility and number of subjects from continuation 
study BEL114333, is anticipated to provide consent to participate in this study.  The 
target sample size of 35 subjects for the long-term discontinuation group is based on 
practical considerations of numbers of subjects anticipated to drop-out and not on 
statistical considerations.
Enrolment of subjects from the 3 belimumab continuation into the long-term 
discontinuation group will remain open while recruitment to the treatment holiday and 
control groups is ongoing or until 36 months have elapsed since study start. A target 
sample size of 35 subjects in the long-term discontinuation group is anticipated.
Because this study is non-randomized, subjects and investigators from study BEL114333 
will jointly decide upon which of the three groups to enrol into.  Subjects recruited from 
the HGS1006-C1066 and the LBSL99 studies may only choose to enter the long-term 
discontinuation group, as they elect to no longer receive further belimumab therapy.
To:
This study proposes to recruit subjects from 3 ongoing open-label continuation studies of 
belimumab in SLE subjects as well as from the open-label period of BEL113750 for 
China subjects in order to obtain an eligible population in the shortest timeframe:

BEL114333: A Phase III open-label continuation of parent study BEL113750, 
which is an ongoing Phase III, double-blind, placebo-controlled study of 
belimumab in SLE subjects conducted in Japan and South Korea.

BEL113750: Only China subjects from the open-label portion of this Phase 
III, randomized, parallel group, double-blind study to evaluate the efficacy 
and safety of 10mg/kg belimumab intravenously at Weeks 0, 2, and 4, and 
then every 4 weeks, compared with placebo over a 52-week treatment period 
in subjects with active systemic lupus erythematosus (SELENA SLEDAI 
score 8) in Northeast Asia. 

HGS1006-C1066: An ongoing Phase III, open-label continuation study of parent 
study HGS1006-C1056 (BLISS 76), which enrolled and treated 268 SLE subjects 
with belimumab conducted in the United States
 
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
LBSL99: An ongoing Phase II, open-label continuation study of parent study 
LBSL02, which enrolled and treated 296 SLE subjects with belimumab conducted 
in the United States and Canada.
Subjects eligible for inclusion in the treatment holiday group will have been treated with 
belimumab for at least 6 months in BEL114333 or for at least 6 months in the 
BEL113750 open-label period for China subjects, and have a SELENA SLEDAI score 
3 and complement (C3 and C4) levels at or above the central laboratory lower limit of 
normal.
Subjects eligible for inclusion in the control group will have been treated with belimumab 
for at least 6 months in BEL114333 or for at least 6 months in the BEL113750 open-
label period for China subjects, and have a SELENA SLEDAI score 3 and 
complement (C3 and C4) levels at or above the central laboratory lower limit of normal 
but elect to continue their current treatment with belimumab 10 mg/kg.
Subjects eligible for inclusion in the long-term discontinuation group may have any level 
of SLE disease activity; will have been treated with belimumab for at least 6 months in 
any of the 3 continuation studies mentioned above, or for at least 6 months in the 
BEL113750 open-label period for China subjects; have discontinued belimumab 
therapy for no longer than 8 weeks prior to entry into this study and intend to remain off 
belimumab treatment for the 12 months of this study but to remain on standard of care 
therapy.
Subjects eligible for inclusion in the treatment holiday group will not be recruited from 
the long-term continuation studies LBSL99 or HGS1006-C1066, due to regulatory 
commitments for completing 10 years and 5 years on treatment, respectively. However, 
subjects who discontinue belimumab treatment in studies LBSL99 or HGS1006-C1066 
can be recruited into the long-term discontinuation group in the present study.
For subjects entering the study, a minimum of 6 months previous participation in an 
open-label continuation studies or China subjects in BEL113750 receiving open-label 
belimumab for at least 6 months, will provide subjects initially randomized to placebo 
in parent studies with the opportunity to reach sufficient biological activity to achieve a 
belimumab pharmacological and/or clinical response.
The target sample size of 50 subjects in each of the treatment holiday and control groups 
is based on estimates of subject eligibility and number of subjects from continuation 
study BEL114333 and China subjects in BEL113750 receiving open-label 
belimumab for at least 6 months, is anticipated to provide consent to participate in this 
study.  The target sample size of 35 subjects for the long-term discontinuation group is 
based on practical considerations of numbers of subjects anticipated to drop-out and not 
on statistical considerations.
Enrolment of subjects from the 3 belimumab continuation studies or from the open-
label period of BEL113750 for China subjects into the long-term discontinuation group 
will remain open while recruitment to the treatment holiday and control groups is 
 
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ongoing or until 36 months have elapsed since study start. A target sample size of 35 
subjects in the long-term discontinuation group is anticipated.
Because this study is non-randomized, subjects and investigators from study BEL114333 
and China subjects and China investigators from study BEL113750 will jointly 
decide upon which of the three groups to enrol into.  Subjects recruited from the 
HGS1006-C1066 and the LBSL99 studies may only choose to enter the long-term 
discontinuation group, as they elect to no longer receive further belimumab therapy.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.  This also makes the correction that China is not participating in the 
BEL114333 study,
Change 6: Inclusion Criteria
This change affects Section 4.2 Inclusion Criterion, All 3 subject groups, Criterion #1.
Change from:
Belimumab therapy:  Received a minimum of 6 months therapy with belimumab 10 
mg/kg in the continuation study BEL114333. Subjects in the long-term discontinuation 
group may additionally be recruited from continuation studies HGS1006-C1066 or 
LBSL99.
To:
Belimumab therapy:  Received a minimum of 6 months therapy with belimumab 10 
mg/kg in the continuation study BEL114333 or from China subjects in BEL113750 
who received open-label belimumab for at least 6 months. Subjects in the long-term 
discontinuation group may additionally be recruited from continuation studies HGS1006-
C1066 or LBSL99.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 7:  Inclusion Criteria
This change affects Section 4.2 Inclusion Criteria, control group, criterion #1.
Change from:
Belimumab therapy: Agree to continue receiving 10mg/kg belimumab intravenous 
infusions every 4 weeks.  Subjects must be able to receive the first dose of belimumab in 
 
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this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in 
their previous continuation study.
To:
Belimumab therapy: Agree to continue receiving 10mg/kg belimumab intravenous 
infusions every 4 weeks.  Subjects must be able to receive the first dose of belimumab in 
this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in 
their previous continuation study, or the open-label period of BEL113750 for China 
subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 8:  Inclusion Criteria
This change affects Section 4.2 Inclusion Criteria, long-term discontinuation group, 
criterion #1.
Change from:
Continuation studies: Voluntarily withdrawn from continuation studies BEL114333, 
HGS1006-C1066, or LBSL99, and have withdrawn from belimumab therapy for no 
longer than 8 weeks prior to entry into this study.
To:
Continuation studies: Voluntarily withdrawn from continuation studies BEL114333, 
HGS1006-C1066, LBSL99, or the open-label period of BEL113750 for China 
subjects, and have withdrawn from belimumab therapy for no longer than 8 weeks prior 
to entry into this study.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
 
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Change 9:  Exclusion Criteria
This change affects Section 4.3 Exclusion Criteria, Any of the 3 subject groups, criterion 
#1.
Change from:
Undue risk: Have developed clinical evidence of significant, unstable or uncontrolled, 
acute or chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, 
gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases), or 
experienced an adverse event (AE) in the belimumab continuation studies BEL114333, 
HGS1006-C1066, or LBSL99 studies, that could, in the opinion of the principal 
investigator, put the subject at undue risk.
To:
Undue risk: Have developed clinical evidence of significant, unstable or uncontrolled, 
acute or chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, 
gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases), or 
experienced an adverse event (AE) in the belimumab continuation studies BEL114333, 
HGS1006-C1066, LBSL99, or in the BEL113750 open-label period for China 
subjects, that could, in the opinion of the principal investigator, put the subject at undue 
risk.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 10: Study Treatments
This change affects Section 5.1 Study treatments, Investigational Product and Other 
Study Treatment, third paragraph.
Change from:
Subjects in the control group will receive belimumab 10 mg/kg IV infused for 1 hour 
every 28 days from Day 0 onwards. Subjects in this group must be able to receive their 
first dose of belimumab on Day 0 of this study 4 weeks (minimum of 2 weeks, maximum 
of 8 weeks) after the last dose in the BEL114333 open-label continuation study.
To:
Subjects in the control group will receive belimumab 10 mg/kg IV infused for 1 hour 
every 28 days from Day 0 onwards. Subjects in this group must be able to receive their 
first dose of belimumab on Day 0 of this study 4 weeks (minimum of 2 weeks, maximum 
of 8 weeks) after the last dose in the BEL114333 open-label continuation study, or after 
the last dose from China subjects in the open-label period of BEL113750.
 
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Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 11:  Study Assessments and Procedures
This change affects Section 6, Study Assessments and Procedures, Time and Events 
Table (year 1) Table 2, footnote 2.
Change from:
The EXIT Visit in the respective feeder continuation studies will serve as the Day 0 visit 
for all 3 subject groups in this study. Assessments covered for both this study at Day 0 
and the Exit visit of the feeder continuation studies need only be performed once and 
recorded in the appropriate case report forms for each study. Subjects in the control group 
must be able to receive the 1st dose of belimumab on Day 0 of this study on average 4 
weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the feeder 
continuation study.
To:
The EXIT Visit in the respective feeder continuation studies and in the open-label 
period of BEL113750 for China subjects will serve as the Day 0 visit for all 3 subject 
groups in this study. Assessments covered for both this study at Day 0 and the Exit visit 
of the feeder continuation studies and the open-label period of BEL113750 for China 
subjects need only be performed once and recorded in the appropriate case report forms 
for each study. Subjects in the control group must be able to receive the 1st dose of 
belimumab on Day 0 of this study on average 4 weeks (minimum of 2 weeks, maximum 
of 8 weeks) after the last dose in the feeder continuation study and in the open-label 
period of BEL113750 for China subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 12:  Study Assessments and Procedures
This change affects Section 6, Study Assessments and Procedures, Time and Events 
Table (year 1) Table 2, footnote 4.
Change from:
For subjects in the control group only, obtain written informed consent to participate in 
this study at the visit prior to the last visit in the relevant SLE feeder continuation study.
 
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To:
For subjects in the control group only, obtain written informed consent to participate in 
this study at the visit prior to the last visit in the relevant SLE feeder continuation study 
and the open-label period of BEL113750 for China subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.
Change 13: Study Assessments and Procedures
This change affects Section 6, Study Assessments and Procedures, Time and Events 
Table (year 1) Table 2, footnote 10.
Change from:
PGx sampling from consenting subjects recruited from all studies except from study 
BEL114333. PGx informed consent must be obtained prior to sampling.
To:
PGx sampling from consenting subjects recruited from all studies except from study 
BEL114333 and except from the open-label period of BEL113750 for China 
subjects. PGx informed consent must be obtained prior to sampling.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750. 
Change 14:  Endpoints
This change affects Section 6.1.2 Endpoints, Secondary Endpoints, Note:
Change from:
Note: baseline is the time before any treatment with belimumab, which was Day 0 of the 
original parent studies that fed into the 3 continuation studies, from which subjects were 
recruited into this study. When Day 0 is used in relation to endpoints, this refers to Day 0 
of this study.
 
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To:
Note: baseline is the time before any treatment with belimumab, which was Day 0 of the 
original parent studies that fed into the 3 continuation studies, and Day 0 of the blinded 
period of BEL113750 for China subjects, from which subjects were recruited into this 
study. When Day 0 is used in relation to endpoints, this refers to Day 0 of this study.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750.  
Change 15:  Critical Baseline Assessments
This change affects Section 6.2 Critical Baseline Assessments, second and third 
Paragraphs.
Change from:
The EXIT visit of the relevant SLE continuation protocol ((BEL114333, HGS1006-
C1066, or LBSL99) from which the subject is recruited will serve as the Day 0 visit in 
this study. Subjects in the control group will be dosed with belimumab at the Day 0 visit 
as part of this protocol. These subjects must be able to receive the Day 0 dose in this 
study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the 
previous open-label continuation study.  Any procedures from this protocol or from the 
relevant previous open-label continuation protocols to be performed pre-dose must be 
completed before dosing subjects in the control group. Subjects in the control group 
should sign the informed consent to participate in this study at the visit immediately prior 
to the EXIT visit to ensure a supply of belimumab for the Day 0 visit in this study.  
Subjects in the treatment holiday and long-term discontinuation groups should sign the 
informed consent at the screening visit and Day 0 visit, respectively of this study.
Procedures necessary for the Day 0 visit of this protocol and for the last visit of the 
relevant SLE open-label continuation protocol from which the subject is recruited need 
only be performed once. Results from Day 0 procedures that are duplicated in the 
relevant SLE continuation study will be recorded in the eCRF for that study and must 
also be transcribed to the relevant eCRFs in this study. Additional Day 0 procedures 
exclusive to this study will be recorded directly in the eCRFs for this study.
To:
The EXIT visit of the relevant SLE continuation protocol ((BEL114333, HGS1006-
C1066, or LBSL99), or the open-label period of BEL113750 for China subjects, from 
which the subject is recruited will serve as the Day 0 visit in this study.  Subjects in the 
control group will be dosed with belimumab at the Day 0 visit as part of this protocol. 
These subjects must be able to receive the Day 0 dose in this study 4 weeks (minimum of 
 
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2 weeks, maximum of 8 weeks) after the last dose in the previous open-label continuation 
study, or the open-label period of BEL113750 for China subjects.  Any procedures 
from this protocol or from the relevant previous open-label continuation protocols, or the 
open-label period of BEL113750 for China subjects to be performed pre-dose must be 
completed before dosing subjects in the control group. Subjects in the control group 
should sign the informed consent to participate in this study at the visit immediately prior 
to the EXIT visit to ensure a supply of belimumab for the Day 0 visit in this study.  
Subjects in the treatment holiday and long-term discontinuation groups should sign the 
informed consent at the screening visit and Day 0 visit, respectively of this study.
Procedures necessary for the Day 0 visit of this protocol and for the last visit of the 
relevant SLE open-label continuation protocol, or the open-label period of BEL113750 
for China subjects, from which the subject is recruited need only be performed once. 
Results from Day 0 procedures that are duplicated in the relevant SLE continuation study 
will be recorded in the eCRF for that study and must also be transcribed to the relevant 
eCRFs in this study. Additional Day 0 procedures exclusive to this study will be recorded 
directly in the eCRFs for this study.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750. 
Change 16:  SELENA SLEDAI
This change affects Section 6.3.1.1 SELENA SLEDAI Score, Scoring for Proteinuria at 
Screening for Eligibility, first sentence.
Change from:
The proteinuria score for SELENA SLEDAI must be 0 at the most recent assessment 
performed in BEL114333.
To:
The proteinuria score for SELENA SLEDAI must be 0 at the most recent assessment 
performed in BEL114333 or in the open-label period of BEL113750 for China 
subjects.
Rationale:
Clarifies that China subjects will be recruited from the open-label period of study 
BEL113750. 
 
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Change 17:  SELENA SLEDAI
This change affects Section 6.3.1.2 Laboratory tests for SELENA SLEDAI, last sentence.
Change from:
Values outside the reference laboratory normal range that require the investigator’s 
assessment of relationship to SLE:
To:
Values outside the reference laboratory normal range require the investigator’s 
assessment of relationship to SLE.
Rationale:
Correction of typographical error.
Change 18: Safety
This change affects new Section 6.4.1.1, Liver Chemistry Stopping and Follow up 
Criteria, Additional Hepatitis B Monitoring.
Add:
Additional Hepatitis B Monitoring
Safety assessment for Hepatitis B during the trial will be as follows:

ALT and/or AST elevations of greater than 2.5 x ULN will require:

Sites to review blinded period screening laboratory results for anti-HBc:
o If screening anti-HBc result was reactive, then obtain HBV DNA.
o If HBV DNA returns reactive, withdraw subject from further treatment and 
enter follow up visit schedule.  Investigator will determine the extent of 
required attention for proper follow up of potential hepatitis B re-activation.
o If screening anti-HBc result was negative, then repeating hepatitis B testing 
is optional per investigator upon investigating for other causes.

Refer to the SPM for guidance on documenting the suspected reason for ALT 
and/or AST elevations of greater than 2.5 x ULN.
Rationale:
Additional hepatitis B monitoring was included in the BEL113750 China specific 
protocol amendment 04, which included obtaining a new HBV DNA test during the 
study, for China subjects with screening reactive anti- HBc but negative screening HBV 
DNA who enrolled, but found to have an ALT and/or AST elevation of 2.5 x ULN as part 
 
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of the new hepatitis B exclusion criterion #17 change in that protocol.  China subjects 
recruited from the open-label period of BEL113750 will continue to have this additional 
hepatitis B monitoring in this study BEL116027.
Change 19:  Pharmacogenetic Research
This change affects Section 6.7 Pharmacogenetic Research, first paragraph.
Change from:
Collect a blood sample for pharmacogenetics (PGx) from consenting subjects except 
those recruited from Study BEL114333 (who have already provided a sample as part of 
that study). Samples for PGx must be drawn prior to dosing as appropriate.
To:
Collect a blood sample for pharmacogenetics (PGx) from consenting subjects except 
those recruited from Study BEL114333 and except from the open-label period of 
BEL113750 for China subjects (who have already provided a sample as part of that 
study). Samples for PGx must be drawn prior to dosing as appropriate.
Rationale:
Obtaining PGx samples has already been addressed for subjects that have participated in 
studies BEL114333 and BEL113750 and PGx samples do not need to be obtained in the 
BEL116027study. 
Change 20:  Appendix 5:  Clinical Laboratory Tests
This change affects Section 11.5, Appendix 5, Clinical Laboratory Tests.
Add:
Hepatitis B Viral DNA PCR Quantitative (HBV DNA), BLyS Protein, ANA, aCL
Rationale:
Provide consistency of laboratory tests with the parent/feeder China specific BEL113750 
protocol amendment 04.
 
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SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL116027
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for BEL116027 A Phase IV, 
Open-label, Non-randomized, 52-Week Study to Evaluate 
Treatment Holidays and Rebound Phenomenon After 
Treatment with Belimumab 10 mg/kg in Systemic Lupus 
Erythematosus Subjects
Compound Number 
:
GSK1550188
Effective Date 
:
30-JAN-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol BEL116027.

This RAP is intended to describe the final analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete deliverable.
RAP Author(s):
Approver
Date
Approval Method
29-Jan-2019
email
Director, Clinical Statistics
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals:
Approver
Date
Approval Method
28-Jan-2019
email
Manager, Immuno-Inflammation, Clinical 
Programming
28-Jan-2019
email
Senior Director, Immuno-Inflammation, 
Clinical Development
28-Jan-2019
email
Manager, Immuno-Inflammation, Clinical 
Data Management
18-Jan-2019
email
Clinical Development Manager, Immuno-
Inflammation, PCPS
24-Jan-2019
email
Medical Writing Director, Immuno-
Inflammation, Clinical Development
22-Jan -2019
email
Director, CPMS
24-Jan -2019
email
SERM Director, II, GCSP
 
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BEL116027
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Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
Line Manager, Immuno-Inflammation, Clinical 
Programming
30-Jan-2019
Pharma TMF 
eSignature
Senior Director, Immuno-Inflammation, Clinical 
Statistics
On behalf of 
 (Line Manager, 
Immuno-Inflammation, Clinical Statistics)
30-Jan-2019
Pharma TMF 
eSignature
.
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................9
2.
KEY PROTOCOL INFORMATION ...........................................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objective(s) and Endpoint(s).............................................................11
2.3.
Study Design ..............................................................................................13
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................14
3.
PLANNED ANALYSES ..........................................................................................15
3.1.
Interim Analyses .........................................................................................15
3.2.
Final Analyses ............................................................................................15
4.
ANALYSIS POPULATIONS ...................................................................................16
4.1.
Protocol Deviations.....................................................................................16
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
5.1.
Study Treatment Descriptors ......................................................................17
5.2.
Parent Studies ............................................................................................17
5.3.
Baseline Definitions ....................................................................................17
5.3.1.
Baseline Definitions1....................................................................17
5.3.2.
Derivations and Handling of Missing Baseline Data.....................19
5.4.
Multicentre Studies .....................................................................................19
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................20
6.
STUDY POPULATION ANALYSES .......................................................................21
6.1.
Overview of Planned Demography, Baseline Characteristics and 
Medical History Analyses............................................................................21
6.2.
Baseline Disease Activity and Other Baseline Endpoints............................21
6.3.
Study Population Data for Maintenance Phase Subject Profile ...................24
7.
EFFICACY ANALYSES..........................................................................................25
7.1.
Primary Efficacy Analyses ..........................................................................25
7.1.1.
Endpoint / Variables.....................................................................25
7.1.2.
Summary Measure ......................................................................25
7.1.3.
Population of Interest...................................................................25
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................25
7.1.5.
Statistical Analyses / Methods .....................................................26
7.2.
Secondary Efficacy Analyses......................................................................26
7.2.1.
Endpoint / Variables.....................................................................26
7.2.1.1.
Rate of Flares.............................................................26
7.2.1.2.
First Severe SFI Flare ................................................26
7.2.1.3.
Rebound.....................................................................26
7.2.1.4.
SELENA SLEDAI Scores............................................26
7.2.2.
Summary Measure ......................................................................27
7.2.2.1.
Rate of Flares.............................................................27
7.2.2.2.
First Severe SFI Flare ................................................27
 
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7.2.2.3.
Rebound.....................................................................27
7.2.2.4.
SELENA SLEDAI Scores............................................27
7.2.2.5.
Changes in Corticosteroid Use ...................................27
7.2.3.
Population of Interest...................................................................27
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................27
7.2.4.1.
Rate of Flares and First Severe SFI Flare ..................27
7.2.4.2.
Rebound and SELENA SLEDAI Scores .....................28
7.2.4.3.
Changes in Corticosteroid Use ...................................28
7.2.4.3.1.
Number of days of daily 
prednisone dose ≥7.5 mg/day 
and/or increased by 25%........................28
7.2.4.3.2.
Number of days of daily 
prednisone dose ≤7.5 mg/day 
and/or decreased by 25%.......................28
7.2.5.
Statistical Analyses / Methods .....................................................28
7.3.
Exploratory Efficacy Analyses.....................................................................29
7.3.1.
Endpoint / Variables.....................................................................29
7.3.1.1.
Physician Global Assessment (PGA)..........................29
7.3.1.2.
SLICC/SDI..................................................................29
7.3.1.3.
Renal Flare.................................................................29
7.3.2.
Summary Measure ......................................................................29
7.3.2.1.
Physician Global Assessment (PGA) and 
SLICC/SDI..................................................................29
7.3.2.2.
Renal Flares...............................................................29
7.3.3.
Population of Interest...................................................................29
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................29
7.3.4.1.
Physician Global Assessment (PGA)..........................29
7.3.4.2.
SLICC/SDI..................................................................30
7.3.4.3.
Renal Flare.................................................................30
7.3.5.
Statistical Analyses / Methods .....................................................30
7.4.
Efficacy Data for Maintenance Phase Subject Profile .................................30
8.
SAFETY ANALYSES .............................................................................................31
8.1.
Adverse Events Analyses ...........................................................................31
8.2.
Adverse Events of Special Interest Analyses..............................................32
8.2.1.
Endpoint / Variables.....................................................................32
8.2.1.1.
Adverse Events of Special Interest.............................32
8.2.1.2.
Post-infusion systemic reactions by infusion...............32
8.2.2.
Summary Measure ......................................................................32
8.2.2.1.
Adverse Events of Special Interest.............................32
8.2.2.2.
Post-infusion systemic reactions by infusion...............33
8.2.3.
Population of Interest...................................................................33
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................33
8.2.5.
Statistical Analyses / Methods .....................................................33
8.3.
Clinical Laboratory Analyses.......................................................................33
8.3.1.
Endpoint / Variables.....................................................................34
8.3.1.1.
Clinical Laboratory Results.........................................34
8.3.1.2.
Clinical Laboratory Toxicity Grades ............................34
8.3.1.3.
Clinical Laboratory Reference Range Shifts ...............34
8.3.1.4.
Immunoglobulin Results Relative to the Lower 
Limit of Normal ...........................................................35
8.3.2.
Summary Measure ......................................................................35
 
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8.3.2.1.
Clinical Laboratory Results.........................................35
8.3.2.2.
Clinical Laboratory Toxicity Grades ............................35
8.3.2.3.
Clinical Laboratory Reference Range Shifts ...............35
8.3.2.4.
Immunoglobulin Results Relative to the Lower 
Limit of Normal ...........................................................35
8.3.3.
Population of Interest...................................................................35
8.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................35
8.3.5.
Statistical Analyses / Methods .....................................................35
8.4.
Other Safety Analyses ................................................................................36
8.4.1.
Endpoint / Variables.....................................................................36
8.4.1.1.
Immunogenicity ..........................................................36
8.4.1.2.
Vital signs...................................................................37
8.4.2.
Summary Measure ......................................................................37
8.4.2.1.
Immunogenicity ..........................................................37
8.4.2.2.
Vital signs...................................................................37
8.4.3.
Population of Interest...................................................................37
8.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................37
8.4.4.1.
Immunogenicity ..........................................................37
8.4.4.2.
Vital signs...................................................................38
8.4.5.
Statistical Analyses / Methods .....................................................38
8.5.
Safety Data for Maintenance Phase Subject Profile....................................38
9.
PHARMACOKINETIC ANALYSES.........................................................................39
9.1.
Primary Pharmacokinetic Analyses.............................................................39
9.1.1.
Endpoint / Variables.....................................................................39
9.1.2.
Summary Measure ......................................................................39
9.1.3.
Population of Interest...................................................................39
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................39
9.1.5.
Statistical Analyses / Methods .....................................................39
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................40
11. BIOMARKER ANALYSES......................................................................................41
11.1.
Primary Biomarker Analyses.......................................................................41
11.1.1.
Endpoint / Variables.....................................................................41
11.1.2.
Summary Measure ......................................................................41
11.1.2.1.
B-Cells........................................................................41
11.1.2.2.
Autoantibodies, Immunoglobulins and 
Complement...............................................................41
11.1.2.3.
BLyS Protein ..............................................................41
11.1.3.
Population of Interest...................................................................41
11.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................41
11.1.5.
Statistical Analyses / Methods .....................................................41
11.2.
Biomarker Data for Maintenance Phase Subjects.......................................42
12. REFERENCES.......................................................................................................43
13. APPENDICES........................................................................................................44
13.1.
Appendix 1: Protocol Deviation...................................................................44
13.2.
Appendix 2: Schedule of Activities ..............................................................45
13.2.1.
Protocol Defined Schedule of Events...........................................45
13.2.2.
Time and Events Table (Year 1) ..................................................45
 
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13.2.3.
Time and Events Table (Additional Years)...................................48
13.3.
Appendix 3: Assessment Windows .............................................................50
13.3.1.
Mapping of the Maintenance Phase Visits for Subjects 
with an Escape Visit.....................................................................50
13.3.2.
Mapping of Week 16 and 6-month Follow-up Visits .....................50
13.3.3.
Analysis Visit and Analysis Visit Number .....................................51
13.3.4.
Windows for Assessment of Post-injection/infusion 
sensitivity reactions (PISR) and hypersensitivity reactions 
(HSR) ..........................................................................................52
13.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................53
13.4.1.
Treatment Phases .......................................................................53
13.4.1.1.
Treatment Holiday Group ...........................................54
13.4.1.2.
Treatment Control Group............................................55
13.4.1.3.
Long-term Discontinuation Group...............................56
13.5.
Appendix 5: Data Display Standards & Handling Conventions....................58
13.5.1.
Reporting Process .......................................................................58
13.5.2.
Reporting Standards....................................................................58
13.5.3.
Reporting Standards for Pharmacokinetic....................................59
13.6.
Appendix 6: Derived and Transformed Data ...............................................60
13.6.1.
General........................................................................................60
13.6.2.
Study Population..........................................................................60
13.6.3.
Efficacy........................................................................................63
13.6.4.
Safety ..........................................................................................70
13.6.5.
Pharmacokinetic ..........................................................................71
13.6.6.
Biomarker ....................................................................................72
13.6.6.1.
Autoantibody, Complement, Immunoglobulins, 
and BLyS Protein .......................................................72
13.6.6.2.
B-cell Subsets ............................................................72
13.7.
Appendix 7: Reporting Standards for Missing Data.....................................76
13.7.1.
Premature Withdrawals................................................................76
13.7.2.
Handling of Missing Data.............................................................76
13.7.2.1.
Handling of Missing and Partial Dates ........................77
13.7.3.
Handling of Prohibited Medications, Withdrawals and 
Deaths.........................................................................................78
13.8.
Appendix 8: Values of Potential Clinical Importance ...................................79
13.8.1.
Laboratory Values........................................................................79
13.8.2.
Adverse Event and Laboratory Value Severity Grade 
Tables..........................................................................................80
13.9.
Appendix 9: Adverse Events of Special Interest..........................................89
13.9.1.
Malignant neoplasms...................................................................89
13.9.2.
Post-infusion systemic reactions..................................................90
13.9.3.
Infections .....................................................................................92
13.9.3.1.
Opportunistic Infections..............................................92
13.9.4.
Mycobacterium Tuberculosis .......................................................92
13.9.5.
Herpes Zoster..............................................................................92
13.9.6.
Pneumonia ..................................................................................92
13.9.7.
Sepsis..........................................................................................92
13.9.8.
Depression/suicide/self-injury ......................................................92
13.9.8.1.
Depression (excluding suicide and self-injury)............92
13.9.8.2.
Suicide and Self-Injury................................................93
13.9.9.
Fatalities ......................................................................................93
 
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13.9.10. GSK SRT Adjudication of Adverse Events of Special 
Interest ........................................................................................93
13.9.10.1. Malignancies ..............................................................93
13.9.10.2. Serious hypersensitivity and post-infusion 
systemic reactions......................................................94
13.9.10.3. Potential opportunistic infections ................................94
13.9.10.4. Suicide/self-injury .......................................................96
13.9.10.5. Fatalities.....................................................................96
13.10. Appendix 10: Abbreviations & Trade Marks ................................................97
13.10.1. Abbreviations...............................................................................97
13.10.2. Trademarks .................................................................................98
13.11. Appendix 11: List of Data Displays..............................................................99
13.11.1. Data Display Numbering..............................................................99
13.11.2. Deliverables.................................................................................99
13.11.3. Study Population Tables............................................................100
13.11.4. Study Population Figures...........................................................101
13.11.5. Efficacy Tables ..........................................................................102
13.11.6. Efficacy Figures .........................................................................103
13.11.7. Safety Tables.............................................................................104
13.11.8. Safety Figures ...........................................................................110
13.11.9. Pharmacokinetic Tables.............................................................111
13.11.10.Pharmacokinetic Figures ...........................................................112
13.11.11.Biomarker Tables.......................................................................112
13.11.12.Biomarker Figures .....................................................................115
13.11.13.ICH Listings ...............................................................................117
13.11.14.Non-ICH Listings........................................................................120
13.12. Appendix 12: Example Mock Shells for Data Displays ..............................121
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 116027:
Revision Chronology:
2012N154810_00
22-Aug-2013
Original
2012N154810_01
04-Oct-2013
Amendment 01
2012N154810_02
14-Jan-2014
Amendment 02 
2012N154810_03
01-Apr-2014
Amendment 03
2012N154810_04
31-Aug-2015
Amendment 04
2012N154810_05
03-Dec-2015
Amendment 05
2012N154810_06
12-Sep-2017
Amendment 06
2.
KEY PROTOCOL INFORMATION
A total of approximately 71 subjects (10 in the treatment holiday group, 26 in the 
treatment control group, and 35 in the long-term discontinuation group) will be enrolled 
in this study.  The total sample size is based on practical considerations on the availability 
of subjects from other ongoing belimumab studies, rather than on statistical 
considerations.  Since this is a non-randomized study, results will be descriptive only, and 
not intended to be inferential.  No power calculations were made in the determination of 
sample size for this study.  However, the total of subjects is expected to provide adequate 
information to characterize time to SLE flare.
Table 1
Flare Rates from Pooled BLISS Studies
ISE Table
Analysis
Placebo
1 mg/kg
10 mg/kg
T57
Percentage of Subjects 
with Flare Over 52 
Weeks
81.5%
74.6%
74.6%
TAC411
Percentage of Subjects
with Flare Over 52 
Weeks Post Week 24
68.5%
54.7%
57.5%
TAC613
Percentage of Subjects 
with Flare Over 52 
Weeks Among SRI Wk
52 Responders
73.4%
69.8%
67.4%
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 2.
 
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Table 2
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Partial prothrombin time (PTT) is 
collected

Activated partial 
prothrombin time (aPTT) 
time is analyzed

aPTT was collected instead of 
PTT

Section 8.1.3 states that for the 
primary analysis of the additional 
efficacy and biomarkers, the 
baseline will be defined as study 
Day 0 of the original parent 
study. Additionally, for some of 
the endpoints, a secondary 
analysis will be performed by 
defining the baseline as Day 0 of 
the BEL116027 study.

The baseline for each 
endpoint is defined per 
Section 6.1 of the protocol.
.

The protocol was inconsistent 
in the definition of baseline.
See RAP Section 5.3 for 
clarification

Immunogenicity is listed as a 
secondary endpoint in Protocol 
Section 6.1.2., but as an 
exploratory laboratory parameter 
in the Time and Events table.

Immunogenicity is defined 
as a secondary endpoint.

The protocol was inconsistent, 
so the correct category was 
used in the RAP.

Renal flares are not listed as an 
endpoint in Protocol Section 
6.1.2 nor described in Protocol 
Section 8, but are defined in 
Protocol Section 6.1.4

Renal flares are included as 
an exploratory endpoint in 
RAP Section 2.2.

The protocol was inconsistent, 
so the endpoint was correctly 
specified in the RAP.

The definition of renal flare 
contained a typographical error 
and referenced an increase 
rather than a decrease in GFR.  
This was corrected in a note to 
file.

The RAP specifies the 
correct definition, 
referencing a decrease in 
GFR.

The protocol was incorrect.

Protocol Section 6.1.3 lists 
percent change in PGA.

The RAP specifies change 
from baseline in PGA 
instead.

Change from baseline is more 
clinically relevant and 
interpretable, particularly in 
the case of low baseline 
scores.

Protocol Section 6.1.2 lists one 
time interval for percent change 
in B-cell subsets from Week 24, 
i.e., Week 24 to 52. 

In addition to this, the RAP 
specifies percent change 
from Week 24 to 32 and 
Week 24 to 40.

The additional time intervals 
facilitate interpretation of the 
changes following the 
treatment holiday phase.

The protocol Section 6.1.2 does 
not list the CD19+ B-cell subset.

The RAP adds the CD19+ 
B-cell subset.

This subset is collected and 
clinically important.

The protocol Section 6.1.3 Other 
Endpoints includes percent 
change in prednisone dose and 
percent of subjects with 
prednisone dose reduced to 
<7.5mg/day from ≥7.5mg/day..

These two exploratory 
endpoints were not 
analysed

The two secondary 
prednisone endpoints
(Protocol Section 6.1.2) will 
be analysed as they are most 
descriptive in that they assess 
daily prednisone use. Given 
the reduced sample size from 
 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
the original protocol, these two 
endpoints allow sufficient 
evaluation of the impact of the 
treatment holiday.

Section 6.1.2 lists percent 
change from baseline in B-Cells, 
immunoglobulins and auto-
antibodies 

Change from baseline will 
also be presented for these 
parameters.

Change from baseline added 
based on regulatory feedback 
on other studies in the 
belimumab development 
program.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

Characterize the efficacy of a 
24-week withdrawal followed by 
a 28-week reintroduction of 
intravenous belimumab therapy 
compared with uninterrupted 
intravenous belimumab therapy 
for 52 weeks in subjects with low 
SLE disease activity receiving 
belimumab 10 mg/kg plus 
standard of care, as measured 
by time to first flare.

Time to any SLE Flare Index flare.
Secondary Objectives
Secondary Endpoints

Evaluate the rate of any flare.

Rate of any SLE Flare Index flare per subject year.

Time to first SLE Flare Index severe flare.

Assess safety.

Adverse events

AESI

Laboratory parameters

Vital signs

Assess SLE disease activity.

Number of subjects in the treatment holiday and long-term 
discontinuation group with evidence of rebound (defined as 
a SELENA SLEDAI score during the first 24 weeks that 
exceeds the baseline SELENA SLEDAI score in the 
subjects’ respective original parent study).

SELENA SLEDAI scores change from baseline.

Assess immunogenicity.

Response (Negative, Transient Positive, Persistent Positive) 
by Visit and Across All Visits

Assess markers of autoimmune 
response (e.g., 
immunoglobulins, complement.)

Change and Percent change from baseline in IgG, IgM, IgA, 
anti-dsDNA, ANA, C3, and C4.

Shifts from baseline in IgG, IgM, IgA, anti-dsDNA, ANA, C3 
and C4.

Change and Percent change in absolute B cell subsets 
 
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Objectives
Endpoints
(CD19+, CD20+, CD20+/27+ memory, CD20+/27– naïve, 
CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ 
plasma cells) at Weeks 0, 8, 16, 24, 32, 40 and 52 and from 
Weeks 24 to 52.

Assess changes in 
corticosteroid use.

Number of days of daily prednisone dose 7.5 mg/day 
and/or increased by 25% from Day 0 of this study to Week 
24, from Day 0 of this study to Week 52, and from Week 24
to Week 52.

Number of days of daily prednisone dose 7.5 mg/day 
and/or decreased by 25% from Day 0 of this study to Week 
24, from Day 0 of this study to Week 52, and from Week 24 
to Week 52.
Exploratory/Other
Exploratory/Other Endpoints

Time to first renal flare

Time to first renal flare among subjects with baseline 
proteinuria >0.5g/24hr equivalent

Change from Baseline in PGA

Change and percentage change from Baseline in BLyS 
Protein

SLICC/SDI

Change from Baseline
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

A phase IIIB, multi-center open-label, non-randomized study.
Dosing

Treatment Holiday (TH) group: Temporary discontinuation 
(24 weeks) and re-introduction of belimumab 10 mg/kg 
therapy. The target enrolment for this group is 10 subjects.

Treatment Control (TC) group: Continued treatment with 
belimumab 10 mg/kg. The target enrolment for this group is 
26 subjects.

Long-term Discontinuation (LTD) group: Discontinued 
therapy with belimumab 10 mg/kg and are expected to remain 
off belimumab therapy for at least 12 months but remain on 
standard of care therapy. The target enrolment for this group is 
35 subjects.
Time & Events

Refer to Appendix 2: Schedule of Activities
Treatment Assignment

Non-randomized, open label
Interim Analysis

The protocol indicated that an interim analysis of the 
data in this trial may be performed to support a 
submission to regulatory authorities relating to 
marketing authorization (e.g., to summarize and submit 
 
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Overview of Study Design and Key Features
this long-term safety data to regulatory authorities in the 
initial BLA and other marketing authorization 
submissions). Additional interim analyses may be 
required to support subsequent safety updates to 
regulatory authorities. No interim analyses were conducted.
Sample Size

The total target sample size was 71 subjects and 80 were 
enrolled.  The target sample size for subjects in the treatment 
holiday and control groups was 10 (12 enrolled) and 26 (29 
enrolled) subjects respectively.  A target sample size of 35 (39 
enrolled) subjects in the long-term discontinuation group was
anticipated. .
Note:  Subjects from China participated in BEL113750 OL phase rather than in BEL114333,and were therefore eligible 
to enter BEL116027 from BEL113750 OL, per a China country-specific protocol amendment 01.
2.4.
Statistical Hypotheses / Statistical Analyses
Since this is a non-randomized study, results will be descriptive only, and any 
comparisons are not intended to be inferential. 
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
The protocol indicated that an interim analysis of the data in this trial may be performed 
to support a submission to regulatory authorities relating to marketing authorization (e.g., 
to summarize and submit this long-term safety data to regulatory authorities in the initial 
BLA and other marketing authorization submissions). Additional interim analyses may 
be required to support subsequent safety updates to regulatory authorities. No interim 
analyses were conducted. 
The SRT performs in stream adjudication of subject-level safety data for Adverse Events 
of Special Interest (AESIs; serious and non-serious) in accordance with the GSK 
Standard Operating Procedures (SOPs) and the belimumab Program Safety Analysis Plan 
(PSAP). AESIs include malignancy; serious hypersensitivity and post-infusion systemic 
reactions; potential opportunistic infections; other infections of interest but not generally 
considered opportunistic i.e. Mycobacterium Tuberculosis and Herpes Zoster; 
suicide/self-injury; and fatalities.
AESIs are flagged in the clinical trial database, according to SRT adjudication.  The SRT 
performs a periodic review of instream study data (at least every 6 months), reviewing 
the cumulative incidence of AEs, SAEs, and adjudicated AESIs.  These periodic reviews 
of cumulative adverse event incidence are compared with previous SRT reviews and 
where appropriate, the pivotal SLE pooled data to assess for any new safety signals.
3.2.
Final Analyses
The final planned primary analyses will be performed after the database cleaning 
activities have been completed and final database release and database freeze has been 
declared by Data Management:
database cleaning activities have been completed and final database release and database 
freeze has been declared by Data Management.
In this open-label, non-randomized study, for dispensing of study drug, randomisation 
codes have been distributed according to RandAll NG procedures.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprises all subjects who enroll in the study, 
including screen failures

Study population
Intent-To-Treat 

Comprises all subjects who enroll in the study, 
excluding screen failures.

Study population

Efficacy

Safety

Biomarker
PK

Comprises all subjects included in the ITT 
population for whom at least one post 
belimumab treatment PK sample was obtained 
and analyzed.  

PK
1.
NOTES: 

Please refer to Appendix 11: 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 identified 
in the Protocol Deviation Management Plan (PDMP).
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the PDMP.

Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 

This dataset will be the basis for the summaries and listings of protocol 
deviations.
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Group 
Code
Group Description
Description
Order [1]
3
Long Term Discontinuation Group
Long-term Discontinuation
1
2
Control Group
Treatment Control
2
1
Treatment Holiday Group
Treatment Holiday
3
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.  Some Tables will only present TC and TH 
groups.
2.
In applicable data listings, Screen Failures will be presented first followed by LTD, TC and TH.
5.2.
Parent Studies
Subjects were eligible to enter BEL116027 from one of four continuation studies, having 
entered the continuation study from a respective parent study. The possible study 
participation sequences are as follows:
Parent Study
Continuation Study
Subjects
BEL113750 DB1
BEL113750 OL1
Subjects from China
BEL1123412
BEL114333
Some subjects from Japan
BEL113750
BEL114333
Subjects from Korea and some subjects from Japan
BEL110751
BEL112233 (C1066)
Subjects from US
LBSL02
LBSL99 (BEL112626)
Subjects from US
1.
BEL113750 was both the parent and continuation study number for subjects enrolled in China.
2.
Subjects from Japan who participated in study BEL112341 were eligible to enrol into the BEL114333 
continuation phase per a BEL114333 protocol amendment, to allow them continued access to study agent 
until belimumab was commercially available in Japan.
5.3.
Baseline Definitions
5.3.1.
Baseline Definitions1
The baseline (BL) definition is dependent upon the endpoint being analyzed.

For the SELENA SLEDAI (including rebound), immunoglobulins, auto-
antibodies, complement, BLyS and B-cell endpoints, baseline is defined as the 
Day 0 assessment in the subject’s respective parent study, prior to exposure with 
study treatment (whether placebo or belimumab). Baseline data for these 
 
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parameters will be extracted from the ADaM data sets from the double blind 
study (LBSL02, BEL110751, BEL113750 or BEL112341)from which the 
patients are enrolled.

For the SLE flares, SLE severe flares, SLICC, prednisone (7 day average prior 
to Day 0), PGA, and immunogenicity2, endpoints, baseline is the Day 0 
assessment in BEL116027.

For other endpoints, baseline is the Day 0 assessment in BEL1160272.
1Feeder study BEL114333 database had not yet completed at the time of BEL116027 
Last Patient Last Visit. Consequently, baseline data for BEL114333 patients has not 
been fully cleaned when extracted from that study’s database for reporting.
2Assessments covered for both Day 0 in BEL116027 and the Exit/Follow-up visit of 
the feeder continuation studies were only to be performed once and were to be 
recorded in the appropriate case report forms for each study. For Day 0 values not 
recorded in BEL116027 CRF but exist in the feeder study, the data will be extracted 
from the appropriate feeder study for inclusion in analysis
In the displays, the baseline value/visit will be denoted as Baseline.
See Section 13.4.1 for a diagram depicting the baseline definitions and phases.
 
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5.3.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
and determine the maximum change
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 5.3.1 Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and baseline will be set to 
missing.
5.4.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site, and in 
selected displays by country and investigative site.
Since this is a non-randomized study, results will be descriptive only, and there will be no 
methods applied to address multiple centers.
 
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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
13.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
13.2
Appendix 2: Schedule of Activities
13.3
Appendix 3: Assessment Windows
13.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
13.5
Appendix 5: Data Display Standards & Handling Conventions
13.6
Appendix 6: Derived and Transformed Data
13.7
Appendix 7: Reporting Standards for Missing Data
13.8
Appendix 8: Values of Potential Clinical Importance
13.9
Appendix 9:  Adverse Events of Special Interest
13.11
Appendix 10: Abbreviations & Trade Marks
13.12
Appendix 11: List of Data Displays
13.12
Appendix 12: Example Mock Shells for Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Demography, Baseline Characteristics
and Medical History Analyses
The study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, medical conditions, prior and 
concomitant medications, and exposure and treatment compliance will be based on the 
ITT population, or for the Screened population where specified.  Data will be presented 
by treatment group and for all subjects combined, unless otherwise specified.
Full details of data displays being presented in Appendix 11: List of Data Displays.
Completion and withdrawal status by treatment phase is defined in Section 13.6.2.
6.2.
Baseline Disease Activity and Other Baseline Endpoints
A summary of baseline disease activity will be provided, including counts and 
percentages for categorical endpoints and descriptive statistics for the continuous 
endpoints and scores.
Table 3 provides indicators of baseline disease activity that will be summarized.  Some of 
these parameters will be summarized on the by visit summary for that parameter 
according to the table specifications.
 
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Table 3
Baseline Disease Activity Endpoints
Endpoint
Categories & Summaries at Baseline
SELENA-SLEDAI category
Continuous
Categorical

0, 1, 2, 3
SELENA SLEDAI by organ domain 
and item at baseline
Categorical

Presented if Yes
Complement & BLyS Levels 
Complement C3 and C4 (mg/dL)
Continuous
Categorical

Positive, Negative

Low, Normal, High
(See Section 13.6.6 for definitions)
BLyS Protein [ng/mL]
Continuous
Categorical

Below LLOQ: <0.061 ng/mL for China samples and 
<0.02048 ng/mL for all others
SLE Flare Index
Categorical

At least 1 flare, At least 1 severe flare  
PGA  
Continuous
Categorical

0-1, >1 – 2.5, > 2.5
SLICC/ACR Damage Index
Continuous
Categorical
0, 1, > 1
 
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Endpoint
Categories & Summaries at Baseline
Proteinuria (based on spot urine using 
protein: creatinine mg/mg ratio)
Continuous
Categorical (units are g/24hr equivalent)
≤ 0.5, > 0.5
Subcategories of > 0.5 

>0.5 - < 1

1 - < 2

≥ 2
B cells: 
CD19+
CD20+
CD20+/27+ memory
CD20+/27– naïve
CD20+/69+ activated
CD20+/138+ plasmacytoid
CD19+/27BRIGHT/38BRIGHT SLE subset
CD20-/138+ plasma
Continuous
Autoantibody Levels
Anti-dsDNA [IU/mL]
Continuous
Categorical

Positive: >=30 IU/mL

Negative: <30 IU/mL
ANA [Titer]
Continuous
Categorical
Positive: Index >=0.80
Negative: Index <0.80
aCL Status
Categorical
Positive, Negative, Missing (See Section 13.6.6 for 
definitions)
anti-dsDNA and/or ANA positive 
Categorical

Yes, No
Immunoglobulin Levels (IgG, IgA, and 
IgM [g/L])
Continuous
Categorical
IgG

Low:  < 6.94 g/L, High:  > 16.18 g/L
IgM
Low: < 0.48 g/L, High:  > 2.71 g/L  
IgA

Low:  < 0.81 g/L, High:  > 4.63 g/L
 
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Endpoint
Categories & Summaries at Baseline
Allowable SLE Medication Usage
Categorical:

Steroid Only

Immunosuppressant Only

Anti-malarial Only

Steroid and Immunosuppressant Only

Steroid and Anti-Malarial Only

Immunosuppressant and Anti-Malarial Only

Steroid and Immunosuppressant and Anti-malarial

Traditional Chinese Medicine - Glycosides of 
Paeony/Tripterygium
Average daily prednisone dose 
(mg/day) at baseline
Continuous
Categorical

0, >0 to ≤7.5, >7.5
PT/aPTT
Continuous
6.3.
Study Population Data for Maintenance Phase Subject 
Profile
Basic demography information will be listed on the subject profile.
 
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7.
EFFICACY ANALYSES
For all efficacy analyses, results for the TH group will be presented for the treatment 
holiday (TH) and re-start (RS) phases separately.
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The time to the first SFI flare over 52 weeks will be estimated for the treatment groups 
using the product-limit method. 
Analyses of SFI flare (defined as mild, moderate, or severe) will be performed on the 
SELENA SLEDAI SLE flare index. Note: Flares in this study are analysed using the 
modified SLE flare index where severe flares that are triggered only by an increase in 
SELENA SLEDAI score to greater than 12 are not categorized as severe in the analysis.
7.1.2.
Summary Measure
Only post-baseline flares will be considered in these analyses.  Flares (not subjects) 
occurring on the Day 0 visit date should be removed from the analysis set prior to 
determining the first flare.
Data observed at or prior to the baseline visit (see Section 5.3.1) will not be included in 
this analysis.  
Time to first SFI flare is defined as the number of days from baseline date (see Section 
5.3.1) to the date the subject has a flare (event date – baseline visit date + 1). 
See Section. 13.6.3 for additional details.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on ITT population.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
The disposition of subjects as it relates to intercurrent events is defined as follows:
Subject Disposition
Event 
Met
Event Date [2]
Subject has a SFI flare or takes a prohibited medication
Subject has a SFI flare during the study 
[1]
Yes
Date of first SFI flare
Subject takes a prohibited medication [1]
Yes
Date of prohibited medication
Subject does not have a SFI flare and did not take a prohibited medication.
Subject withdraws from the study or is 
lost to follow-up
No
Censored at last available date where 
flare is assessed.
Subject dies during the study
No
Censored at date of death.
 
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Subject completes the study
No
Censored at last study visit where flare is 
assessed.
[1] If a subject has a SFI flare and takes a prohibited medication, the event date is the earliest of 
the first SFI flare date and takes a prohibited medication date.
[2] If a subject meets multiple criteria, then the event date is the earliest date.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
The table will display the number and percentage of subjects with a SFI flare, as well as 
the median, 25th, and 75th percentile of days to first SFI flare, estimated using the 
product-limit method.  For subjects who experience a SFI flare, the study day of the SFI 
flare will be summarized and the table will display the median, 25th and 75th percentiles 
and minimum and maximum.
A cumulative incidence curve for time to first SFI flare will also be produced for the 52-
week treatment phase.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
7.2.1.1.
Rate of Flares
The unadjusted rate of flares per subject-year over 52 weeks will be summarized by 
treatment group.
7.2.1.2.
First Severe SFI Flare
The time to the first severe SFI flare over 52 weeks will be estimated for the treatment 
groups using the product-limit method.
7.2.1.3.
Rebound
Rebound is defined as a SELENA SLEDAI score during the first 24 weeks that exceeds 
the baseline SELENA SLEDAI score in the subject’s respective original parent study.
7.2.1.4.
SELENA SLEDAI Scores
SELENA SLEDAI assessments consist of 24 individual weighted items in which signs 
and symptoms, laboratory tests, and physician’s assessment for each of 8 organ systems 
are given a weighted score and summed if present (marked ‘Yes’) at the time of the visit 
or in the preceding 10 days. The maximum theoretical score is 105 (all 24 descriptors 
 
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present simultaneously) with 0 indicating inactive disease (marked ‘No’), but in practice 
few subjects have scores > 45 [Buyon, 2005; Petri, 2005]. 
See Section 13.6.3 for further details.
7.2.2.
Summary Measure
7.2.2.1.
Rate of Flares
The total number of flares, total subject-years of follow-up in the time interval, and the 
unadjusted rate per subject-year will be presented.
7.2.2.2.
First Severe SFI Flare
See Section 7.1.2.
7.2.2.3.
Rebound
The frequencies and percentages of subjects who rebound will be presented by visit 
through the Week 24 visit, and at any time during the first 24 weeks.
7.2.2.4.
SELENA SLEDAI Scores
Summary statistics for the change from baseline in SELENA SLEDAI scores will be 
presented at each visit in the 52-week treatment phase.
7.2.2.5.
Changes in Corticosteroid Use
The frequencies and percentages of subjects who meet each definition will be presented 
at each visit in the 52-week treatment phase. Steroid doses will be converted to the 
prednisone-equivalent dose per the derivations in Section. 13.6.3
7.2.3.
Population of Interest 
The secondary efficacy analyses for all endpoints will be based on the ITT population.
For rebound, the analysis also will be performed by the SELENA SLEDAI score at the 
BEL116027 Day 0 visit, categorized as ≤3 and >3. 
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
7.2.4.1.
Rate of Flares and First Severe SFI Flare
See Section 7.1.4. 
If a subject withdraws from the study, dies or takes a prohibited medication, the subject 
will be considered as having a SFI flare.
 
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7.2.4.2.
Rebound and SELENA SLEDAI Scores
Missing data will be imputed using the principle of Last Observation Carried Forward 
(LOCF).  For the TH group, LOCF will not be applied across the TH and RS phases.  If 
an individual SS item data is missing at the first timepoint in the RS phase, the item will 
be considered not present.  
7.2.4.3.
Changes in Corticosteroid Use
7.2.4.3.1.
Number of days of daily prednisone dose ≥7.5 mg/day and/or increased 
by 25% 
The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) imputation will be 
applied.  If a subject withdraws from the study and/or receives a protocol-prohibited 
medication, the subject will be considered to have met this endpoint criteria (i.e, dose ≥ 
7.5 mg/day and/or increased by 25%) after the date of dropout or the date that the 
medication is started, whichever comes first, up until the visit date, and for those days in 
intervals for subsequent attended visits. Before this date, the evaluated endpoint will be 
assessed using available data.  
7.2.4.3.2.
Number of days of daily prednisone dose ≤7.5 mg/day and/or 
decreased by 25%
The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) imputation will be 
applied.  If a subject withdraws from the study and/or receives a protocol-prohibited 
medication, the subject will be considered a non-responder for this endpoint criteria (i.e., 
dose >7.5 mg/day and/or did not decreased by 25%) after the date of dropout or the date 
that the medication is started, whichever comes first, and for those days in intervals for 
subsequent attended visits. Before this date, the evaluated endpoint will be assessed using 
available data.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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7.3.
Exploratory Efficacy Analyses
7.3.1.
Endpoint / Variables
7.3.1.1.
Physician Global Assessment (PGA)
The change from baseline in PGA score will be assessed at each visit in the 52-week 
treatment phase.  See Section. 13.6.3 for additional details on the instrument.
7.3.1.2.
SLICC/SDI
The change from baseline in SLICC/SDI score will be assessed at each visit in the 52-
week treatment phase.
7.3.1.3.
Renal Flare
The time to the first renal flare over 52 weeks will be estimated for the treatment groups 
using the product-limit method. See Section 13.6.3 for additional details.
7.3.2.
Summary Measure
7.3.2.1.
Physician Global Assessment (PGA) and SLICC/SDI
These endpoints will be analyzed using summary statistics.
7.3.2.2.
Renal Flares
Only post-baseline renal flares will be considered in these analyses.  Renal flares (not 
subjects) occurring on the Day 0 visit date should be removed from the analysis set prior 
to determining the first renal flare.
Data observed at or prior to the baseline visit (see Section 5.3.1) will not be included in 
this analysis.  
Time to first renal flare is defined as the number of days from baseline date (see Section 
5.3.1) to the date the subject has a renal flare (event date – baseline visit date + 1).
7.3.3.
Population of Interest 
The analyses for all exploratory endpoints will be based on the ITT population.
For renal flares, the analysis will be repeated for subjects with baseline proteinuria 
proteinuria >0.5g/24hr equivalent.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
7.3.4.1.
Physician Global Assessment (PGA)
Missing data will be imputed using LOCF.  For the TH group, LOCF will not be applied 
across the TH and RS phases.
 
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7.3.4.2.
SLICC/SDI
Missing data due to study withdrawal will be imputed using LOCF. For the TH group, 
LOCF will not be applied across the TH and RS phases.
The SLICC/ACR Damage Index increases over time. Once a subject meets the criteria for 
positive scoring of an item, that item should always be marked as present, even if the 
subject subsequently recovered.  
In the event the SLICC/ACR Damage Index is scored inconsistently (a decrease relative 
to previous items has occurred) and the data are unable to be queried and/or corrected, a 
worst observation carried forward (WOCF) approach will be used at the item level for the 
SLICC/ACR Damage Index questions.  These WOCF values will then be used to 
calculate the total score which will be the value summarized and displayed for reporting.
7.3.4.3.
Renal Flare
The disposition of subjects as it relates to intercurrent events is defined as follows:
Subject Disposition
Event Met
Event Date [2]
Subject has a renal flare or takes a prohibited medication
Subject has a renal flare [1]
Yes
Date of first renal flare
Subject takes a prohibited 
medication [1]
Yes
Date of prohibited medication
Subject does not have a renal flare and did not take a prohibited medication
Subject withdraws
No
Censored at last flare 
assessment date
Subject dies
No
Censored at date of death
Subject completes 
No
Censored at the Week 52 
study visit
[1] If a subject has a renal flare and takes a prohibited medication, the event date is the earliest of 
the first renal flare date and takes a prohibited medication date.
[2] If a subject meets multiple criteria, then the event date is the earliest date.
7.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.4.
Efficacy Data for Maintenance Phase Subject Profile
Flare data will be listed on the subject profile.
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the ITT population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), serious adverse 
events (SAEs), and other significant AEs will be based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 11: List of Data Displays.
Adverse events will be coded to the current MedDRA dictionary version available at the 
time of reporting.
Only treatment emergent AEs will be summarized (see Section 13.4.1).  Any AEs that 
were ongoing in the upon entry into this will be listed and flagged with a footnote  
An overall summary of AEs will be presented showing the number (%) of subjects with 
at least one of the following: AE, related AE, SAE, severe AE, SAE and/or severe AE, 
AE resulting in study treatment discontinuation, and deaths. 
The number of events and the number (%) of subjects experiencing an AE by SOC, SOC 
and PT, and PT will be summarized for each of the AE categories below.

All

Serious

Severe

Study agent Related

Resulting in discontinuation of study treatment
The data will be sorted by overall decreasing frequency of the SOC, by overall 
decreasing frequency of the SOC and then decreasing frequency of PT within the SOC, 
and by overall decreasing frequency of the PT, as applicable. Only SOCs with observed 
AE PTs will be presented. If the frequency for any two or more adverse events is equal, 
the events will be presented in alphabetical order by SOC/PT as applicable.
Summaries of AEs frequency by SOC and severity will also be provided.  For these 
displays, the number and percentage of subjects will be summarized as mild, moderate, or 
severe based on the maximum severity observed across all PTs within the SOC for a 
given subject.
The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text will be 
displayed in a table for all AEs.
A listing of which subjects reported each AE will be produced.  AEs will be grouped and 
sorted by SOC and PT. A listing of Infusion Related Systemic Reactions will be 
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8.2.
Adverse Events of Special Interest Analyses
8.2.1.
Endpoint / Variables
8.2.1.1.
Adverse Events of Special Interest
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
Adverse events of special interest for belimumab have been identified over the course of 
the development program. The Benlysta Program Safety Analysis Plan (PSAP) includes 
the definitions and adjudication criteria for the AESI.  The definitions are based on 
standard and custom MedDRA queries (SMQs and CMQs).  Categorizations for the 
AESI are listed in Section 13.9.
GSK will adjudicate neoplasms of unspecified malignancy, opportunistic infections, 
herpes zoster, serious suicide, and serious PISR events as described in the PSAP. In 
addition, GSK will review malignancy events to prevent counting an event multiple times 
in the case where a given malignancy has multiple events (e.g., a diagnostic test and the 
diagnosis).  GSK will review all fatal events and assign a category of death.
8.2.1.2.
Post-infusion systemic reactions by infusion
For the TH group in the RS phase, summaries of post-infusion systemic reactions will be 
presented by the first six infusions in the RS phase and PT for the following categories:

Post-Infusion Systemic Reactions per Anaphylactic Reaction CMQ broad search (on 
the day of the infusion or within 3 days after the infusion)

Serious Post-Infusion Systemic Reactions per Anaphylactic Reaction CMQ broad 
search (on the day of the infusion or within 3 days after the infusion)

Serious Acute Post-Infusion Systemic Reactions/Hypersensitivity per GSK 
adjudication

Serious Delayed Acute Hypersensitivity Reactions per GSK adjudication

Serious Delayed Non-Acute Hypersensitivity Reactions per GSK adjudication
8.2.2.
Summary Measure
8.2.2.1.
Adverse Events of Special Interest
An overall summary of AESIs by category will be presented, and each specific category 
of AESI will be presented separately by PT.  The number and percentage of subjects with 
at least one occurrence and the number of events will be presented. 
 
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Infection AESIs that are serious, severe, serious/severe, and that lead to discontinuation 
will be presented by category and PT.
8.2.2.2.
Post-infusion systemic reactions by infusion
The number and percentage of subjects with at least one occurrence and the number of 
events will be presented.
8.2.3.
Population of Interest 
The analyses will be based on the ITT population.
8.2.4.
Strategy for Intercurrent (Post-Randomization) Events
For both endpoints, observed data will be used with no imputation.
8.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
An issue was identified at Q2 Solutions (central lab) in Valencia, California, USA, 
regarding equipment malfunction which affected some serum creatinine results reported 
from one of the analyzers used at the lab.  Unusually high serum creatinine results were 
noted for two different GSK clinical trials, and further investigation revealed one of the 
analyzers had been producing intermittent high serum creatinine results between 01 
October 2016 to 13 January 2017, potentially due to an intermittent wash line blockage of 
the analyzer.  BEL116027 investigators were notified of this issue by a Dear Investigator 
Letter (DIL) 22 February 2017.  The subsequent evaluation concluded that there was no 
impact on data integrity and patient safety for clinical trial BEL116027.  Therefore, there 
will be no modification to the analysis of serum creatinine. BEL116027 investigators 
were notified by a follow up DIL dated 25 July 2017, and the root cause was identified as 
a sporadic failure of the wash system due to debris causing intermittent obstruction.
Baseline is defined as described in Section 5.2.
A list of laboratory parameters collected and definition of the toxicity grades are provided 
in Appendix 8: Values of Potential Clinical Importance.
Listings will be generated for all laboratory results, and additionally for Grade 3 or Grade 
4 laboratory toxicity results.
 
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Line graphs will be produced for each analyte displaying the mean value by visit and 
treatment group.
8.3.1.
Endpoint / Variables
8.3.1.1.
Clinical Laboratory Results
Laboratory parameters which are continuous numeric values will be analyzed using 
summary statistics, and those with categorical results will be summarized using 
frequencies and percentages.
8.3.1.2.
Clinical Laboratory Toxicity Grades
The endpoints evaluated will be:

Worst toxicity grade

Worsening by at least 2 toxicity grades 
Toxicities will be reported as derived by the central laboratory, as protocol toxicity 
grading was applied.
For potassium, glucose, calcium, and sodium, toxicities are bi-directional (i.e., high and 
low directions) and both will be summarized by name of the toxicity.

Potassium:  hypokalemia, hyperkalemia

Glucose:  hypoglycemia, hyperglycemia

Calcium:  hypocalcemia, hypercalcemia

Sodium:  hyponatremia, hypernatremia
For example, calcium will have two toxicity sections, one for hypocalcemia and one for 
hypercalcemia and mapped to their high or low form as:

RESULT < (LLN+ULN)/2 = “Hypo” toxicity

RESULT > (LLN+ULN)/2 = “Hyper” toxicity
8.3.1.3.
Clinical Laboratory Reference Range Shifts
For laboratory tests without toxicity grades, shifts relative to the normal range will be 
summarized for each analyte as shifts ‘to low’ and shifts ‘to high.’
For the ‘to low category’ the percentage of subjects with at least one low post-baseline 
value relative to the baseline (i.e. baseline and post baseline data available) will be 
displayed using the categories:  no shift to low and normal/high to low. 
For the ‘to high category’ the percentage of subjects with at least one high post-baseline 
value relative to baseline (i.e. baseline and post baseline data available) will be displayed 
using the categories:  no shift to high and normal/low to high. 
 
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A laboratory value that is above the testing laboratory’s normal range will be considered 
a high abnormal laboratory value. A laboratory value that is below the testing 
laboratory’s normal range will be considered a low abnormal value.
8.3.1.4.
Immunoglobulin Results Relative to the Lower Limit of Normal
Immunoglobulins (IgG, IgA, IgM) will be classified relative to the reference range for the 
following categories:  < LLN and ≥LLN.
8.3.2.
Summary Measure
8.3.2.1.
Clinical Laboratory Results
Laboratory parameters which are continuous numeric values will be analyzed using 
summary statistics, and those with categorical results will be summarized using 
frequencies and percentages. Results will be presented by visit during the 52-week 
treatment phase, and at any time post-baseline where specified.
8.3.2.2.
Clinical Laboratory Toxicity Grades
The frequencies and percentages of subjects meeting each of the toxicity grade endpoints 
will be summarized by visit during the 52-week treatment phase, and at any time post-
baseline where specified.
8.3.2.3.
Clinical Laboratory Reference Range Shifts
The frequencies and percentages of subjects meeting each shift criteria will be 
summarized by visit during the 52-week treatment phase.
8.3.2.4.
Immunoglobulin Results Relative to the Lower Limit of Normal
The frequencies and percentages of subjects who are <LLN and ≥LLN will be 
summarized by visit during the 52-week treatment phase.  The analyses will be repeated 
for the subgroup of patients who are ≥LLN and who are <LLN at baseline, respectively.
8.3.3.
Population of Interest 
For all clinical laboratory endpoints, the analyses will be based on the ITT population.
8.3.4.
Strategy for Intercurrent (Post-Randomization) Events
For all clinical laboratory endpoints, observed data will be used with no imputation.
8.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.3.1 will be
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including immunogenicity and vital 
signs will be based on GSK Core Data Standards, unless otherwise specified. The details 
of the planned displays are presented in Appendix 11: List of Data Displays.
8.4.1.
Endpoint / Variables
8.4.1.1.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from 
subjects per the protocol
For the immunogenicity assessment, two types of antibody assays will be performed, i.e. 
a binding assay and neutralizing assay. For the binding assay, there will be 3-testing 
steps.  A screening assessment is performed which produces a result of positive or 
negative. For samples with a positive screening result, a confirmation assay is then 
carried out, which also produces a result of positive or negative. For samples with a 
positive confirmation result, a titer value will also be obtained to quantify the degree of 
binding in a titration assay step. Patients will be viewed as positive for the binding assay 
if the confirmation assay was positive. Subjects, who tested positive for the binding 
assay, will be tested for the neutralizing assay, which again produces a result of positive 
or negative.
 
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8.4.1.2.
Vital signs
Vital signs will be collected per the protocol.  Parameters along with units for reporting 
are listed below.
Vital Sign Parameter
(Units)
Systolic Blood Pressure (sitting) (mmHg)
Diastolic Blood Pressure (sitting) (mmHg)
Heart Rate (beats/min)
Temperature (C)
Weight (kg)
BMI (kg / m 2)
8.4.2.
Summary Measure
8.4.2.1.
Immunogenicity
Immunogenic response will be summarized by visit and anytime postbaseline for the 52-
week treatment phase.
Categories of response are Negative, Transient Positive (defined as a single positive 
response that does not occur at the final assessment, or Persistent Positive (defined as a
positive response that occurs on at least 2 consecutive assessments or a single result at the 
final assessment).
8.4.2.2.
Vital signs
Change from baseline in vital signs will be presented using summary statistics by visit.
Baseline body mass index (BMI) will be calculated from weight and height 
measurements.
BMI (kg/m2) =
Weight (kg)
[Height (m)]2
BMI will be derived at each visit using the baseline value for height and the weight at the 
visit.  Since height is collected in centimeters (cm), it will be converted to meters (m) by 
dividing by 100 before using it in the formula above.
8.4.3.
Population of Interest 
For immunogenicity and vital signs endpoints, the analyses will be based on the ITT
population.
8.4.4.
Strategy for Intercurrent (Post-Randomization) Events
8.4.4.1.
Immunogenicity
Observed data will be used with no imputation.
 
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8.4.4.2.
Vital signs
Observed data will be used with no imputation. If weight or height is missing, then BMI 
will be missing.
8.4.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.4.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.5.
Safety Data for Maintenance Phase Subject Profile
AE data, grade 3 or 4 laboratory data, and immunogenicity data will be listed on the 
subject profile.
 
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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
The primary PK analysis will be of the serum belimumab concentrations.
9.1.1.
Endpoint / Variables
Refer Section 13.5.3 Reporting Standards for Pharmacokinetic.
9.1.2.
Summary Measure
Descriptive statistics for serum belimumab concentrations will be displayed for each 
visit. The tables will display the mean value, standard deviation, 95% CI of mean,
geometric mean, % CV, 95% CI of geometric mean, median, 25th and 75th percentiles, 
minimum and maximum. 
9.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the PK population, unless 
otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Observed data will be used with no imputation.
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
Population Pharmacokinetic Analysis are not applicable to this study.  
 
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11.
BIOMARKER ANALYSES
11.1.
Primary Biomarker Analyses
11.1.1.
Endpoint / Variables
Autoantibodies (anti-dsDNA, ANA), BLyS protein, B-cells (CD19+, CD20+, 
CD20+/27+ memory, CD20+/27–naïve, CD20+/69+activated, 
CD20+/138+plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ 
plasma cells), immunoglobulins (IgG, IgA, and IgM), and complement (C3 and C4) will 
be assessed.  See Section 13.6.6.2 for additional details.
11.1.2.
Summary Measure
11.1.2.1.
B-Cells
For the B-cells, the change and percent change from baseline in the original parent study
will be summarized at Weeks 0, 8, 16, 24, 32, 40 and 52 and from Week 24 to 32, Week 
24 to 40, and Week 24 to 52. 
11.1.2.2.
Autoantibodies, Immunoglobulins and Complement
For autoantibodies, immunoglobulins and complement, the change and percent change 
from baseline in the original parent study to each visit including the Day 0 visit in the 52-
week treatment phase will be assessed.
Shifts from baseline in IgG, IgM, IgA, anti-dsDNA, ANA, C3 and C4.
11.1.2.3.
BLyS Protein
The change and percent change from baseline in the original parent study to each visit in 
the 52-week treatment phase will be assessed.
11.1.3.
Population of Interest
For all endpoints in Section 11.1.1, the primary biomarker analyses will be based on the 
ITT population.
11.1.4.
Strategy for Intercurrent (Post-Randomization) Events
For all endpoints in Section 11.1.1, observed data will be used with no imputation.
11.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 11.1.1 will be
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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11.2.
Biomarker Data for Maintenance Phase Subjects
By subject line plots for subjects who enter the maintenance phase for all visits for each 
B-cell parameter will be presented.
 
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12.
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Eibl MM, Rosen FS. Intravenous gamma globulin and plasmapheresis. In: Frank 
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Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with 
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Yamini MH, Avery RK, Mawhorter SD, Young JB, Ratliff NB, Hobbs RE, 
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Hypogammaglobulinemiafollowing cardiac transplantation: a link between rejection and 
infection. J Heart Lung Transplant. 2001;20(4):425-30.
 
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13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation 
See Section 4.1 for details.
 
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13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
13.2.2.
Time and Events Table (Year 1)
Screen
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up to 
-30 1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
140
7d
168 
7d
196
7d
224 
7d
252 
7d
280
7d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
Written Informed Consent 4
X
Demography
X
Medical History
X
SLE History
X
Therapy History
X
Physical Examination
X
Inclusion/Exclusion
X
Efficacy Assessments
DAS: SS, SLE Flare Index, 
PGA 5
X 1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR Damage Index
X
X
X
Safety Assessments
Vital Signs 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, height 6, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom-driven Physical 
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology & Modified 
Chem 20 (non-fasting) 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spot urine (protein to 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Screen
Treatment Holiday Study
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--
--
Study Day
Up to 
-30 1
0 2
28 
7d
56 
7d
84 
7d
112 
7d
140
7d
168 
7d
196
7d
224 
7d
252 
7d
280
7d
308 
7d
336 
7d
364 7d or 
Exit
16-wk 
7d 3
6 mo 
7d
Study Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
--
--
creatinine ratio) 8
Pregnancy Test 6, 9
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Pharmacogenetic Sampling 10
X
aCL Autoantibody
X
X
C3/C4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-dsDNA Autoantibodies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA Autoantibodies 
X
X
X
IgG, IgA & IgM 11
X
X
X
X
X
X
X
X
PT/ PTT
X
Exploratory Lab Assessments
Pharmacokinetic Sampling 12
X
X
X
X 12
X
X 12
Immunogenicity 6, 13
X
X
X 13
X
X
X
X
X 13
BLyS Protein 14
X
X
X
B cell Markers 15
X
X
X
X
X
X
X
X
Investigational Product (IP)
IP Administration 16
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
1.
DAS = disease activity scales; SS = SELENA SLEDAI; SLE = systemic Lupus Erythematosus; PGA = Physician’s Global Assessment; SLICC/ACR = Systemic Lupus 
International Collaborating Clinics/American College of Rheumatology; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; PT/PTT = prothrombin time/partial 
thromboplastin time; BlyS = B Lymphocyte Stimulator; IP = investigational product; aCL = anticardiolipin
2.
A screening visit of up to 30 days prior to the Day 0 visit will be scheduled for subjects in the treatment holiday and control groups for assessment of SELENA SLEDAI score to 
assess eligibility.
3.
The EXIT Visit in the respective feeder continuation studies will serve as the Day 0 visit for all 3 subject groups in this study. Assessments covered for both this study at Day 0 
and the Exit visit of the feeder continuation studies need only be performed once and recorded in the appropriate case report forms for each study. Subjects in the control group 
must be able to receive the 1st dose of belimumab on Day 0 of this study on average 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in the feeder 
continuation study.
4.
The 16 week follow-up visit will occur at approximately 16 weeks after last dose of investigational product for subjects in the control group who withdraw at any time during the 
study, or for subjects in the treatment holiday group who withdraw from the study from Week 24 onwards (Visit 7) during the belimumab re-introduction period. The 16-week and 6 
month follow-up visits do not apply to subjects in the long-term discontinuation group. 
5.
Obtain written informed consent to participate in this study at the Screening visit.
 
 
 
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6.
Guidelines for scoring proteinuria for SELENA SLEDAI are provided in protocol Section 6.3.1.1 .
7.
Complete assessment prior to belimumab dosing for subjects in the control group (to Week 48) and for subjects in the treatment holiday group (during Weeks 24 to 48 or earlier in 
the event of a flare).  Immunogenicity testing includes quantifying the amount of belimumab present in the samples using the belimumab PK assay.
8.
For any subject whose weight changes by more than 5% from that recorded at Day 0, use the weight at the current visit for calculating the belimumab dose to be administered. 
Height measured only at Day 0.
9.
A 24-hour urine may be done as an additional assessment if clinically indicated (e.g., renal flare).
10. Urine pregnancy test results for women of child-bearing potential must be available prior to dosing (during Weeks 0 to 48 in the control group and during Weeks 24 to 48 or earlier 
in the event of a flare in the treatment holiday group).Can be performed at any time during the visit for females of child-bearing potential in the long-term discontinuation group.
11. PGx sampling from consenting subjects recruited from all studies except from study BEL114333. PGx informed consent must be obtained prior to sampling.
12. Serum immunoglobulin isotypes: IgG, IgM, IgA.
13. Pharmacokinetic sampling at select sites for subjects in the control and treatment holiday groups; subjects in the treatment holiday group can have PK sampling performed at any 
time during the visit between Weeks 0 and 16.  Otherwise, if on a dosing day, sampling must be performed prior to dosing. Collect blood samples pre-dose and post-dose at the 
end of the infusion at Weeks 24 and 52 (or earlier if belimumab is re-started before Week 24 in the event of a severe flare by using the escape option).   Subjects in the long-term 
discontinuation group will have one PK sampling performed at any time during the visit between Weeks 0 and 24.  PK sampling for the long-term discontinuation group is not 
performed after Week 24.  Long-term discontinuation subjects withdrawing before Week 24 will have one PK sampling performed at any time during the EXIT visit.   PK sampling 
for long-term discontinuation subjects withdrawing after Week 24 is not performed at the EXIT visit.
14. Blood sample for immunogenicity will be taken at Weeks 12, 24, 36 and 52 for all three groups.  In addition, a blood sample for immunogenicity will also be taken 4 weeks prior
to the reintroduction of belimumab (at Week 20 since belimumab will be reintroduced at Week 24) in the treatment holiday group. A blood sample for immunogenicity must be 
taken at least 6 months after the final dose of investigational product for any subjects in the control group or treatment holiday group who had an anti-belimumab antibody 
response at the 16-week follow-up visit (or at the last immunogenicity assessment if 16-week follow-up is not available). Note that serum samples for immunogenicity must be 
collected pre-dose at the time of dosing from subjects in the treatment holiday group who experience a severe flare prior to Week 24 and consequently receive open-label 
belimumab as rescue.  Immunogenicity blood sample will not be collected at the 6-month follow up visit for subjects in the long-term discontinuation group as this visit does not 
apply to this subject group.
15. Measured in treatment holiday group at Weeks 16 and pre-dose at Week 24. Measured in long-term discontinuation group at Weeks 16, 24 and 32. Not measured in control 
group.
16. Biological Markers include FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells). Note: B cell markers will not be collected at the 6-month follow up visit for subjects in the long-term 
discontinuation group as this visit does not apply to this subject group.
17. Only subjects in the control group will receive belimumab 10 mg/kg during Weeks 0 through 20 inclusive;  subjects in the control group must be able to receive the first dose of 
belimumab in this study 4 weeks (minimum of 2 weeks, maximum of 8 weeks) after the last dose in their previous open-label continuation study  Subjects in the control group 
and treatment holiday groups will receive belimumab from Weeks 24 through 48 although subjects in the treatment holiday group may be treated with belimumab prior to Week 
24 as determined by the investigator in the event of increased SLE activity. When belimumab therapy is re-started, subjects in the treatment holiday group will remain under 
clinical supervision for 3 hours after completion of the first 2 infusions. At the Week 52 visit, only subjects in the treatment holiday and control groups who are continuing 
belimumab therapy beyond this time will be dosed.
 
 
 
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13.2.3.
Time and Events Table (Additional Years)
Study Visit (Weeks) 1
4
8
12
16
20
24
28
32
36
40
44
48
Study Day
28   
7d
56   
7d
84   
7d
112 
7d
140 
7d
168 
7d
196 
7d
224 
7d
252 
7d
280 
7d
308 
7d
336 
7d
Efficacy Assessments
Disease Activity Scales: SELENA SLEDAI, 
SLE Flare Index, and PGA 2
X
X
SLICC/ACR Damage Index
X
Safety Assessments
Symptom-driven Physical Exam
X
X
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs 3, 4
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology & Modified Chem 20 (non-
fasting) 3, 5
X
X
Urinalysis 5, 6
X
X
Spot urine (protein to creatinine ratio) 3, 5, 6
X
X
Urine Pregnancy Test 3, 5, 7
X
X
X
X
X
X
X
X
X
X
X
X
C3, C4, Anti-dsDNA Autoantibodies 3, 5
X
X
IgG 3, 5,  8
X
IgA & IgM 3, 5, 8
X
Exploratory Lab Assessments
Immunogenicity 3 ,9
X
X
B cell Markers 10
X
Investigational Product
Belimumab  Administration 4, 11
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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1.
Calendar represents a yearly (48-week) ongoing visit schedule until the subject is terminated from the study.
2.
Guidelines for scoring proteinuria for SELENA SLEDAI are provided in protocol Section 6.3.1.1.
3.
Assessments performed prior to dosing.
4.
For any subject whose weight changes by more than 5% from that recorded at Day 0, use the weight at the current visit for calculating the belimumab dose to be administered.
5.
During “Additional years”, investigators can obtain any of the same laboratory assessments that are mentioned for Year 1 (haematology, modified Chem 20, urinalysis, spot urine 
to creatinine ratio, urine pregnancy, C3, C4, anti-ds DNA autoantibodies, IgG, IgA, and IgM), as unscheduled laboratory tests at any time during Year 2 and beyond, if clinically 
indicated.  Any additional laboratory tests beyond this, if not related to the protocol, will be the responsibility of the investigator and subject.
6.
A 24-hour urine may be done as an additional assessment if clinically indicated (e.g., renal flare). 
7.
Results of urine pregnancy tests in women of child-bearing potential must be available prior to belimumab dosing.
8.
Serum immunoglobulin isotypes: IgG, IgM, IgA.
9.
Immunogenicity testing includes quantifying the amount of belimumab present in the samples using the belimumab PK assay.
10. Biological Markers include FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT SLE subset and CD20-/138+ plasma cells).
11. After completion of the Week 48 visit during year 1 of the study, subjects in the treatment holiday and control groups can continue to receive belimumab therapy at 4-weekly 
intervals in the maintenance phase of this study. Subjects who withdraw from belimumab therapy during this maintenance phase will complete the Exit and follow-up visits detailed 
in the Year 1 Time and Events Table. The Exit visit Schedule should be scheduled 4 weeks after the final belimumab dose and the 16-week follow-up visit 16 weeks after the final 
belimumab dose.
 
 
 
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13.3.
Appendix 3: Assessment Windows
13.3.1.
Mapping of the Maintenance Phase Visits for Subjects with an 
Escape Visit
In the eCRF, the next visit provided following the Escape visit is the Year 2 Week 8 visit, 
when chronologically the next visit would be the Year 2 Week 4 visit.  Therefore, the
maintenance phase visits for subjects with an Escape visit will be re-mapped in the 
ADaM analysis data sets to the maintenance phase visit, so that the visits align
chronologically with those for subjects who complete the 52-week treatment phase and 
subsequently enter the maintenance phase.
If an Escape visit is present, mapping will occur as follows:
SDTM Variable
ADAM Variable
Domain
VISITNUM
VISIT
AVISITN
AVISIT
All
190
ESCAPE
190
ESCAPE
All
220
YEAR 2 WEEK 8
210
YEAR 2 WEEK 4
All
230
YEAR 2 WEEK 12
220
YEAR 2 WEEK 8
All
240
YEAR 2 WEEK 16
230
YEAR 2 WEEK 12
The mapping will continue in this pattern for subsequent visits.
13.3.2.
Mapping of Week 16 and 6-month Follow-up Visits
The 16-week and 6-month follow-up visits will be re-mapped in the ADaM analysis data 
sets so that they sort in chronological sequence when using the numeric visit number.
 
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SDTM Variable
ADAM Variable
Domain
VISITNUM
VISIT
AVISITN
AVISIT
All
170
16 WK FOLLOW-UP
9100
16 WK FOLLOW-UP
All
180
6 MO FOLLOW-UP
9200
6 MO FOLLOW-UP
13.3.3.
Analysis Visit and Analysis Visit Number
The data are analyzed according to the planned visit assignment in the data.  
Exit/withdrawal visits must be slotted to the appropriate planned visit according to the 
study phase. This will only be done for subjects that withdrew early and did not complete 
the 52-week treatment phase. Unscheduled laboratory visits will also be slotted to the 
appropriate planned visit. 
The Analysis Visit is assigned based on the interval in which the Study Day for the 
exit/withdrawal visit or unscheduled laboratory visit falls according to intervals 
(inclusive) provided below. For completeness, the table also includes visits which are not 
slotted; these visits will have ‘na’ for ‘not available’ listed for the Interval Start and End 
Day.
Analysis Visit
Analysis 
Visit Number
Target Study Day1
Interval Start Day
Interval End Day
Screening
10
-34
na
na
52-week Treatment Phase visits:
Baseline
20
1
na
na
Week 4
30
29
22
42
Week 8
40
57
43
70
Week 12
50
85
71
98
Week 16
60
113
99
126
Week 20
70
141
127
154
Week 24
80
169
155
182
Week 28
90
197
183
210
Week 32
100
225
211
238
Week 36
110
253
239
266
Week 40
120
281
267
294
Week 44
130
309
295
322
Week 48
140
337
323
350
Week 52
150
365
351
378
 
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Analysis Visit
Analysis 
Visit Number
Target Study Day1
Interval Start Day
Interval End Day
1Day 0 visit date in study 116027 = Study Day 1.
13.3.4.
Windows for Assessment of Post-injection/infusion sensitivity 
reactions (PISR) and hypersensitivity reactions (HSR)
The windows for assessment of PISR/HSR, as described in the AESI definitions in 
Section 13.9.2, are as follows:
Date of Infusion
Day 1
Day 2
Day 3
SMQ narrow, broad and algorithmic searches (On day of injection/infusion or within 3 
days of injection/infusion)
 
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13.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
13.4.1.
Treatment Phases

Visits, assessments and events will be classified according to the time of occurrence 
relative to the following cut-point dates for each treatment group.

For convenience and ease of data presentation, the 52-Week Treatment Phase has the 
same name designation for all three treatment groups, even though the LTC group 
does not receive treatment at all during this phase and the TH group receives 
treatment for only the second half of the phase.

Only the TC and TH groups are eligible to participate in the Maintenance Phase.

If an AE start date falls on the Day 0 date, then it will be considered treatment 
emergent (i.e., fall in the 52-week treatment phase).  If a concomitant medication 
start date falls on the Day 0 visit date, the concomitant medication will be considered 
to fall in the 52-week treatment phase. Any other assessments that fall on the Day 0 
visit date will be considered to occur in the pre-study phase.

For the TC group, if the first infusion date differs from the Day 0 visit date, then the 
first infusion date will be used as the phase cut-point.

Other than Day 0, if an assessment or event occurs on the same date as a phase cut-
point, then the event will be considered to fall in the previous phase.  For example, if 
a new prednisone dose starts on the same date as the Week 24 visit date and then 
continues for a total of 7 days, then the first day of that prednisone dose will fall into 
the Holiday Phase and the remaining 6 will fall into the Re-start phase.

For AEs, if the AE Onset date is missing, then the AE will be considered to occur in 
the 52-week treatment phase.

For the TH group, a subject who re-starts treatment prior to Week 24 will not have a 
Re-Start phase.
 
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13.4.1.1.
Treatment Holiday Group
Endpoint
Day 0 Visit
Parent 
Study
Day 0 Visit
BEL116027 
Study
Week 24/
TX Re-start 
Visit
Week 52/
Exit/Escape 
Visit
Week 
16 
Follow-
up Visit
Baseline
Flare, PGA, Prednisone, 
SLICC
N/A
52-Week Treatment Phase
Maintenance 
Phase
N/A
Holiday Phase
Re-start Phase
Baseline
SS, Auto-antibodies 
Immunoglobulins, 
B-cells [1], BLyS
Pre-Study 
Phase
52-Week Treatment Phase
Maintenance 
Phase
N/A
Holiday Phase
Re-start Phase
Baseline
Rebound [2]
Pre-Study 
Phase
52-Week Treatment Phase
N/A
N/A
Holiday Phase
N/A
Baseline
Adverse Events, Lab 
Parameters, Vital Signs, Con 
Meds  Immunogenicity [1]
N/A
52-Week Treatment Phase
Maintenance 
Phase
N/A
Holiday Phase
Re-start Phase
N/A = Not Applicable.
[1] Immunogenicity and B-cells may also be collected at the 6-month follow-up visit.  The 6-month follow-up 
visit is not represented in the diagram since it does not define a treatment phase of the study.
[2] Rebound is only assessed up to the Week 24/Treatment re-start visit.
 
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13.4.1.2.
Treatment Control Group
Endpoint
Day 0 Visit
Parent Study
Day 0 Visit
BEL116027 
Study [1]
Week 24 Visit
Week 52/
Exit Visit
Week 
16 
Follow
-up 
Visit
Baseline
Flare, PGA, Prednisone, 
SLICC
N/A
52-Week Treatment Phase
Maintenance 
Phase
N/A
Baseline
SS, Auto-antibodies 
Immunoglobulins, 
B-cells [2], BLyS
Pre-Study 
Phase
52-Week Treatment Phase
Maintenance 
Phase
N/A
Baseline
Rebound [3]
52-Week Treatment Phase
Pre-Study 
Phase
First 24 Weeks
N/A
N/A
N/A
Baseline
Adverse Events, Lab 
Parameters, Vital Signs, Con 
Meds , Immunogenicity [2]
N/A
52-Week Treatment Phase
Maintenance 
Phase
N/A
N/A = Not Applicable.
[1] If the first infusion date differs from the Day 0 visit date, then the first infusion date will be used as the 
phase cut-point.
[2] Immunogenicity and B-cells may also be collected at the 6-month follow-up visit.  The 6-month follow-up 
visit is not represented in the diagram since it does not define a treatment phase of the study.
[3] Rebound is only assessed up to the Week 24 visit.
 
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13.4.1.3.
Long-term Discontinuation Group
Endpoint
Day 0 Visit
Parent 
Study
Day 0 Visit
BEL116027 Study
Week 24 Visit
Week 52/
Exit Visit
Baseline
Flare, PGA, Prednisone, 
SLICC
N/A
N/A
52-Week Treatment 
Phase
N/A
Baseline
SS, Auto-antibodies 
Immunoglobulins, BLyS
N/A
Pre-Study Phase
52-Week Treatment 
Phase
N/A
Baseline
Rebound
N/A
Pre-Study Phase
52-Week Treatment 
Phase
N/A
First 24 
Weeks
N/A
Baseline
Adverse Events, Lab 
Parameters, Vital Signs,
Con Meds 
N/A
N/A
52-Week Treatment 
Phase
N/A
N/A = Not Applicable.
 
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Treatment 
State
Treatment 
Group
Definition
Treatment 
Emergent
TH, LTD
AE Onset Date ≥ Day 0 visit date
Treatment 
Emergent
TC
AE Onset Date ≥ Date of First Infusion in BEL116027
Onset Time 
Since 1st
Dose (Days)
TH, TC
If Date of First Infusion in BEL116027˃ AE Onset Date:
= AE Onset Date - Date of First Infusion in BEL116027
If Date of First Infusion in BEL116027≤ AE Onset Date
= AE Onset Date - Date of First Infusion in BEL116027+1
=Missing otherwise.
Onset Time 
Since Study 
Start (Days)
TH, TC, LTD
If Day 0 visit date ˃ AE Onset Date:
= AE Onset Date – Day 0 visit date
If Day 0 visit date ≤ AE Onset Date
= AE Onset Date - Day 0 visit date +1
=Missing otherwise.
Duration 
(Days) 
TH, TC, LTD
AE Resolution Date – AE Onset Date + 1
Drug-related
TH, TC, LTD
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
1.
NOTES:

If the AE Onset date is missing, then the AE will be considered as treatment emergent.
 
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13.5.
Appendix 5: Data Display Standards & Handling 
Conventions
13.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
US1SALX00259
HARP Compound
and Reporting effort
GSK1550188/BEL116027/final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0).
Generation of RTF Files

RTF files will be generated for all tables in the final_cdisc RE
13.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study agent dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will be included in figures unless their inclusion contributes adversely to 
 
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visual presentation or interpretation of the figure.

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, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
13.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of log transformed data and between geometric coefficient of variation (CVb 
(%)) will be reported.
CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
N, n mean, 95% CI, standard deviation (SD), median, 25th and 75th
percentile, minimum and maximum will be reported.
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters
 
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13.6.
Appendix 6: Derived and Transformed Data
13.6.1.
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.

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 the Day 0 Visit Date (i.e., Day 1) to the assessment 
date or visit date of interest (Ref Date)

Ref Date = Missing             → Study Day = Missing 

Ref Date < Day 0 Visit Date   → Study Day = Ref Date – Day 0 Visit Date    

Ref Data ≥Day 0 Visit Date   → Study Day = Ref Date –Day 0 Visit Date + 1
13.6.2.
Study Population
Demographics
Study Phases Definitions for Disposition

Completion/withdrawal for the 52-Week Treatment Phase will be derived as follows:
o
Withdrawn if the subject completion status is marked as No and the subject has no 
visits during the maintenance phase.
o
Complete if the subject completion status is marked as Yes and the subject has no 
visits during the maintenance phase.

Completion/withdrawal for the Maintenance Phase will be derived as follows:
o
Withdrawn if the subject completion status is marked as No and the subject has at 
least one visit during the maintenance phase.
o
Complete if the subject completion status is marked as Yes and the subject has at 
least one visit during the maintenance phase.
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Analysis age is derived in years relative to the Day 0 visit date, and is calculated in SAS as 
follows:
Analysis Age (years) 
=
INTCK('year', Date of Birth, Day 0 Date) 
-  (  MONTH(Day 0 Date) < MONTH(Date of Birth) 
 
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Demographics
      or (MONTH(Day 0 Date) eq MONTH(Date of Birth) 
             and DAY(Day 0 Date) < DAY(Date of Birth)  )  )
Proteinuria

For analysis, urine protein in g/24-hour will be approximated by the urine protein:creatinine ratio 
(uPCR).

The value for reporting and analysis is stored in the uPCR result variable corresponding to the 
original unit in the SI dataset. Depending on the study, units for uPCR may be reported in g/g or 
mg/mg.  As long as the units are the same in the numerator and denominator, the ratio will be 
the same.  

The SI dataset standard unit is reported in mg/mmol is not used for reporting and analysis 
purposes in this study.
Concomitant medications

Concomitant medications are defined as 
a.
Medications that start on or before the Day 0 visit date and end on or after the Day 0 visit 
date, or 
b.
Medications that start after the Day 0 visit date

Medications that meet criterion ‘a’ are considered to be in use at baseline. 

Medications will be assigned to the 52-week treatment or maintenance phases, as per the 
definitions in Section 13.4.1.

Medications with partial or missing start and/or stop dates will be assumed to be concomitant 
unless there is evidence through comparison of partial dates to suggest otherwise, for example 
if the day is missing, then the month and year will be compared to the month and year of the 
first dose date of study treatment and if the month and year are the same or later, then the 
medication will be considered concomitant.
Allowable SLE Medications at Baseline
There are 5 medication categories that are evaluated.  These medication categories are defined in the table 
below and stored in the variable CMSCAT.  Only medications providing systemic exposure are evaluated.  
Systemic exposure is based on the route of administration.  A flag variable for systemic exposure when 
CMSCAT is not blank is defined below and stored in the variable SYSTEMIC.  The medication must have 
one of the defined medication categories below (CMSCAT ne blank) and must provide systemic exposure 
(SYSTEMIC=’Y’).   
Medication Category (CMSCAT)
Rule
Anti-malarials
Set CMSCAT to "ANTIMALARIALS" if the preferred 
term begins with "QUINACRINE", "QUININE", 
"HYDROXYCHLOROQUINE",
"MEPACRINE", or "CHLOROQUINE" 
Steroids
Set CMSCAT to ‘STEROIDS’ if at least one 
associated ATC code (ATCCD1 – ATCCD6) begins 
with ‘H02’ 
 
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Allowable SLE Medications at Baseline
Immunosuppressants
Set CMSCAT to ‘IMMUNOSUPPRESSANTS’ if at 
least one associated ATC code (ATCCD1 –
ATCCD6) begins with ‘L04A’ or the preferred term 
begins with “CYCLOPHOSPHAMIDE” or 
“MERCAPTOPURINE”.
NSAIDs
Set CMSCAT to NSAIDs if at least one associated 
ATC code (ATCCD1 – ATCCD6) begins with ‘M01A’.
Aspirin
Set CMSCAT to "ASPIRIN" if CMDECOD contains 
"ACETYLSALICYLIC ACID" or 
"ACETYLSALICYLATE LYSINE".
Prohibited
Set to "PROHIBITED" if any of
the following conditions are met, if CMDECOD 
equals "INVESTIGATIONAL DRUG", 
"IMMUNOGLOBULIN",
"ADALIMUMAB", "ETANERCEPT", "INFLIXIMAB", 
"RITUXIMAB", "ABATACEPT", "ANAKINRA",
"GOLIMUMAB", "CERTOLIZUMAB" 
and/or 
A review of the surgeries/procedures form indicates 
the subject had "PLASMAPHERESIS".
Traditional Chinese medications Glycosides of 
Paeony and Tripterygium
These medications will be identified based on a 
clinical review of all the concomitant medications 
assigned the following drug collection codes in the 
GSK drug dictionary:  50119401, 54654601, 
40987301, 50192401, 53020201, 53060901, 
53766001, 53927401, 53959101, 53959201, 
53990601, 54619401, 54731901, 54908201, 
59164101
Systemic (SYSTEMIC)
Rule
Blank 
If CMSCAT=blank
Y
‘Y’ if CMSCAT ne blank and the route of 
administration is "INTRADERMAL” “PO” 
"INTRAMUSCULAR", "INTRAVENOUS", "ORAL", or 
"SUBCUTANEOUS" 
N
‘N’ otherwise and CSMCAT ne blank
Treatment Compliance

Treatment compliance for patients completing the 52 week treatment phase or withdrawals is 
calculated as:

Prescribed number of infusions will be 7 for the TH arm and 13 for the TC arm, except for TH subjects 
who escape to the Maintenance Phase.  For TH subjects who escape, the treatment compliance will be 
missing. The Week 52 infusion is considered to be the first infusion of the maintenance phase.

NB: for withdrawals the  number of infusions prescribed is the number  from Day 0 up to the withdrawal 
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Extent of Exposure

Number of days of exposure to study treatment during the 52-week Treatment Phase will be 
calculated based on the formula:  
Duration of Exposure in Days = (Date of last infusion in BEL116027 52-week treatment 
Phase– Date of first infusion in BEL116027) + 28

The Week 52 infusion is considered to be the first infusion in the Maintenance Phase, and will 
not be considered in this calculation.

Subjects who were enrolled in the TH and TC groups but did not receive an infusion will be 
categorised as having zero days of exposure. 

Exposure will not be calculated for the LTD group.

Only complete dates will be used when calculating duration of exposure.  

Exposure will not be adjusted for skipped infusions.
13.6.3.
Efficacy
SLE Flares and Severe Flares, and Renal Flares
Baseline Flares

Baseline flares will be summarized using the data from the eCRF SFI data collection 
for the Day 0 visit.  Per eCRF completion guidelines, the data collected at the Day 0 
visit represents the flare data since the previous visit (i.e. the last visit in the feeder 
continuation study). 
SLE Flares and Severe SLE Flares
 
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SLE Flares and Severe Flares, and Renal Flares

SFI reports the first mild /moderate or severe flare occurrence since the last visit 
assessment.  

The SLEDAI criteria will be assessed programmatically to determine if the SELENA 
SLEDAI criteria for a flare has been met and used for the assessment of flare, 
irrespective of what was recorded on the SFI form.  

Although there are boxes on the form for the investigator to classify the most recent 
flare to mild/moderate or severe, the classification will be re-derived from the 
subcategory scores. Flares originally marked severe will be downgraded to “Not 
Severe” if the only reason marked is a change in SELENA SLEDAI score to > 12.  

In this case, if any of the mild/moderate reasons are checked or if the modified 
SELENA SLEDAI score has a change from previous visit of at least 3, then the flare 
will be considered Mild/Moderate.

Flares that are marked mild/moderate where the only reason checked is SELENA 
SLEDAI increase of at least 3 points but not more than 12 points will be re-derived 
using the modified SELENA SLEDAI score.  

If it’s found that the change is not actually ≥ 3, and no other reasons are checked, 
 
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SLE Flares and Severe Flares, and Renal Flares
then the flare will not be counted.
Renal Flares
A SLE Renal flare is defined as the occurrence of at least 1 or more of the following in 2 
or more consecutive visits during the study. (NB: at least 1 of the same criteria must be 
present on at least 2 consecutive visits)
Increased Proteinuria (using spot urine)
A reproducible increase in 24-hour urine protein levels (as measured in uPCR) to:

>1g if the baseline (Day 0)value was <0.2g  
OR

>2g if the baseline (Day 0) value was between 0.2g and 1g
OR

More than twice the value at baseline (Day 0) if the baseline value (Day 0)was >1g
Impaired Renal Function

A reproducible decrease in GFR of >20%, accompanied by proteinuria (>1), and/or 
cellular (RBC and WBC) casts.

[Alarcón-Segovia, 2003].
GFR is estimated by the Cockcroft-Gault equation [Cockcroft, 1976] for creatinine 
clearance in mL/min.
Cockcroft-Gault Equation
Clcr (mL/min) =
(140-age (yrs)) x weight (kg)
x 0.85 if female
72 x serum creatinine (mg/dL)
“Reproducible” requires the criterion to be met at two consecutive visits, including 
unscheduled visits.
The following table identifies the lab parameters to be used to evaluate the criteria in the 
renal flare definition above.  
Criterion
Parameter
SI Dataset 
LBTESTCD
Proteinuria 
Urine Protein:Creatinine Ratio (mg/mg)
PRTCRT_URQ
GFR
Creatinine Clearance estimated by the 
Cockcroft-Gault equation (mL/min)
CRTCE_PLR
Cellular casts:
WBC cellular casts
WBC cellular casts
WBCSTM_URQ
dysmorphic RBCs
dysmorphic RBCs
DRBCM_URQ
 
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SLE Flares and Severe Flares, and Renal Flares
Derivation for rates of SFI flares

Within a treatment group, the unadjusted flare (severe flare) rate per subject-year in a 
given phase will be calculated as:
Unadjusted flare (severe flare) rate per subject-year =
total number of flares (severe flares) in the phase / total number of years of follow-up 
time in the phase.

The calculation will not include baseline flares in the 116027 study.
Follow-up time derivation for rates of SFI flares
Phase
Treatment 
Group
Definition
52-week 
Treatment 
Phase
TC, LTD
(Week 52/Exit visit date – Day 0 date + 1)/ 365.25.
TH Phase 
TH
(Week 24/TX re-start date – Day 0 date + 1)/ 365.25.
RS Phase 
TH
(Week 52/Exit visit – Week 24/TX re-start date)/ 365.25.
SELENA SLEDAI Organ System Domains
SELENA SLEDAI assessments consist of 24 individual weighted items in which signs and symptoms, 
laboratory tests, and physician’s assessment for each of 8 organ systems are given a weighted score and 
summed if present (marked ‘Yes’) at the time of the visit or in the preceding 10 days. The maximum 
theoretical score is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease (marked 
‘No’), but in practice few subjects have scores > 45 [Buyon, 2005; Petri, 2005]. 
Organ system domain scores are the sum of the weights of items within the organ domain as defined in the 
table below.  
In this study, proteinuria is evaluated using spot-urine protein [represented as protein-creatinine ratio or PC 
Ratio (Add ref to 9.3.13) in the laboratory dataset] in lieu of the 24-hour urine collection. PC ratio in mg/mg is 
considered equivalent to g/24-hr urine protein.
If the P/C ratio value is missing, then the value from the previous visit will be used. Specifically, the 
assessment for proteinuria indicated on the CRF will be used to calculate the SELENA SLEDAI score. 
In the eCRF, laboratory items on the SLEDAI may also be ticked ‘unknown’ to indicate the lab test was not 
available.  The laboratory items are: urinary casts, hematuria, proteinuria, pyuria, low complement, increased 
DNA binding, thrombocytopenia, and leukopenia.  Responses of ‘Unknown’ will be managed via LOCF 
  
List of organ systems, items, and weights for the assessments are provided.
 
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Organ System
Descriptor
Weight
[1] CNS
Seizure
8
Psychosis
8
Organic Brain Syndrome
8
Visual Disturbance
8
Cranial Nerve Disorder
8
Lupus Headache
8
CVA
8
[2] Vascular
Vasculitis
8
[3] Musculoskeletal
Arthritis
4
Myositis
4
[4] Renal
Urinary Casts
4
Hematuria
4
Proteinuria
4
Pyuria
4
[5] Mucocutaneous
Rash
2
Alopecia
2
Mucosal Ulcers
2
[6] Cardiovascular & Respiratory
Pleurisy
2
Pericarditis
2
[7] Immunologic
Low Complement
2
Increased DNA Binding
2
[8] Constitutional
Fever 
1
[9] Hematologic
Thrombocytopenia
1
Leukopenia
1
PGA

The PGA is collected on a 10cm visual analogue scale (VAS).  

The standard scoring range for the PGA is 0 to 3, and the score will be rescaled for 
standard reporting by multiplying the collected score by 3/10.  

During study conduct, it was noted that some sites erroneously received PGA scales 
that were 9.5cm in length due to a printing error, and some subjects utilized these 
scales before the error was discovered.  Per Notes to File (08Jan2015, and 
20Sep2017), an evaluation was performed and the decision was taken that this would 
result in minimal differences and not expected to affect any outcomes, and therefore it 
was unnecessary to adjust the analysis.
Prednisone Equivalent Conversion
Identification of Steroids

A concomitant medication is identified as a steroid if 
At least one associated ATC code (ATCCD1 – ATCCD6) begins with ‘H02.’  
AND
The route meets the following criteria:

Provides systemic exposure: oral, subcutaneous, intramuscular, intradermal, 
and intravenous.  

Although not systemic, intra-articular steroids are also identified for 
 
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prohibited medication rules.  

Topical routes of administration are excluded (e.g., topical, conjunctival, 
intranasal).  

Steroid doses will be converted to the prednisone-equivalent dose.

At data base release, all preferred terms identified with an ATC code beginning with 
‘H02’ will be reviewed to ensure a conversion factor exists for all terms with a 
systemic or intra-articular 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 or intra-articular 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).
Prednisone Equivalent Daily Dose (mg) = Collected Dose (mg) x Conversion 
Factor x Frequency Factor
Average Daily Dose Derivation

Average daily prednisone dose at baseline is based on all days from the Screening 
visit date up to and including the Day 0 visit date.

Post-baseline, average daily prednisone dose is based on all days between visits 
including the current visit date.

Average Daily Dose (mg/day) = Sum of Prednisone Equivalent Daily Dose (mg) 
across all days in the visit interval / Number of days in the visit interval
 
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Prednisone Conversion Factors (mg) 
Preferred term
Conversion factor for converting to a 
prednisone-equivalent dose
BETAMETHASONE
8.3333
BETAMETHASONE DIPROPIONATE
8.3333
BETAMETHASONE SODIUM PHOSPHATE
8.3333
BETROSPAM
8.3333
BUDESONIDE
0.3333
CELESTONA BIFAS
7.5
CORTISONE
0.2
CORTISONE ACETATE
0.2
CRONOLEVEL
8.3333
DEFLAZACORT
0.8333
DEPO-MEDROL MED LIDOKAIN
1.25
DEXAMETHASONE
6.6667
DEXAMETHASONE ACETATE
6.6667
DEXAMETHASONE SODIUM PHOSPHATE
6.6667
FLUOCORTOLONE
3
HYDROCORTISONE
0.25
HYDROCORTISONE ACETATE
0.25
HYDROCORTISONE SODIUM SUCCINATE
0.25
MEPREDNISONE
1.25
METHYLPREDNISOLONE
1.25
METHYLPREDNISOLONE ACETATE
1.25
METHYLPREDNISOLONE SODIUM 
SUCCINATE
1.25
PARAMETHASONE
2.5
PREDNISOLONE
1
PREDNISOLONE ACETATE
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
Frequency Factors
Frequency
Factor
BID
2
BIW
2/7
OAM
1/30
Once
1
PRN
null
Q2H
12
Q2W
1/14
Q3H
8
 
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Q3MO
1/84
Q3w
1/21
Q4H
6
Q4W
1/28
Q6H
4
Q8H
3
QAM
1
QD
1
QH
24
QHS
1
QID
4
QOD
1/2
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
EVERY 2 WEEKS
1/14
EVERY 3 WEEKS
1/21
EVERY 4 Weeks 
1/28
EVERY WEEK
1/7
13.6.4.
Safety
Adverse Events
Adverse Events of Special Interest (AESI)
AESI will be defined per the version of the PSAP/MedDRA in effect at the time of DBR.
Malignant Neoplasms

Malignancies Excluding non-melanoma skin cancer (NMSC)

Malignancies Including NMSC
Solid Tumour
Hematologic
Skin (All)
NMSC
Excluding NMSC

Tumours of unspecified malignancy adjudicated as malignant per GSK
Post-Infusion Systemic Reactions (PISR)

PISR per Anaphylactic Reaction Customized MedDRA Query (CMQ) narrow search

PISR per Anaphylactic Reaction CMQ broad search

PISR per Anaphylactic Reaction CMQ algorithmic search

Serious Anaphylaxis per Sampson Criteria per GSK adjudication

Serious Acute PISR/Hypersensitivity Per GSK adjudication

Serious Acute PISR Excluding Hypersensitivity per GSK adjudication
 
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Adverse Events
Adverse Events of Special Interest (AESI)

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 (Opportunistic Infections (OI), Herpes Zoster (HZ), Tuberculosis 
(TB), And Sepsis; All and Serious, separately)

All opportunistic infections (OI) per GSK adjudication

OI per GSK adjudication excluding Tuberculosis and Herpes Zoster

Active Tuberculosis

Non-Opportunistic 

Opportunistic

Herpes Zoster

Non-Opportunistic 

Opportunistic

Recurrent 

Disseminated

Sepsis
Depression (including mood disorders and anxiety)/suicide/self-injury (All and Serious, separately)

Depression (including mood disorders and anxiety) (excluding suicide and self-injury)

Suicide/self-injury

Serous suicide/self-injury per GSK adjudication

Suicidal Behaviour

Completed Suicide

Suicidal Ideation

Self-injurious Behaviour without Suicidal Intent

Deaths
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of 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. 
o
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1

Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
13.6.5.
Pharmacokinetic
Belimumab concentration

Assign zero to NQ values (Refer to GUI_51487 for further details)
 
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13.6.6.
Biomarker
13.6.6.1.
Autoantibody, Complement, Immunoglobulins, and BLyS Protein
Biomarker Categorical Definitions
Anti-ds DNA

Positive: ≥ 30 IU /mL

Negative:  < 30 IU /mL
ANA

Positive: index ≥ 0.80

Negative: index < 0.80
aCL status

Positive:  if any of the three isotypes IgG, IgA or IgM are above the lower limit of quantification

Negative: if at least one isotype is non-missing and none of the isotypes are above the lower limit of 
quantification

Missing:  if all three isotypes are missing
BLyS Protein

Below LOQ: <0.02048 ng/mL 

Above LOQ: ≥0.02048 ng/mL 
C3

Positive: < 90 mg/dL

Negative: ≥ 90 mg/dL

Low: < 90 mg/dL

High: > 180 mg/dL
C4

Positive: < 10 mg/dL

Negative: ≥ 10 mg/dL

Low: < 10 mg/dL

High:  > 40 mg/dL
Immunoglobulin G

Low: < 6.94 g/L

Normal/High:  ≥ 6.94 g/L
Immunoglobulin A

Low: < 0.81 g/L 

Normal/High:  ≥ 0.81 g/L
Immunoglobulin M

Low: < 0.48 g/L

Normal/high:  ≥ 0.48 g/L  
13.6.6.2.
B-cell Subsets
Flow Assays
B-cells can be assayed using 3 different flow panels (identification of the flow panel 
responsible for each record is stored in BIMETHCD in the data transfer): Not all assays 
 
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will have the full list of B-cells assessed, but data relating to CD19 B-cells are collected 
using all 3 assay methods, i.e. concentration of CD19 cells from the TBNK panel and 
CD19 event counts on the Plasma and Transitional panels (see detail in the table below). 
Because the numbers of cells observed for the rare B-cell subsets are small, the 
concentration data cannot be adequately summarised in the units provided in the 
SI/SDTM data. Therefore, these subsets are normalized and converted to an appropriate 
unit of measurement, i.e. count/mL. To normalize a rare B-cell subset and convert to 
count/mL, the CD19+ B-cell event count from the same flow panel as the B-cell subset 
being converted is used in the derivation.  For example, the CD19+ event count from the 
plasma flow panel is used to normalize B-cell subsets found in the plasma panel, whereas 
the CD19+ event count from the transitional panel is used when converting rare B-cell 
subsets from the transitional panel.  The study RAP should detail which rare B-cell 
subsets will be normalized and converted. 
Source data
Below are the important variables included in a source data transfer for the B-cells to be 
reported in this study.
Flow Panel
Biomarker 
testing 
method 
code 
Biomarker 
category 
code 
(BICATCD)1
Analyte name
Biomarker 
test code 
(BITESTCD)
Units of 
Measurement 
(BIORRESU)
TBNK
FLWTBNK
CD19
CD19+
CONC
GI/L
TBNK
FLWTBNK
CD19
CD19+
%LYMPH
%
PLASMA
FLWPLSM
CD19
CD19+
EVENTS
EVENTS
TRANSITIONAL
FLWTRANS
CD19
CD19+
EVENTS
EVENTS
PLASMA
FLWPLSM
CD20
CD20+
CONC
GI/L
PLASMA
FLWPLSM
CD20
CD20+
%CD19+
%
PLASMA
FLWPLSM
CD20
CD20+
EVENTS
EVENTS
PLASMA
FLWPLSM
CDX136
Naïve CD20+ CD27-
CONC
GI/L
PLASMA
FLWPLSM
CDX136
Naïve CD20+ CD27-
%CD19+
%
PLASMA
FLWPLSM
CDX136
Naïve CD20+ CD27-
EVENTS
EVENTS
PLASMA
FLWPLSM
CDX137
Memory CD20+ CD27+
CONC
GI/L
PLASMA
FLWPLSM
CDX137
Memory CD20+ CD27+
%CD19+
%
PLASMA
FLWPLSM
CDX137
Memory CD20+ CD27+
EVENTS
EVENTS
PLASMA
FLWPLSM
CDX141
Activated CD20+ CD69+
CONC
GI/L
PLASMA
FLWPLSM
CDX141
Activated CD20+ CD69+
%CD19+
%
PLASMA
FLWPLSM
CDX143
Plasma CD20- CD138+
CONC
GI/L
PLASMA
FLWPLSM
CDX143
Plasma CD20- CD138+
%CD19+
%
PLASMA
FLWPLSM
CDX143
Plasma CD20- CD138+
EVENTS
EVENTS
PLASMA
FLWPLSM
CDX145
Plasmacytoid CD20+ CD138+
CONC
GI/L
PLASMA
FLWPLSM
CDX145
Plasmacytoid CD20+ CD138+
%CD19+
%
PLASMA
FLWPLSM
CDX145
Plasmacytoid CD20+ CD138+
EVENTS
EVENTS
PLASMA
FLWPLSM
CDX156
SLE Subset CD27+CD38+CD19+
CONC
GI/L
PLASMA
FLWPLSM
CDX156
SLE Subset CD27+CD38+CD19+
%CD19+
%
PLASMA
FLWPLSM
CDX156
SLE Subset CD27+CD38+CD19+
EVENTS
EVENTS
1Note: The SI data for Activated B-cells includes BICATCD=CDX141 for its concentration and %CD19 records, and 
CDX155 for its EVENTS record. For all other B-cell subsets, the BICATCD is the same for all 3 records.
 
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B-cell unit conversions and Normalization of Rare B-cell Subsets
The Benlysta program standard is to report common B-cells (CD19, CD20, naïve, and 
memory) in counts per microliter (uL). Common B-cells are not normalized but they 
must be converted to uL for reporting. To convert values reported from GI/L (= 109/L) to 
count per uL (= cells/mm3), multiply the value by 103 or 1000.
Example: (0.25 GI/L) x (1000) = 250/uL  
Rare B-cell subsets are reported in counts per milliliter (mL). Rare B-cell subsets 
reported in GI/L will be converted to cells/ml using the following formula:
Normalized count/mL = (rare cell events) / (CD19+ events) * (CD19+ count/uL) * 1000
Note, the total B-cell (CD19+) concentration from the TBNK panel should be converted 
to count/uL prior to the normalization and conversion of the Rare B-cell subset. 
Example: Normalization and conversion of Plasma CD20-CD138+ to count/mL
Given:

Plasma CD20-CD138+ number of events = 16

CD19+ number of events on Plasma panel = 10250

CD19+ concentration on TBNK panel =  0.35 GI/L
Then:
Plasma CD20-CD138+ Normalized (count/mL) = 16 / 10250 * (0.35*1000) * 1000 = 546.34 count/mL
Reporting B cell subsets
The table below includes variables, labels and details of derivations used in the reporting 
of the B-cell subsets for this study.
B-cell subset label for displays
Lab Test 
Code 
(LBTESTCD)
Derivation for Normalization and / or Conversion 
of B-cell Subsets
Common B-cells
CD19 (/uL)
CD19
May require conversion to /uL
CD20 (/uL)
CD20
May require conversion to /uL
Naive CD19+CD20+CD27- (/uL)
CDX136
May require conversion to /uL
Naive CD19+CD20+CD27- (%CD19)
CDX13619
N/A
Memory CD19+CD20+CD27+ (/uL)
CDX137
May require conversion to /uL
Memory CD19+CD20+CD27+ (%CD19)
CDX13719
N/A
Rare B-cells
Activated CD19+CD20+CD69+ 
Normalized (COUNT/mL)
CDX141N
CDX155 EVENTS, CD19 EVENTS from Plasma 
Panel and CD19 concentration from TBNK Panel
 
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Plasma CD19+CD20-CD138+ 
Normalized (COUNT/mL)
CDX143N
CDX143 EVENTS, CD19 EVENTS from Plasma 
Panel and CD19 concentration from TBNK Panel
Plasmacytoid CD19+CD20+CD138+ 
Normalized (COUNT/mL)
CDX145N
CDX145 EVENTS, CD19 EVENTS from Plasma 
Panel and CD19 concentration from TBNK Panel
SLE Subset CD19+CD38b+CD27b+Lymph 
Normalized (COUNT/mL)
CDX156N
CDX156 EVENTS, CD19 EVENTS from Plasma 
Panel and CD19 concentration from TBNK Panel
 
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13.7.
Appendix 7: Reporting Standards for Missing Data
13.7.1.
Premature Withdrawals
Element
Reporting Detail
General
Subject study completion (i.e. as specified in the protocol) was defined as s

Treatment holiday group: completion of the 24-week treatment 
holiday period plus the belimumab re-introduction treatment period 
to Week 52. 

Control and long-term discontinuation groups: completion of all 
visits to Week 52.
For reporting purposes, withdrawal from the maintenance phase is defined 
in Section 13.6.2.
Withdrawn subjects were not replaced in the study
All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will 
be summarised as withdrawal visits.
13.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will 
be documented along with the reason for exclusion in the clinical study report.
LOCF

In the LOCF dataset, missing values will be carried forward from the 
previous, non-missing available on-treatment assessment.

For the TH group, LOCF will not be applied across the TH and RS 
phases.
SLICC/ACR 
Damage Index

Missing data due to prohibited medication or study withdrawal will be 
imputed using LOCF

For the TH group, LOCF will not be applied across the TH and RS 
phases.
SELENA 
SLEDAI, 

Missing data will be imputed using LOCF.

For the TH group, LOCF will not be applied across the TH and RS 
phases.
 
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Element
Reporting Detail
Rebound, PGA

If an individual SELENA SLEDAI item data is missing at the first 
timepoint in the RS phase, the item will be considered not present.  
Reduction in 
Daily Prednisone 
Dose

The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) 
imputation will be applied.  If a subject withdraws from the study and/or 
receives a protocol-prohibited medication prior to a scheduled visit, the 
subject will be considered a non-responder (i.e. no reduction in 
prednisone) for that and subsequent visits.   
Average daily 
prednisone dose

Observed data will be used with no imputation.
Auto-antibodies, 
immunoglobulins, 
biomarkers, BLyS 
protein

Observed data will be used with no imputation
Immunogenicity

Observed data will be used with no imputation.
13.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the Day 0 visit date (LTD and TH 
arms) or the study treatment start date (TC arm) will be used and hence the 
event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications and 
Medical History

Medications with partial or missing start and/or stop dates will be assumed 
to be concomitant unless there is evidence through comparison of partial 
dates to suggest otherwise, for example if the day is missing, then the 
month and year will be compared to the month and year of the first dose 
date of study treatment and if the month and year are the same or later, 
then the medication will be considered concomitant.
 
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13.7.3.
Handling of Prohibited Medications, Withdrawals and Deaths
Element
Reporting Detail
Time to SFI 
Flares

Evaluated up to Week 52 

If a subject takes a prohibited medication during the time period being 
analyzed, the subject will be considered as having a SFI flare at the start 
date of the prohibited medication.   

If a subject withdraws from the study, the will be censored at last flare
assessment date

If a subject dies, censor at the date of death
Time to Renal 
Flare

Evaluated up to Week 52 

If a subject withdraws from the study, the will be censored at last renal  flare 
assessment date

If a subject dies, censor at the date of death
Number of SFI 
Flares

If a subject withdraws from the study, dies or takes a prohibited medication, 
the subject will be considered as having a SFI flare. 
Number of days 
of daily 
prednisone dose 
≥7.5 mg/day 
and/or 
increased by 
25%

The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) 
imputation will be applied.  If a subject withdraws from the study and/or 
receives a protocol-prohibited medication, the subject will be considered to 
have met this endpoint criteria (i.e, dose ≥ 7.5 mg/day and/or increased by 
25%) after the date of dropout or the date that the medication is started, 
whichever comes first, up until the visit date, and for those days in intervals 
for subsequent attended visits. Before this date, the evaluated endpoint will 
be assessed using available data.
Number of days 
of daily 
prednisone dose 
≤7.5 mg/day 
and/or 
decreased by 
25%

The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) 
imputation will be applied.  If a subject withdraws from the study and/or 
receives a protocol-prohibited medication, the subject will be considered a 
non-responder for this endpoint criteria (i.e., dose >7.5 mg/day and/or did 
not decreased by 25%) after the date of dropout or the date that the 
medication is started, whichever comes first, and for those days in intervals 
for subsequent attended visits. Before this date, the evaluated endpoint will 
be assessed using available data.
Reduction in 
Daily 
Prednisone 
Dose

The Dropout (DO)/Prohibited Medication (PM)=Non-responder (NR) 
imputation will be applied.  If a subject withdraws from the study and/or 
receives a protocol-prohibited medication prior to a scheduled visit, the 
subject will be considered a non-responder (i.e. no reduction in prednisone) 
for that and subsequent visits.
 
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13.8.
Appendix 8: Values of Potential Clinical Importance
13.8.1.
Laboratory Values
The following laboratory parameters are collected per the protocol.
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)
Partial thromboplastin time (PTT)
  
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Dysmorphic RBC
Casts (specified by 
type e.g., RBC, WBC)
Spot Urine (protein : creatinine 
ratio)
Urine Pregnancy
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutanyl transpeptidase (GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
        Hepatitis B Viral DNA PCR
            Quantitative (HBV DNA)
Estimated Creatinine Clearance/ GFR 
(Cockroft-Gault)
Liver event follow-up assessments:
       Hepatitis A IgM antibody
       HBsAg and hep B Core antibody (IgM)
       Hepatitis C RNA
       Hepatitis delta antibody
       Cytomegalovirus IgM antibody
       Epstein-Barr viral capsid antigen IgM
            antibody
       Hepatitis E IgM antibody
       CPK
       Anti-smooth muscle antibody
       Type 1 anti-liver kidney microsomal
             antibodies
       PK
       IgG
       Fractionated bilirubin
       Serum acetaminophen
Biological Markers
BLyS protein
Serum complement (C3 and C4) 
B-cell subtypes
Immunoglobulins
Serum immunoglobulin isotypes:  IgG, IgM, IgA
Immunogenicity
Autoantibodies
ANA
Anti-dsDNA
aCL
 
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13.8.2.
Adverse Event and Laboratory Value Severity Grade Tables
HEMATOLOGY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Hemoglobin
> 9.5 - 11.0 g/dL
> 8.0 – 9.5 g/dL
6.5 - 8.0 g/dL
< 6.5 g/dL
Leukocytes
3000-3999/mm3
2000-2999/mm3
1000-1999/mm3
< 1000/mm3
Absolute Neutrophil Count
1500-1999/mm3
1000-1499/mm3
500-999/mm3
< 500/mm3
Platelets
75,000 -
99,999/mm3
50,000 – 74,999/mm3 25,000 - 49,999/mm3
< 25,000/mm3
Prothrombin Time (PT)
> 1.0-1.25 x ULN*
> 1.25-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0 x ULN
Partial Thromboplastin Time (PTT)
> 1.0-1.66 x ULN
> 1.66-2.33 x ULN
> 2.33-3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0-10.0 %
10.1-15.0 %
15.1-20.0 %
> 20%
(continued)
1.
*ULN = Upper Limit of Normal                                                        Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
CARDIOVASCULAR
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cardiac Arrhythmia
-
Asymptomatic/transient; 
dysrhythmia; no treatment req
Recurrent/persistent 
dysrhythmia. Symptomatic; 
treatment req
Unstable dysrhythmia hospitalization
and treatment required
Hypotension
Transient orthostatic 
hypotension, no treatment
Symptoms correctable 
with oral fluid treatment
IV fluid req,
no hospitalization req
Hospitalization req
Hypertension
Transient, increase
> 20 mm/Hg; no treatment
Recurrent; chronic increase
> 20 mm/Hg, treatment req
Acute treatment req; out patient 
hospitalization possible
Hospitalization req
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion,
pain, ECG changes
Tamponade OR pericardiocentesis 
OR surgery req
Hemorrhage, Blood Loss
-
Mildly symptomatic; 
no treatment required
Gross blood loss OR
1-2 units transfused
Massive blood loss OR
> 2 units transfused
Modified from DMID Adult Toxicity Tables, 2001(continued)
  
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
CHEMISTRIES
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Sodium
  Hyponatremia
130-135 meq/L
123-129 meq/L
116-122 meq/L
< 116 meq/L
  Hypernatremia
146-150 meq/L
151-157 meq/L
158-165 meq/L
> 165 meq/L
Potassium
  Hypokalemia
3.0-3.4 meq/L
2.5-2.9 meq/L
2.0-2.4 meq/L
< 2.0 meq/L
  Hyperkalemia
5.6-6.0 meq/L
6.1-6.5 meq/L
6.6-7.0 meq/L
> 7.0 meq/L
Phosphate
  Hypophosphatemia
2.0-2.4 mg/dL
1.5-1.9 mg/dL
1.0-1.4 mg/dL
< 1.0 mg/dL
Calcium- (Corrected For Albumin)
  Hypocalcemia
7.8-8.4 mg/dL
7.0-7.7 mg/dL
6.1-6.9 mg/dL
< 6.1 mg/dL
  Hypercalcemia
10.6-11.5 mg/dL
11.6-12.5 mg/dL
12.6-13.5 mg/dL
>13.5 mg/dL
Magnesium
  Hypomagnesemia
1.2-1.4 meq/L
0.9-1.1 meq/L
0.6-0.8 meq/L
< 0.6 meq/L
Albumin
  Hypoalbuminemia
3.00-3.49 g/dL
2.50-2.99 g/dL
2.00-2.49 g/dL
< 2.00 g/dL
Bilirubin (Total)
  Hyperbilirubinemia (Total)
> 1.0-1.5 x ULN
> 1.5-2.5 x ULN
> 2.5-5 x ULN
> 5 x ULN
Glucose
  Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
< 30 mg/dL
  Hyperglycemia 
116-160 mg/dL
161-250 mg/dL
251-500 mg/dL
> 500 mg/dL
  (nonfasting & no prior diabetes)
  Triglycerides
151-399 mg/dL
400-750 mg/dL
751-1200 mg/dL
> 1200 mg/dL
Creatinine
> 1.0-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0-6.0 x ULN
> 6.0 x ULN
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
CHEMISTRIES (continued)
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Uric Acid
  Hyperuricemia
7.5-10.0 mg/dL
10.1-12.0 mg/dL
12.1-15.0 mg/dL
> 15.0 mg/dL
Liver Transferases (AST, ALT, and 
GGT)
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Alkaline Phosphatase
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Pancreatic Enzymes
Amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Pancreatic amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Lipase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Hypoglobulinemia (IgG)*
550-700 mg/dL
400-549 mg/dL
250-399 mg/dL
< 250 mg/dL
(continued)
1.
*Eibl , 1995; Goldfarb, 2001; Yamini, 2001.                                                                                                                                      Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
GASTROINTESTINAL
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Nausea
Mild OR transient; 
reasonable intake 
maintained
Mod discomfort 
OR intake decreased 
for < 3 days
Severe discomfort OR 
minimal intake 
for 3 days
Hospitalization required
Vomiting
Mild OR transient; 
2-3 episodes/day OR 
mild vomiting lasting 
< 1 week
Mod OR persistent; 
4-5 episodes per day; 
OR vomiting lasting 
1 week
Severe vomiting of all 
foods/fluids in 24 hours 
OR orthostatic hypotension
OR IV treatment req
Hypotensive shock OR hospitalization 
required for IV treatment req
Diarrhea
Mild or transient; 
3-4 loose stools per day 
OR mild diarrhea lasting 
< 1 week
Mod OR persistent; 
5-7 loose stools per day 
or diarrhea lasting 
1 week
Bloody diarrhea; 
OR orthostatic hypotension 
OR > 7 loose stools/day 
OR IV treatment req
Hypotensive shock 
OR hospitalization req
Oral Discomfort/Dysphagia
Mild discomfort, no difficulty 
swallowing
Difficulty swallowing but able 
to eat and drink
Unable to swallow solids
Unable to drink fluids; 
IV fluids req
Constipation
Mild
Moderate
Severe
Distention with vomiting
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
RESPIRATORY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cough 
(for aerosol studies) 
Transient; no treatment
Treatment associated 
cough; inhaled bronchodilator
Uncontrolled cough; 
systemic treatment req
Bronchospasm Acute
Transient; no treatment; 
FEV1 70% to 
< 80% 
(or peak flow)
treatment req; normalizes with 
bronchodilator; 
FEV1 50% to < 70% 
(or peak flow)
No Normalization 
with bronchodilator; 
FEV 25% to < 50% 
(or peak flow), retractions
Cyanosis; FEV1 < 25% 
(or peak flow) OR intubated
Dyspnea
Dyspnea on exertion
Dyspnea with 
normal activity
Dyspnea at rest
Dyspnea requiring O2 therapy
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
URINALYSIS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Proteinuria
Dispstick
Protein
1 +
2-3 +
4 +
Nephrotic syndrome
Spot Urine:    
Protein:Creatinine 
Ratio mg/mg
0.2-1.0
> 1.0-2.0
> 2.0-3.5
> 3.5
24 Hour Urine:
Protein
200 mg - 1g loss/day
> 1-2 g loss/day
> 2-3.5 g loss/day
Nephrotic syndrome
OR > 3.5 g loss/day
Hematuria
Microscopic only
> 3 to < 10 RBC/hpf
Gross, No clots
10 RBC/hpf
Gross plus clots OR 
RBC casts
Obstructive OR transfusion required
(continued)
RBC = red blood cell; hpf = high power field.
Modified from DMID Adult Toxicity Tables, 2001
Adverse Event and Laboratory Value Severity Grade Tables (continued)
MISCELLANEOUS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Fever (oral > 12 hours)
37.7-38.5C or
100.0-101.5F
38.6-39.5C OR
101.6-102.9F
39.6-40.5C OR
103-105F
> 40.5C OR > 105F
Headache
Mild; No treatment req
Mod; or non-narcotic analgesia 
treatment
Severe; OR responds to initial 
narcotic treatment
Intractable; OR requiring 
repeated narcotic treatment
Allergic Reaction
Pruritus without rash
Localized urticaria
Generalized urticaria 
angioedema
Anaphylaxis
 
 
 
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MISCELLANEOUS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cutaneous/Rash/ Dermatitis
Erythema, pruritus rash 
OR dry desquamation
Diffuse maculopapular 
OR dry desquamation
Vesiculation OR moist 
desquamation ulceration
ANY ONE: mucous membrane involvement, 
suspected 
Stevens-Johnson (TEN), erythema multiforme, 
necrosis req surgery, exfoliative dermatitis
Local Reaction (secondary 
to parenteral treatment- not 
vaccination or skin test)
Erythema
Induration < 10 mm 
OR inflammation 
OR phlebitis
Induration > 10 mm 
OR ulceration
Necrosis of skin
Fatigue
Normal activity 
Reduced < 25%
Normal activity 
Reduced 25-50%
Normal activity 
reduced > 50%; 
cannot work
Unable to care for self
(continued)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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Adverse Event and Laboratory Value Severity Grade Tables (continued)
NEUROLOGIC
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Neuro-cerebellar
Slight incoordination OR 
dysdiadochokinesia
Intention tremor OR 
dysmetria OR slurred speech 
OR nystagmus
Ataxia requiring assistance to walk 
or arm incoordination interfering 
with ADLs
Unable to stand
Neuro-psych/ mood
none
Severe mood changes requires 
medical intervention
Acute psychosis requiring 
hospitalization
Paresthesia 
(burning, tingling, etc)
Mild discomfort; 
no treatment needed
Mod discomfort 
non-narcotic analgesia req
Severe discomfort; OR narcotic 
analgesia req with symptomatic 
improvement
Incapacitating; OR not responsive 
to narcotic analgesia
Neuro-motor
Mild weakness in muscle 
of feet but 
able to walk and/or mild 
increase or decrease in 
reflexes
Mod weakness in feet (unable to walk on 
heels and/or toes), mild weakness in 
hands, still able to do most hand tasks 
and/or loss of previously present reflex 
or development of hyperreflexia 
and/or unable to do deep knee 
bends due to weakness
Marked distal weakness (unable to 
dorsiflex toes or foot drop), and 
mod proximal weakness ie, in 
hands interfering with ADLs and/or 
requiring assistance to walk and/or 
unable to rise from chair 
unassisted
Confined to bed or wheelchair 
because of muscle weakness
Neuro-sensory
Mild impairment 
sensations, 
(ie, vibratory, pinprick, 
hot/cold in great toes) in 
focal area or symmetrical 
distribution
Mod impairment mod de-sensation, 
(ie, of vibratory, pinprick, hot/cold to 
ankles) and/or joint position or mild 
impairment that is not symmetrical.
Severe impairment (dec or loss of 
sensation to knees or wrists) or 
loss of sensation of at least mod 
degree in multiple different body 
areas (ie, upper and lower 
extremities)
Sensory loss involves limbs 
and trunk
(concluded)
Modified from DMID Adult Toxicity Tables, 2001
 
 
 
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13.9.
Appendix 9: Adverse Events of Special Interest
The primary source for rules governing identification, adjudication, and reporting of 
Adverse Events of Special Interest is the Program Safety Analysis Plan (PSAP).  AESI 
are defined using preferred terms from the current version of MedDRA.  The intent is to 
update these definitions semi-annually using the newest MedDRA version.  Preferred 
terms used in the current and prior versions of MedDRA can be found in IMMS at the 
following path /Study File/GSK1550188/_Project/Meta Analysis/PSAP/AESI_201.csv.
13.9.1.
Malignant neoplasms
Malignant neoplasms are identified using the sub-SMQs of Malignant or unspecified 
tumours (20000091), malignancy related conditions (20000092), haematological 
malignant tumours (20000227), non-haematological malignant tumours (20000228), 
haematological tumours of unspecified malignancy (20000229) and non-haematological 
tumours of unspecified malignancy (20000230) under the current version of MedDRA.  
The sub-SMQ of Malignant or unspecified tumours contains two further subcategories: 
“Malignant Tumours” and “Tumours of unspecified malignancy.”  Tumours of 
unspecified malignancy will be reviewed by GSK and identified as malignant or non-
malignant for reporting.
Malignancies other than those in the “Tumours of unspecified malignancy” category will 
be categorized as hematologic, skin, or solid, based on a CMQ developed by the MAH.  
In addition, the following customizations have been made since MedDRA v19.1:

The term “Paraneoplastic glomerulonephritis” has been removed from the SMQ as it 
is a complication of malignancy. 

The term “Mismatch repair cancer syndrome” has been added as a tumour of 
unspecified malignancy

The term “Malignant meningioma metastatic” has been added as a solid tumor type.

The term “Marginal zone lymphoma recurrent” has been added as a hematological 
tumor type.

The term “Skin neoplasm bleeding” has been added as a tumour of unspecified 
malignancy.

The term “Astroblastoma” has been added as a solid tumour type.

The term “Epstein Barr virus positive mucocutaneous ulcer” has been added as a 
hematological tumour type.

The term “Langerhans cell sarcoma” has been added as a solid tumour type.

The term “Naevoid melanoma” has been added as a skin tumour type.

The term “Nasopharyngeal cancer metastatic” has been added as a solid tumour type.

The term “Phospaturic mesenchymal tumour” has been added as a solid tumour type.

The term “Primary gastrointestinal follicular lymphoma” has been added as a 
hematological tumour type.
 
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
The term “Squamous cell breast carcinoma” has been added as a solid tumour type.

The term “Transformation to acute myeloid leukaemia” has been added as a 
hematological tumour type.

The term “FIP1L1/PDGFR alpha fusion kinase positive” has been added as a 
hematological tumour type.

The term “Gleason grading score” has been added as a solid tumour type.

The term “Oncotype test” has been added as a solid tumour type.

The term “Intestinal metastasis” has been added as an unspecified tumour type.

The term “Maternal cancer in pregnancy” has been added as an unspecified tumour 
type.

The term “Microsatellite instability cancer” has been added as an unspecified tumour 
type.

The term “Pulmonary tumour thrombotic microangiopathy” has been added as an 
unspecified tumour type.

The term “Tumour cavitation” has been added as an unspecified tumour type.

The term “Malignant urinary tract obstruction” has been added as a solid tumour type.
Non-melanoma skin cancer (NMSC) will be categorized using a CMQ developed by the 
Marketing authorization holder (MAH) 
Note beginning with MedDRA v20.0 in 2017, there will be two new sub-SMQs of 
Hematological Malignancies. These do not result in any changes to how malignant 
neoplasms are identified.
13.9.2.
Post-infusion systemic reactions
Post-infusion systemic reactions will be identified using a customization of the 
Anaphylactic Reaction SMQ (20000021). This SMQ includes a broad list of preferred 
terms including symptoms of systemic injection/infusion reactions and hypersensitivity 
reactions and anaphylaxis. For the Anaphylactic Reaction query, 4 categories of preferred 
terms are considered, including a set of core anaphylactic terms (Category A), upper 
airway/respiratory terms (Category B), angioedema/urticaria/pruritus/flush terms 
(Category C), and cardiovascular/hypotension terms (Category D).
The customizations of the SMQ involve terms in Categories A, B and C. Category A has 
been modified to include the following additional terms: “Infusion-related reaction”,
“Drug hypersensitivity”, “Hypersensitivity”, and “Urticarial vasculitis”. Category B has 
been modified to include the following additional terms: “Oropharyngeal oedema” and 
“Pharyngeal oedema”.  Category C has been modified to include the following additional 
term: “Fixed eruption”.  GSK has also removed three terms that are not relevant for an 
analysis of hypersensitivity reactions to belimumab (“Anaphylactic transfusion reaction”, 
“Dialysis membrane reaction”, and “First use syndrome”). Anaphylactic transfusion 
reaction is an adverse event associated with a blood transfusion, not related to study 
 
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medication.  First use syndrome and dialysis membrane reaction are associated with 
adverse events related to kidney transplants and dialysis, not related to study medication.
Algorithmic Search Criteria
The post-infusion systemic reactions per Anaphylactic Reaction SMQ algorithmic search 
are defined as follows:
Subjects must have the following associated with the same infusion/injection: 
a.
at least 1 AE coding to a Category A preferred term or
b.
2 AEs, 1 coding to a Category B preferred term and the other coding to a Category C 
preferred term or
c.
2 AEs, 1 coding to a Category D preferred term and the other coding to either a 
Category B preferred term or to a Category C preferred term.
For the algorithmic search, if any event at a given infusion/injection meets the definition 
under criteria a, b or c, then all events in Categories A, B, C and D associated with that 
injection/infusion will be considered AESI.
For CSR reporting, all post-infusion systemic reaction AESIs defined via narrow, broad, 
or algorithmic search, the AEs need to have occurred on the day of an infusion/injection 
or within 3 days after an infusion/injection. See Section 13.3.4 for the definition of the 3-
day assessment window.  GSK will review all serious events identified via the broad 
search occurring within 21 days after an infusion/injection, and adjudicate these events as 
post-infusion systemic reactions or hypersensitivity reactions per the criteria in Section
13.9.10.2.  Adverse events with partial or missing start dates will be included unless there 
is evidence through comparison of partial dates to suggest otherwise.
Sampson Criteria
Sampson et al define anaphylaxis as a severe, potentially fatal, systemic allergic reaction 
that occurs suddenly after contact with an allergy-causing substance. In addition, one of 
the following 3 criteria must be met: (1) acute onset of illness with involvement of skin or 
mucosal tissue, accompanied with either respiratory compromise, reduced blood pressure, 
or hypotension-related symptoms of end-organ dysfunction (2) reduced blood pressure 
associated with a known allergen or (3) two or more of the following that occur rapidly 
after exposure to an allergen: a) involvement of skin-mucosal tissue b) respiratory 
compromise c) reduced blood pressure d) persistent GI symptoms. 
With the exception of GI symptoms, all symptoms required to assess anaphylaxis per 
Sampson criteria would be identified by Broad Anaphylaxis SMQ or the Anaphylactic 
Reaction SMQ algorithmic. Therefore, any events falling under the below criteria will be 
adjudicated by GSK prior to database release to determine if serious anaphylaxis per 
Sampson criteria is met.
Possible cases of serious anaphylaxis per Sampson criteria will be identified as follows:
a.
Any Infusion/Injection-related Reaction per Anaphylactic Reaction SMQ broad 
 
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search SAE which occurs on the day of an injection.
b.
Any AE or SAE in the “Gastrointestinal disorders” SOC that occurs on the day that 
criterion in a) above is met.
c.
Any anaphylaxis and hypersensitivity reactions per Anaphylactic Reaction SMQ 
algorithmic search SAE which occurs on the day of an infusion/injection.
13.9.3.
Infections
The infections of special interest are described below.
13.9.3.1.
Opportunistic Infections
Opportunistic infections will be identified using a broad CMQ developed by the MAH.
Any events falling under these preferred terms will be adjudicated by GSK prior to 
database release to determine if criteria are met for an opportunistic infection, per the 
criteria in Section 13.9.10.3.  
13.9.4.
Mycobacterium Tuberculosis
Tuberculosis events will be identified using a CMQ developed by the MAH. Any events 
falling under these preferred terms will be adjudicated by GSK prior to database release 
to determine if criteria are met for an opportunistic infection (Section 13.9.10.3).  
13.9.5.
Herpes Zoster
Herpes Zoster events will be identified using a CMQ developed by the MAH.  Additional 
manual adjudication by GSK prior to database release will identify events that are 
recurrent or disseminated (Section 13.9.10.3).
13.9.6.
Pneumonia
Pneumonia events will be identified using a CMQ developed by the MAH.  Pneumonia 
events will not be reported separately, but are being flagged in the event further 
evaluation is necessary.
13.9.7.
Sepsis
Sepsis events will be identified using a CMQ developed by the MAH.
13.9.8.
Depression/suicide/self-injury
13.9.8.1.
Depression (excluding suicide and self-injury)
Depression events will be identified using a CMQ including the preferred terms from the 
depression (excluding suicide and self injury) SMQ (20000035) plus additional terms 
added by the MAH.
 
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13.9.8.2.
Suicide and Self-Injury
Suicide and self-injury events will be identified using the SMQ (20000035) preferred 
terms.
13.9.9.
Fatalities
All fatalities will be identified in the clinical database and subsequently adjudicated by 
the GSK SRT into a general category of death (Section 13.9.10.5).
Post-study fatalities that are captured in ARGUS prior to CSR approval, but are not 
captured in the clinical database, will be described within the CSR text but cannot be 
included in statistical post-text displays. 
13.9.10.
GSK SRT Adjudication of Adverse Events of Special Interest
Adverse events of special interest (AESI) are identified per the preferred terms and other 
criteria described in Section 13.9.  The following AESI are adjudicated at the subject 
level by the GSK SRT during regular SRT meetings or during quarterly adjudication.  
The adjudication occurs prior to database release and is performed for reporting purposes, 
per the criteria described below.
Assignment of adjudication flags in the clinical database will occur as part of the 
quarterly SRT review process.  In addition, as part of individual study close-out 
procedures, the adjudications should be finalized as follows:

Just preceding data base release (DBR), allowing time to send queries or update the 
eCRF/database as necessary prior to DBR.

After DBR to provide final confirmation of adjudications and ensure there are no new 
AESI or relevant data changes to adjudicated events since the pre-DBR adjudication.  
This would be a requirement for declaring data a freeze (DBF).
13.9.10.1. Malignancies
All malignancies identified via the preferred terms will be reviewed by GSK SRT.  The 
classification of malignancies as solid tumor, hematological, and skin will be reviewed 
against the verbatim term to confirm an appropriate and accurate preferred term has been 
assigned, or to recommend follow-up with the investigator for additional specificity on 
the verbatim term. In addition, malignancies that are flagged more than once, e.g., based 
on a term for both a diagnostic procedure and a diagnosis, will be adjudicated as one 
event.
Tumors of unspecified malignancy, as identified via preferred terms, will be reviewed 
clinically by the GSK SRT for reporting.  In general, non-serious events in the tumours of 
unspecified malignancy with insufficient information will be categorized as not 
malignant. Serious adverse events with insufficient information will be categorized as 
either not malignant or malignant based on the type of tumor and likelihood the tumor 
type is malignant (e.g., thyroid nodules are common in SLE patients and are generally not 
 
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malignant; tumor types with higher likelihood for malignancy would be assumed to be 
malignant).
13.9.10.2. Serious hypersensitivity and post-infusion systemic reactions
Before the data base is released, GSK SRT will review all serious cases identified from 
the Broad Anaphylaxis SMQ as described in Section 13.9, applying clinical judgment to 
determine if the preferred terms are indicative of a hypersensitivity or infusion/injection
reaction. Time to onset after an infusion/injection and details provided in the clinical 
narratives with respect to the nature and likely cause of the events are taken into 
consideration. Time to onset within 24 hours is generally applied to post 
infusion/injection reactions. The GSK SRT adjudicates serious hypersensitivity reactions 
into a category based primarily on time to onset: acute (onset ≤ 1 day), delayed acute 
(onset 2-3 days), or delayed, non-acute (onset 4-21 days).  In addition to time to onset, 
description of associated symptoms is taken into account for this categorization. 
In addition, possible cases of serious anaphylaxis per Sampson criteria will be identified 
per the criteria in Section 13.9. Any events falling under these criteria will be adjudicated 
by GSK prior to database release to determine if serious anaphylaxis per Sampson criteria 
is met.
13.9.10.3. Potential opportunistic infections
Opportunistic infections (OIs) will be identified using a list of preferred terms, designed 
to cast a wide net for events potentially indicative of an opportunistic infection. Any 
identified events will be adjudicated by the GSK SRT prior to database release to 
determine if criteria are met for an opportunistic infection. Targeted follow-up is sought 
for events with insufficient information. In general, potential OIs that are non-serious 
with insufficient information to adjudicate will be considered non-opportunistic. Potential 
OI SAEs with insufficient information to adjudicate will be considered opportunistic. See 
below for a list of agreed upon pathogens and infections considered to be opportunistic
for the purpose of adjudication.
Pathogens and Infections Considered Opportunistic:

Acinetobacter infection

Aspergillosis

Blastomycosis, extrapulmonary

Candidiasis of esophagus, bronchi, trachea or lungs

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis infection, chronic intestinal (greater than 1 month duration)

CMV disease other than liver, spleen, or nodes

Herpes simplex – bronchitis, pneumonitis, or esophagitis

Herpes Zoster (adjudication details are below)

Histoplasmosis disseminated or extrapulmonary

Human polyomavirus infection

Isosporiasis, chronic intestinal (greater than one month duration)
 
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
Listeriosis

Mycobacterium avium complex or M. Kansasii, disseminated or extrapulmonary

Nocardiosis

Other non-tuberculous mycobacterium (NTM) infections (other species or 
unidentified species), disseminated or extrapulmonary*

Polyomavirus (JC virus or BK virus) associated nephropathy (including PML)

Pneumocystis jiroveci infection

Toxoplasmosis of brain
* Extra pulmonary NTM infections are generally considered an OI unless the affected 
extra pulmonary area followed a wound or trauma.
In addition, GSK SRT will review all SAEs, including those coded under preferred terms 
not in the preferred term definition, and utilizing the supplemental/narrative information, 
will adjudicate the SAEs as OI if warranted based on medical judgment. 
Other Infections of Interest but not generally considered opportunistic:

Mycobacterium tuberculosis (adjudication details are below)
Herpes Zoster
Herpes Zoster events will be identified per preferred terms. Adjudication by GSK SRT 
will identify events that are recurrent or disseminated. Herpes Zoster is considered 
disseminated if there is involvement of other organs other than the skin or if skin lesions 
(1) cross the midline of the body or (2) are in non-adjacent dermatomes or (3) are located 
in more than three adjacent dermatomes.  Herpes zoster is considered an opportunistic 
infection if it is adjudicated as recurrent or disseminated.  However, there may be some 
uncommon occurrences of a herpes zoster case that is adjudicated as an OI but is neither 
recurrent or disseminated.
Mycobacterium Tuberculosis
Tuberculosis (TB) cases are reviewed by the GSK SRT to determine if a case is an OI. 
The following principles are applied: Pulmonary TB in an endemic area is not considered 
an OI. Pulmonary TB in a non-endemic area would be considered an OI unless the 
subject had close contact with a person infected with TB. Extra pulmonary TB is 
generally considered an OI unless the affected extra pulmonary area followed a wound or 
trauma.
 
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13.9.10.4. Suicide/self-injury
Suicide and self-injury SAEs will be identified using the preferred terms and 
subsequently adjudicated into the following categories:
Adjudicated Category
Suicidal Behaviour
      Completed Suicide
Suicidal Ideation
Self-Injurious Behaviour without Suicidal Intent
In addition, GSK SRT will review all SAEs, including those coded under preferred terms 
not in the definition, and utilizing the supplemental/narrative information, will adjudicate 
the SAEs as suicide/self-injury if warranted based on medical judgment. 
13.9.10.5. Fatalities
All fatalities will be identified in the clinical database and subsequently adjudicated by 
the GSK SRT into a general category of death.
All fatalities will be adjudicated into one of the following categories:
Adjudicated Category of Death
SLE-Related
Infectious
Vascular
Gastrointestinal
Respiratory
Malignancy
Hypersensitivity
Suicide
Surgical Complication
Unknown
Hematologic
Trauma
Additional ‘categories of death’ may be added in the future should a fatality not clearly 
fit into one of the ‘categories’ listed above.  The ‘categories’ will not change unless 
agreed upon by the GSK SRT.  
 
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13.10.
Appendix 10: Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
aCL
Anti-cardiolipin Antibody
ACR
American College of Rheumatology
AE
Adverse Event
AESI
AEs of Special Interest
Anti-dsDNA
Anti-double-stranded DNA
ANA
Anti-nuclear Antibody
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
BUN
Blood urea nitrogen
CDISC
Clinical Data Interchange Standards Consortium
C3 / C4
Complement 3 / Complement 4
CI
Confidence Interval
CNS
Central Nervous System
CRF
Case Report Form
CS
Clinical Statistics
CSR
Clinical Study Report
eCRF
Electronic Case Report Form
DO
Dropout
DOB
Date of Birth
DP
Decimal Places
DQE
Data Quality Evaluation Report
eCRF
Electronic Case Report Form
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
GUI
Guidance
hpf
High-power Field
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IgA, G, M
Immunoglobulin A, G, M
IM
Intramuscular
IMMS
International Modules Management System
ITT
Intention-to-treat
IV
Intravenous
LLN
Lower Limit of Normal
LOCF
Last Observation Carried Forward
LOQ
Limit of Quantification
LTD
Long-term discontinuation
MedDRA
Medical Dictionary for Regulatory Activities
MHE
Mental Health Enhanced Score
NMSC
Non-melanoma skin cancer
NR
Non-responder
OI
Opportunistic Infections
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
 
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Abbreviation
Description
PDMP
Protocol Deviation Management Plan
PGA
Physician’s Global Disease Assessment
PK
Pharmacokinetic
PM
Prohibited medication
PopPK
Population Pharmacokinetic 
PSAP
Program Safety Analysis Plan
PT
Preferred Term/Prothrombin Time
PTT
Partial thromboplastin Time
QC
Quality Control
RAP
Reporting and Analysis Plan
RAMOS
Randomization & Medication Ordering System
RBC
Red blood cell
RS
Re-start Phase
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SC
Subcutaneous
SD
Standard deviation
SDTM
Study Data Tabulation Model
SE
Standard error
SELENA
Safety of Estrogen in Lupus National Assessment
SI
System independent
SFI
SLE Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SMQ
Standardized MedDRA Query
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operation Procedure
SS
SELENA SLEDAI 
TC
Treatment Control
TH
Treatment Holiday
TLFs
Tables, Listings, and Figures
TX
Treatment
ULN
Upper Limit of Normal
uPCR
Urine Protein: Creatinine Ratio.
VAS
Visual Analogue Scale
WOCF
Worst Observation Carried Forward
13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
BENLYSTA
SAS
BLyS
 
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13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.17
1.1 to 1.1
Efficacy
2.1 to 2.12
2.1 to 2.3
Safety
3.1 to 3.52
3.1 to 3.6
Pharmacokinetic
4.1 to 4.1
4.1 to 4.2
Biomarker
5.1 to 5.23
5.1 to 5.10
Section
Listings
ICH Listings
1 to 39
Other Listings
40 to 51
13.11.2.
Deliverables
Priority
Description
H
Included in Headline Data Package
 
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13.11.3.
Study Population Tables
Study Population Tables
No.
Population
Title
Programming Notes
Priority
Headline Results 
denoted by H
Subject Disposition
1.1.
ITT
Subject Enrollment
1.2.
ITT
Enrolment by Country and Site
EudraCT/Clinical Operations
1.3.
Screened
Study Populations
IDSL
1.4.
Screened
Screening Status and Reasons for Failing Screening
Journal Requirements
1.5.
ITT
Subject Disposition for the Subject Conclusion Record (52-
Week Treatment Phase)
ICH E3, FDAAA, EudraCT
1.6.
ITT
Subject Disposition for the Subject Conclusion Record 
(Maintenance Phase)
ICH E3, FDAAA, EudraCT
1.7.
ITT
Time to Withdrawal from the Study
Benlysta Standard
1.8.
ITT
Subject Disposition at Each Study Epoch
ICH E3
Protocol Deviation
1.9.
ITT
Subjects with Important Protocol Deviations
ICH E3
Demographic and Baseline Characteristics
1.10.
ITT
Demographic and Baseline Characteristics
ICH E3, FDAAA, EudraCT
H
1.11.
ITT
Age Ranges
EudraCT
1.12.
ITT
Race and Racial Combination Details
ICH E3, FDA, FDAAA, EudraCT
Current and Prior Medical History
1.13.
ITT
General Medical History
ICH E3 
 
 
 
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Study Population Tables
No.
Population
Title
Programming Notes
Priority
Headline Results 
denoted by H
Baseline Disease Activity and SLE Medication Use
1.14.
ITT
Baseline Disease Activity
Benlysta Standard
H
1.15.
ITT
SELENA SLEDAI Organ and Item Involvement at Baseline
Benlysta Standard
H
1.16.
ITT
Allowable SLE Medication Usage at Baseline
Benlysta Standard
1.17.
ITT
Steroid, Anti-malarial and Immunosuppressant Use at Baseline
Benlysta Standard
13.11.4.
Study Population Figures
Study Population: Figure
No.
Population
Title
Programming Notes
Priority
Time to Withdrawal
1.1
ITT
Time to Withdrawal
Study Population
H
 
 
 
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13.11.5.
Efficacy Tables
Efficacy: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results 
denoted by H
Flares
2.1.
ITT
Time to First SFI Flare to Week 52
Primary endpoint
H
2.2.
ITT
SFI Flares per Subject-year from Day 0 to Week 52
Secondary endpoint
2.3.
ITT
Time to First SFI Severe Flare to Week 52
Secondary endpoint
H
2.4.
ITT
Time to First Renal Flare to Week 52 
Exploratory endpoint
H
2.5.
ITT
Time to First Renal Flare to Week 52 [1] Among Subjects with 
Baseline Proteinuria >0.5g/24hr Equivalent
Exploratory endpoint
Rebound and SELENA-SLEDAI
2.6.
ITT
SELENA SLEDAI Rebound (LOCF) (52-Week Treatment 
Phase)
Secondary endpoint
H
2.7.
ITT
SELENA SLEDAI Change from Baseline (LOCF) (52-Week 
Treatment Phase)
Secondary endpoint
PGA
2.8.
ITT
PGA Change from Baseline (52-Week Treatment Phase)
Other/exploratory endpoint
Prednisone
2.9.
ITT
Number of Days of Daily Prednisone Dose >=7.5 mg/day 
and/or Increased by 25%
Secondary endpoint
2.10.
ITT
Number of Days of Daily Prednisone Dose <=7.5 mg/day 
and/or Decreased by 25%
Secondary endpoint
 
 
 
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Efficacy: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results 
denoted by H
2.11.
ITT
Prednisone Percent Change from Baseline (52-Week 
Treatment Phase)
Other/exploratory endpoint
2.12.
ITT
Prednisone Reduced to <= 7.5 mg/day by Visit (DO/TF=NR) 
among Subjects with Baseline Prednisone Dose > 7.5 mg/day 
(52-Week Treatment Phase)
Other/exploratory endpoint
13.11.6.
Efficacy Figures
Efficacy: Figures
No.
Population
Title
Programming Notes
Priority
Flares
2.1.
ITT
Time to First SFI Flare to Week 52 
Primary endpoint
H
2.2.
ITT
Time to First Severe SFI Flare to Week 52 
Secondary endpoint
H
Rebound and SELENA-SLEDAI
2.3.
ITT
SELENA SLEDAI Change from Baseline by Visit (LOCF) 
(52-Week Treatment Phase)
Secondary endpoint
 
 
 
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13.11.7.
Safety Tables
Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
Concomitant Medications
3.1.
ITT
Concomitant Medications by ATC Level 1 and ATC Level 4 
Term for the 52-Week Treatment Phase
ICH E3
Study Agent Exposure
3.2.
ITT
Study Agent Exposure (52-Week Treatment Phase)
ICH E3
SLICC
3.3.
ITT
SLICC/ACR Damage Index Change from Baseline (52-
Week Treatment Phase)
Other/exploratory endpoint
Adverse Events
3.4.
ITT
Adverse Events (52-Week Treatment Phase)
Benlysta standard
H
3.5.
ITT
Adverse Events by SOC (52-Week Treatment Phase)
Benlysta standard
3.6.
ITT
Serious Adverse Events by SOC (52-Week Treatment 
Phase)
Benlysta standard
3.7.
ITT
Study Agent Related Adverse Events by SOC (52-Week 
Treatment Phase)
Benlysta standard
3.8.
ITT
Adverse Events Resulting in Study Agent Discontinuation 
by SOC (52-Week Treatment Phase)
Benlysta standard
 
 
 
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Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
3.9.
ITT
Adverse Events by SOC and PT (52-Week Treatment 
Phase)
ICH E3
H
3.10.
ITT
Serious Adverse Events by SOC and PT (52-Week Treatment 
Phase)
Benlysta Standard
H
3.11.
ITT
Study Agent Related Adverse Events by SOC and PT (52-Week 
Treatment Phase)
ICH E3
3.12.
ITT
Adverse Events Resulting in Study Agent Discontinuation by 
SOC and PT (52-Week Treatment Phase)
IDSL
H
3.13.
ITT
Adverse Events by PT (52-Week Treatment Phase)
Benlysta Standard
3.14.
ITT
Serious Adverse Events by PT (52-Week Treatment Phase)
Benlysta Standard
3.15.
ITT
Study Agent Related Adverse Events by PT (52-Week 
Treatment Phase)
Benlysta Standard
3.16.
ITT
Adverse Events Resulting in Study Agent Discontinuation by PT 
(52-Week Treatment Phase)
Benlysta Standard
3.17.
ITT
Common (>5%) Non-Serious Adverse Events by SOC and PT 
(52-Week Treatment Phase)
(Number of Subjects and Occurrences)
FDAAA, EudraCT
3.18.
ITT
Serious Adverse Events by SOC and PT (52-Week 
Treatment Phase) (Number of Participants and 
Occurrences)
FDAAA, EudraCT
H
3.19.
ITT
Adverse Events by SOC and PT and Maximum Severity (52-
Week Treatment Phase)
IDSL
 
 
 
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Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
3.20.
ITT
Relationship Between System Organ Class and Verbatim Text 
(52-Week Treatment Phase)
IDSL
3.21.
ITT
Adverse Events of Special Interest by Category (52-Week 
Treatment Phase)
Benlysta Standard
H
3.22.
ITT
Adverse Events of Special Interest by Category and 
Infusion for Treatment Holiday Group Re-Start Phase
Benlysta Standard
Laboratory Parameters
3.23.
ITT
Laboratory Results by Visit: Hematology (52-Week 
Treatment Phase
3.24.
ITT
Laboratory Results by Visit: Liver Function (52-Week Treatment 
Phase)
3.25.
ITT
Laboratory Results by Visit: Electrolytes (52-Week 
Treatment Phase)
3.26.
ITT
Laboratory Results by Visit: Other Chemistries (52-Week 
Treatment Phase)
3.27.
ITT
Laboratory Results by Visit: Urinalysis (52-Week Treatment 
Phase)
3.28.
ITT
Laboratory Results by Visit: Immunoglobulins (52-Week 
Treatment Phase)
3.29.
ITT
Worst Laboratory Toxicity Grade: Hematology (52-Week 
Treatment Phase)
ICH E3
 
 
 
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Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
3.30.
ITT
Worst Laboratory Toxicity Grade: Liver Function (52-Week 
Treatment Phase)
ICH E3
3.31.
ITT
Worst Laboratory Toxicity Grade: Electrolytes (52-Week 
Treatment Phase)
ICH E3
3.32.
ITT
Worst Laboratory Toxicity Grade: Other Chemistries (52-Week 
Treatment Phase)
ICH E3
3.33.
ITT
Worst Laboratory Toxicity Grade: Urinalysis (52-Week 
Treatment Phase)
ICH E3
3.34.
ITT
Worst Laboratory Toxicity Grade: Immunoglobulins (52-Week 
Treatment Phase)
ICH E3
3.35.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Hematology (52-Week Treatment Phase)
Benlysta Standard
3.36.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Liver Function (52-Week Treatment Phase)
Benlysta Standard
3.37.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Electrolytes (52-Week Treatment Phase)
Benlysta Standard
3.38.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Other Chemistries (52-Week Treatment Phase)
Benlysta Standard
3.39.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Urinalysis (52-Week Treatment Phase)
Benlysta Standard
3.40.
ITT
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Immunoglobulins (52-Week Treatment Phase)
Benlysta Standard
3.41.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: 
Hematology (52-Week Treatment Phase)
Benlysta Standard
 
 
 
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Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
3.42.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: Liver 
Function (52-Week Treatment Phase)
Benlysta Standard
3.43.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: 
Electrolytes (52-Week Treatment Phase)
Benlysta Standard
3.44.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: Other 
Chemistries (52-Week Treatment Phase)
Benlysta Standard
3.45.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: 
Urinalysis (52-Week Treatment Phase)
Benlysta Standard
3.46.
ITT
Laboratory Reference Range Shifts from Baseline by Visit: 
Immunoglobulins (52-Week Treatment Phase)
Benlysta Standard
Immunoglobulins
3.47.
ITT
Immunoglobulin Levels below the Lower Limit of Normal (LLN) 
by Visit (52-Week Treatment Phase)
Benlysta Standard
3.48.
ITT
Immunoglobulins below the Lower Limit of Normal (LLN) at each 
Visit among Subjects with Immunoglobulins >= LLN at Baseline 
(52-Week Treatment Phase)
Benlysta Standard
3.49.
ITT
Immunoglobulins above the Lower Limit of Normal (LLN) at each 
Visit (52-Week Treatment Phase)
Benlysta Standard
3.50.
ITT
Immunoglobulins above the Lower Limit of Normal (LLN) at 
each Visit among Subjects with Immunoglobulins <= LLN 
at Baseline (52-Week Treatment Phase)
Benlysta Standard
Immunogenicity
3.51.
ITT
Immunogenic Response by Visit (52-Week Treatment Phase)
Benlysta Standard
 
 
 
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Safety: Tables
No.
Population
Title
Programming Notes
Priority
Headline Results
Denoted by H
Vital Signs
3.52.
ITT
Vital Signs Change from Baseline by Visit (Observed) (52-Week 
Treatment Phase)
ICH E3
 
 
 
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13.11.8.
Safety Figures
Safety: Figures
No.
Population
Title
Programming Notes
Priority
Laboratory
3.1.
ITT
Laboratory Results by Visit: Hematology (52-Week 
Treatment Phase)
3.2.
ITT
Laboratory Results by Visit: Liver Function (52-Week Treatment 
Phase)
3.3.
ITT
Laboratory Results by Visit: Electrolytes (52-Week Treatment 
Phase)
3.4.
ITT
Laboratory Results by Visit: Other Chemistries (52-Week 
Treatment Phase)
3.5.
ITT
Laboratory Results by Visit: Other Chemistries (52-Week 
Treatment Phase)
3.6.
ITT
Laboratory Results by Visit: Immunoglobulins (52-Week 
Treatment Phase)
 
 
 
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13.11.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
Title
Programming Notes
Priority
Belimumab Concentrations
4.1.
PK
Belimumab Concentrations (ug/ml)
 
 
 
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13.11.10. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
Title
Programming Notes
Priority
Belimumab Concentrations
4.1.
PK
Median Belimumab Concentrations (ug/mL): 52-Week 
Treatment Phase
4.2.
PK
Geometic Mean Belimumab Concentrations (ug/mL): 52-Week 
Treatment Phase
13.11.11. Biomarker Tables
Biomarker Tables
No.
Population
Title
Programming Notes
Priority
Autoantibodies
5.1.
ITT
Autoantibody Levels Change from Baseline by Visit 
(Observed) (52-Week Treatment Phase)
5.2.
ITT
Autoantibody Levels Percent Change from Baseline by 
Visit (Observed) (52-Week Treatment Phase)
5.3.
ITT
Autoantibody Levels Change from Baseline by Visit among 
Subjects Positive at Baseline (Observed) (52-Week Treatment 
Phase)
 
 
 
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Biomarker Tables
No.
Population
Title
Programming Notes
Priority
5.4.
ITT
Autoantibody Levels Percent Change from Baseline by Visit 
among Subjects Positive at Baseline (Observed) (52-Week 
Treatment Phase)
5.5.
ITT
Autoantibody Levels Shift from Baseline by Visit 
(Observed) (52-Week Treatment Phase)
Complement
5.6.
ITT
Complement Levels Change from Baseline by Visit (Observed) 
(52-Week Treatment Phase)
5.7.
ITT
Complement Levels Percent Change from Baseline by Visit 
(Observed) (52-Week Treatment Phase)
5.8.
ITT
Complement Levels Change from Baseline by Visit among 
Subjects Low at Baseline (Observed) (52-Week Treatment 
Phase)
5.9.
ITT
Complement Levels Percent Change from Baseline by Visit 
among Subjects Low at Baseline (Observed) (52-Week 
Treatment Phase)
5.10.
ITT
Complement Levels Shift from Baseline by Visit (Observed) (52-
Week Treatment Phase)
 
 
 
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Biomarker Tables
No.
Population
Title
Programming Notes
Priority
Immunoglobulins
5.11.
ITT
Immunoglobulins Change from Baseline by Visit (Observed) (52-
Week Treatment Phase)
5.12.
ITT
Immunoglobulins Percent Change from Baseline by Visit 
(Observed) (52-Week Treatment Phase)
5.13.
ITT
Immunoglobulins Change from Baseline by Visit among 
Subjects Low at Baseline (Observed) (52-Week Treatment 
Phase)
5.14.
ITT
Immunoglobulins Percent Change from Baseline by Visit 
among Subjects Low at Baseline (Observed) (52-Week 
Treatment Phase)
5.15.
ITT
Immunoglobulin Levels Shift from Baseline by Visit (Observed) 
(52-Week Treatment Phase)
B-cells
5.16.
ITT
B-cells Change from Baseline by Visit (Observed) (52-Week 
Treatment Phase)
5.17.
ITT
B-cells Percent Change from Baseline by Visit (Observed) (52-
Week Treatment Phase)
5.18.
ITT
B-cells Change from Baseline by Visit (Observed) (52-Week 
Treatment Phase)
5.19.
ITT
B-cells Percent Change from Baseline by Visit (Observed) (52-
Week Treatment Phase)
5.20.
ITT
B-cells Change from Week 24 by Visit (Observed) (Maintenance 
Phase)
 
 
 
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Biomarker Tables
No.
Population
Title
Programming Notes
Priority
5.21.
ITT
B-cells Percent Change from Week 24 by Visit (Observed) 
(Maintenance Phase)
BLyS Protein
5.22.
ITT
BLyS ProteinChange from Baseline by Visit (Observed) (52-
Week Treatment Phase)
5.23.
ITT
BLyS Protein Percent Change from Baseline by Visit (Observed) 
(52-Week Treatment Phase)
13.11.12. Biomarker Figures
Biomarker Figures
No.
Population
Title
Programming Notes
Priority
Autoantibodies
5.1.
ITT
Autoantibody Levels Percent Change from Baseline by 
Visit (52-Week Treatment Phase)
5.2.
ITT
Autoantibody Levels Percent Change from Baseline by 
Visit among Subjects Positive at Baseline (52-Week 
Treatment Phase)
Complement
5.3.
ITT
Complement Levels Percent Change from Baseline by 
Visit (52-Week Treatment Phase)
5.4.
ITT
Complement Levels Percent Change from Baseline by 
Visit among Subjects Positive at Baseline (52-Week 
Treatment Phase)
 
 
 
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Biomarker Figures
No.
Population
Title
Programming Notes
Priority
Immunoglobulins
5.5.
ITT
Immunoglobulin Levels Percent Change from Baseline by 
Visit (52-Week Treatment Phase)
5.6.
ITT
Immunoglobulin Levels Percent Change from Baseline by 
Visit among Subjects Positive at Baseline (52-Week 
Treatment Phase)
BLyS Protein
5.7.
ITT
BLyS Protein Percent Change from Baseline by Visit (52-Week 
Treatment Phase)
B cell Subsets
5.8.
ITT
B Cell Percent Change from Baseline by Visit (52-Week 
Treatment Phase)
5.9.
B Cell Percent Change from Week 24 by Visit (52-Week 
Treatment Phase)
5.10.
ITT
B Cell Absolute Values by Visit and Subject for Subjects 
who Enter the Maintenance Phase
 
 
 
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13.11.13. ICH Listings
ICH: Listings
No.
Population
Title
Programming Notes
Priority
Subject Disposition
1.
Screened
Reasons for Screen Failure  
Journal requirements
2.
Screened
Re-Screened Subjects
3.
ITT
Subject Disposition and Population Status
ICH E3
4.
ITT
Previous Trial History
ICH E3
5.
ITT
Reasons for Study Withdrawal
ICH E3
Protocol Deviations
6.
Screened
Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
7.
Screened
Important Protocol Deviations
ICH E3
Demographic and Baseline Characteristics
8.
ITT
Demographic and Baseline Characteristics
ICH E3
9.
ITT
General Medical History
ICH E3
10.
ITT
Subjects Who Took Prohibited Medications
Study specific
Prior and Concomitant Medications
11.
ITT
Concomitant Medications
ICH E3
Exposure and Treatment Compliance
12.
ITT
Study Agent Administration
ICH E3
Adverse Events
13.
ITT
All Adverse Events
ICH E3
 
 
 
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ICH: Listings
No.
Population
Title
Programming Notes
Priority
14.
ITT
Subject Numbers for Individual Adverse Events
ICH E3
15.
ITT
Relationship Between Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text
IDSL
Serious and Other Significant Adverse Events
16.
ITT
Serious Adverse Events
Study specific/ ICH E3 (other 
significant events)
17.
ITT
Deaths
ICH E3
18.
ITT
Non-Fatal Serious Adverse Events
ICH E3
19.
ITT
Study Treatment Related Adverse Events
Study specific/ ICH E3 (other 
significant events)
20.
ITT
Adverse Events Resulting in Study Treatment Discontinuation
ICH E3
21.
ITT
Pre-treatment Adverse Events
Study specific/ ICH E3 (other 
significant events)
22.
ITT
Adverse Events of Special Interest
Study specific/ ICH E3 (other 
significant events)
23.
ITT
Malignancy Adverse Events of Special Interest
Study specific/ ICH E3 (other 
significant events)
24.
ITT
Reasons for Considering as a Serious Adverse Event
ICH E3
25.
ITT
Infusion Related Systemic Reactions
Study specific
26.
ITT
Concomitant Procedures/Surgery
Study specific
Vital Signs
27.
ITT
Vital Signs 
IDSL
All Laboratory
28.
ITT
Laboratory Results: Hematology
 
 
 
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ICH: Listings
No.
Population
Title
Programming Notes
Priority
29.
ITT
Laboratory Results: Liver Function
30.
ITT
Laboratory Results: Electrolytes
31.
ITT
Laboratory Results: Other Chemistries
32.
ITT
Laboratory Results: Urinalysis
33.
ITT
Laboratory Results: Immunoglobulins
34.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Hematology
35.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: Liver 
Function
36.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Electrolytes
37.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: Other 
Chemistries
38.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Urinalysis
39.
ITT
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Immunoglobulins
Hepatobiliary (Liver)
40.
ITT
Liver Monitoring Stopping Event Reporting
41.
ITT
Medical Conditions for Participants with Liver Stopping Events
42.
ITT
Substance Use for Participants with Liver Stopping Events
 
 
 
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13.11.14. Non-ICH Listings
Non-ICH: Listings
No.
Population
Title
Programming Notes
Priority
Efficacy Endpoints
43.
ITT
SFI Flares
Study specific
44.
ITT
SELENA-SLEDAI Analysis Results
Study specific
45.
ITT
Physician’s Global Assessment (PGA) Analysis Results
Study specific
46.
ITT
Average Daily Prednisone Dose
Study specific
Immunogenicity
47.
ITT
Immunogenicity Results
Study specific
SLICC
48.
ITT
SLICC/ACR Damage Index Analysis Results
Study specific
Belimumab PK Concentration
49.
PK
Serum Belimumab PK Concentration-Time Data
Study specific
Biomarkers
50.
ITT
Autoantibody and Complement Results
Study specific
51.
ITT
B Cell Results
Study specific
 
 
 
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13.12.
Appendix 12: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
 
 
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