Conditions: Systemic Lupus Erythematosus
Keywords: Systemic Lupus Erythematosus African Continental Ancestry Group Autoimmune Disease Antibodies Minority Groups Black Race African Americans SLE Belimumab Lupus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 503
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of belimumab in adult patients of black race with systemic lupus erythematosus (SLE; lupus).

Detailed description:
Study participants receive stable standard therapy for lupus in addition to receiving either placebo (no active medicine) or belimumab. The controlled period of the study is 52 weeks. The random assignment in this study is "2 to 1" which means that for every 3 participants, 2 will receive belimumab and 1 will receive placebo. Participants who successfully complete the 52-week study may enter into a 6-month open-label extension. All participants in the open-label extension receive belimumab plus standard therapy.

Arms:
arm 1: Placebo IV plus standard therapy; placebo administered on Days 0, 14, 28, and every 28 days thereafter through Week 48, with a final evaluation at Week 52 in the double-blind period. In the open-label extension period, placebo patients who opt to participate will receive belimumab 10 mg/kilogram (kg) IV every 28 days for an additional 6 months. arm 2: Belimumab 10 mg/kg IV plus standard therapy; belimumab administered on Days 0, 14, 28, and then every 28 days thereafter through Week 48, with a final evaluation at Week 52 in the double-blind period. In the open-label extension period, patients who opt to participate will continue to receive belimumab 10 mg/kg IV every 28 days for an additional 6 months.

Interventions: intervention 1: Placebo plus standard therapy intervention 2: Belimumab 10 mg/kg plus standard therapy intervention 3: Standard therapy
Intervention descriptions: intervention 1: Placebo plus standard therapy intervention 2: Belimumab 10mg/kg plus standard therapy intervention 3: Standard therapy comprises any of the following (alone or in combination): corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), and immunosuppressives; biologics and intravenous cyclophosphamide are not permitted.

Protocol document:
SAP_002.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL115471
1
Author(s)
Author
Date
14-FEB-2019
Statistics Leader (Clinical Statistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited.
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for BEL115471, A Phase 3/4, 
Multi-Center, Randomized, Double-Blind, Placebo-
Controlled, 52-Week Study to Evaluate the Efficacy and 
Safety of Belimumab (HGS1006) in Adult Subjects of Black 
Race with Systemic Lupus Erythematosus (SLE) Open-label
Phase, End of Study
Compound Number 
:
GSK1550188
Effective Date 
:
14-FEB-2019
Description:

This is a Phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult 
subjects of black race with active systemic lupus erythematosus (SLE). All subjects 
will receive stable background standard of care therapy throughout the study. 
Efficacy will be measured by the SLE Responder Index (SRI) at Week 52, defined 
by a composite SELENA SLEDAI score (Protocol Amendment 2 modified the 
primary endpoint to use the modified SLEDAI-2K scoring for proteinuria), 
Physician’s Global Assessment (PGA) and BILAG A and B organ domain scores. In 
addition, oral corticosteroid use, flares and biomarkers (serum immunoglobulins 
anti-dsDNA, complement, and B cell) will be assessed. Safety will be assessed by 
adverse events, clinical laboratory evaluations, immunogenicity, and vital signs. In 
addition, subjects who successfully complete the double-blind phase may enter into 
an open-label, 6-month extension phase of the study and receive IV belimumab at a 
dose of 10 mg/kg. This Reporting and Analysis Plan (RAP) prospectively describes 
the efficacy and safety analyses that will be performed for the open-label phase of 
the study. Details regarding the analyses and summaries for the double-blind phase 
of the study were described in a separate RAP.  
 
 
 
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The GlaxoSmithKline group of companies
BEL115471
2
RAP Team Review Confirmations
(Method: E-mail)
Reviewer
Date
14-FEB-2019
Principal Programmer (Clinical Programming)
13-FEB-2019
Clinical Development Manager (Clinical Development)
14-FEB-2019
Senior Clinical Development Director (Clinical Development)
14-FEB-2019
SERM Director (Safety Evaluation and Risk Management)
13-FEB-2019
Medical Writer (Clinical Development)
13-FEB-2019
Clinical Development Manager (Clinical Development)
14-FEB-2019
Clinical Data Manager (Clinical Data Management)
Clinical Statistics & Clinical Programming Line Approvals
(Method: Signature)
Approver
Date
14-FEB-2019
Director Statistics (Clinical Statistics)
 
13-FEB-2019
Director Programming (Clinical Programming)
Approved by:
_________________________
_______________
               
Date
Director Statistics
GSK
Approved by:
_________________________
_______________
Date
Director Programming
GSK
 
 
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Open-label Study Objective(s) and Endpoint(s) ............................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Multicenter Studies .....................................................................................13
5.4.
Examination of Covariates, Other Strata and Subgroups............................13
5.4.1.
Covariates and Other Strata ........................................................13
5.4.2.
Examination of Subgroups...........................................................13
5.5.
Multiple Comparisons and Multiplicity .........................................................13
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
EFFICACY ANALYSES..........................................................................................14
7.1.
Primary Efficacy Analyses ..........................................................................14
7.1.1.
SRI-S2K Response......................................................................14
7.1.2.
Population of Interest...................................................................15
7.1.3.
Statistical Analyses / Methods .....................................................15
7.1.3.1.
Statistical Methodology Specification..........................15
7.2.
Secondary Efficacy Analyses......................................................................16
7.2.1.
Endpoint / Variables.....................................................................16
7.2.2.
Population of Interest...................................................................17
7.2.3.
Statistical Analyses / Methods .....................................................17
7.2.3.1.
Statistical Methodology Specification..........................18
8.
SAFETY ANALYSES .............................................................................................21
8.1.
Adverse Events Analyses ...........................................................................21
8.2.
Adverse Events of Special Interest Analyses..............................................21
8.3.
Clinical Laboratory Analyses.......................................................................22
8.4.
Other Safety Analyses ................................................................................22
9.
PHARMACOKINETIC ANALYSES.........................................................................22
 
 
 
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9.1.
Primary Pharmacokinetic Analyses.............................................................22
9.1.1.
Endpoint / Variables.....................................................................22
9.1.1.1.
Drug Concentration Measures....................................22
10. BIOMARKER ANALYSES......................................................................................22
10.1.
Biomarker Analyses – Open-label Phase....................................................22
10.1.1.
Endpoint / Variables.....................................................................22
10.1.2.
Population of Interest...................................................................23
10.1.3.
Statistical Analyses / Methods .....................................................23
10.1.3.1.
Statistical Methodology Specification..........................23
10.2.
Biomarker Analyses – for the Double-blind Phase ......................................24
10.2.1.
Endpoint / Variables.....................................................................25
10.2.2.
Population of Interest...................................................................25
10.2.3.
Statistical Analyses / Methods .....................................................25
11. REFERENCES.......................................................................................................26
12. APPENDICES........................................................................................................27
12.1.
Appendix 1: Schedule of Activities ..............................................................27
12.1.1.
Protocol Defined Schedule of Events...........................................27
12.2.
Appendix 2: Assessment Windows .............................................................29
12.2.1.
Definitions of Visits for Analyses ..................................................29
12.3.
Appendix 3: Study Phases, and Treatment Emergent Open-label 
Adverse Events...........................................................................................30
12.3.1.
Study Phases ..............................................................................30
12.3.1.1.
Study Phases for OL Concomitant Medication............30
12.3.2.
Treatment Emergent Open-label Flag for Adverse Events ...........30
12.4.
Appendix 4: Data Display Standards & Handling Conventions....................31
12.4.1.
Reporting Process .......................................................................31
12.4.2.
Reporting Standards....................................................................31
12.5.
Appendix 5: Derived and Transformed Data ...............................................33
12.5.1.
General........................................................................................33
12.5.2.
Study Population..........................................................................33
12.5.3.
Efficacy........................................................................................33
12.6.
Appendix 6: Reporting Standards for Missing Data.....................................36
12.6.1.
Premature Withdrawals................................................................36
12.6.2.
Handling of Missing Data.............................................................36
12.6.2.1.
Handling of Missing and Partial Dates ........................36
12.7.
Appendix 7: Values of Potential Clinical Importance ...................................38
12.7.1.
Laboratory Values........................................................................38
12.8.
Appendix 8: Abbreviations & Trade Marks ..................................................39
12.8.1.
Abbreviations...............................................................................39
12.8.2.
Trademarks .................................................................................40
12.9.
Appendix 9: List of Data Displays ...............................................................41
12.9.1.
Data Display Numbering..............................................................41
12.9.2.
Deliverables.................................................................................41
12.9.3.
Study Population Tables..............................................................42
12.9.4.
Efficacy Tables ............................................................................45
12.9.5.
Safety Tables...............................................................................49
12.9.6.
Health Outcomes Tables .............................................................55
12.9.7.
Pharmacokinetic Tables...............................................................56
12.9.8.
Biomarker Tables.........................................................................56
 
 
 
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12.9.9.
ICH Listings .................................................................................61
12.9.10. Non-ICH Listings..........................................................................65
12.10. Appendix 10: Example Mock Shells for Data Displays ................................68
 
 
 
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1.
INTRODUCTION
This reporting and analysis plan (RAP) documents the planned analyses for the open-
label phase of the BEL115471 study.  
This is a phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 10mg/kg belimumab administered 
monthly, compared with placebo over a 52-week treatment period (i.e. double-blind 
phase) in subjects of black race with active systemic lupus erythematosus (SLE) (defined 
as Safety of Estrogen in Lupus National Assessment Systemic Lupus Erythematosus 
Disease Activity Index (SELENA SLEDAI) score 8). Subjects who complete the initial 
52-week double-blind treatment period may choose to enter a 6-month open-label 
extension and receive IV belimumab at a dose of 10 mg/kg. 
The Double-blind phase was reported separately and there is a double-blind phase RAP.  
This Open-label phase RAP is based upon the following study documents:
[1] Study Protocol Amendment 2 (February 9, 2017)
[2] Final Case Report Form (CRF) (August 2, 2017)
[3] Program Safety Analysis Plan (PSAP) Version 5 (December 13, 2017). Note: for 
reporting purposes, the most current version of the PSAP and associated MedDRA 
version at the time of database release (DBR) will be used.
[4] Double-blind Phase RAP (July 19, 2018)
[5] Double-blind Phase CSR (February 01, 2019)
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol and/or 
DB phase RAP are outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
[1] Day 0 as Baseline/Treatment 
Start date
Baseline/Treatment Start date 
will appear as Day 1 in the 
displays and will be referenced 
as Day 1 in this document. A 
table indicating the target open-
label study day for each planned 
visit starting at Day 1 (instead of 
Day 0) is in Section 12.2.1.
The CDISC standard is to refer 
to the Baseline/Treatment Start 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
[2] Indicates the prednisone 
analyses will be conducted using 
dosing on all days between visits
Average daily prednisone dose 
is based on the 7-day average 
prednisone dose
Consistent with the DB RAP and 
reporting of prior Belimumab 
studies.
2.2.
Open-label Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To explore the efficacy of belimumab 
in adult SLE subjects of black race.

Systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K scoring for 
proteinuria at OL Week 24 (or Week 28/Exit if Week 24 
missing)

To evaluate the safety and tolerability 
of belimumab in adult SLE subjects of 
black race.

Safety will be evaluated by adverse events, changes in 
laboratory parameters, and immunogenicity.
Secondary Objectives
Major Secondary Endpoints


SRI-SS Response rate with the SELENA SLEDAI for 
scoring of proteinuria at OL Week 24 (or Week 28/Exit if 
Week 24 missing)


Time to first severe flare (as measured by the modified 
SLE Flare Index; with SELENA SLEDAI as the SLEDAI 
criterion of the SFI).


Percent of subjects whose average prednisone dose has 
been reduced to ≤7.5 mg/day at Open-Label Phase 
Week 28/Exit, in subjects receiving greater than 7.5 
mg/day at pre-belimumab baseline.
The Double-blind primary and major secondary analyses are described in the double-
blind phase RAP.  Analyses of the Open-label phase will be descriptive only.
 
 
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
(a)The last dose of study agent is given on the Day 337 (Week 48) visit to subjects NOT 
participating in the 6-month open-label extension phase of the study.
(b)Subjects participating in the 6-month open-label extension phase of the study are dosed 
on the Day 365 (Week 52) visit of the double-blind period after the completion of all Day 
365(Week 52) assessments. This Day 365 (Week 52) represents the first dose (i.e., Day 
1) of the 6-month open-label extension phase. For subjects not participating in the 6-
month open-label extension phase of the study, the Day 365 (Week 52) visit serves as 
the Exit visit with follow-up visits occurring 8 weeks after the last dose of study agent. 
(c)The primary treatment period includes 48 weeks of study agent administration (Day 1 to 
the Day 337 visit) and a final visit for the primary endpoint assessment at Week 52 
which is 4 weeks after the last dose of the study agent. 
(d) An Exit visit (1-4 weeks after the last dose of study agent) and a follow-up visit 8 weeks 
after the last dose of study agent will be performed for subjects withdrawing at any time 
during the study. The 8-week follow-up visit is not required in subjects entering the 
separate continuation protocol.
(e) At the end of the 6-month extension period, subjects who wish to continue treatment 
may do so by being prescribed the IV commercially available product. If IV belimumab is 
not commercially available in a subject’s country of participation, subjects may continue 
to receive belimumab administered intravenously every 4 weeks under a separate 
continuation protocol.
NOTE:  This schematic uses Day 0 nomenclature consistent with the protocol.  To be 
consistent with CDISC reporting, add 1 to any Day 0. For the PLACEBO group, there 
should be an arrow at the end of the treatment period immediately before the Exit/Follow-
up box which points to the Belimumab 10 mg/kg 6-month extension box.
Dosing

During the open-label phase belimumab 10 mg/kg IV every 28 days for 6 
months
Time & 
Events

Refer to Appendix 1: Schedule of Activities
 
 
 
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Overview of Study Design and Key Features
Treatment 
Assignment

During the open-label extension phase all subjects will receive belimumab 10 mg/kg 
IV every 28 days for 6 months
Interim 
Analysis

No interim analysis is planned for this study.
2.4.
Statistical Hypotheses / Statistical Analyses
There is no planned hypothesis testing for the Open-label phase data.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned for this study.
3.2.
Final Analyses
There will be two database locks for this study corresponding to the primary analysis 
(end of double-blind) and the end of study (end of open-label). The database was locked 
for the primary analysis (SRI-S2K at Week 52) after data through the Week 52 visit (or 
Exit visit for those subjects who withdraw during double-blind treatment) for all subjects 
had been collected, verified and validated. This RAP is for the analysis following the 
second database lock which will occur after data for the 6-month open-label phase 
through the 8-week follow-up period have been collected, verified and validated. All 
subjects and study site personnel are unblinded for the OL phase treatment.  All subjects 
and study site personnel (except the unblinded site pharmacist) remain blinded to the DB 
treatment until after the Final database lock. This RAP details the analyses for the open-
label phase, all outputs required for the open-label phase analyses will be listed in the 
Mock Tables, Listings and Figures (TLFs) Shells document.  A separate RAP was 
provided for the double-blind phase. 
The start of the open-label phase is defined as follows:

The first dose date of open-label medication. 
The final planned open-label phase analyses will be performed after the completion of the 
following sequential steps:
1.
All open-label participants have completed through week 28 of the open-label phase 
and 8-week follow-up visit if not entering the continuation protocol 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
In addition to the open-label phase data, any data from the double-blind that was not 
available at the time of the data cut for the double-blind phase report will be reported.  
 
 
 
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This includes the following laboratory parameters which were not delivered at the time of 
the double-blind phase report.  
Beta-2-glycoprotein IgA Category
Beta-2-glycoprotein IgG Category
Beta-2-glycoprotein IgM Category
Anti-Ribosomal P
Anti-Ro (SS-A)
Anti-Ro (SS-B)
Anti-RNP
In case of any other changes to DB phase data the DB phase data will be reported in 
listings.
4.
ANALYSIS POPULATIONS
The Double-blind phase analysis sets are defined in the double-blind phase RAP Section 
6.  The definition of the Safety population from the double-blind phase is repeated here as 
it will be used for reports on the DB phase data.
Population
Definition / Criteria
Analyses 
Evaluated
Safety 
(referred to as 
ITT in protocol)

The Safety population is defined as all subjects who are 
randomized and treated with at least one dose of study 
treatment in the double-blind phase. The safety population will 
be summarized according to the treatment that a subject was 
randomized to receive, regardless of the actual treatment 
received.  The DB phase has completed and all subjects 
received their randomized treatment for the majority of their 
administrations. 

All double-blind listings will be presented for the safety 
population unless otherwise specified.

DB phase 
safety data
mITT

During the study three sites (
, 
 and 
) were 
investigated for potential GCP non-compliance; consequently,
all three sites were terminated by the sponsor. A multi-functional 
team reviewed these concerns and agreed that data from these 
three sites should be excluded from all efficacy analyses. The 
team were confident that the subjects had been dosed and 
therefore agreed data from these sites should be retained in the 
safety analyses. 

The Modified Intention-To-Treat (mITT) population is defined as 
the safety population excluding subjects who had any 
assessment at three sites (
, 
 or 
). The 
database records subjects under final site and so subjects 
moved to 
, 
 or 
, but randomized at other 
sites are also excluded.  Additionally, subjects randomized at 
one of the three sites but subsequently moved to another site 
will be excluded from the mITT. All double-blind efficacy 
analyses were performed on the mITT population. 

Double-blind
phase 
Biomarker 
data
 
 
 
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Population
Definition / Criteria
Analyses 
Evaluated
PK

The pharmacokinetic (PK) population will comprise all subjects 
included in the mITT population for whom at least one post 
belimumab treatment PK sample was obtained and analyzed. 
Summaries using this population will be based on the actual 
treatment received if this differs from that to which the subject 
was randomized.

Double-blind
phase PK 
data
Intent-to-Treat 
Open-label

All randomized participants who received at least one dose of 
open-label treatment (i.e. an OL study treatment at DB Week 
52/OL Day 1 or a later OL visit).

All open-label listings will be presented for the ITT OL 
population unless otherwise specified.

Open-label
Safety and 
listings
Modified 
Intent-to-Treat 
Open-label

The Modified Intent-To-Treat Open-label (mITT OL) population 
is defined as the Intent to Treat Open-label population excluding 
subjects who had any assessment at three sites (
, 
 or 
). All open-label efficacy analyses will be 
performed on the mITT OL population unless otherwise 
specified. 

Open-label
Efficacy
Completer 
Open-label

The Completer OL population is defined as all subjects who 
complete all 28 weeks of the planned open-label treatment 
period. A summary for the primary efficacy endpoint will be 
produced for the Completers OL population. This population is a 
subset of the mITT OL population.

Open-label
Efficacy
Refer to Appendix 9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations in the Open-label phase (including deviations related to 
study inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarized and listed.  Important deviations up to and including the 
first day of OL treatment were reported in the DB phase CSR, Important PDs on or after 
the first day of OL treatment will be reported in this OL CSR.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP): Dated:  10 July 
2017 (Version 2.0).
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorized on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of Open-label
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Data Displays for Reporting 
Description
Order in 
TLF 
Color
SAS 
Color
Line 
Style
Symbol
Placebo to Belimumab 10mg/kg
3
Purple
CX703070
Solid
Circle (filled)
Belimumab 10mg/kg to Belimumab 
10mg/kg
4
Blue
CX0000FF
Dashed
Triangle 
(filled)
For the Open-label phase subjects will be reported in treatment groups based on their 
double-blind phase randomized treatment group.  In the Open-label treatment group 
labels the first treatment is the double-blind randomized treatment and the second is the 
open-label phase treatment.  The labels used for Open-label phase reporting will be 
Placebo to Belimumab 10mg/kg and Belimumab 10mg/kg to Belimumab 10mg/kg.  For 
all tables, a total column for both open-label treatment groups combined will also be 
presented for subjects in the open-label phase.
5.2.
Baseline Definitions
There are three baselines used in the Open-label reports:
Study Baseline
This is the same as the double-blind phase baseline (defined in Section 9.4.1 of the 
double-blind phase RAP) and is used for study population reports.
OL Baseline (pre-belimumab) (used for efficacy (except time to flare), laboratory 
values, concomitant medications and vital signs)
The main OL baseline is defined as the last available value prior to the initiation of 
treatment with belimumab. For subjects switching from placebo to belimumab 10 mg/kg 
IV in the open-label phase, baseline was defined as the last assessment at the end of the 
double-blind phase (i.e. Week 52) pre-OL treatment. For subjects that received 
belimumab 10 mg/kg IV during the double-blind phase and continued to receive 
belimumab 10 mg/kg IV during the open-label phase, baseline was defined as Day 1 of 
the double-blind phase (i.e. equivalent to Study baseline and defined as for baseline in 
section 9.4.1 of the double-blind phase RAP).
Open-label Phase Baseline (used for adverse events, and time to flare)
The open-label phase baseline value of a variable is defined as the last available value 
measured prior to dosing on or before the date of first open-label dose (Open-label Day 
 
 
 
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1). If the last available value occurs on Open-label Day 1 but the time of the assessment 
is not collected, then the assessment will be assumed to be prior to dosing. 
For adverse events, these are considered present at open-label baseline if the start date is 
prior to open-label Day 1 and the end date is on or after open-label Day 1. Events with a 
start date on open-label Day 1 are considered as being open-label treatment-emergent.
Flares that occur on or prior to the open-label treatment start date, are considered as 
double-blind flares rather than Open-label flares.
5.3.
Multicenter Studies
This is a multi-center trial and subjects were centrally randomized at the start of the 
double-blind phase.  Analyses will not be adjusted for center.  
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Refer to Section 8.2 in the Double-Blind Phase RAP for details of Other Strata and 
Covariates used in the DB phase.
5.4.2.
Examination of Subgroups
Refer to Section 8.3 in the Double-Blind Phase RAP for definitions of subgroups used in 
the Double-blind phase.  Subgroups used for the Open-label phase will be:

OL phase completers

Region (US/Canada and Rest of World)

SLICC/ACR Damage Index Subgroup at Pre-Belimumab Baseline (No Damage 
and Damage Index >=1)

Pre-Belimumab Baseline Proteinuria >0.5 g/24hr

Pre-Belimumab Baseline Prednisone Dose (>7.5 mg/day and <=7.5 mg/day)

Autoantibody positive at Pre-Belimumab Baseline

Low complement at Pre-Belimumab Baseline
5.5.
Multiple Comparisons and Multiplicity
There is no statistical testing of efficacy endpoints planned for the open-label phase.
5.6.
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
12.2
Appendix 2: Assessment Windows
12.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
 
 
 
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Section
Component
12.4
Appendix 4: Data Display Standards & Handling Conventions
12.5
Appendix 5: Derived and Transformed Data
12.6
Appendix 6: Reporting Standards for Missing Data
12.7
Appendix 7: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT Open-label and modified ITT OL
population and use the study baseline, unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics (using study baseline), prior and 
concomitant medications, and Open-label exposure will be based on GSK Core Data 
Standards.  Details of the planned displays are presented in Appendix 9: List of Data 
Displays.
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
SRI-S2K Response
The primary endpoint is the systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K (S2K) scoring for proteinuria. This S2K 
rule scores proteinuria as 4 points anytime the value is >0.5 g/24hr. This
endpoint will be referred to as the SRI-S2K for reporting and is defined as:

>= 4-point reduction from OL baseline (pre-belimumab) in SELENA SLEDAI 
score using the SLEDAI-2K proteinuria scoring [SS-S2K 4pt],
AND

No worsening (increase of <0.3 points from OL baseline) in Physician’s Global 
Assessment (PGA) [PGA No Worsening],
AND

No new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ 
domain score or 2 new BILAG B organ domain scores compared with OL 
baseline at the time of assessment (i.e., at OL Week 24 visit) [BILAG No new 
1A/2B].
The following text is instead of Section 9.3.3 in the DB phase RAP.  
For the SRI-S2K response endpoint and its components (SS-S2K 4-point reduction from 
OL baseline, PGA no worsening, BILAG no new 1A/2B), observed data will be used.  If 
OL baseline (pre-Belimumab) is missing for any of the components of the SRI-S2K, then 
 
 
 
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the SRI-S2K will be missing. Subjects who have a SS-S2K score <4 at OL baseline (pre-
Belimumab) will be excluded from this analysis as they have no opportunity to meet the 
responder criteria.
For the SLE Disease Activity Scales these are performed at OL Week 24, or OL Week 28 
if not done at OL Week 24.  For the OL Week 24/Week 28 timepoint the OL Week 24 
values are used for a subject in the first instance and Week 28 only used if Week 24 is 
missing.  
If the partial data of the primary efficacy endpoint at OL baseline are missing (including 
individual items of any component of the primary endpoint), the LOCF method will be 
used for the missing item or component. This will be modified for laboratory items in the 
BILAG for which scoring is dependent on both the actual score and the change from the 
previous visit as described in Section 9.3.5 of the DB phase RAP.   
7.1.2.
Population of Interest 
The Open-label efficacy summaries will be based on the modified Intent-To-Treat Open-
label population and use the OL baseline (pre-Belimumab), unless otherwise specified.
7.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK data standards and statistical principles.
The endpoints / variables defined in Section 7.1.1 will be summarized using descriptive 
statistics and listed.
7.1.3.1.
Statistical Methodology Specification
Endpoint / Variables

SRI-S2K Response
Model Specification

No model will be applied
Model Checking & Diagnostics

NA
Model Results Presentation

The number and percentage responding at OL Week 24, OL Week 28 and OL Week 24/Week 
28/Exit will be presented.
Subgroup Analyses

The number and percentage responding by region will be presented.
Sensitivity and Supportive Analyses

The analysis will be repeated on the subgroup of OL completers.

The 3 component responder endpoints (SS-S2K 4-point reduction from OL baseline (pre-
 
 
 
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belimumab), PGA no worsening, BILAG no new 1A/2B) will also be summarized.

The Disposition of SRI-S2K Response at the Open-Label Phase Week 24/Week 28 will 
be summarized by treatment group and overall.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables

SRI-SS Response. The SRI will also be derived as described in Section 7.1.1
requiring a 4-point reduction using the SELENA SLEDAI proteinuria scoring as was 
originally recorded on the SELENA SLEDAI disease activity scale.  Apart from 
proteinuria scoring the SRI-S2K response and the SRI-SS Response are equivalent.

SRI5-S2K, SRI6-S2K, SRI7-S2K and SRI8-S2K.  SRI5-S2K to SRI8-S2K are 
defined identically to the SRI-S2K except for using higher thresholds of improvement 
for SS-S2K reduction for a patient to be declared a responder (e.g., SS-S2K 5-point
reduction for SRI5-S2K).  Patients with baseline SS-S2K <5, <6, <7 or <8, will have 
SRI5-S2K - SRI8-S2K response missing respectively.

EMA modified SRI-S2K response. This endpoint is defined in Section 9.4.20 of the 
DB phase RAP except using the OL baseline and for the timepoints OL Week 24, OL 
Week 28 and OL Week24/Week 28 rather than DB Week 52.

Time to first severe SFI flare.  See Section 12.5.3.  Analysis excludes severe flares 
that were triggered only by an increase in SELENA SLEDAI score to >12. Data 
censored at last available assessment by Open-Label week 24/28 visit. For subjects 
who died, data are censored at death if no flares occurred before death. Time to first 
flare is defined as (event date - Open-Label treatment start date + 1). This endpoint 
will use the OL Phase baseline.

Time to first SFI flare. See Section 12.5.3 and information for severe SFI flare above.
This endpoint will use the OL Phase baseline.

SLICC/ACR Damage Index, See Section 9.4.14 in DB phase RAP, except use the OL 
baseline.

SLICC/ACR Damage Index Worsening. See Section 9.4.14 in DB phase RAP, except 
use the OL baseline.

SELENA SLEDAI and SLEDAI-S2K.  See Section 9.4.15 in the DB phase RAP, 
except use the OL baseline.

SS-S2K >=4-point reduction.  See Section 9.4.15.1 in the DB phase RAP, except use 
the OL baseline.

SELENA SLEDAI and SLEDAI-S2K Organ system improvement.  See Section 
9.4.15 in the DB phase RAP.  An improvement is defined as a decrease (compared to 
OL baseline (pre-Belimumab)) in the SELENA SLEDAI score within the same organ 
system at a post-Belimumab visit.

BILAG no New 1A/2B Organ Domain scores compared with OL baseline (Pre-
belimumab) at Open-Label Phase Week 24/Week 28. See Section 9.4.16.3 in the DB 
phase RAP.
 
 
 
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
BILAG no 1A/2B Organ Domain scores.  See Section 9.4.16.4 in the DB phase RAP, 
except use the OL baseline.

BILAG improvement. See Section 9.4.16.1 in the DB phase RAP, except use the OL 
baseline.

BILAG worsening. See Section 9.4.16.2 in the DB phase RAP, except use the OL 
baseline.

PGA. See Section 9.4.17 of the DB phase RAP, except use the OL baseline.

PGA No Worsening (Increase of <0.3 points from OL baseline (pre-belimumab)) See 
Section 9.4.17.1 of the DB phase RAP

PGA improvement (increase of >=0.3 from OL baseline (pre-Belimumab)).  See 
Section 9.4.17.2 of the DB phase RAP. Subjects with baseline PGA score < 0.3 will 
be treated as having no improvement.

Time to first renal flare.  See Section 9.4.28 in the DB phase RAP and Section 12.5.3.
Time to first renal flare is defined as [date of first renal flare - Open-Label treatment 
start date + 1]. This endpoint will use the OL phase baseline.

Proteinuria.  See Section 9.4.12 in the DB phase RAP. For Proteinuria shifts from OL 
baseline (pre-Belimumab) Normal is <=0.5 g/24 hour and High is >0.5 g/24 hour.

Doubling of serum creatinine (patients whose serum creatinine attains a level double 
that of the OL baseline (pre-Belimumab) value and is confirmed with a second 
measurement at least 3 weeks later). 

Change from OL baseline in prednisone (based on 7-day average at the visits).  See 
Section 9.4.13 in the DB phase RAP, except use the OL baseline, and Section 12.5.3.

Any increase prednisone (based on 7-day average at the visits).  See Section 9.4.13 in 
the DB phase RAP, except use the OL baseline, and Section 12.5.3.

Prednisone reduced to <=7.5mg/day.  Daily prednisone dose reduced to 7.5 mg/day 
from >7.5 mg/day at OL baseline (pre-Belimumab) by visit (based on 7-day average 
at the visits). See Section 12.5.3.

Prednisone increased to >7.5mg/day. Daily prednisone dose increased to >7.5 mg/day 
from 7.5 mg/day at OL baseline (pre-Belimumab) by visit (based on 7-day average 
at the visits). See Section 12.5.3.

FACIT – Fatigue Scale score.  See section 9.4.30 of the DB phase RAP, except use 
the OL baseline.
7.2.2.
Population of Interest 
The Open-label efficacy summaries will be based on the modified Intent-To-Treat Open-
label population, unless otherwise specified.
7.2.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK data standards and statistical principles.
 
 
 
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Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarized using descriptive statistics and listed.
7.2.3.1.
Statistical Methodology Specification
Endpoint / Variables

SRI-SS Response

SRI5-S2K to SRI8-S2K

EMA modified SRI-S2K response

SLICC/ACR Damage Index Worsening (Change >0) Compared with OL Baseline (pre-
Belimumab)

SS-S2K >= 4-point Reduction from OL Baseline (pre-Belimumab)

BILAG no New 1A/2B Organ Domain scores

BILAG no 1A/2B Organ Domain scores

PGA No Worsening (Increase of <0.3 points from OL Baseline (pre-Belimumab))

PGA Improvement (Increase of >=0.3 points from OL Baseline (pre-Belimumab))

Doubling of Serum Creatinine from OL Baseline (pre-Belimumab)

Any Increase in Prednisone Compared to OL Baseline (pre-Belimumab)

Prednisone Reduced to <=7.5 mg/day

Prednisone Increased to > 7.5 mg/day

Improvement in FACIT-Fatigue Scale Score exceeding the MCID (>=4)
Model Specification

No model will be applied
Model Checking & Diagnostics

NA
Model Results Presentation

The number and percentage responding/worsening (xx (xx.x%)) will be presented.

The number of patients ‘n’ that the percentage is out of will also be presented if this is not 
equal to N= for the population in the column heading.
Subgroup Analyses

The SLICC/ACR Damage Index Worsening analyses will be repeated by SLICC/ACR Damage 
Index Subgroup at OL Baseline (pre-Belimumab) (No Damage vs. Damage Index >=1).

The Doubling of Serum Creatinine from OL Baseline (pre-Belimumab) analyses will be run on 
the subgroup with OL Baseline (pre-Belimumab) Proteinuria >0.5 g/24hr.

The Prednisone Reduced to <=7.5 mg/day analysis will be run on the subgroup with OL 
Baseline (pre-Belimumab) Prednisone Dose >7.5 mg/day.

The Prednisone Increased to > 7.5 mg/day analysis will run on the subgroup with OL Baseline 
(pre-Belimumab) Prednisone Dose <=7.5 mg/day.
 
 
 
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Endpoint / Variables

Time to First Severe SFI Flare

Time to First SFI Flare

Time to First Renal Flare
Model Specification

PROC LIFETEST will be used to estimate the median, 25th, and 75th percentile of OL days to 
first (severe) flare
Model Checking & Diagnostics

NA
Model Results Presentation

The table will display the number and percentage of subjects with a (severe SFI) flare over 
24/28 weeks, the median, 25th, and 75th percentile of days to first (severe) flare. For subjects 
who experience a (severe) flare, the OL study day of the flare will be summarized and the table 
will display the median, 25th and 75th percentiles and minimum and maximum.
Sensitivity and Supportive Analyses

The time to first renal flare analysis will be repeated on the subgroup with OL Phase 
Proteinuria > 0.5 g/24hr.
Endpoint / Variables

SLICC/ACR Damage Index Change from OL Baseline (pre-Belimumab)
Model Specification

The data will be summarized only, no model will be applied.

Only subjects with a OL Baseline (pre-Belimumab) and post Belimumab assessment are 
included in the analysis.
Model Checking & Diagnostics
•
NA
Model Results Presentation

The number, mean, SD, SE, median and minimum and maximum will be presented.

The OL Baseline (pre-Belimumab), OL Week 28 and Change from OL Baseline (pre-
Belimumab) timepoints will be summarized.
Subgroup Analyses

The analyses will be repeated by SLICC/ACR Damage Index Subgroup at OL Baseline (pre-
Belimumab) (No Damage vs. Damage Index >=1).
Endpoint / Variables

SELENA SLEDAI Organ System Improvement among Subjects with Organ System 
Involvement at OL Baseline (pre-Belimumab)

BILAG Improvement by Organ Domain among Subjects with an A or B Domain Score at OL 
 
 
 
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Baseline (pre-Belimumab).

BILAG Worsening by Organ Domain among Subjects with no A Domain Score at OL Baseline 
(pre-Belimumab).
Model Specification

The data will be summarized only, no model will be applied.
Model Checking & Diagnostics

NA
Model Results Presentation

For SELENA SLEDAI the number with involvement at OL Baseline (pre-Belimumab) will be 
presented then the number with improvement at OL Week 24, OL Week 28 and OL Week 
24/Week 28 and the percentage this is of subjects with involvement at OL Baseline (pre-
Belimumab).

For BILAG Improvement the number with A/B at OL Baseline (pre-Belimumab) will be 
presented then the number with improvement at OL Week 24, OL Week 28 and OL Week 
24/Week 28 and the percentage this is of subjects with A/B at OL Baseline (pre-Belimumab).

For BILAG Worsening the number with no A at OL Baseline (pre-Belimumab) will be presented 
then the number with worsening at OL Week 24, OL Week 28 and OL Week 24/Week 28 and 
the percentage this is of subjects with no A at OL Baseline (pre-Belimumab).
Subgroup Analyses

For SELENA SLEDAI for each organ domain separately the Subjects with Organ System 
Involvement at OL Baseline (pre-Belimumab) are included.

For BILAG Improvement for each organ domain separately the Subjects with Organ Domain 
A/B at OL Baseline (pre-Belimumab) are included.

For BILAG Worsening for each organ domain separately the Subjects with no A in Organ 
Domain at OL Baseline (pre-Belimumab) are included.
Endpoint / Variables

SELENA SLEDAI Percent Change from OL Baseline (pre-Belimumab)

SELENA SLEDAI Change from OL Baseline (pre-Belimumab)

PGA Percent Change from OL Baseline (pre-Belimumab)

PGA Change from OL Baseline (pre-Belimumab)

Proteinuria Percent Change from OL Baseline (pre-Belimumab)

Proteinuria Change from OL Baseline (pre-Belimumab)

Prednisone Change from OL Baseline (pre-Belimumab)

FACIT-Fatigue Scale Score Change from OL Baseline (pre-Belimumab)
Model Specification

The data will be summarized only, no model will be applied.

For percent change from OL Baseline (pre-Belimumab) subjects with a OL Baseline (pre-
Belimumab) score of zero are excluded from the analysis due to division by zero.
 
 
 
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Model Checking & Diagnostics

NA
Model Results Presentation

The number, mean, SD, SE, median, 25th and 75th percentile and minimum and maximum will 
be presented.

The OL Baseline (pre-Belimumab) and change from OL Baseline (pre-Belimumab) timepoints 
will be summarized.
Subgroup Analyses

The Proteinuria Percent Change from OL Baseline (pre-Belimumab) analyses will be run on 
the subgroup with OL Baseline (pre-Belimumab) Proteinuria > 0.5 g/24hr.
Endpoint / Variables

Proteinuria Shifts from OL Baseline (pre-Belimumab)
Model Specification

The data will be summarized only, no model will be applied.
Model Checking & Diagnostics

NA
Model Results Presentation

The number of subjects with OL Baseline (pre-Belimumab) values will be presented, then the 
number and percentage that are Normal or High at OL Baseline (pre-Belimumab).

For ‘Any time post-baseline’, the baseline categories Normal and High will be split into n, No 
Change and Normal to High or High to Normal.

For OL Week 24 and Week 28 the same breakdown will be presented as for ‘Any time post 
baseline’.
8.
SAFETY ANALYSES
The safety analyses will be based on the Intent to Treat Open-label population and utilize
the open-label baseline, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
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 
 
 
 
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update these definitions semi-annually using the newest MedDRA version.  See Section 
18.12 (Appendix 12) of the Double-blind phase RAP for further details.  The details of 
the planned Open-label displays are provided in Appendix 9: List of Data Displays.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests (Electrolytes, 
Other Chemistries, Immunoglobins), 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 9: List of Data Displays.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including vital signs will be based on
GSK Core Data Standards, unless otherwise specified. The details of the planned displays 
are presented in Appendix 9: List of Data Displays.
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
PK data is not collected in the Open-label phase of this study and so no OL tables or 
listings are planned.  
In the DB phase there were 2 cases of PK samples being assigned to the same date.  This 
has since been corrected.  Two subjects and 4 samples were affected.  A subset of the DB 
PK reports, i.e. DB listing 5.01 and DB table 5.01, will be re-run using the updated PK 
data. 
10.
BIOMARKER ANALYSES
10.1.
Biomarker Analyses – Open-label Phase
10.1.1.
Endpoint / Variables

Immunoglobin Levels
o
Immunoglobulin isotype IgG, 
o
Immunoglobulin isotype IgA, 
o
Immunoglobulin isotype IgM, 

Autoantibody levels
o
Autoantibody anti-dsDNA, 

Complement Levels
o
complement C3 
o
complement C4

B-cells
 
 
 
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o
CD19 (/uL)
o
CD20 (/uL)
o
Naive CD19+CD20+CD27- (/uL)
o
Naive CD19+CD20+CD27- (%CD19) – only change from baseline 
table (not percent change)
o
Activated CD19+CD20+CD69+ Normalized (COUNT/mL)
o
Memory CD19+CD20+CD27+ (/uL)
o
Memory CD19+CD20+CD27+ (%CD19) – only change from baseline 
table (not percent change)
o
Plasmacytoid CD19+CD20+CD138+ Normalized (COUNT/mL)
o
Plasma CD19+CD20-CD138+ Normalized (COUNT/mL)
o
Short-lived Plasma CD19+CD20-CD27b+ Normalized
o
SLE Subset CD19+CD38b+CD27b+Lymph Normalized
(COUNT/mL)
o
Transitional CD19+CD24b+CD38b+CD27- Normalized
(COUNT/mL)
10.1.2.
Population of Interest
The biomarker analyses will be based on the modified Intent-To-Treat Open-label
population, unless otherwise specified.
10.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarized using descriptive statistics and listed.
10.1.3.1.
Statistical Methodology Specification
Endpoint / Variables

Immunoglobulin Levels Percent Change from OL Baseline (pre-Belimumab)

Immunoglobulin Levels Change from OL Baseline (pre-Belimumab)

Autoantibody Levels Percent Change from OL Baseline (pre-Belimumab)

Autoantibody Levels Change from OL Baseline (pre-Belimumab)

Complement Levels Percent Change from OL Baseline (pre-Belimumab)

Complement Levels Change from OL Baseline (pre-Belimumab)

B-cells Percent Change from OL Baseline (pre-Belimumab)

B-cells Change from OL Baseline (pre-Belimumab)
Model Specification

The data will be summarized only, no model will be applied.
 
 
 
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Model Checking & Diagnostics

NA
Model Results Presentation

The number, mean, SD, SE, median, 25th and 75th percentiles, minimum and maximum will be 
presented.

The OL Baseline (pre-Belimumab) and Change from OL Baseline timepoints will be 
summarized.
Subgroup Analyses

The Autoantibody Levels Percent Change from OL Baseline (pre-Belimumab) and 
Autoantibody Levels Change from OL Baseline will be repeated for the subgroup positive at OL 
Baseline.

The Complement Levels Percent Change from OL Baseline (pre-Belimumab) and Complement 
Levels Change from OL Baseline will be repeated for the subgroup with Low complement at 
OL Baseline.
Endpoint / Variables

Immunoglobulin Levels Shifts from OL Baseline (pre-Belimumab)

Autoantibody Levels Shifts from OL Baseline (pre-Belimumab)

Complement Levels Shifts from OL Baseline (pre-Belimumab)
Model Specification

The data will be summarized only, no model will be applied.
Model Checking & Diagnostics

NA
Model Results Presentation

The number of subjects with OL Baseline (pre-Belimumab) values will be presented, then the 
number and percentage that are Low or Normal/High at OL Baseline (pre-Belimumab).

For OL Week 24 and Week 28, the Baseline Categories Low and Normal/High will be split into 
n, Low to Normal/High, Low to Low, Normal/High to Normal/High, and Normal/High to Low (this 
is the breakdown using the levels for Immunoglobin and Complement).

The levels for the Autoantibodies are Positive or Negative, and for the shifts with no change 
the label “No change” will be used.
10.2.
Biomarker Analyses – for the Double-blind Phase
These parameters were not available to be reported in the DB CSR so will be summarized 
for the DB period in this End of study RAP/Report.
 
 
 
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10.2.1.
Endpoint / Variables
The following subset of parameters excluded from the DB phase laboratory data delivery 
will be summarized:

Autoantibody levels
o
beta-2-glycoprotein IgA, 
o
beta-2-glycoprotein IgG, 
o
beta-2-glycoprotein IgM, 
o
Anti-RNP, 
o
Anti-Ro (SS-A), 
o
Anti-Ro (SS-B), 
o
Anti-Ribosomal P
10.2.2.
Population of Interest
These laboratory parameters were excluded from the DB phase lab data delivery, these 
will be reported for the DB phase using the mITT population.
10.2.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.2.1 will be 
summarized using descriptive statistics and listed.
 
 
 
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11.
REFERENCES
GlaxoSmithKline Document Number 2018N366586_00. Double-blind Phase CSR,
Effective Date February 1, 2019
 
 
 
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12.
APPENDICES
12.1.
Appendix 1: Schedule of Activities
12.1.1.
Protocol Defined Schedule of Events
Table 2
Study calendar 6-month open-label extension
Study Day
Day 0 visit 
(Week 52/Exit 
Visit On-
Treatment 
Ph
)
Day 28 visit 
7 days
Day 56 visit
7 days
Day 84 visit 
7 days
Day 112 visit
7 days
Day 140 visit
7 days
Day 168 visit
7 days
Day 196/EXIT 
(4 weeks post 
l
t d
)
8-week
Follow-up (8 wks 
post last dose)
+ 7 Daysf
Study Week
Day 0
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
IV administration of study 
agenth
X
X
X
X
X
X
X
Clinical Assessments:
Weightd
See Day 364/Exit visit in Week 52 
Treatment Period
X
X
X
X
X
X
Symptom-driven Physical 
Exam
C-SSRS Since Last Visit
Assess/Record Adverse 
Events
X
X
X
X
X
X
X
X
Record all current 
medications
X
X
X
X
X
X
X
X
SLE Disease Activity 
Scales i
X
Xe
SLICC/ACR Damage 
Index
X
FACIT-Fatigue Scaleg
X
Laboratory Assessments:
Labs: Hematology & 
Modified Chem 20 
(non-fasting)  
See Day 364/Exit visit in Week 52 Treatment Period
X
Xe
X
PT/PTT
X
Urinalysis
X
Xe
X
Spot urine (protein to 
creatinine ratio)
X
Xe
Urine Pregnancy Testc
X
X
X
X
X
X
X
X
Pharmacokinetic 
Sampling 
Immunogenicityf
X
Xe
X
B cells
X
Xe
Complement (C3/C4) and 
anti-dsDNA
X
Xe
Extractable nuclear 
antigens (ENAs)
Anti-phospholipid 
antibodies (aCL, lupus 
anticoagulant, ±beta-2-
glycoprotein-1)
Serum Immunoglobulin 
IgG, IgA, IgM
X
X
Xe
 
 
 
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a.
Day 0 of the 6-month open-label extension is the Day 364/Week 52/Exit study visit from the On-Treatment phase 
of the study (see Table 6-1 in the protocol) and represents the first belimumab administration for those subjects 
continuing in the 6-month open-label extension.
b.
All subjects, including subjects who have discontinued study agent prior to Day 196, will return for an Exit visit 
approximately 4 weeks after their last dose of study agent as well as a follow-up visit approximately 8 weeks after 
the last dose of study agent.  
c.
Urine pregnancy test, as required, with results available prior to dosing. Women of child-bearing potential must be 
reminded of the requirement to report any pregnancy that occurs through 16 weeks following the last dose of 
study agent (see Section 7.6 in the protocol).
d.
The weight at the current visit will be used for calculating the dose. At sites where it is impractical to use the 
subject’s current body weight to calculate the dose, it is permissible to use the subject’s body weight from the 
previous visit.  However, the subject’s body weight will be measured prior to dosing and if the previous visit weight 
and current visit weight vary by more than 10%, then the weight measured at the current visit must be used.
e.
Assessment to be performed only if assessment was not done at Day 168/Week 24.
f.
The 8-week follow up visit is not required for subjects entering the separate continuation protocol.
g.
Must be completed by the subject prior to any study-related discussion with the investigator or study coordinator.  
The FACIT-Fatigue Scale will only be completed by subjects for whom a survey exists in the subject’s language.
h.
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 infusions.  Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be appropriate, based on clinical 
judgment.
i.
SLE Disease Activity Scales: SELENA SLEDAI, SLE Flare Index, BILAG, and PGA. Refer to Section 6.8.1 in the 
protocol for guidelines for scoring proteinuria for SELENA SLEDAI evaluation
 
 
 
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12.2.
Appendix 2: Assessment Windows
12.2.1.
Definitions of Visits for Analyses
All visits including the exit visit used the CRF visit and were not slotted based on OL 
study day. See Section 9.4.3 of the double-blind phase RAP for details of the windows 
for the double-blind phase visits.  See Section 12.5.1 for the OL study day definition.  For 
completeness, the table also includes the open-label follow up visit and the baseline 
visits.
Analysis Visit
Analysis 
Visit Number 
Target OL Study Daya
Open-label extension visits:
DB baseline
15
DB day 1 (needed for DB phase reports)
OL Baseline
155
DB day 1 (DB belimumab) or OL day 1 (DB 
placebo) the pre-belimumab baseline
Week 52/Exit DB
160
1 (OL Phase baseline, analysis visit name 
selected to be suitable for DB phase too)
OL Week 4
180
29
OL Week 8
190
57
OL Week 12
200
85
OL Week 16
210
113
OL Week 20
220
141
OL Week 24
230
169
OL Week 28/Exit
240
197 (The Exit visit is also mapped to this 
analysis visit and does not have a target 
day)
OL Week 24/Week 28/Exit
245
169 (OL Week 24 or OL Week 28/Exit if OL 
Week 24 missing)
OL Follow-upb
250
225 (or 8 weeks post last dose i.e. target day 
not relevant for early withdrawal)
a.
OL Study Day with OL Treatment Start Date as OL Day 1. 
b.
The open-label extension follow-up occurs 4-weeks after early withdrawal or 8 weeks after last dose (e.g. Week 
32) for subjects who complete the open-label extension phase.
Some subjects were not administered their first OL treatment until OL Week 4 or OL 
Week 8 so it is possible that the OL Day 1 visit and the OL Week 4 visit will have a 
negative OL study day.  
 
 
 
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12.3.
Appendix 3: Study Phases, and Treatment Emergent Open-
label Adverse Events
12.3.1.
Study Phases
Study Phase
Definition
Pre-OL Treatment 
Date < OL Study Treatment Start Date
On-OL Treatment
OL Study Treatment Start Date <= Date 
Note that Adverse Events and Concomitant Medications on the first Open-label treatment 
start date will be included for both the primary (Double-blind) and final (Open-label) 
reporting.
12.3.1.1.
Study Phases for OL Concomitant Medication
Study Phase
Definition
Prior DB Phase
If medication end date is not missing and is before Double-blind Treatment Start Date
DB Concomitant 
Prior OL phase
If medication is not Prior DB Phase and medication end date is not missing and is 
before Open-label Treatment Start Date
OL Concomitant
Any medication that is not Prior DB phase nor DB Concomitant Prior OL phase
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
In the OL Concomitant medication analysis dataset all Prednisone medication data is 
required in order to calculate the OL (pre-belimumab) baseline 7-day average prednisone 
dose.  
12.3.2.
Treatment Emergent Open-label Flag for Adverse Events
Flag
Definition
Treatment 
Emergent Open-
label

An OL treatment-emergent AE is an adverse event that starts on or after the first 
open-label treatment dose.  

AEs with missing start dates will be assumed to be treatment-emergent OL.

Open-label Treatment Start Date ≤ AE Start Date.
NOTES: 

Time of open-label treatment dosing and start time of AEs should be considered, if collected.
 
 
 
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12.4.
Appendix 4: Data Display Standards & Handling 
Conventions
12.4.1.
Reporting Process
Software

The currently supported versions of SAS software 9.4 will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Compound
: GSK1550188 / bel115471
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0]. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent.
Generation of RTF Files

RTF files will be generated.
12.4.2.
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:
o
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.
o
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 
o
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
o
Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
 
 
 
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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.
 
 
 
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12.5.
Appendix 5: Derived and Transformed Data
12.5.1.
General
Multiple Measurements at One Analysis Time Point

If there are multiple visits within a visit window, the visit closest to the target date will be used. If 
there are two visits equidistant from the target date, the first will be used.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for 
safety parameters will be counted in both the High and Low categories of “Any visit post-baseline” 
row of related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables.
OL Study Day
Open-label study Day is the number of days from the open-label treatment start date to a study date of 
interest (e.g., adverse event start date) and is calculated as follows:

Calculated as the number of days from First OL Dose Date:
o
Ref Date = Missing              → Study Day = Missing 
o
Ref Date < First OL Dose Date → Study Day = Ref Date – First OL Dose Date
o
Ref Data ≥ First OL Dose Date → Study Day = Ref Date – (First OL Dose Date) + 1    
Note: Study Day cannot be zero. If either date is missing, then Study Day is missing.
Windows for Assessment of Post-injection/infusion sensitivity reactions (PISR) and hypersensitivity 
reactions (HSR)

See Section 9.4.35 of the DB phase RAP.
12.5.2.
Study Population
Extent of Exposure

Number of days of exposure to OL study drug will be calculated based on the formula:  
Duration of OL Exposure in Days = Last infusion date in open-label – (First infusion in open-
label) + 28

Participants who did not report a OL treatment start date will be categorized as having zero days of OL 
exposure. 

First and last OL infusion dates will be used, regardless of any missed doses.
12.5.3.
Efficacy
SLE Flare Index (SFI) Scoring

SFI is used to report the first mild /moderate or severe flare occurrence since the last assessment.  In 
the OL phase there is a LOG question and an assessment at OL Week 24 or OL Week 28 (if Week 24 
not done).

The change in SELENA SLEDAI criteria will be assessed via the SFI form.

The mild/moderate or severe classification will be re-derived using 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.
o
In this case, if any of the mild/moderate reasons are checked, then the flare will be considered 
Mild/Moderate; otherwise the flare will not be counted.
 
 
 
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Time to First SFI Flare, Censoring and Disposition Rules

The rules described in this section apply to SLE Flares and SLE Severe Flares.
Up to Open-label 28 Weeks
Time to first (severe) SLE flare is defined as the number of days from first open-label exposure until the 
subject meets an event (event date – first open-label exposure date + 1). The disposition of subjects is 
defined as follows in Table 3. Only flares post first open-label treatment are included in the analysis, 
therefore flares (not subjects) occurring on the open-label treatment start date should be removed from the 
analysis set prior to determining the first open-label flare. For the Open-label phase, time to first flare over 
28 weeks is calculated as:
Time to first OL flare (days) = Date of first OL flare – Open-label treatment start date +1.
Table 3
Subject Disposition Rules for SLE Flare (Open-label Phase)
Subject disposition
Event met
Event date
Subject has an OL flare 
Subject has an OL flare
Yes
Date of first OL flare
Subject does not have an OL flare
Subject withdraws
No
Censored at last OL flare assessment date
Subject dies
No
Censored at date of death
Subject completes
No
Censored at last OL flare assessment date
Baseline Prednisone Dose
The OL reports will use the OL baseline from before the first dose of belimumab.  For subjects on 
Belimumab in the DB phase the baseline average daily prednisone dose is the sum of all prednisone doses 
over 7 consecutive days up to, but not including DB Day 1, divided by 7. For subjects on Placebo in the DB 
phase the baseline average daily prednisone dose is the sum of all prednisone doses over 7 consecutive 
days up to, but not including OL Day 1, divided by 7.
Prednisone Change from OL Baseline (Observed)
While on treatment, the average daily prednisone dose at the visit is the sum of all prednisone doses over 7 
consecutive days up to and including the day of interest, divided by 7, unless otherwise specified. Days on 
which a subject does not have prednisone use recorded will be considered as 0 mg for the day in the 
calculation of average daily prednisone dose. 
The average daily prednisone equivalent dose will be calculated for OL Week 28/Exit. For subjects who 
withdraw from the study without an Exit scheduled visit, the average dose will be calculated at the date of 
withdrawal. For a subject who withdrew at OL baseline then the average dose will be the OL baseline value
(i.e. zero change from OL baseline).
The time period considered is the 7 days up to and including the OL Week 28 / Exit visit.  No imputation will 
be done for missing data.
Any Increase in Prednisone at Week 28/Exit Compared to OL Baseline (Observed)
Subjects are considered to have ‘any increase’ from OL baseline (pre-belimumab) when the change from 
baseline in average daily prednisone dose is >0.  
The time period considered is the 7 days up to and including the OL Week 28 / Exit visit.
 
 
 
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Prednisone Reduced to <=7.5 mg/day at Open-Label Phase Week 28/Exit (Observed)
A responder is defined as a subject who decreased their daily prednisone dose to <=7.5 mg/day from an OL
baseline dose >7.5 mg/day. This endpoint is only defined for subjects who used prednisone >7.5 mg/day at 
OL baseline.
The time period considered is the 7 days up to and including up to the OL Week 28 / Exit visit.  If a subject 
misses their Week 28 or Exit visit, then the subject will be missing for that visit (Observed).
Prednisone Increased to > 7.5 mg/day at Open-Label Phase Week 28/Exit (Observed)
This is a summary of subjects who increased their daily prednisone dose to >7.5 mg/day from an OL
baseline dose <=7.5 mg/day. This endpoint is only defined for subjects who used prednisone <=7.5 mg/day 
at OL baseline.
The time period considered is the 7 days up to and including up to the OL Week 28 / Exit visit.
Time to First Renal Flare, Censoring and Disposition Rules
Time to first renal flare is defined as the number of days from first open-label exposure until the subject 
meets an event (event date – first open-label exposure date + 1). The disposition of subjects is defined as 
follows in Table 4.
Open-label Renal flares are defined as reproducible results comparative to Open-label Phase Baseline 
values, so can only occur post-open-label Baseline.
Time to first renal flare over 28 weeks is calculated as:
Time to first OL flare (days) = Date of first OL flare – open-label treatment start date +1
NB: Patients who withdraw or are lost to follow up without an OL renal flare assessment will be censored at 
zero days. Patients who withdraw or are lost to follow up with only one renal flare assessment (which 
therefore cannot be reproduced) will be censored at their last open-label flare assessment date. It is 
possible for a renal flare to occur at the Week 28/Exit visit as it could be reproduced at an unscheduled visit 
or the 8 week follow up visit.
Table 4
Subject Disposition Rules for Renal Flares (Open-label Phase)
Subject disposition
Event met
Event date
Subject has an OL flare 
Subject has an OL renal 
flare
Yes
Date of first renal flare which has been reproduced by a 
later assessment
Subject does not have an OL flare
Subject withdraws
No
Censored at last OL flare assessment date
Subject dies
No
Censored at last OL flare assessment date
Subject completes
No
Censored at last OL flare assessment date
 
 
 
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12.6.
Appendix 6: Reporting Standards for Missing Data
12.6.1.
Premature Withdrawals
Element
Reporting Detail
Premature 
Withdrawals
General

Subjects who drop out and do not complete the OL study will return for an OL Exit visit 
4 weeks after their final dose of study agent.

During the 6-month open-label extension, the assessments for the Week 28 visit will be 
performed for the OL Exit visit.

All post OL treatment data from participants who were withdrawn from the OL study will 
be listed and all available data will be included in summary tables and figures, unless 
otherwise specified.

The SLE Disease Activity Scales are completed at OL Week 24, and OL Week 28/Exit
should be completed only if Week 24 is missing.  
12.6.2.
Handling of Missing Data
Element
Reporting Detail
Last 
Observation 
Carried 
Forward 
(LOCF)

The LOCF principle is applied whereby missing values will be replaced with the 
last previous non-missing value.   

If a subject withdraws the LOCF value will be handled by using the result from 
the last visit post OL day 1 and prior to the date of withdrawal.

If any observed dates exist, the date for the LOCF record will be determined from 
the observed dates. If there are multiple observed dates, the latest of these dates 
(closest to the scheduled visit) will be taken as the derived date. If the record is 
completely missing then the date will be missing, otherwise missing dates will be 
imputed as the target open-label study day from the schedule of events.
Observed

Observed data are the data collected or observed for the subject with no 
imputation for missing data.  The observed case analysis includes all data collected 
including data post IP withdrawal.
Worst 
Observation 
Carried 
Forward 
(WOCF)

The worst observation carried forward (WOCF) principle will be applied to the 
SLICC/ACR Damage Index data at an item level.  As the SLICC/ACR Damage Index 
is meant to be a monotonic, non-decreasing value (except for renal domain), items 
that decrease over the course of the study will be replaced with the highest previous 
item score achieved among previous visits (including study baseline). Within the renal 
domain, damage scored on the first two items (estimated glomerular filtration rate < 
50%, proteinuria > 3.5 gm/24hours) should only be carried forward to OL Week 24/28 
if the third item (end stage renal disease) has not been scored at OL Week 24/28. The 
reason for this is that scores on the first two items can decrease but only if the third 
item is then scored.
12.6.2.1.
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 does not allow for the possibility of partial AE dates.

Completely missing start or end dates will remain missing, with no imputation applied. 
 
 
 
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Element
Reporting Detail
Consequently, time to onset and duration of such events will be missing.  AEs with 
missing start dates will be considered as OL treatment emergent.
Concomitant 
Medications/
Partial dates for any concomitant medications recorded in the CRF will be imputed using the 
following convention:
Medication Start Date (CMSTDT)

If CMENDT is missing OR CMENDT >= Belimumab TRTSDT (whether CMENDT is a 
complete or partial date) then CMSDT is imputed as the Belimumab TRTSDT. 

If CMENDT is < Belimumab TRTSDT (whether CMENDT is a complete or partial date) 
then CMSTDT is imputed with JAN for missing month and 01 for missing day, whatever 
is applicable. 
Medication End Date (CMENDT)

If month and year are present, then set to the earlier of (last contact date or last day of 
that month of the CMENDT).

If only year present, then set to the earlier of (31DEC of the year or last contact date).
Missing dates for any concomitant medications recorded in the CRF will be imputed using 
the following convention:
Medication Start Date (CMSTDT)
CMSTDT is imputed as Belimumab TRTSDT unless:

CMENDT is < Belimumab TRTSDT (whether CMENDT is a complete (DD/MM/YY) or 
partial date (some combination of CMENDT day, month or year imputed) OR

The month and/or month and year of the partial CMENDT date are before the month 
and/or year of Belimumab TRTSDT OR 

“Taken prior to study?” is checked.
Medication End Date (CMENDT)

End dates for concomitant medications will not be imputed, and the medication will be 
considered ongoing.
Note that medications with partial or missing start and/or stop dates will be assumed to be 
OL 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.
See Section 9.3.1 and Section 9.3.2 of the DB phase RAP.
 
 
 
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12.7.
Appendix 7: Values of Potential Clinical Importance
12.7.1.
Laboratory Values
The Adverse Event and Laboratory Toxicity Grading Tables for this study can be found 
in the Double-Blind Phase RAP in Section 18.11 (Appendix 11).
 
 
 
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12.8.
Appendix 8: Abbreviations & Trade Marks
12.8.1.
Abbreviations
Abbreviation
Description
ACR
American College of Rheumatology
ADaM
Analysis Data Model
AE
Adverse Event
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BILAG No 
1A/2B
No new BILAG A organ domain score or 2 new BILAG B organ domain scores 
compared with baseline
BMI
Body mass index
CDISC
Clinical Data Interchange Standards Consortium
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DB
Double-blind
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
IV
Intravenous
IVRS
Interactive Voice Recognition System
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
mITT OL
Modified Intention-To-Treat Open-label
OL
Open-label
OLE
Open-label extension
PDMP
Protocol Deviation Management Plan
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PSAP
Program Safety Analysis Plan
PSRQ
Possible Suicidality Related Questionnaire
PT
Preferred Term
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDL
Source Data Lock
 
 
 
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Abbreviation
Description
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
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
System Organ Class
SOP
Standard Operation Procedure
SRI
SLE Responder Index
SRI-S2K
SLE Responder Index (SRI) using the SELENA SLEDAI modified with S2K 
scoring for proteinuria
TFL
Tables, Figures & Listings 
WBC
White Blood Cell
WOCF
Worst Observation Carried Forward
See also the Abbreviation section of the DB phase RAP.
12.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
 
 
 
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12.9.
Appendix 9: List of Data Displays
12.9.1.
Data Display Numbering
The following numbering will be applied for Open-label extension RAP generated 
displays:
Section
Tables
Figures
Study Population
11.1 to 11.n
11.1 to 11.n
Efficacy
12.1 to 12.n
12.1 to 12.n
Safety
13.1 to 13.n
13.1 to 13.n
Health Outcomes
14.1 to 14.n
14.1 to 14.n
Pharmacokinetic
15.1 to 15.n
15.1 to 15.n
Biomarker
16.1 to 16.n
16.1 to 16.n
12.9.2.
Deliverables
Delivery [Priority] [1]
Description
SAC [X]
Final Statistical Analysis Complete
NOTES: 

Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
 
 
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12.9.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
11.1.
mITT OL
ES1/ 
ES1A /
ES8 / 
ES8A
Subject Completion Status by End of Open-Label 
Phase Week 28
ICH E3, FDAAA, EudraCT
SAC [1]
11.2.
Intent-to-Treat Open-label
ES1/ 
ES1A /
ES8 / 
ES8A
Subject Completion Status by End of Open-Label 
Phase Week 28
ICH E3, FDAAA, EudraCT
SAC [1]
Protocol Deviation
11.3.
Intent-to-Treat Open-label
DV1
Subjects with Important Protocol Deviations (Open-
Label Phase)
ICH E3
SAC [1]
Population Analyzed
11.4.
Intent-to-Treat Open-label
SP1 / 
SP1A
Summary of Study Populations (Open-Label 
Phase)
IDSL
SAC [1]
Demographic and Baseline Characteristics
11.5.
mITT OL
DM1 / DM3
Demographic and Baseline Characteristics (Open-
Label Phase)
ICH E3, FDAAA, EudraCT
SAC [1]
11.6.
Intent-to-Treat Open-label
DM1 / DM3
Demographic and Baseline Characteristics (Open-
Label Phase)
ICH E3, FDAAA, EudraCT
SAC [1]
11.7.
mITT OL
Baseline Disease Activity (Open-Label Phase)
Duration is defined as (Belimumab 
treatment start date - SLE diagnosis date + 
1)/365.25. Baseline is pre-Belimumab.
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
11.8.
Intent-to-Treat Open-label
Baseline Disease Activity (Open-Label Phase)
Duration is defined as (Belimumab 
treatment start date - SLE diagnosis date + 
1)/365.25.  Baseline is pre-Belimumab.
SAC [1]
11.9.
mITT OL
Summary of Race and Racial Combination (Open-
Label Phase)
SAC [1]
11.10.
mITT OL
SELENA SLEDAI Organ and Item Involvement at 
Baseline (Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.11.
Intent-to-Treat Open-label
SELENA SLEDAI Organ and Item Involvement at 
Baseline (Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.12.
mITT OL
Immunoglobulin Levels at Baseline (Open-Label 
Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.13.
Intent-to-Treat Open-label
Immunoglobulin Levels at Baseline (Open-Label 
Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.14.
mITT OL
Complement Levels and Other Biomarkers at 
Baseline (Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.15.
Intent-to-Treat Open-label
Complement Levels and Other Biomarkers at 
Baseline (Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.16.
Intent-to-Treat Open-label
Allowable SLE Medication Usage at Baseline 
(Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
11.17.
Intent-to-Treat Open-label
Steroid, Anti-malarial and Immunosuppressant Use 
at Baseline (Open-Label Phase)
Baseline is Pre-belimumab baseline.
SAC [1]
Prior and Concomitant Medications
11.18.
Intent-to-Treat Open-label
CM1
Concomitant Medications by ATC Level 1 and ATC 
Level 4 Term (Open-Label Phase)
ICH E3
SAC [1]
11.19.
Intent-to-Treat Open-label
Concomitant Medications by ATC Level 4 and 
Preferred Term (Open-Label Phase)
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
11.20.
Modified Intent-to-Treat 
Open-label
EX1 / 
EX5
Study Drug Exposure during Open-Label Phase 
Week 24
ICH E3
For ClinPharm, a listing often substitutes 
for a table.
SAC [1]
11.21.
Intent-to-Treat Open-label
EX1 / 
EX5
Study Drug Exposure during Open-Label Phase 
Week 24
ICH E3
SAC [1]
Biomarker parameters missed from DB phase delivery
11.22.
mITT
Autoantibody Levels at Baseline Continued 
(Double-blind Phase)
Report 

Beta-2-glycoprotein IgA (U/mL), 

Beta-2-glycoprotein IgG (U/mL) 

Beta-2-glycoprotein IgM (U/mL) 
as not delivered at time of DB report.
(format as the DB phase report)
SAC [1]
 
 
 
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12.9.4.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example
Shell
Title
Programming Notes
Deliverable 
[Priority]
SRI-S2K Response
12.1.
mITT OL
SRI-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed)
SAC [1]
12.2.
mITT OL
SRI-S2K Response at Open-Label Phase Week 24 /Week 28 and the 3 
Components (Observed)
SAC [1]
12.3.
mITT OL
Disposition of SRI-S2K Response at Open-Label Phase Week 24 /Week 
28 (Observed)
SAC [1]
12.4.
Completer
OL
SRI-S2K Response at Open-Label Phase Week 24 /Week 28 (Completer 
Sensitivity Analysis) (Observed)
SAC [1]
12.5.
mITT OL
SRI-SS Response at Open-Label Phase Week 24 /Week 28 (SELENA 
SLEDAI) [1] (Observed)
SAC [1]
12.6.
mITT OL
SRI5-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed)
SAC [1]
12.7.
mITT OL
SRI6-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed)
SAC [1]
12.8.
mITT OL
SRI7-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed)
SAC [1]
12.9.
mITT OL
SRI8-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed)
SAC [1]
12.10.
mITT OL
EMA Modified SRI-S2K Response [1] at Open-Label Week 24 /Week 28
(Observed)
SAC [1]
12.11.
mITT OL
SRI-S2K Response at Open-Label Phase Week 24 /Week 28
(Observed) by Region
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example
Shell
Title
Programming Notes
Deliverable 
[Priority]
SFI Flare
12.12.
mITT OL
Time to First Severe SFI Flare over Open-Label Phase [1] (DO=Censor)
SAC [1]
12.13.
mITT OL
Time to First SFI Flare over Open-Label Phase [1] (DO=Censor)
SAC [1]
SLICC/ACR Damage Index
12.14.
mITT OL
SLICC/ACR Damage Index Change from OL Baseline at Open-Label 
Phase Week 28 (Observed Case, Corrected)
Pre-Belimumab Baseline
SAC [1]
12.15.
mITT OL
SLICC/ACR Damage Index Change from OL Baseline at Open-Label 
Phase Week 28 by SLICC/ACR Damage Index Subgroup at OL Baseline
(No Damage vs. Damage Index >=1) (Observed Case, Corrected)
Pre-Belimumab Baseline
SAC [1]
12.16.
mITT OL
SLICC/ACR Damage Index Worsening (Change >0) Compared with OL
Baseline at Open-Label Phase Week 28 (WOCF)
Pre-Belimumab Baseline
SAC [1]
12.17.
mITT OL
SLICC/ACR Damage Index Worsening (Change >0) Compared with OL
Baseline at Open-Label Phase Week 28 (WOCF) by SLICC/ACR 
Damage Index Subgroup at OL Baseline (No Damage vs. Damage Index 
>=1)
Pre-Belimumab Baseline
SAC [1]
SS-S2K
12.18.
mITT OL
SS-S2K >= 4-point Reduction from OL Baseline at Open-Label Phase 
Week 24/Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.19.
mITT OL
SELENA SLEDAI-S2K Organ System Improvement by Organ System at 
Open-Label Phase Week 24/Week 28 (Observed) among Subjects with 
Organ System Involvement at OL Baseline [1] 
Pre-Belimumab Baseline
SAC [1]
12.20.
mITT OL
SS-S2K Percent Change from OL Baseline at Open-Label Phase Week 
24 and Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.21.
mITT OL
SS-S2K Change from OL Baseline at Open-Label Phase Week 24 and
Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example
Shell
Title
Programming Notes
Deliverable 
[Priority]
SELENA SLEDAI
12.22.
mITT OL
SELENA SLEDAI Percent Change from OL Baseline at Open-Label 
Phase Week 24 and Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.23.
mITT OL
SELENA SLEDAI Change from OL Baseline at Open-Label Phase Week 
24 and Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
BILAG
12.24.
mITT OL
BILAG no New 1A/2B Organ Domain scores compared with OL Baseline
at Open-Label Phase Week 24/Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.25.
mITT OL
BILAG no 1A/2B Organ Domain scores at Open-Label Phase Week 
24/Week 28 (Observed)
SAC [1]
12.26.
mITT OL
BILAG Improvement by Organ Domain at Open-Label Phase Week 
24/Week 28 (Observed) among Subjects with an A or B Domain Score at 
OL Baseline [1] 
Pre-Belimumab Baseline
SAC [1]
12.27.
mITT OL
BILAG Worsening by Organ Domain at Open-Label Phase Week 
24/Week 28 (Observed) among Subjects with no A Domain Score at OL
Baseline [1] 
Pre-Belimumab Baseline
SAC [1]
PGA
12.28.
mITT OL
PGA No Worsening (Increase of <0.3 points from OL Baseline) at Open-
Label Phase Week 24/Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.29.
mITT OL
PGA Percent Change from OL Baseline at Open-Label Phase Week 24 
and Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.30.
mITT OL
PGA Change from OL Baseline at Open-Label Phase Week 24 and
Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.31.
mITT OL
PGA Improvement (Increase of >=0.3 points from OL Baseline) at Open-
Label Phase Week 24 or Week 28 (Observed)
Subjects with baseline PGA score 
< 0.3 will be treated as having no 
improvement.
Pre-Belimumab Baseline.
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example
Shell
Title
Programming Notes
Deliverable 
[Priority]
Renal Flare
12.32.
mITT OL
Time to First Renal Flare over Open-Label Phase 28 weeks [1] 
(DO=Censor)
SAC [1]
12.33.
mITT OL
Time to First Renal Flare over Open-Label Phase 28 weeks [1] 
(DO=Censor) among Subjects with OL Phase Baseline Proteinuria > 0.5 
g/24hr 
SAC [1]
Proteinuria
12.34.
mITT OL
Proteinuria Percent Change from OL Baseline at Open-Label Phase 
Week 24 and Week 28 (Observed) among Subjects with OL Baseline
Proteinuria > 0.5 g/24hr 
Pre-Belimumab Baseline
SAC [1]
12.35.
mITT OL
Proteinuria Change from OL Baseline at Open-Label Phase Week 24 
and Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.36.
mITT OL
Proteinuria Shifts from OL Baseline at Open-Label Phase Week 24 and
Week 28 (Observed)
Pre-Belimumab Baseline
SAC [1]
12.37.
mITT OL
Percent of Subjects with Doubling of Serum Creatinine from OL Baseline
at Open-Label Phase Week 24 and Week 28 (Observed) among 
Subjects with OL Baseline Proteinuria >0.5 g/24hr
Pre-Belimumab Baseline
SAC [1]
Prednisone
12.38.
mITT OL
Prednisone Change from OL Baseline at Open-Label Phase Week 
28/Exit (Observed)
Pre-Belimumab Baseline
SAC [1]
12.39.
mITT OL
Any Increase in Prednisone Compared to OL Baseline at Open-Label 
Phase Week 28/Exit (Observed)
Pre-Belimumab Baseline
SAC [1]
12.40.
mITT OL
Prednisone Reduced to <=7.5 mg/day at Open-Label Phase Week 
28/Exit (Observed) among Subjects with OL Baseline Prednisone Dose 
>7.5 mg/day
Pre-Belimumab Baseline
SAC [1]
12.41.
mITT OL
Prednisone Increased to > 7.5 mg/day at Open-Label Phase Week 
28/Exit (Observed) among Subjects with OL Baseline Prednisone Dose 
<=7.5 mg/day
Pre-Belimumab Baseline
SAC [1]
 
 
 
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12.9.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Adverse Events (AEs)
13.1.
Intent-to-Treat 
Open-label
Similar to 
AE13
Adverse Events Summary (Open-Label Phase)
ICH E3
SAC [1]
13.2.
Intent-to-Treat 
Open-label
Adverse Events by SOC (Open-Label Phase)
ICH E3
.
SAC [1]
13.3.
Intent-to-Treat 
Open-label
As AE1 but 
with total 
column
Adverse Events by SOC and PT (Open-Label Phase)
SAC [1]
13.4.
Intent-to-Treat 
Open-label
Adverse Events by PT (Open-Label Phase)
SAC [1]
13.5.
Intent-to-Treat 
Open-label
AE15
Common [1] Non-Serious Adverse Events by SOC and PT (Number of Subjects and 
Occurrences) (Open-Label Phase)
FDAAA, 
EudraCT
‘
SAC [1]
13.6.
Intent-to-Treat 
Open-label
Adverse Events by SOC and Severity (Open-Label Phase)
SAC [1]
13.7.
Intent-to-Treat 
Open-label
Adverse Events by SOC and PT and Severity (Open-Label Phase)
SAC [1]
13.8.
Intent-to-Treat 
Open-label
Relationship between System Organ Class and Verbatim Text (Open-Label Phase)
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
13.9.
Intent-to-Treat 
Open-label
Serious Adverse Events by SOC (Open-Label Phase)
FDAAA, 
EudraCT
SAC [1]
13.10.
Intent-to-Treat 
Open-label
AE1
Serious Adverse Events by SOC and PT (Open-Label Phase)
SAC [1]
13.11.
Intent-to-Treat 
Open-label
Serious Adverse Events by PT (Open-Label Phase)
SAC [1]
13.12.
Intent-to-Treat 
Open-label
AE16
Serious Adverse Events by SOC and PT (Number of Subjects and Occurrences) (Open-
Label Phase)
As DB Phase 
table 3.21
SAC [1]
13.13.
Intent-to-Treat 
Open-label
Study Agent Related Adverse Events by SOC (Open-Label Phase)
SAC [1]
13.14.
Intent-to-Treat 
Open-label
AE1
Study Agent Related Adverse Events by SOC and PT (Open-Label Phase)
SAC [1]
13.15.
Intent-to-Treat 
Open-label
Study Agent Related Adverse Events by PT (Open-Label Phase)
SAC [1]
13.16.
Intent-to-Treat 
Open-label
Adverse Events Resulting in Study Agent Discontinuation by SOC (Open-Label Phase)
SAC [1]
13.17.
Intent-to-Treat 
Open-label
AE1
Adverse Events Resulting in Study Agent Discontinuation by SOC and PT (Open-Label 
Phase)
SAC [1]
13.18.
Intent-to-Treat 
Open-label
AE3
Adverse Events Resulting in Study Agent Discontinuation by PT (Open-Label Phase)
SAC [1]
13.19.
Intent-to-Treat 
Open-label
AE1
Study Agent Related Serious Adverse Events by SOC and PT (Open-Label Phase)
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
13.20.
Intent-to-Treat 
Open-label
AE1
Fatal Serious Adverse Events by SOC and PT (Open-Label Phase)
SAC [1]
13.21.
Intent-to-Treat 
Open-label
Adverse Events of Special Interest by Category (Open-Label Phase)
SAC [1]
13.22.
Intent-to-Treat 
Open-label
Malignant Neoplasm Adverse Events of Special Interest by Category and PT (Open-Label 
Phase)
SAC [1]
13.23.
Intent-to-Treat 
Open-label
Post-Infusion Systemic Reactions Adverse Events of Special Interest by Category and PT 
(Open-Label Phase)
SAC [1]
13.24.
Intent-to-Treat 
Open-label
Serious Post-Infusion Systemic Reactions Adverse Events of Special Interest by Category 
and PT (Open-Label Phase)
SAC [1]
13.25.
Intent-to-Treat 
Open-label
Infection Adverse Events of Special Interest by Category and PT (Open-Label Phase)
SAC [1]
13.26.
Intent-to-Treat 
Open-label
Infection Adverse Events of Special Interest Leading to Study Agent Discontinuation by 
Category and PT (Open-Label Phase)
SAC [1]
13.27.
Intent-to-Treat 
Open-label
Depression/Suicide/Self-injury Adverse Events of Special Interest by Category and PT 
(Open-Label Phase)
SAC [1]
13.28.
Intent-to-Treat 
Open-label
Deaths by Category and PT (Open-Label Phase)
SAC [1]
13.29.
Intent-to-Treat 
Open-label
Post-Infusion Systemic Reactions per Anaphylactic Reactions CMQ Broad Search by PT 
in First Six Infusions (Open-Label Phase)
SAC [1]
13.30.
Intent-to-Treat 
Open-label
Serious Post-Infusion Systemic Reactions per Anaphylactic Reactions CMQ Broad Search 
by PT in First Six Infusions (Open-Label Phase)
SAC [1]
13.31.
Intent-to-Treat 
Open-label
Serious Post-Infusion Systemic Reactions/Hypersensitivity per GSK Adjudication by PT in 
First Six Infusions (Open-Label Phase)
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Laboratory: Chemistry 
13.32.
Intent-to-Treat 
Open-label
Laboratory Results by Visit: Electrolytes (Open-Label Phase)
SAC [1]
13.33.
Intent-to-Treat 
Open-label
Laboratory Results by Visit: Other Chemistries (Open-Label Phase)
SAC [1]
13.34.
Intent-to-Treat 
Open-label
Laboratory Results by Visit: Immunoglobulins (Open-Label Phase)
SAC [1]
13.35.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Electrolytes (Open-Label Phase)
SAC [1]
13.36.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Other Chemistries (Open-Label Phase)
SAC [1]
13.37.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Immunoglobulins (Open-Label Phase)
SAC [1]
13.38.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: Electrolytes 
(Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.39.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: Other 
Chemistries (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.40.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: 
Immunoglobulin G (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.41.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Electrolytes (Open-Label 
Phase)
Pre-
Belimumab 
Baseline
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
13.42.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Other Chemistries (Open-
Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.43.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Immunoglobulins (Open-
Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.44.
Intent-to-Treat 
Open-label
Immunoglobulin Levels below the Lower Limit of Normal (LLN) by Visit (Open-Label 
Phase)
SAC [1]
13.45.
Intent-to-Treat 
Open-label
Immunoglobulin Levels below the Lower Limit of Normal (LLN) at each Visit among 
Subjects with Immunoglobulins >= LLN at OL Baseline (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.46.
Intent-to-Treat 
Open-label
Immunoglobulin Levels above the Lower Limit of Normal (LLN) by Visit (Open-Label 
Phase)
SAC [1]
13.47.
Intent-to-Treat 
Open-label
Immunoglobulin Levels above the Lower Limit of Normal (LLN) at each Visit among 
Subjects with Immunoglobulins < LLN at OL Baseline (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
Laboratory: Hematology
13.48.
Intent-to-Treat 
Open-label
Laboratory Results by Visit: Hematology (Open-Label Phase)
SAC [1]
13.49.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Hematology (Open-Label Phase)
SAC [1]
13.50.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: Hematology 
(Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
13.51.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Hematology (Open-Label 
Phase)
Pre-
Belimumab 
Baseline
SAC [1]
Laboratory: Urinalysis
13.52.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Urinalysis (Open-Label Phase)
SAC [1]
13.53.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: Urinalysis 
(Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.54.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Urinalysis (Open-Label 
Phase)
Pre-
Belimumab 
Baseline
SAC [1]
Laboratory: Hepatobiliary (Liver)
13.55.
Intent-to-Treat 
Open-label
Laboratory Results by Visit: Liver Function (Open-Label Phase)
SAC [1]
13.56.
Intent-to-Treat 
Open-label
Worst Laboratory Toxicity Grade: Liver Function (Open-Label Phase)
SAC [1]
13.57.
Intent-to-Treat 
Open-label
Laboratory Toxicity Grade Worsening of at Least 2 Grades from OL Baseline: Liver 
Function (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
13.58.
Intent-to-Treat 
Open-label
Laboratory Reference Range Shifts from OL Baseline by Visit: Liver Function (Open-Label 
Phase)
Pre-
Belimumab 
Baseline
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Immunogenicity
13.59.
Intent-to-Treat 
Open-label
Immunogenic Response by Visit (Open-Label Phase)
SAC [1]
Vital Signs
13.60.
Intent-to-Treat 
Open-label
VS1
Vital Signs by Visit (Observed) (Open-Label Phase)
ICH E3
SAC [1]
13.61.
Intent-to-Treat 
Open-label
Vital Signs Change from OL Baseline by Visit (Observed) (Open-Label Phase)
Pre-
Belimumab 
Baseline
SAC [1]
12.9.6.
Health Outcomes Tables
Efficacy: Tables
No.
Population
IDSL / Example
Shell
Title
Programming Notes
Deliverable 
[Priority]
FACIT- Fatigue Scale
14.1.
mITT OL
FACIT-Fatigue Scale Score Change from OL Baseline (Observed) at Open-
Label Phase Week 28
Pre-Belimumab 
Baseline
SAC [1]
14.2.
mITT OL
Improvement in FACIT-Fatigue Scale Score exceeding the MCID (>=4) at 
Open-Label Phase Week 28
SAC [1]
 
 
 
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12.9.7.
Pharmacokinetic Tables
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Belimumab Concentration
15.1
PK
Belimumab Concentrations (ug/mL) (Observed) (Double-Blind 
Phase)
As DB table 5.01
SAC [1]
12.9.8.
Biomarker Tables
Biomarker: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunoglobin Levels
16.1.
Modified Intent-
to-Treat Open-
label
Immunoglobulin Levels Percent Change from OL Baseline by Visit
(Observed) (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.2.
Modified Intent-
to-Treat Open-
label
Immunoglobulin Levels Change from OL Baseline by Visit
(Observed) (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.3.
Modified Intent-
to-Treat Open-
label
Immunoglobulin Levels Shifts from OL Baseline by Visit (Open-
Label Phase)
Pre-Belimumab Baseline
SAC [1]
Autoantibody levels
16.4.
Modified Intent-
to-Treat Open-
label
Autoantibody Levels Percent Change from OL Baseline by Visit
(Observed) (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
 
 
 
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Biomarker: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
16.5.
Modified Intent-
to-Treat Open-
label
Autoantibody Levels Percent Change from OL Baseline by Visit 
among Subjects Positive at OL Baseline (Observed) (Open-Label 
Phase)
Pre-Belimumab Baseline
SAC [1]
16.6.
Modified Intent-
to-Treat Open-
label
Autoantibody Levels Change from OL Baseline by Visit (Observed)
(Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.7.
Modified Intent-
to-Treat Open-
label
Autoantibody Levels Change from OL Baseline by Visit among 
Subjects Positive at OL Baseline (Observed) (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.8.
Modified Intent-
to-Treat Open-
label
Autoantibody Levels Shifts from OL Baseline by Visit (Open-Label 
Phase)
Pre-Belimumab Baseline
SAC [1]
Complement Levels
16.9.
Modified Intent-
to-Treat Open-
label
Complement Levels Percent Change from OL Baseline by Visit
(Observed) (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.10.
Modified Intent-
to-Treat Open-
label
Complement Levels Percent Change from OL Baseline by Visit 
among Subjects with Low Complement at OL Baseline (Observed)
(Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.11.
Modified Intent-
to-Treat Open-
label
Complement Levels Change from OL Baseline by Visit (Observed)
(Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.12.
Modified Intent-
to-Treat Open-
label
Complement Levels Change from OL Baseline by Visit among 
Subjects with Low Complement at OL Baseline (Observed) (Open-
Label Phase)
Pre-Belimumab Baseline
SAC [1]
 
 
 
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58
Biomarker: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
16.13.
Modified Intent-
to-Treat Open-
label
Complement Levels Shifts from OL Baseline by Visit (Open-Label 
Phase)
Pre-Belimumab Baseline
SAC [1]
16.14.
Modified Intent-
to-Treat Open-
label
B-cells Percent Change from OL Baseline by Visit (Observed)
(Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
16.15.
Modified Intent-
to-Treat Open-
label
B-cells Change from OL Baseline by Visit (Open-Label Phase)
Pre-Belimumab Baseline
SAC [1]
 
 
 
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59
Biomarker: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Autoantibody levels Double-blind Phase
16.16.
mITT
Autoantibody Levels Percent Change from Baseline by Visit 
continued (Observed) (Double-Blind Phase)
Report parameters not delivered in 
time for DB phase report:
a.
Beta-2 Glycoprotein 1 IgA 
Antibody, 
b.
Beta-2 Glycoprotein 1 IgG 
Antibody, 
c.
Beta-2 Glycoprotein 1 IgM 
Antibody, 
d.
Anti-Ribosomal P Antibody 
(U/mL), 
e.
Sjogrens SS-A Antibody 
(INDEX), 
f.
Sjogrens SS-B Antibody 
(INDEX), 
g.
Anti-RNP, 
NB: should use Wilcoxon rank sum. 
(format as the DB phase report)
SAC [1]
16.17.
mITT
Autoantibody Levels Percent Change from Baseline by Visit 
(Observed) among Subjects Positive at Baseline continued 
(Double-Blind Phase)
Parameters as above. NB: should 
use Wilcoxon rank sum. (format as 
the DB phase report)
SAC [1]
16.18.
mITT
Autoantibody Levels Change from Baseline by Visit continued 
(Observed) (Double-Blind Phase)
Parameters as above NB: should use 
Wilcoxon rank sum. (format as the 
DB phase report)
SAC [1]
 
 
 
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60
Biomarker: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
16.19.
mITT
Autoantibody Levels Change from Baseline by Visit (Observed) 
among Subjects Positive at Baseline continued (Double-Blind 
Phase)
Parameters as above NB: should use 
Wilcoxon rank sum. (format as the 
DB phase report)
SAC [1]
16.20.
mITT
Autoantibody Levels Shifts from Baseline by Visit continued
(Double-Blind Phase)
Parameters as above. (format as the 
DB phase report)
SAC [1]
 
 
 
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61
12.9.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
11.01
Intent-to-Treat 
Open-label
ES2 / ES3
Reasons for Study Withdrawal (Open-Label Phase)
ICH E3
SAC [1]
11.02
Intent-to-Treat 
Open-label
TA1 / CP_RD1x
Listing of Planned and Actual Treatments (Open-Label Phase)
IDSL (some subjects 
received Placebo rather 
than Belimumab in the 
OL phase these should 
be identified here)
SAC [1]
Protocol Deviations
11.03
Intent-to-Treat 
Open-label
DV2
Important Protocol Deviations (Open-Label Phase)
ICH E3
SAC [1]
Populations Analyzed
11.04
Intent-to-Treat 
Open-label
SP3/SP3a
Listing of Participants Excluded from Any Population (Open-Label 
Phase)
ICH E3 (list subjects 
excluded from mITT 
OL)
SAC [1]
Demographic and Baseline Characteristics
11.05
Intent-to-Treat 
Open-label
DM2 / DM4
Demographic and Baseline Characteristics (Open-Label Phase)
ICH E3
SAC [1]
Prior and Concomitant Medications
11.06
Intent-to-Treat 
Open-label
CP_CM3 / 
CP_CM4
Concomitant Medications (Open-Label Phase)
IDSL
SAC [1]
 
 
 
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62
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
11.07
Intent-to-Treat 
Open-label
Concomitant Procedures/Surgeries (Open-Label Phase)
SAC [1]
Exposure and Treatment Compliance
11.08
Intent-to-Treat 
Open-label
EX3 / EX4
Treatment Exposure (Open-Label Phase)
ICH E3
SAC [1]
11.09
Intent-to-Treat 
Open-label
Study Agent Administration (Open-Label Phase)
SAC [1]
Double-blind phase Prior and Concomitant Medications
11.10
Safety
Listing 1.08 in DB 
Phase
Concomitant Medications (Double-Blind Phase)
IDSL (Listing of DB 
Phase concomitant 
medications, to 
capture any changes)
SAC [1]
11.11
Safety
Listing 3.08 in DB 
phase
Concomitant Procedures/Surgeries (Double-Blind Phase)
IDSL (Listing of DB 
Phase Concomitant 
Procedures/Surgeries 
to capture any 
changes)
SAC [1]
Adverse Events
13.01
Intent-to-Treat 
Open-label
AE8 / AE8CP / 
AE9 / AE9CP
All Adverse Events (Open-Label Phase)
ICH E3
SAC [1]
Serious and Other Significant Adverse Events
13.02
Intent-to-Treat 
Open-label
Serious Adverse Events (Open-Label Phase)
SAC [1]
13.03
Intent-to-Treat 
Open-label
Study Agent Related Adverse Events (Open-Label Phase)
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
13.04
Intent-to-Treat 
Open-label
AE8 / AE8CPa / 
AE9 / AE9CPa
Deaths (Open-Label Phase)
SAC [1]
13.05
Intent-to-Treat 
Open-label
AE8 / AECP8 / 
AE9 / AE9CP
Adverse Events Resulting in Study Agent Discontinuation (Open-Label 
Phase)
ICH E3
SAC [1]
13.06
Intent-to-Treat 
Open-label
Adverse Events of Special Interest (Open-Label Phase)
SAC [1]
Hepatobiliary (Liver)
13.07
Intent-to-Treat 
Open-label
Laboratory Results: Liver Function (Open-Label Phase)
SAC [1]
13.08
Intent-to-Treat 
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Liver Function (Open-
Label Phase)
SAC [1]
All Laboratory
13.09
Intent-to-Treat 
Open-label
Laboratory Results: Hematology (Open-Label Phase)
SAC [1]
13.10
Intent-to-Treat 
Open-label
Laboratory Results: Electrolytes (Open-Label Phase)
SAC [1]
13.11
Intent-to-Treat 
Open-label
Laboratory Results: Other Chemistries (Open-Label Phase)
SAC [1]
13.12
Intent-to-Treat 
Open-label
Laboratory Results: Urinalysis (Open-Label Phase)
SAC [1]
13.13
Intent-to-Treat 
Open-label
Laboratory Results: Immunoglobulins (Open-Label Phase)
SAC [1]
13.14
Intent-to-Treat 
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Hematology (Open-
Label Phase)
SAC [1]
 
 
 
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64
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
13.15
Intent-to-Treat 
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Electrolytes (Open-
Label Phase)
SAC [1]
13.16
Intent-to-Treat 
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Other Chemistries 
(Open-Label Phase)
SAC [1]
13.17
Intent-to-Treat
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Urinalysis (Open-Label 
Phase)
SAC [1]
13.18
Intent-to-Treat 
Open-label
Grade 3 or Grade 4 Laboratory Toxicity Results: Immunoglobulins 
(Open-Label Phase)
SAC [1]
Vital Signs
13.19
Intent-to-Treat 
Open-label
VS4 / VS5
Vital Signs (Open-Label Phase)
IDSL
SAC [1]
Double-blind Phase Adverse Events
13.20
Safety
As DB Listing 3.01
All Adverse Events (Double-Blind Phase)
ICH E3 (Listing of DB 
Phase Adverse Events 
to capture any 
changes. If no changes 
this is not required)
SAC [1]
 
 
 
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65
12.9.10.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
12.01
Intent-to-Treat 
Open-label
SRI-S2K Results (Open-Label Phase)
SAC [1]
12.02
Intent-to-Treat 
Open-label
SELENA-SLEDAI and SS-S2K Results (Open-Label Phase)
SAC [1]
12.03
Intent-to-Treat 
Open-label
PGA Results (Open-Label Phase)
SAC [1]
12.04
Intent-to-Treat 
Open-label
BILAG Results (Open-Label Phase)
SAC [1]
12.05
Intent-to-Treat 
Open-label
Daily Prednisone Dose (Open-Label Phase)
SAC [1]
12.06
Intent-to-Treat 
Open-label
SFI Flares (Open-Label Phase)
SAC [1]
12.07
Intent-to-Treat 
Open-label
SLICC/ACR Damage Index Results (Open-Label Phase)
SAC [1]
Health Outcomes
14.01
Intent-to-Treat 
Open-label
FACIT-Fatigue Scale Questionnaire (Open-Label Phase)
SAC [1]
Pharmacokinetic
15.01
Randomized
Serum Belimumab PK Concentration-Time Data
As DB listing 5.01 (Possibly 
restrict listing to only subjects 
with updated data since DB 
phase)
SAC [1]
 
 
 
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66
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarker
16.01
Intent-to-Treat 
Open-label
Immunogenicity Results (Open-Label Phase)
SAC [1]
16.02
Intent-to-Treat 
Open-label
Biomarker Results (Open-Label Phase)
As well as expected OL 
Biomarker parameters include 
any unscheduled OL biomarker 
results e.g. Antinuclear 
Antibody, B-Lymphocyte 
Stimulator, Cardiolipin IgA 
Antibody, Cardiolipin IgG 
Antibody, Cardiolipin IgM 
Antibody etc
SAC [1]
16.03
Intent-to-Treat 
Open-label
B Cell Results (Open-Label Phase)
SAC [1]
 
 
 
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67
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
16.04
Safety
Biomarker Results continued (Double-blind phase)
Report parameters not 
delivered in time for DB phase 
report:

Beta-2 Glycoprotein 1 IgA 
Antibody, 

Beta-2 Glycoprotein 1 IgG 
Antibody, 

Beta-2 Glycoprotein 1 IgM 
Antibody, 

Anti-Ribosomal P Antibody 
(U/mL), 

Sjogrens SS-A Antibody 
(INDEX), 

Sjogrens SS-B Antibody 
(INDEX), 

Anti-RNP.
SAC [1]
 
 
 
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68
12.10.
Appendix 10: Example Mock Shells for Data Displays
These will be defined in a separate document.
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL115471
1
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan Addendum
Title:
Addendum to the Reporting and Analysis Plan (RAP) for 
BEL115471, A Phase 3/4, Multi-Center, Randomized, Double-
Blind, Placebo-Controlled, 52-Week Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Adult Subjects
of Black Race with Systemic Lupus Erythematosus (SLE)
Compound Number:
GSK1550188
Effective Date:
08-AUG-2018
Description: This is a Phase 3/4, multi-center, international, randomized, double-blind, 
placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in
adult subjects of black race with active systemic lupus erythematosus (SLE). All subjects 
will receive stable background standard of care therapy throughout the study. Efficacy 
will be measured by the SLE Responder Index (SRI) at Week 52, defined by a composite 
SELENA SLEDAI score (Protocol Amendment 2 modified the primary endpoint to the 
SRI-S2K), Physician’s Global Assessment (PGA) and BILAG A and B organ domain 
scores. In addition, oral corticosteroid use, flares and biomarkers (immunoglobulins, 
complement, anti-dsDNA and ANA autoantibodies, and B cell subsets) will be assessed. 
Safety will be assessed by adverse events, clinical laboratory evaluations, 
immunogenicity, and vital signs. In addition, subjects who successfully complete the 
double-blind phase may enter into an open-label, 6-month extension phase of the study. 
Subject: Systemic Lupus Erythematosus, SLE, belimumab, GSK1550188, Benlysta, 
black race, efficacy, safety, placebo, SRI, SRI-S2K, SELENA SLEDAI, BILAG, PGA, 
Lymphostat-B, superiority, logistic regression
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL
BEL115471
2
Addendum Author’s Name, Title and Functional Area: 
Statistics Leader
Clinical Statistics
Addendum Approved by:
Date
Principal Programmer
Clinical Programming
Date
Director Clinical Programming
Clinical Programming
Date
Clinical Development Director,
Clinical Development
Date
 MD
Senior Clinical Development Director,
Clinical Development
Date
Statistics Director
Clinical Statistics
Date
SERM Senior Director
Safety Evaluation and Risk Management
Date
Clinical Development Manager
Clinical Development
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
BEL115471
3
Clinical Data Manager
Clinical Data Management
Date
PPD


CONFIDENTIAL
BEL115471
4
TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................5
1.
INTRODUCTION......................................................................................................6
2.
ADDITIONS TO THE RAP .......................................................................................6
2.1.
Alternate Imputation Approach for Primary Endpoint continuous 
components..................................................................................................6
2.1.1.
SELENA SLEDAI and SS-S2K ......................................................7
2.1.2.
PGA...............................................................................................7
2.2.
Evaluation of Treatment Effect on SS-S2K and key secondary 
endpoints, ignoring treatment failures ...........................................................7
2.3.
Point Estimates and 95% CI for Difference in Proportions for SS-
S2K Endpoint................................................................................................7
2.4.
BILAG Scoring..............................................................................................7
2.5.
Date of last Double-Blind Treatment Phase/Period.......................................8
3.
REFERENCE...........................................................................................................8


CONFIDENTIAL
BEL115471
5
ABBREVIATIONS
ADaM
Analysis Data Model
ANCOVA
Analysis of Covariance
BILAG
British Isles Lupus Assessment Group of SLE Clinics
CI
Confidence Interval
CRF
Case Report Form
DBR
Database Release
DO=NR
Dropout = Non-Responder
DO/TF=NR
Dropout/Treatment Failure = Non-Responder
FDA
Food and Drug Administration 
ITT
Intention-to-treat
LOCF
Last Observation Carried Forward
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intention to Treat
PGA
Physician’s Global Assessment
PSAP
Program Safety Analysis Plan
RAP
Reporting and Analysis Plan
SAC
Statistical Analysis Complete
SD
Standard deviation
SDTM
Study Data Tabulation Model
SE
Standard Error
SELENA
Safety of Estrogen in Lupus National Assessment
SFI
SLE Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SRI
SLE Responder Index
SRI-S2K
SLE Responder Index (SRI) using the SELENA SLEDAI 
modified with S2K scoring for proteinuria
SS
SELENA SLEDAI
SS-S2K
SELENA SLEDAI (SS) with the modified S2K scoring for 
proteinuria 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
PASS
SAS


CONFIDENTIAL
BEL115471
6
1.
INTRODUCTION
After finalization of the reporting and analysis plan (RAP), but before database freeze 
and unblinding of the database to the blinded study team, a response was received from 
the FDA requesting additional analyses and data displays for BEL115471. This 
addendum to the RAP documents these additions to the RAP for the BEL115471 study. 
These additional analyses may not be included as part of the main Statistical Analysis 
Complete (SAC) package, but will be available soon after. In addition to the FDA 
requests this RAP Addendum documents some clarifications about BILAG renal scoring 
and the last visit in the double-blind phase.
The RAP and this addendum were based upon the following study documents:

Study Protocol Amendment 2 (February 9, 2017)

Final Case Report Form (CRF) (August 2, 2017)

Program Safety Analysis Plan (PSAP) Version 5 (December 13, 2017). Note: for 
reporting purposes, the most current version of the PSAP and associated 
MedDRA version at the time of database release (DBR) will be used.
2.
ADDITIONS TO THE RAP
2.1.
Alternate Imputation Approach for Primary Endpoint
continuous components
The supportive analyses of the components of SRI-S2K were defined in the RAP to use 
LOCF imputation. The following endpoints will have their observed data summarized by 
visit and Week 52 analyses repeated:

SS-S2K Percent Change from baseline

SELENA SLEDAI Percent Change from baseline

SS-S2K Change from baseline

SELENA SLEDAI Change from baseline

PGA Percent Change from baseline

PGA change from baseline
The observed data will be summarized by visit. At Week 52 belimumab and placebo will 
be compared using an ANCOVA model with treatment group, baseline SS-S2K score (9 
vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world) as covariates.  


CONFIDENTIAL
BEL115471
7
Further exploration of the impact of missing data for the above endpoints may be 
performed post-SAC. 
2.1.1.
SELENA SLEDAI and SS-S2K
If a subject misses an entire visit, the missing data on SELENA SLEDAI will not be 
imputed and the score will remain missing. If a subject is a treatment failure, and has post 
treatment failure efficacy assessments, then the reported post treatment failure SELENA 
SLEDAI data will be used i.e., the pre-treatment failure data will not be carried forward.  
The SS-S2K will be managed in the same manner.
If the data for one or more items of the 24 SELENA SLEDAI questions are missing, then 
the last available answer(s) to the corresponding question(s) from the most recent visit 
where the corresponding item(s) are non-missing will be assigned to the missing item(s) 
to obtain a total score.  The SS-S2K will be managed in the same manner.
2.1.2.
PGA
For the Observed Case analysis if a subject does not have a value recorded for the visit 
being evaluated, then the PGA value will remain missing. If a subject is a treatment 
failure and has post treatment failure PGA assessment then this post treatment failure 
PGA data will be included in the analysis.  If the baseline PGA score was zero (or 
missing) then the percent change from baseline will be missing.
2.2.
Evaluation of Treatment Effect on SS-S2K and key 
secondary endpoints, ignoring treatment failures
As per FDA request the Observed Case Analyses described in Section 11.4.1 “Observed 
Case Analyses” of the RAP will be performed regardless of the criteria of more than 5% 
of subjects contributing off treatment efficacy data.
2.3.
Point Estimates and 95% CI for Difference in Proportions for 
SS-S2K Endpoint
The primary analysis will be repeated displaying the point estimates and respective 95% 
CIs for the proportions and the difference in proportions for the primary endpoint SS-
S2K. In addition, the 95% CIs will be included for the key secondary endpoint SRI 
response.  For the proportions of responders in each treatment group the 95% CI for the 
proportion will be produced using the Wald method (simple asymptotic) without 
continuity correction.  For the difference in proportions the 3 binary covariates will be 
consolidated to give 8 strata levels and the Cochran-Mantel-Haenszel strata-adjusted 
proportion difference and stratified Wald 95% confidence intervals will be produced 
(Kim 2013).
2.4.
BILAG Scoring
In Section 9.4.16 of the RAP for the BILAG Renal scoring replace “For items 72 and 73, 
use item b recorded as urine protein-creatinine ratio (mg/mmol).” with “For item 72 use 


CONFIDENTIAL
BEL115471
8
item b recorded as urine protein-creatinine ratio (mg/mmol) and for 73, use item a or b
recorded as yes/no.”
Question 72
As a change from RAP Section 9.3.5 if a subject completed Question 72a “24-hour 
urinary protein(g)“ this value will not be used to calculate the BILAG.  This is consistent 
with Section 9.4.16 of the RAP which refers to 72B but not 72A.
Question 73
Several subjects had 73A completed but not 73B for these subjects replace 73B with 73A 
in Section 9.4.16 BILAG system Renal function of the RAP.
2.5.
Date of last Double-Blind Treatment Phase/Period
This is to supplement Section 9.4.31 and Section 9.4.32 in the RAP. In the ADaM 
datasets when all parts of that endpoint are missing for a visit then the analysis date will 
be imputed.  Some imputed visit dates (Week 52/Exit in particular) may fall after the date 
of first open label dose.  In this circumstance the imputed visit will be assigned to the 
double-blind period and/or phase based on the visit number regardless of if the imputed 
date falls after the first open label treatment.
3.
REFERENCE
Kim Y, Won S “Adjusted proportion difference and confidence interval in stratified 
randomized trials” PharamSUG 2013 Paper SP04


CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL115471
1
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:
Reporting and Analysis Plan (RAP) for BEL115471, A Phase 
3/4, Multi-Center, Randomized, Double-Blind, Placebo-
Controlled, 52-Week Study to Evaluate the Efficacy and Safety 
of Belimumab (HGS1006) in Adult Subjects of Black Race with 
Systemic Lupus Erythematosus (SLE)
Compound Number:
GSK1550188
Effective Date:
19-Jul-2018
Description: This is a Phase 3/4, multi-center, international, randomized, double-blind, 
placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in
adult subjects of black race with active systemic lupus erythematosus (SLE). All subjects 
will receive stable background standard of care therapy throughout the study. Efficacy 
will be measured by the SLE Responder Index (SRI) at Week 52, defined by a composite 
SELENA SLEDAI score (Protocol Amendment 2 modified the primary endpoint to the 
SRI-S2K), Physician’s Global Assessment (PGA) and BILAG A and B organ domain 
scores. In addition, oral corticosteroid use, flares and biomarkers (immunoglobulins, 
complement, anti-dsDNA and ANA autoantibodies, and B cell subsets) will be assessed. 
Safety will be assessed by adverse events, clinical laboratory evaluations, 
immunogenicity, and vital signs. In addition, subjects who successfully complete the 
double-blind phase may enter into an open-label, 6-month extension phase of the study. 
This Reporting and Analysis Plan (RAP) prospectively describes the efficacy and safety 
analyses that will be performed for the double-blind phase of the study. Details regarding 
the analyses and summaries for the open-label phase of the study will be reported in a 
separate RAP.  
Subject: Systemic Lupus Erythematosus, SLE, belimumab, GSK1550188, Benlysta, 
black race, efficacy, safety, placebo, SRI, SRI-S2K, SELENA SLEDAI, BILAG, PGA, 
Lymphostat-B, superiority, logistic regression
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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Author’s Name, Title and Functional Area: 
Statistics Leader
Clinical Statistics
Approved by:
Date
Principal Programmer
Clinical Programming
Date
Director Clinical Programming
Clinical Programming
Date
Clinical Development Director,
Clinical Development
Date
 MD
Senior Clinical Development Director,
Clinical Development
Date
Statistics Director
Clinical Statistics
Date
SERM Senior Director
Safety Evaluation and Risk Management
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Clinical Development Manager
Clinical Development
Date
Clinical Data Manager
Clinical Data Management
Date
PPD
PPD


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BEL115471
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................10
1.
INTRODUCTION....................................................................................................12
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................13
2.1.
Study Objectives.........................................................................................13
2.2.
Study Endpoints..........................................................................................13
2.2.1.
Primary Endpoint .........................................................................13
2.2.2.
Secondary Endpoints...................................................................13
2.2.3.
Other Endpoints...........................................................................14
2.3.
Statistical Hypotheses.................................................................................16
3.
STUDY DESIGN ....................................................................................................17
4.
PLANNED ANALYSES ..........................................................................................20
4.1.
Interim Analyses .........................................................................................20
4.2.
Final Analysis .............................................................................................20
4.3.
Changes from Protocol Specified Analyses ................................................20
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................22
5.1.
Sample Size Assumptions ..........................................................................22
5.2.
Sample Size Re-estimation.........................................................................22
6.
ANALYSIS POPULATIONS ...................................................................................24
6.1.
Analysis Datasets .......................................................................................25
7.
TREATMENT COMPARISONS..............................................................................27
7.1.
Data Display Treatment and Other Sub-Group Descriptors.........................27
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................28
8.1.
Multicenter Studies .....................................................................................29
8.2.
Other Strata and Covariates .......................................................................29
8.3.
Examination of Subgroups..........................................................................29
8.4.
Multiple Comparisons and Multiplicity .........................................................30
9.
DATA HANDLING CONVENTIONS .......................................................................31
9.1.
Treatment Failures......................................................................................31
9.2.
Dropouts.....................................................................................................31
9.3.
Missing Data Rules.....................................................................................31
9.3.1.
Missing Dates..............................................................................31
9.3.2.
Partial Dates................................................................................32
9.3.3.
SRI-S2K ......................................................................................32
9.3.4.
SELENA SLEDAI and SS-S2K ....................................................33
9.3.5.
BILAG..........................................................................................33
9.3.6.
PGA.............................................................................................34
9.3.7.
Proteinuria ...................................................................................34
9.3.8.
FACIT Fatigue .............................................................................34
9.3.9.
FACIT Fatigue Scale Score Improvement Exceeding the 
MCID (>=4 points) .......................................................................34


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9.4.
Derived and Transformed Data...................................................................35
9.4.1.
Baseline.......................................................................................35
9.4.2.
Study Day....................................................................................35
9.4.3.
Analysis Visit and Analysis Visit Number .....................................35
9.4.4.
Change from Baseline .................................................................37
9.4.5.
Percent Change from Baseline ....................................................37
9.4.6.
SLE Disease Duration..................................................................37
9.4.7.
Analysis Age................................................................................37
9.4.8.
Body Mass Index (BMI)................................................................38
9.4.9.
Race Hierarchical Rule ................................................................38
9.4.10.
ACR Criteria at Baseline..............................................................38
9.4.11.
B Cell Unit Conversions and Normalization for Rare B Cell 
Subsets .......................................................................................39
9.4.12.
Proteinuria ...................................................................................40
9.4.13.
Average Daily Prednisone Equivalent..........................................40
9.4.13.1.
Baseline Prednisone Dose .........................................41
9.4.13.2.
Average Daily Prednisone Dose Between 
Visits ..........................................................................41
9.4.13.3.
Average Daily Prednisone Dose at the Visit ...............41
9.4.13.4.
Average Daily Prednisone Dose during Weeks 
40 to 52 ......................................................................42
9.4.13.5.
Prednisone Increase by 50% from Baseline 
by a Minimum 5 mg/day............................................42
9.4.13.6.
Prednisone Reduction by 50% from Baseline...........42
9.4.13.7.
Any Increase from Baseline........................................42
9.4.14.
SLICC/ACR Scoring ....................................................................42
9.4.15.
SELENA SLEDAI and SLEDAI-S2K scoring ................................43
9.4.15.1.
SLEDAI 4-point reduction ...........................................45
9.4.15.2.
SLEDAI Organ System Improvement and 
Worsening ..................................................................45
9.4.16.
BILAG Scoring.............................................................................46
9.4.16.1.
BILAG Improvement...................................................52
9.4.16.2.
BILAG Worsening.......................................................52
9.4.16.3.
BILAG No New 1A/2B ................................................53
9.4.16.4.
BILAG No 1A/2B ........................................................53
9.4.17.
PGA Scoring................................................................................53
9.4.17.1.
PGA No Worsening ....................................................53
9.4.17.2.
PGA Improvement......................................................53
9.4.18.
SRI-S2K ......................................................................................53
9.4.19.
SRI using SELENA SLEDAI proteinuria scoring...........................54
9.4.20.
European Medicines Agency (EMA) modified SRI 
response at week 52 (EMA SRI-S2K)..........................................54
9.4.21.
Date of SRI-S2K Response .........................................................54
9.4.22.
SRI-S2K Durable Response from Week 44 through Week 
52 ................................................................................................54
9.4.23.
SRI-S2K Duration of Longest Response......................................55
9.4.24.
SRI-S2K Duration of Week 52 Response ....................................55
9.4.25.
SLE Flare Index (SFI) Scoring .....................................................56
9.4.26.
Time to First SFI Flare, Censoring and Disposition Rules............57
9.4.27.
Severe SFI flare rate per subject-year over 52 weeks..................58
9.4.28.
Renal Flare..................................................................................58


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9.4.29.
Time to First Renal Flare, Censoring and Disposition 
Rules ...........................................................................................59
9.4.30.
FACIT Fatigue Scale Scoring and MCID indicator .......................61
9.4.31.
Date of Last Double-Blind Treatment Phase................................62
9.4.32.
Date of Last Double-Blind Treatment Period................................63
9.4.33.
Extent of Exposure ......................................................................63
9.4.34.
Treatment-Emergent AEs and AE Duration .................................63
9.4.35.
Windows for Assessment of Post-injection/infusion 
sensitivity reactions (PISR) and hypersensitivity reactions 
(HSR) ..........................................................................................64
9.4.36.
Laboratory Assessments .............................................................64
9.4.36.1.
Clinical Laboratory Toxicity Grades ............................64
9.4.36.2.
Laboratory Toxicity Worsening of at Least 2 
Grades .......................................................................65
9.4.36.3.
C3 and C4 Unit Conversions ......................................65
10. STUDY POPULATION...........................................................................................66
10.1.
Disposition of Subjects................................................................................66
10.2.
Protocol Deviations.....................................................................................66
10.3.
Demographic and Baseline Characteristics.................................................67
10.4.
Concomitant Medications............................................................................72
10.5.
Extent of Exposure .....................................................................................72
10.6.
Subjects for Whom the Treatment Blind was Broken ..................................73
11. EFFICACY ANALYSES..........................................................................................74
11.1.
Primary Efficacy Analysis............................................................................74
11.1.1.
Supportive Summaries of the Primary Efficacy Endpoint .............75
11.1.1.1.
Components of Primary Endpoint...............................75
11.1.1.2.
Disposition of SRI-S2K Response ..............................76
11.1.1.3.
Additional SRI-S2K Analyses .....................................76
11.1.1.4.
SRI-S2K by subgroup.................................................77
11.1.1.5.
SRI-S2K by visit .........................................................77
11.1.1.6.
EMA Modified SRI-S2K Response .............................77
11.2.
Secondary Efficacy Analyses......................................................................78
11.2.1.
SRI response rate with the SELENA SLEDAI scoring of 
proteinuria by visit (SRI)...............................................................78
11.2.2.
Time to first severe SFI flare over 52 weeks ................................78
11.2.3.
Percent of subjects with prednisone reduction by 25% 
from baseline to 7.5 mg/day during week 40 through 
week 52 (DO/TF=NR)..................................................................78
11.2.4.
Estimand Definition......................................................................79
11.3.
Other Efficacy Analyses..............................................................................81
11.3.1.
Disease Activity ...........................................................................81
11.3.1.1.
Durable SRI-S2K Response from Week 44 -
Week 52.....................................................................81
11.3.1.2.
Time to first SRI-S2K response that is 
maintained through week 52.......................................81
11.3.1.3.
Duration of longest SRI-S2K response .......................81
11.3.1.4.
Duration of week 52 SRI-S2K response by 
month .........................................................................82


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11.3.1.5.
SLICC/ACR Damage Index change from 
baseline at Week 52/Exit Visit (Observed 
Case, Corrected)........................................................82
11.3.1.6.
SLICC/ACR Damage Index Worsening at 
Week 52 (WOCF).......................................................82
11.3.1.7.
SELENA SLEDAI Organ System Improvement 
by Organ System and Visit among Subjects 
with Organ System Involvement at Baseline 
(DO/TF=NR)...............................................................83
11.3.1.8.
SELENA SLEDAI Organ System Worsening by 
Organ System and Visit among Subjects with 
No Organ System Involvement at Baseline 
(LOCF) .......................................................................83
11.3.1.9.
SS-S2K Percent Change from Baseline by Visit 
(LOCF) .......................................................................83
11.3.1.10. SS-S2K Change from Baseline by Visit (LOCF) .........84
11.3.1.11. PGA Percent Change from Baseline by Visit 
(LOCF) .......................................................................84
11.3.1.12. PGA change from baseline by visit (LOCF) ................85
11.3.1.13. PGA percent of subjects with 0.3 point 
improvement from baseline by visit 
(DO/TF=NR)...............................................................85
11.3.1.14. BILAG no 1A/2B organ domain scores by visit 
(supportive of EMA SRI-S2K) .....................................86
11.3.1.15. BILAG improvement by organ domain and visit 
in subjects with an A or B domain score at 
baseline (DO/TF=NR).................................................86
11.3.1.16. BILAG worsening by organ domain and visit 
among subjects with no A domain score at 
baseline (LOCF).........................................................86
11.3.2.
Flares ..........................................................................................87
11.3.2.1.
Time to first severe SFI flare over 52 weeks...............87
11.3.2.2.
Time to first severe SFI flare from week 24 to 
week 52......................................................................87
11.3.2.3.
Time to first SFI flare over 52 weeks ..........................87
11.3.2.4.
Time to first SFI flare from week 24 to week 52..........87
11.3.2.5.
Severe SFI flare rate per subject-year over 52 
weeks.........................................................................87
11.3.2.6.
SFI flare rate per subject-year over 52 weeks.............88
11.3.3.
Organ-specific Measures.............................................................88
11.3.3.1.
Time to first renal flare over 52 weeks ........................88
11.3.3.2.
Proteinuria percent change from Baseline by 
visit among subjects with baseline proteinuria 
>0.5 g/24hr (Observed) ..............................................88
11.3.3.3.
Proteinuria change from baseline by visit 
(Observed) .................................................................89
11.3.3.4.
Proteinuria shifts from Baseline by visit 
(Observed) .................................................................89
11.3.3.5.
Percent of subjects with doubling from baseline 
of serum creatinine by visit (Observed).......................89
11.3.4.
Prednisone ..................................................................................90
11.3.4.1.
Cumulative Prednisone dose......................................90


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11.3.4.2.
Prednisone Change from Baseline by Visit 
(Observed) .................................................................90
11.3.4.3.
Prednisone Reduction by 50% from Baseline 
by Visit among subjects using Prednisone at 
Baseline (DO/TF=NR) ................................................91
11.3.4.4.
Prednisone Increase by 50% from Baseline 
and by a Minimum of 5 mg/day by Visit 
(LOCF) .......................................................................91
11.3.4.5.
Prednisone Any Increase from Baseline by 
Visit (LOCF)................................................................92
11.3.4.6.
Percent of Subjects with Daily Prednisone 
Dose Reduced to 7.5 mg/day from >7.5 
mg/day at Baseline by Visit (DO/TF=NR)....................92
11.3.4.7.
Percent of Subjects with Daily Prednisone 
Dose Increased to >7.5 mg/day from 7.5 
mg/day at Baseline by Visit (LOCF)............................93
11.4.
Missing Data Sensitivity Analyses...............................................................93
11.4.1.
Observed Case Analyses ............................................................93
11.4.2.
Tipping Point Analyses ................................................................94
11.4.2.1.
Tipping Point Methodology for Responder 
Endpoints ...................................................................94
11.4.2.2.
Tipping Point Methodology for Time to First 
Severe Flare endpoint ................................................95
12. SAFETY ANALYSES .............................................................................................97
12.1.
Adverse Events...........................................................................................97
12.2.
Deaths, Serious Adverse Events, and Survival Status ................................98
12.3.
Adverse Events Leading to Discontinuation of Investigational 
Product.......................................................................................................99
12.4.
Adverse Events of Special Interest .............................................................99
12.4.1.
Post-infusion systemic reactions by infusion..............................101
12.5.
Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................101
12.5.1.
C-SSRS suicidal ideation or behavior during treatment..............102
12.5.2.
C-SSRS suicidal ideation or behavior relative to pre-
treatment ...................................................................................102
12.5.3.
C-SSRS shift changes in categories from pre-treatment to 
on-treatment ..............................................................................102
12.6.
Clinical Laboratory Evaluations.................................................................102
12.6.1.
Laboratory descriptive statistics by visit .....................................103
12.6.2.
Worst laboratory toxicity grade post-baseline.............................103
12.6.3.
Laboratory toxicity 2 grade shift post-baseline .........................103
12.6.4.
Immunoglobulin reference range shifts from baseline by 
visit ............................................................................................103
12.6.5.
Immunoglobulin below LLN by visit............................................104
12.6.6.
Immunoglobulin above LLN by visit............................................104
12.6.7.
Immunogenicity..........................................................................104
12.7.
Other Safety Measures.............................................................................105
12.7.1.
Vital Signs..................................................................................105
12.7.2.
Concomitant Procedures/Surgery..............................................105
13. HEALTH OUTCOMES ANALYSES......................................................................106
13.1.
FACIT-Fatigue Scale score change from baseline by visit (LOCF) ...........106


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13.2.
FACIT-Fatigue Scale Score Improvement exceeding the MCID (4 
points) by visit (DO/TF=NR)......................................................................106
14. CLINICAL PHARMACOLOGY DATA ANALYSES................................................107
14.1.
Pharmacokinetic Analyses........................................................................107
15. BIOMARKER DATA ANALYSIS...........................................................................108
15.1.
Immunoglobulins, Autoantibodies, and Complement ................................108
15.1.1.
Percent change from baseline in immunoglobulins, 
autoantibodies, and complement by visit (Observed).................108
15.1.2.
Change from baseline in immunoglobulins, 
autoantibodies, and complement by visit (Observed).................109
15.1.3.
Shifts in immunoglobulins, autoantibodies, and 
complement by visit ...................................................................109
15.2.
B cell Analyses .........................................................................................110
15.2.1.
B cell percent change from baseline by visit (Observed)............110
15.2.2.
B cell change from baseline by visit (Observed).........................111
16. PHARMACOGENETIC DATA ANALYSES...........................................................112
17. REFERENCES.....................................................................................................113
18. APPENDICES......................................................................................................115
18.1.
Appendix 1 Allowable Medication Categories ...........................................115
18.2.
Appendix 2 Prednisone Equivalent Conversion.........................................116
18.3.
Appendix 3 Treatment Failure Rules.........................................................119
18.4.
Appendix 4 ACR Criteria at Baseline ........................................................125
18.5.
Appendix 5 SLICC/ACR Damage Index....................................................127
18.6.
Appendix 6 BILAG Assessment................................................................129
18.7.
Appendix 7: SLE Flare Index ....................................................................131
18.8.
Appendix 8 Important Protocol Deviations ................................................132
18.9.
Appendix 9 Per Protocol Population Exclusions........................................134
18.10. Appendix 10 Laboratory Parameters.........................................................135
18.11. Appendix 11 Adverse Event and Laboratory Toxicity Grading Tables.......136
18.12. Appendix 12 Adverse Events of Special Interest.......................................139
18.13. Appendix 13 B Cells .................................................................................147
18.14. Appendix 14 Headline Results..................................................................150
19. ATTACHMENTS ..................................................................................................151
19.1.
Attachment 1: Table of Contents for Data Display Specifications..............151
19.2.
Attachment 2: Data Display Specifications................................................151
19.3.
Attachment 3: AESI Preferred Term Definitions under MedDRA 
v20.1.........................................................................................................151


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ABBREVIATIONS
ACR
American College of Rheumatology
AE
Adverse Event
AESI
AEs of special interest
ANA 
Anti-nuclear antibody
ANCOVA
Analysis of Covariance
AUC
Area under the curve
aCL
Anti-cardiolipin
Anti-dsDNA
Anti-double-stranded DNA
ATC
Anatomical Therapeutic Chemical
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BILAG No 1A/2B
No new BILAG A organ domain score or 2 new BILAG B 
organ domain scores compared with baseline
BMI
Body mass index
CI
Confidence Interval
CMQ
Customized MedDRA Query
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
DO/TF=NR
Dropout/Treatment Failure = Non-Responder
ENA
Extractable nuclear antigen
FACIT
Functional Assessment of Chronic Illness Therapy
hpf
High-power field
IDSL
Integrated Data Standards Library
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IM
Intramuscular
ITT
Intention-to-treat
IV
Intravenous
LLN
Lower Limit of Normal
LOCF
Last Observation Carried Forward
LOQ
Limit of Quantification
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MCID
Minimally Clinically Important Difference
mITT
Modified Intention to Treat
NMSC
Non-melanoma skin cancer
NTM
Non-tuberculous mycobacterium
PD
Pharmacodynamic
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PP
Per Protocol
PSAP
Program Safety Analysis Plan
PSRQ
Possible Suicidality Related Questionnaire
PT
Preferred Term
RAP
Reporting and Analysis Plan
RBC
Red blood cell


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SAE
Serious Adverse Event
SC
Subcutaneous
SD
Standard deviation
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
System Organ Class
SRI
SLE Responder Index
SRI-S2K
SLE Responder Index (SRI) using the SELENA SLEDAI 
modified with S2K scoring for proteinuria
SRT
Safety Review Team
SS
SELENA SLEDAI
SS-S2K
SELENA SLEDAI (SS) with the modified S2K scoring for 
proteinuria 
TB
Tuberculosis
TLFs
Tables, Listings and Figures
ULN
Upper Limit of Normal
WOCF
Worst Observation Carried Forward
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
PASS
SAS


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1.
INTRODUCTION
This reporting and analysis plan (RAP) documents the planned analyses for the 
BEL115471 study.  
This is a phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 10mg/kg belimumab administered 
monthly, compared with placebo over a 52-week treatment period in subjects of black 
race with active systemic lupus erythematosus (SLE) (defined as Safety of Estrogen in 
Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index 
(SELENA SLEDAI) score 8).
This RAP is based upon the following study documents:

Study Protocol Amendment 2 (February 9, 2017)

Final Case Report Form (CRF) (August 2, 2017)

Program Safety Analysis Plan (PSAP) Version 5 (December 13, 2017). Note: for 
reporting purposes, the most current version of the PSAP and associated MedDRA 
version at the time of database release (DBR) will be used.


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objectives

To evaluate the efficacy of belimumab in adult subjects of black race with SLE. 

To evaluate the safety and tolerability of belimumab in adult subjects of black race
with SLE. 
2.2.
Study Endpoints
2.2.1.
Primary Endpoint
The primary efficacy endpoint is the Systemic lupus erythematosus Responder Index 
(SRI) response rate with the modified SLEDAI-2K (S2K) scoring for proteinuria at Week 
52. This S2K rule scores proteinuria as 4 points anytime the value is >0.5 g/24hr. This 
endpoint will be referred to as the SRI-S2K for reporting and is defined as: 

4-point reduction from baseline in SELENA SLEDAI score with the modified 
SLEDAI-2K scoring for proteinuria (SS-S2K), 
AND 

No worsening (increase of <0.30 points from baseline) in Physician’s Global 
Assessment (PGA), 
AND 

No new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ 
domain score or 2 new BILAG B organ domain scores compared with baseline 
at the time of assessment (i.e., at Week 52). 
2.2.2.
Secondary Endpoints
Major secondary efficacy endpoints: 
1.
SRI response rate with the SELENA SLEDAI (SS) scoring of proteinuria at Week 
52.
2.
Time to first severe flare (as measured by the modified SLE Flare Index (SFI); 
performed with SS as the SLEDAI criterion of the SFI).
3.
Percent of subjects whose average prednisone dose has been reduced by 25% from 
baseline to 7.5 mg/day during Weeks 40 through 52, in subjects receiving greater 
than 7.5 mg/day at baseline.


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2.2.3.
Other Endpoints
Components of SRI and other SRI related Endpoints Supporting Primary Efficacy 
Endpoint: 

SRI-S2K by visit.

SRI (without proteinuria correction) by visit.

Percent of subjects with a 4-point reduction from baseline in SS-S2K at Week 52 
and by visit (referred to as SS-S2K 4-point reduction).

Percent of subjects with no new BILAG A organ domain score or 2 new BILAG B 
organ domain scores compared with baseline at Week 52 and by visit (referred to as 
BILAG No 1A/2B).

Percent of subjects without PGA worsening (increase of <0.30 points from baseline) 
at Week 52 and by visit (referred to as PGA No Worsening).

Percent of subjects with durable SRI-S2K from Week 44-52.

Time to the 1st SRI-S2K response that is maintained through Week 52.

Duration of longest SRI-S2K response among subjects with at least 1 SRI-S2K 
response.

SRI5-S2K to SRI8-S2K at Week 52 and by visit. 
The SRI5-S2K to SRI8-S2K are defined identically to the SRI-S2K except for using 
higher thresholds of improvement for SS-S2K reduction for a patient to be declared a 
responder (e.g., SS-S2K 5 point reduction for SRI5-S2K)
Disease activity: 

Percent change and change in PGA by visit. 

Percent change and change in SELENA SLEDAI (modified to use SLEDAI-2K 
scoring for proteinuria) score by visit (referred to as SS-S2K). 
Organ Specific: 

Percent of subjects with SELENA SLEDAI organ improvement by visit. The renal 
domain will use the SS-S2K proteinuria scoring.

Percent of subjects with SELENA SLEDAI organ worsening by visit. The renal 
domain will use the SS-S2K proteinuria scoring. 

Percent of subjects with BILAG organ improvement by visit. 

Percent of subjects with BILAG organ worsening by visit. 

Proteinuria change and percent change by visit among patients with proteinuria at 
baseline.

Time to first renal flare over 52 weeks (see Section 9.4.27).

Percent of patients developing at least one renal flare over 52 weeks.


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
Percent of subjects with doubling of serum creatinine (patients whose serum 
creatinine attains a level double that of the baseline value and is confirmed with a 
second measurement at least 3 weeks later). 
SFI Flare (using SELENA SLEDAI scoring for Proteinuria):

Time to first SFI flare over 52 weeks. 

Time to first SFI flare after Week 24. 

Time to first severe SFI flare after Week 24. 

Rate of SFI flare per 100 subject years. 

Rate of severe SFI flare per 100 subject years. 
Steroids (based on 7-day average at the visits):

Percent of subjects with daily prednisone dose reduced to 7.5 mg/day from >7.5 
mg/day at baseline by visit 

Percent of subjects with daily prednisone dose increased to >7.5 mg/day from 7.5 
mg/day at baseline by visit. 

Percent of subjects with any increase in prednisone use by visit 

Percent of subjects with a 50% decrease in prednisone dose by visit (in patients 
receiving steroids at baseline). 

Percent of subjects with a 50% increase in prednisone dose by a minimum 5 
mg/day by visit (in all patients). 

Changes in prednisone dose (mg/day) by visit. 
Systemic Lupus International Collaborating Clinics (SLICC)/ American College of 
Rheumatology (ACR) Damage Index:

Change from baseline in SLICC Damage Index at Week 52. 

Percent of patients with any SLICC Damage Index worsening (change >0) at Week 
52 compared with baseline. 
Patient Reported Outcome:

Change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score 
at Week 52 and by visit. 

Percent of patients with improvement in FACIT-Fatigue score exceeding the 
Minimally Clinically Important Difference (MCID) (4) by visit.  
Biomarkers:
Percent change and change from baseline in 


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
absolute B cell subsets (CD19+, CD20+, CD20+/27+ memory, CD20+/27–
naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, CD27+ 
BRIGHT/CD20– Short-lived plasma cells, CD19+/27BRIGHT/38BRIGHT SLE 
subset, CD19+/CD24HIGH/CD38HIGH transitional B cell, and CD20-/138+ 
plasma cells) by visit. (Only in regions/countries where assessment of B cells is 
feasible.)
Change from baseline in 

CD20+/27– naïve and CD20+/27+ memory B cell subsets expressed as a 
percentage of CD19.

Autoantibodies* (anti-dsDNA, ANA, aCL (IgA, IgG, IgM), lupus anticoagulant, 
beta-2-glycoprotein, anti-sm, anti-RNP, anti-SS-A, anti-SS-B, anti-ribosomal 
P]). 

Complement (C3, C4) levels. 
Percent of patients with normalized serological activity at Week 52 and over time 

IgG, IgM and IgA (high to normal/low). 

Autoantibodies* [anti-dsDNA, ANA, aCL (IgA, IgG, IgM), lupus anticoagulant, 
beta-2-glycoprotein-1, present to absent. 

Complement (C3, C4, and C3 AND C4) levels low to normal/high. 
* Anti-dsDNA will be collected monthly throughout the double-blind phase of the study 
for SELENA SLEDAI scoring. ANA will be collected at screening and baseline only. 
Other autoantibodies will be collected from all patients at baseline, then at regular 
intervals in patients positive at baseline.
2.3.
Statistical Hypotheses
The goal of this study is to demonstrate superiority of belimumab over placebo when 
comparing the SRI-S2K response rate at Week 52 in subjects of black race with SLE. A 
logistic regression analysis controlling for baseline SS-S2K score (9 vs. 10), baseline 
complement level (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs rest of the world) using a two-sided test at the α=0.05 significance level will be used to 
test the following null hypothesis.  Low C3 is defined as less than the lower limit of 
normal (LLN) which is <90 mg/dL and low C4 is defined as less than the LLN which is 
<10 mg/dL.
Null Hypothesis
There is no difference between belimumab 10mg/kg and placebo in terms of the SRI -
S2K response rate at Week 52 of the double blinded period.
Alternative Hypothesis
Belimumab 10mg/kg differs from placebo in terms of the SRI-S2K response rate at Week 
52 of the double blinded period.


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3.
STUDY DESIGN
This is a Phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult
subjects of black race with active SLE. Approximately 501 SLE subjects will be 
randomized, with a target of about 334 subjects receiving belimumab and 167 subjects 
receiving placebo. 
In addition to receiving stable standard therapy, subjects will be randomized in a 2:1 ratio 
to treatment with either 10mg/kg belimumab or placebo. At randomization, subjects will 
be stratified by their screening SELENA SLEDAI score (8-9 vs. 10), complement level 
(C3 and/or C4 low vs. other), and region (US/Canada vs. rest of the world). Subjects will 
be dosed with study agent on Days 1, 15, 29, and then every 28 days through 48 weeks, 
with a final evaluation at Week 52 (4 weeks after the last dose). Study agent will be 
administered intravenously (IV) over 1 hour. Subjects will remain under clinical 
supervision for 3 hours after completion of the first 2 infusions during the 52-week 
double-blind phase and 6-month open-label extension.
All subjects will continue the stable standard therapy they were receiving during the 
screening period. Subjects who complete dosing up to 48 weeks will return for a Day 
365/Week 52 (final evaluation) visit. Subjects who successfully complete the initial 52-
week double blind phase may enter into a 6-month open-label extension phase of this 
study. The Day 365/Week 52 visit will serve as the Day 1 visit for subjects entering the 
6-month open-label extension phase. During the open-label extension phase, all subjects 
will receive belimumab 10 mg/kg IV every 28 days for 6 months. The first dose of the 6-
month open-label extension will be given on the Day 365 (Week 52) visit of the double-
blind treatment phase following the completion of all Day 365 (Week 52) assessments. 
Subjects participating in the extension phase will continue to be monitored for safety and
more latitude will be permitted for background medication changes as outlined in 
Protocol Section 5.5. At the end of the 6-month open-label extension period, subjects 
who wish to continue treatment may do so by being prescribed commercially available 
product. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate 
continuation protocol. Subjects will be required to sign a new informed consent to 
participate in the separate continuation protocol. Subjects who complete the 52-week 
double blind phase, but do not enter the extension phase will be required to return for an 
additional follow up visit 8 weeks after the last dose of study agent. For subjects 
withdrawing at any other time during the study, an Exit visit (1-4 weeks after the last 
dose of study agent) and a follow-up visit (approximately 8 weeks after the last dose of 
study agent) will be performed.  The 8-week follow-up visit is not required in subjects 
entering the separate continuation protocol. In the event that a subject discontinues study 
agent at any time during the study or withdraws consent, an attempt will be made to 
ascertain survival status at approximately 52 weeks after the first dose of study agent.
Serum samples for anti-belimumab measurements will be obtained from all randomized 
subjects before administration of study agent on Day 1, and at any time on Days 57 
(Week 8), 169 (Week 24), 365/Exit (Week 52), and at the 8-week follow-up visit. Prior to 
amendment 2, for any subject who had a positive antibody response at the 8-week follow-


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up visit (or last study visit at which immunogenicity was assessed if 8-week follow-up 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent 
or after completion and/or unblinding of the study, whichever is later.  Amendment 2 
removed the follow-up immunogenicity assessment for subjects with a positive 
anti-belimumab antibody test at the 8-week follow-up visit.
A schematic of the study is provided in Figure 1.


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Figure 1
Study schematic
(a)The last dose of study agent is given on the Day 337 (Week 48) visit to subjects NOT participating in the 6-month open-label extension phase of the 
study.
(b)Subjects participating in the 6-month open-label extension phase of the study are dosed on the Day 365 (Week 52) visit of the double-blind period 
after the completion of all Day 365(Week 52) assessments. This Day 365 (Week 52) represents the first dose (i.e., Day 1) of the 6-month open-label 
extension phase. For subjects not participating in the 6-month open-label extension phase of the study, the Day 365 (Week 52) visit serves as the 
Exit visit with follow-up visits occurring 8 weeks after the last dose of study agent. 
(c)The primary treatment period includes 48 weeks of study agent administration (Day 1 to the Day 337 visit) and a final visit for the primary endpoint 
assessment at Week 52 which is 4 weeks after the last dose of the study agent. 
(d) An Exit visit (1-4 weeks after the last dose of study agent) and a follow-up visit 8 weeks after the last dose of study agent will be performed for 
subjects withdrawing at any time during the study. The 8 week follow-up visit is not required in subjects entering the separate continuation protocol.
(e) At the end of the 6 month extension period, subjects who wish to continue treatment may do so by being prescribed the IV commercially available 
product. If IV belimumab is not commercially available in a subject’s country of participation, subjects may continue to receive belimumab 
administered intravenously every 4 weeks under a separate continuation protocol.
NOTE:  This schematic uses Day 0 nomenclature consistent with the protocol.  To be consistent with CDISC reporting, add 1 to any Day 0. For the 
PLACEBO group, there should be an arrow at the end of the treatment period immediately before the Exit/Follow-up box which points to the 
Belimumab 10 mg/kg 6-month extension box.


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4.
PLANNED ANALYSES
4.1.
Interim Analyses
No interim analysis is planned for this study.
4.2.
Final Analysis
There will be two database locks for this study corresponding to the primary analysis
(end of double-blind) and the end of study (end of open-label). The database will be 
locked for the primary analysis (SRI-S2K at Week 52) after data through the Week 52 
visit (or Exit visit for those subjects who withdraw during double-blind treatment) for all 
subjects have been collected, verified and validated. The second database lock will occur 
after data for the 6-month open-label phase through the 8-week follow-up period have 
been collected, verified and validated. All subjects and study site personnel (except the 
unblinded site pharmacist) will remain blinded until the second database lock. This RAP 
details the analyses for the double-blind phase, all outputs required for the double-blind 
analyses will be listed in the Mock Tables, Listings and Figures (TLFs) Shells document.  
A separate RAP will be created to document the analyses for the open-label phase. 
The end of the double-blind treatment phase is defined as follows:
For subjects continuing in the open-label phase:

The first dose date of open-label medication. 
For subjects not continuing in the open-label phase the latest of these dates will be used:

8-week follow-up visit date

Week 52/Exit visit date

Early termination date 
4.3.
Changes from Protocol Specified Analyses

Average daily prednisone dose for each study visit is defined in the protocol as the 
average dose between visits (Protocol Section 8.5.4). To align with BEL112341 and 
BEL114055, average steroid use at each visit will be defined as the sum of all
prednisone doses over 7 consecutive days up to and including the day of interest, 
divided by 7, unless otherwise specified.

Section 8.5.2.1 of the protocol specified that a multivariate analysis will also be 
performed to evaluate how response to belimumab relative to placebo varied across 
different categories within relevant baseline demographic or disease characteristics.  
As the relationship between belimumab response and baseline demographic/disease 
characteristics is now well understood this analysis will not be performed. 


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
Section 8.5.3 of the protocol listed the second major secondary endpoint as Time to 
first severe flare (as measured by the modified SLE Flare Index; with SLEDAI-2K 
and SELENA SLEDAI as the SLEDAI criterion of the SFI). This is clarified to make 
it clear that Time to first severe flare, as assessed by the SELENA SLEDAI will be 
considered the second major secondary endpoint in the testing hierarchy.  Time to 
first severe flare, using the SLEDAI-2K criteria is an equivalent endpoint (not 
different) and so will not be assessed.

Due to study conduct concerns at three sites a modified ITT population has been 
defined. For clarity, the protocol defined ITT population has been renamed the 
Safety population; see Section 6 for further details. 

The protocol defined sub-group analysis of SRI by Baseline average daily 
prednisone dose [or equivalent] (7.5 mg/day vs. >7.5 mg/day) will not be 
performed. In previous studies this analysis has not been clinically important as this
baseline steroid dose categorization has not been relevant when assessing the 
risk/benefit of belimumab. 

The protocol definition of renal flares has been modified to remove the hematuria 
criterion in keeping with the current practice in assessment of renal disease.

Population Pharmacokinetics as described in protocol Section 8.7.1 are no longer 
planned. The key patient characteristic which may affect belimumab exposure that is 
expected to differ between this study and the prior global Phase 3 studies, is body 
size. The impact of body size on belimumab exposure will be addressed by 
stratifying the summaries of observed serum concentrations by body weight quartiles 
and BMI categories. 


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5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
The original protocol required a sample size of 816 subjects with a target of at least 544 
subjects in the arm receiving belimumab and 272 subjects in the arm receiving placebo. 
This sample size provides at least 90% power at a 5% level of significance to detect a 
minimum of a 12% absolute improvement in the response rate for the 10 mg/kg
belimumab group (assumed rate = 56%) relative to the placebo group (assumed rate = 
44%) at Week 52. The selection of the 12% absolute improvement is evidence-based and 
is based on the observed response rate in the Phase 3 studies [BLISS 76 (HGS1006-
C1056) and BLISS 52 (HGS1006-C1057)]. The sample size calculation uses the most 
conservative estimate for the standard deviation (SD) in the population (i.e., population 
SD = 50%).
5.2.
Sample Size Re-estimation
Following completion of BEL112341 and BEL113750 and the final pooled data from 
these two studies for the SRI endpoint, the sample size was re-estimated. The protocol
was modified (Amendment 2) to amend the sample size to 501 and the primary endpoint 
to the SRI-S2K. 
Approximately 501 subjects will be randomized and treated in the study, with a target of 
at least 334 subjects in the arm receiving belimumab and 167 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 15.55% absolute improvement in the SRI response 
rate with the modified SLEDAI-2K scoring for proteinuria for the 10 mg/kg belimumab 
group relative to the placebo group (assumed rate =43.95%) at Week 52. This sample size 
is also sufficient to provide approximately 80% power at a 5% level of significance to 
detect a minimum of a 13.4% absolute improvement in the SRI response rate with the 
SELENA SLEDAI scoring for proteinuria for the 10 mg/kg belimumab group relative to 
the placebo group (assumed rate = 44.8%).
The selection of the assumed treatment differences is based on the observed SRI data 
from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 (Northeast 
Asia), which are two efficacy studies that concluded in 2015 and 2016, respectively, and 
have nearly identical eligibility criteria to study BEL115471 (HGS1006-C1112, 
EMBRACE) including requiring a screening SS score 8. SRI results, calculated using 
the SS results and calculated using a modification to the proteinuria scoring based on 
SLEDAI-2K rules, are shown in Table 1.


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Table 1
SRI Results from Studies BEL112341 and BEL113750
SRI
SRI-S2K
Dataset
Placebo
Belimumab

Placebo
Belimumab

BEL112341*
48.4%
61.4%
12.98%
46.6%
61.7%
15.14%
BEL113750**
40.1%
54.3%
14.17%
40.2%
56.3%
16.16%
Pooled 
BEL112341 and 
BEL113750
44.8%
(222/496)
58.2%
(582/1000)
13.44%
43.95%
(218/496)
59.50%
(595/1000)
15.55%
* Inclusion criterion SS8, 200 mg SC dose used.
**Inclusion criterion SS8, 10 mg/kg IV dose used. 
All sample size calculations were performed using Power Analysis and Sample Size 
software (PASS 2012).


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6.
ANALYSIS POPULATIONS
Screened
The Screened population is defined as all subjects who were screened for the trial, 
irrespective of whether they were randomized or not.  
This study was initiated prior to the requirement to fully document screening failure 
information. The definitive source of screening events and reasons for screening failure 
will be provided by Data Management for summary in the CSR, Statistics and 
Programming will not create any summaries using the screened population. 
Randomized
The Randomized population is defined as all subjects who are randomized. Summaries 
using the Randomized population will group subjects according to the treatment that a 
subject was randomized to receive, regardless of the actual treatment received.
Safety (referred to as ITT in protocol)
The Safety population is defined as all subjects who are randomized and treated with at 
least one dose of study treatment. The safety population will be summarized according to 
the treatment that a subject was randomized to receive, regardless of the actual treatment 
received. All safety summaries will be performed on the safety population unless 
otherwise specified. 
mITT
During the study three sites 
and 
were investigated for potential
GCP non-compliance; as a consequence all three sites were terminated by the sponsor. A 
multi-functional team reviewed these concerns and agreed that data from these three sites 
should be excluded from all efficacy analyses. The team were confident that the subjects 
had been dosed and therefore agreed data from these sites should be retained in the safety 
analyses. 
The Modified Intention-To-Treat (mITT) population is defined as the safety population
excluding subjects who had any assessment at three sites
or
 
The database records subjects under final site and so subjects moved to
or
 but randomized at other sites are excluded.  Additionally, subjects randomized
at one of the three sites but subsequently moved to another site will be excluded from the 
mITT. All efficacy analyses will be performed on the mITT population unless otherwise 
specified. 
Per Protocol
Prior to breaking the blind, data for all subjects in the mITT Population will be reviewed 
to identify protocol violations which could affect the primary endpoint. Subjects with 
violations with the potential to impact the efficacy analyses will be excluded from the PP
Population; see Section 18.8 for definitions.
PPD
PPD
PPD
PPD
PPD
PPD


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A sensitivity analysis for the primary efficacy endpoint will be performed on the Per 
Protocol population if more than 15% of mITT subjects had a violation that could affect 
the primary efficacy endpoint.
Completers
The Completers population is defined as all subjects who complete all 52 weeks of the 
planned double-blind treatment period. A sensitivity analysis for the primary efficacy 
endpoint will be performed on the Completers population. This population is a subset of 
the mITT population. 
As-Treated
The As-Treated population is defined as all subjects who receive at least one dose of 
study treatment.  Summaries using the As-Treated population will group subjects 
according to the actual treatment administered to the subject. If a subject receives an 
incorrect treatment, the As-Treated analysis will be performed according to the treatment 
that the subject receives most of the time (>50% of the time).  
A sensitivity analysis using the As-treated population will be performed on the primary 
efficacy endpoint if more than 15% of subjects received the incorrect treatment. This
population is a subset of the mITT population. 
PK
The pharmacokinetic (PK) population will comprise all subjects included in the As-
Treated population for whom at least one post belimumab treatment PK sample was 
obtained and analyzed.  Summaries using this population will be based on the actual 
treatment received if this differs from that to which the subject was randomized.
6.1.
Analysis Datasets
Drop Out/Treatment Failure = Non-Responder (DO/TF=NR)
The DO/TF=NR dataset (as described in Section 9.1 and Section 9.2) will be used for the 
primary response endpoint and each of the three components of the primary response, as 
well as the majority of other responder endpoints.  The basic premise of the DO/TF=NR 
is that a subject who drops out prior to the Week 52 visit (and does not have a visit with 
assessments in a 28 day window around the Week 52 visit) and/or uses a prohibited 
medication or a non-allowed dose of a restricted medication resulting in a treatment 
failure will thus be counted as a non-responder in the analysis.  Note, this analysis dataset 
was referred to in the protocol as the DO=F or Drop Out=Failure dataset which did not 
make it clear that the intent was that treatment failures were also to be imputed as non-
responders.  DO/TF=Non-Responder was the intention and is consistent with the analyses 
of previous belimumab studies.


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Last Observation Carried Forward (LOCF)
The LOCF principle is applied whereby missing values will be replaced with the last 
previous non-missing value.  If the first assessment of the Treatment period is missing 
then the missing data will be imputed with the baseline value.
If a subject withdraws or takes a protocol-prohibited medication or a dose of allowable 
(but protocol restricted) medication that results in treatment failure designation (see 
Section 9.1) prior to the study visit being evaluated, the LOCF value will be handled by 
using the result from the last visit on or prior to the date of withdrawal or date of 
treatment failure, whichever is first.
If any observed dates exist, the date for the LOCF record will be determined from the 
observed dates. If there are multiple observed dates, the latest of these dates (closest to 
the scheduled visit) will be taken as the derived date. If the record is completely missing
then the date will be missing, otherwise missing dates will be imputed as the (treatment 
start date + planned study day [e.g. Week 8 visit planned study day as day 1+ 8*7=57
day]). 
Observed
Observed data are the data collected or observed for the subject with no imputation for 
missing data.  The observed case analysis includes all data collected including data post 
IP withdrawal and post treatment failure.
Worst Observation Carried Forward (WOCF)
The worst observation carried forward (WOCF) principle will be applied to the 
SLICC/ACR Damage Index data at an item level.  As the SLICC/ACR Damage Index is 
meant to be a monotonic, non-decreasing value (except for renal domain), items that 
decrease over the course of the study will be replaced with the highest previous item 
score achieved among previous visits (including baseline). Within the renal domain, 
damage scored on the first two items (estimated glomerular filtration rate < 50%, 
proteinuria > 3.5 gm/24hours) should only be carried forward to Week 52 if the third item 
(end stage renal disease) has not been scored at Week 52. The reason for this is that 
scores on the first two items can decrease but only if the third item is then scored


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7.
TREATMENT COMPARISONS
The primary comparison of interest is the comparison between belimumab and placebo 
for the SRI-S2K response at Week 52 in the mITT population at the 0.05 significance 
level imputing a non-responder for dropouts and treatment failures as described in 
Section 6.1.
Other comparisons of interest include components of the primary endpoint, SRI at Week 
52, Time to first severe flare, steroid reduction. 
For further details on the hierarchy of comparisons see Section 8.4.
7.1.
Data Display Treatment and Other Sub-Group Descriptors
The following treatment descriptors (Table 2) will be used on all data tabulations for the 
double-blind phase:
Table 2
Treatment Descriptors, Colors, Line Style and Symbols for 
Reporting in Double-Blind Phase
Treatment 
Descriptor
Color
SAS Color
Line Style
Symbol
Belimumab 
10mg/kg
Blue
CX0000FF
Dashed
Triangle (filled)
Placebo
Black
CX000000 
Solid
Circle (open)
For tables presenting baseline demographics and characteristics described in Section 10, a 
total column for both treatment groups combined will also be presented for subjects in the
double-blind phase.  


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8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES

All data summaries and analyses will be performed using the latest available version 
of SAS software (as available at GSK). R may be used to quality check statistical 
analyses. The latest available version of R will be used and the version will be 
documented in the CSR.

Data displays will follow the shells outlined in Attachment 1 and Attachment 2
which will follow the Benlysta program standards and, as far as possible, follow the 
GSK Integrated Data Standards Library (IDSL).  
Unless otherwise stated, the following will apply:

Continuous variables will be summarized with the statistics mean, median, standard 
deviation (SD), 25th and 75th percentiles, minimum and maximum.

Categorical variables will be summarized with frequency counts and percentages, or 
proportions where specified.  A ‘Missing' category will be added to frequency counts 
if there is at least one missing record. 

Percentages will be calculated using the number of non-missing observations as the 
denominator. If the unit of measurement is a subject, the percentage will be based on 
the total N for the population that are still in the study at the respective visit

The minimum and maximum will be reported to the same number of decimal places 
as the raw data recorded in the database.  

The mean, median, 25th percentile and 75th percentile will be reported to one more 
decimal place than the raw data recorded in the database.  

The SD will be reported to two more decimal places than the raw data recorded in 
the database.  

A maximum of four decimal places will be used for any statistics displayed.  

The same decimal point rules described above apply to scores calculated in the 
derived datasets.  

Percentages will be presented to one decimal place.  

A count of zero will have no corresponding percentage.

For statistical analyses, all tests will be two-sided and p-values will be presented to a 
maximum of 4 decimal places.

When the data are summarized by visit, only scheduled visits will be presented. 
Unscheduled visits will be included in patient listings

Listings will be sorted by treatment group, site ID, unique subject ID, and visit 
(where appropriate).

Figures displaying means or medians also will include standard error bars or 
interquartile ranges, respectively.


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
Distributions will be reviewed and if there is significant evidence of skewness,
medians will be used as the summary measure instead of means; in this case the
corresponding figures will display medians.
8.1.
Multicenter Studies
This is a multi-center trial and subjects will be centrally randomized.  Analyses will not 
be adjusted for center.  
8.2.
Other Strata and Covariates

Randomization will include stratification by subjects’ screening SELENA SLEDAI 
score (8- 9 vs. 10), complement level (C3 and/or C4 low vs. other), and region 
(US/Canada vs. rest of the world).  Note, no subjects were enrolled in Canada but
cross program region subgroup labels have been retained for consistency. 

The screening value is used for stratification for SELENA SLEDAI and complement 
level as these factors require the results of lab tests to be available to the sites prior to 
randomization (baseline). 

Analyses will control for baseline values of SELENA SLEDAI and complement as 
the baseline values represent the status of the subject at the time study treatment is 
first administered.  

To be consistent with the primary endpoint, the SS-S2K at baseline will be used to 
control for baseline disease activity in the statistical models (except for sensitivity
analyses using SS, in these cases baseline SS will be used).
8.3.
Examination of Subgroups
The comparison of the primary efficacy endpoint between belimumab and placebo will 
be performed by the following subgroups:

Baseline SS-S2K score (9 vs. 10)

Baseline anti-dsDNA (30 IU/mL vs. <30 IU/mL)

Baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low, where low 
is defined as less than the LLN which is <90 mg/dL for C3 and <10 mg/dL for C4)

Baseline complement & anti-dsDNA (At least one C3/C4 low and anti-dsDNA >=30 
IU/mL vs. Not (At least one C3/C4 low and anti-dsDNA >=30 IU/mL)

Region (US/Canada vs. Rest of World)

Age Group (<65 years, ≥65 years)

Baseline BLyS Protein (75th Percentile vs. <75th Percentile).
Gender sub-group analysis will not be performed due to the low number of male subjects.
Subgroup analyses will be adjusted for the relevant covariates (however some covariates 
may have to be dropped due to the convergence issues for small subgroups).  The p-


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values for the treatment by subgroup interaction effect will be presented and evaluated 
for significance at the α=0.10 significance level.
8.4.
Multiple Comparisons and Multiplicity
For the analysis of the primary and the major secondary efficacy endpoints, a step-down 
sequential testing procedure will be used to control the overall type 1 error rate. With this 
procedure, the primary and three major secondary endpoints will be evaluated for 
statistical significance based on a pre-specified sequence for interpretation: (1)SRI-S2K 
response rate at Week 52 (2) SRI response rate with the SELENA SLEDAI for scoring of 
proteinuria at week 52, (3) time to first severe SFI flare using the SELENA SLEDAI 
without the proteinuria adjustment, and (4) percent of subjects with average prednisone 
dose that has been reduced by 25% from baseline to 7.5 mg/day during Weeks 40 
through 52. Specifically, endpoints will be tested in the sequence above (2-sided 
alpha=0.05) provided that statistical significance is achieved by all prior tests. If at any 
point in the sequence statistical significance is not met, then subsequent endpoints in the 
sequence cannot be deemed statistically significant, although nominal p-values will be 
reported and considered descriptive. 
Analyses of other efficacy endpoints other than the major secondary efficacy endpoints 
will not be subject to any multiple comparison procedure. All statistical tests will be 
2-sided and performed at an overall significance level of 0.05.


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9.
DATA HANDLING CONVENTIONS
This section describes data handling conventions for the efficacy data during the double-
blind treatment period including handling of premature withdrawal and missing data.  
Missing data for analyses at time points other than Week 52 will be managed in a similar 
manner.  
9.1.
Treatment Failures
A treatment failure is defined as any subject who:

receive a protocol-prohibited medication or a dose of allowable (but protocol 
restricted) medication that results in treatment failure designation prior to Week 52.
The treatment failure rules are detailed in the protocol (Section 5.5) with the 
programming rules further clarified in Appendix 3.  
9.2.
Dropouts
For the purposes of the analysis imputation, a dropout is defined as any subject who:

withdraws from the study prior to Week 52 and has no visit within ± 28 days of the 
target Week 52 visit date (excluding follow up visits).
This rule is applied consistently across all efficacy endpoints. The assessment of whether 
or not a subject had a visit within the ± 28 day of Week 52 is performed at the domain 
level [e.g., a subject who had visit within 28 days for SLEDAI but not SLICC would be
assessed on their observed data for SLEDAI but would be considered a dropout in 
SLICC].
9.3.
Missing Data Rules
9.3.1.
Missing Dates
Element
Reporting Detail
Concomitant 
Medications
Medication Start Date (CMSTDT)
CMSTDT is imputed as TRTSDT unless:

CMENDT is < TRTSDT (whether CMENDT is a complete
(DD/MM/YY) or partial date (some combination of CMENDT day, 
month or year imputed) OR

The month and/or month and year of the partial CMENDT date are 
before the month and/or year of TRTSDT OR 

“Taken prior to study?” is checked.
Medication End Date (CMENDT)

End dates for concomitant medications will not be imputed, and the 
medication will be considered ongoing.


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Element
Reporting Detail
Adverse 
Events 

The eCRF does not allow for the possibility of partial AE dates.

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.  AEs with missing start dates will be 
considered as treatment emergent.
9.3.2.
Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listings.
Concomitant 
Medications
Medication Start Date (CMSTDT)

If CMENDT is missing OR CMENDT >= TRTSDT (whether 
CMENDT is a complete or partial date) then CMSDT is imputed as 
the TRTSDT. 

If CMENDT is < TRTSDT (whether CMENDT is a complete or 
partial date) then CMSTDT is imputed with JAN for missing month
and 01 for missing day, whatever is applicable. 
Medication End Date (CMENDT)

If month and year are present, then set to the earlier of (last contact 
date or last day of that month of the CMENDT).

If only year present, then set to the earlier of (31DEC of the year or 
last contact date).
SLE Disease 
Duration

For records where month and day are missing for start date, impute 
with 01 for day and January for month to assume that the duration 
was the longest possible duration.

For records where the day only is missing for start date, impute with 
01 for day to assume that the duration was the longest possible 
duration.
9.3.3.
SRI-S2K
For the SRI-S2K endpoint and its components (SS-S2K 4-point reduction from baseline, 
PGA no worsening, BILAG no new 1A/2B), any subject who is classified as a drop out 
or a treatment failure will be considered a non-responder for the primary efficacy analysis 
and the supportive analyses of the primary efficacy endpoint.  This imputation method is
referred to as “Drop Out/Treatment Failure = Non-Responder” (DO/TF=NR). If baseline 
is missing for any of the components of the SRI-S2K, then the SRI-S2K will be missing.
Subjects who have a SS-S2K score <4 at baseline will be excluded from this analysis as 
they have no opportunity to meet the responder criteria. 
Any subject not otherwise classified as a drop out or treatment failure who misses the 
Week 52 visit will be handled as follows:

If the subject does not have a visit within ± 28 days of Day 365 (Week 52) Visit, 
the subject will be considered a dropout for the Week 52 analysis.


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
If a subject has 1 visit within 28 days of the target Week 52 visit, the data 
from that visit will be used for the Week 52 primary efficacy analysis.

If a subject has more than 1 visit within 28 days of the target Week 52 visit, 
the data from the visit closest to the target Week 52 visit will be used for the 
Week 52 primary efficacy analysis.

If a subject has 2 visits with equal distance within 28 days of the target Week 
52 visit, the data from the visit prior to the Week 52 visit will be used for the 
Week 52 primary efficacy analysis. If a subject has a visit within the required 
window, but partial data of the primary efficacy endpoint are missing (including 
individual items of any component of the primary endpoint), the LOCF method 
will be used for the missing item or component. This will be modified for
laboratory items in the BILAG for which scoring is dependent on both the actual 
score and the change from the previous visit as described in Section 9.3.5. 
9.3.4.
SELENA SLEDAI and SS-S2K
The LOCF method will be employed for subjects with missing data on SELENA 
SLEDAI (SS) score at the visit being evaluated.  The LOCF method is consistent with 
how missing data in previous trials was handled. Inclusion of this methodology will 
enable comparison to previously reported studies. See Section 6.1 for further details
Specifically, if a subject misses a scheduled visit or if partial data are missing from a 
subject’s visit, the missing data will be handled by using the last observation (or item) 
carried forward method. For example, if the data on one or more items of the 24 
SELENA SLEDAI questions are missing, the last available answer(s) to the 
corresponding question(s) from the most recent visit where the corresponding item(s) are 
non-missing will be assigned to the missing item(s) to obtain a total score. If a subject 
misses an entire visit, the missing data on SELENA SLEDAI will be handled by using 
the last score from the previous visit. However, if a subject withdraws or is a treatment 
failure prior to the study visit being evaluated, the SELENA SLEDAI data will be 
handled by using the score from the last visit on or prior to the date of withdrawal or date
of treatment failure, whichever is first.  The SS-S2K will be managed in the same 
manner.
9.3.5.
BILAG
The LOCF method will be employed for subjects with missing data on BILAG score at 
the visit being evaluated, see Section 6.1 for further details. Specifically, if a subject 
misses a scheduled visit or if partial data are missing from a subject’s visit, the missing 
data will be handled by using the last observation (or item) carried forward method. For 
example, if the data on one or more items of the 86 BILAG questions are missing, the last 
available answer(s) to the corresponding question(s) from the previous visit will be 
assigned to the missing item(s) to obtain a score for each organ system domain. 
For the following laboratory items, both the actual value from the last visit and the 
change observed at that visit will be carried forward: 

24-hour urinary protein (g) (Question 72a), 


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
urine protein-creatinine ratio (mg/mmol) (Question 72b), 

serum creatinine (mg/dl) (Question 75), and 

creatinine clearance (ml/min) (Question 76).  
If a subject misses an entire visit, the missing data on BILAG will be handled by using 
the last score from the previous visit. However, if a subject withdraws or is a treatment 
failure prior to the study visit being evaluated, the BILAG data will be handled by using 
the score from the last visit on or prior to the date of withdrawal or the date of treatment 
failure, whichever is first.
9.3.6.
PGA
The LOCF method will be employed for subjects with missing data on PGA score at the 
visit being evaluated, see Section 6.1 for further details. Specifically, if a subject misses 
the visit being evaluated; the missing data will be handled by using the last observation 
available. However, if a subject withdraws or is a treatment failure prior to the visit being 
evaluated, the PGA data will be handled by using the score from the last visit on or prior 
to the date of withdrawal or date of treatment failure, whichever is first.
9.3.7.
Proteinuria
All proteinuria endpoints will use Observed data. 
9.3.8.
FACIT Fatigue
The LOCF method will be employed for subjects with a missing total score data on the 
FACIT Fatigue scale.  Specifically, if a subject misses a scheduled visit, missing data will 
be handled by using the last observation carried forward method.
If a subject misses an entire visit, the total score from the previous visit will be carried 
forward. However, if a subject withdraws or is a treatment failure prior to the study visit
being evaluated, the FACIT Fatigue data will be handled by using the score from the last 
visit on or prior to the date of withdrawal or treatment failure date whichever is first.
Details for calculating FACIT for items that are not scored at any visit are described in 
Section 9.4.29.
9.3.9.
FACIT Fatigue Scale Score Improvement Exceeding the MCID 
(>=4 points)
The DO/TF=NR method will be employed for subjects with missing data on the endpoint 
for FACIT Fatigue Scale score improvement exceeding the MCID.  For visits occurring 
on or after study dropout or treatment failure, the endpoint will be set to ‘No’.


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9.4.
Derived and Transformed Data
9.4.1.
Baseline
The baseline value of a variable is defined as the last available value measured prior to 
dosing on or before the date of first dose (Day 1), unless otherwise specified.  If the last 
available value occurs on Day 1 but the time of the assessment is not collected, then the 
assessment will be assumed to be prior to dosing. For concomitant medications and 
adverse events, these are considered present at baseline if the start date is prior to Day 1 
and the end date is on or after Day 1.  Medications or events with a start date on Day 1 
are considered as being on-treatment and treatment-emergent, respectively; see Appendix 
3 Steroids or Anti-Malarials section for slightly different baseline definition comparing 
Steroids and non-Steroid medications.
Baseline flares are flares that occur on or prior to the treatment start date.
The protocol specifies Day 0 as Baseline/Treatment Start date, but the CDISC standard is 
to refer to the Baseline/Treatment Start date as Day 1; therefore Baseline/Treatment Start 
date will appear as Day 1 in the displays and will be referenced as Day 1 in this 
document.  A table indicating the target study day for each planned visit starting at Day 1 
(instead of Day 0) is in Section 9.4.3.
9.4.2.
Study Day
Study Day is the number of days from the treatment start date to a study date of interest
(e.g., adverse event start date) and is calculated as follows:
If condition is…
Then Study Day is…
study date< treatment start date
study date – treatment start date
study date is treatment start date
study date – treatment start date +1
Note: Study Day cannot be zero. If either date is missing then Study Day is missing.
9.4.3.
Analysis Visit and Analysis Visit Number
The data are analyzed according to the planned visit assignment.  
Exit/withdrawal visits (listed below) must be slotted to the appropriate planned visit
according to the study phase. This will only be done for subjects who withdrew prior to 
the end of the respective study phase. Unscheduled laboratory visits will also be 
remapped into the appropriate planned visit based on the original visit number (e.g. if 
unscheduled visit number =80.01, set analysis visit number= 80). The following
hierarchy rules may apply for all the analysis flag in the dataset:
1.
If Scheduled visit exists, take as the first hierarchy;
2.
If no scheduled visit exists, take the unscheduled visit closest to the target study day.
3.
If the Exit visit was slotted into the same visit as the visit prior to withdrawal, select 
the visit closest to the target study day. For instance, if subject already had scheduled 


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Week 20 assessment, and the Exit visit assessment was mapping as another Week 20 
assessment, select the visit closest to the target study day.
Phase
Visit
Visit Number
Double-Blind
Week 52/EXIT
160
Open-Label Extension
OL Week 28/OL EXIT
240
The Analysis Visit is assigned based on the interval in which the Study Day for the 
exit/withdrawal 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 a
Target Study
Dayb
Interval Start Day
Interval End Day
Screening
10
-35
na
na
Double-Blind visits:
Week 0
20
1
-35
1
Week 2
30
15
2
21
Week 4
40
29
22
42
Week 8
50
57
43
70
Week 12
60
85
71
98
Week 16
70
113
99
126
Week 20
80
141
127
154
Week 24
90
169
155
182
Week 28
100
197
183
210
Week 32
110
225
211
238
Week 36
120
253
239
266
Week 40
130
281
267
294
Week 44
140
309
295
322
Week 48
150
337
323
350
Week 52
160
365
351
378
Survivalc
163
365
na
na
Follow-upd
170
393
na
na
Open-label extension visits:
EXT Week 4
180
393
379
406
EXT Week 8
190
421
407
434
EXT Week 12
200
449
435
462
EXT Week 16
210
477
463
490
EXT Week 20
220
505
491
518
EXT Week 24
230
533
519
546
EXT Week 28
240
561
547
574
EXT Follow-upe
250
589
na
na


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Analysis Visit
Analysis 
Visit Number a
Target Study
Dayb
Interval Start Day
Interval End Day
a.
If there are multiple visits within a visit window, the visit closest to the target date will be used. If there are two 
visits equidistant from the target date, the first will be used.
b.
Study Day with Baseline/Treatment Start Date as Day 1. Baseline record will be derived in each analysis dataset, 
analysis visit number will be 15.
c.
Survival visit for subjects who withdraw from the double-blind phase but consent to the Week 52 survival 
assessment.
d.
The double-blind follow-up occurs 4-weeks after early withdrawal or 8 weeks after last dose (e.g. Week 56) for 
subjects who complete and do not enter the open-label extension phase. 
e.
The open-label extension follow-up occurs 4-weeks after early withdrawal or 8 weeks after last dose (e.g. Week 
32) for subjects who complete the open-label extension phase.
9.4.4.
Change from Baseline
Change from baseline will be calculated as:
Visit value – baseline value.
If either value is missing the change from baseline will be missing.
9.4.5.
Percent Change from Baseline
Percent change from baseline will be calculated as 
Visit Value  -  Baseline Value
X  100.
Baseline Value
Subjects with a baseline value of zero will not have a value calculated due to division by 
zero.  If the baseline value is zero or missing then the percent change will be set to 
missing.  
9.4.6.
SLE Disease Duration
SLE Disease Duration (years) is defined as 
Treatment Start date - SLE diagnosis date + 1
365.25
If either date is missing then SLE Disease Duration will be missing.
9.4.7.
Analysis Age
Analysis age is derived in years relative to the treatment start date for randomized 
subjects, and is calculated in SAS as follows:
INTCK (‘YEAR’, Date of birth, Date of first treatment, ’C’), 
in the case that a subject was randomized but not treated then age is defined as 


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INTCK (‘YEAR’, Date of birth, Date of randomization, ’C’).
9.4.8.
Body Mass Index (BMI)
Baseline body mass index (BMI) will be calculated from baseline weight and height 
measurements as:
BMI (kg/m2) =
Weight (kg)
[Height (m)]2
Since height is collected in centimetres (cm), it must to be converted to meters (m) by 
dividing by 100 before using it in the formula above.  If weight or height is missing, then 
BMI will be missing.
9.4.9.
Race Hierarchical Rule
If multiple race categories are checked on the CRF, the subject will be assigned to a 
unique race group based on which of the races checked appears first in the list below:

Black/African American/African Heritage

Native Hawaiian or Other Pacific Islander

American Indian or Alaska Native

Asian

White/Caucasian
For example, if Black and Asian are both checked, then the subject will be assigned as 
Black since it appears highest in the list.  Race assigned based on this hierarchical rule 
will be applied to all analyses related to race.  In the baseline demographic characteristics 
table and the race and racial combination details table, subjects with multiple race 
categories checked will be reported in the race per the hierarchical rule as well as in the 
multiracial category.
9.4.10.
ACR Criteria at Baseline

Subjects were required to meet at least 4 of the 11 criteria to be eligible for the study.

The criteria consist of the following:  malar “Butterfly” rash, discoid rash, 
photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, 
hematologic disorder, immunologic disorder, and anti-nuclear antibody (ANA). See 
Appendix 4 for an example of the form.

Sub-criteria exist for serositis, renal disorder, neurologic disorder, hematologic
disorder, and immunologic disorder.

The number of ACR criteria met will be summed for a total score with a maximum 
possible score of 11.

Sub-criteria are not summed as part of the total score, but if at least one sub-criterion 
is met for the overall criterion category, then the category will count as one for the 
total score.  For example, the neurologic criterion includes sub-criteria of seizures 


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and psychosis.  Neurologic will only count as one toward the total ACR criteria even 
when both seizures and psychosis are applicable.
9.4.11.
B Cell Unit Conversions and Normalization for Rare B Cell 
Subsets

The Benlysta program standard is to report common B cells (CD19, CD20, naïve, 
and memory) in counts per L (/L). 

To convert values reported as count per GI/L (= 109/L) to L (= cells/mm3) simply 
multiply the value by 103 or 1000
Example:  (0.25 GI/L) x (1000) = 250 /L

Rare B cell subsets reported in GI/L (=109/L) will be normalized and converted to 
cells/ml using the following formula:
Normalized count/mL = [(rare cell event count) / (CD19+ event count)] * (CD19+ 
count per mm3 or L) * 1000.

Note that the CD19+ concentration from the TBNK panel should be converted to 
count/µL prior to the normalization and conversion of the Rare B-cell subset.
For additional detail, please see Section 8.6.3 of the PSAP located in IMMS at the 
following path: /Study File/GSK1550188/_Project/Meta Analysis/PSAP.
The list of B cell item mappings and display labels are listed in Appendix 13.
Endpoints to be normalized and values to be substituted into the formula are given in
Appendix 13.
Table 3
Rare B cell subsets requiring normalization
Rare B cell subset
Rare cell event count
CD19+ Event 
Count [1]
CD19+ 
Counts [2]
Activated
CD20+CD69+ (EVENTS)
CD19+ (EVENTS) [a]
CD19+ (/L)
Plasmacytoid
CD20+ CD138+ (EVENTS)
CD19+ (EVENTS)[a]
CD19+ (/L)
Plasma
CD20- CD138+ (EVENTS)
CD19+ (EVENTS) [a]
CD19+ (/L)
Short-lived plasma
CD27+b CD20- (EVENTS)
CD19+ (EVENTS) [a]
CD19+ (/L)
SLE subset
CD27+CD38+CD19+ (EVENTS)
CD19+ (EVENTS) [a]
CD19+ (/L)
Transitional
CD19+ CD24b+ CD38b+ CD27-
(EVENTS)
CD19+ (EVENTS) [b]
CD19+ (/L)
[1] From corresponding panel – [a] Plasma panel, [b] Transitional panel.
[2] Source data require conversion from GI/L to /L.
The required parameters in the source data can be identified in Table 4.


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Table 4
SDTM data required for Normalization of Rare B Cell Subsets
(SDTM.LB)
Rare B cell subset
Lab Test Code 
(LBTESTCD)
Lab Test
(LBTEST)
B cell Panel 
(LBMETHOD) 
[1]
Units of 
Measurement
(LBORRESU)
CD19 Concentration from TBNK Panel
CD19[2]
CD19
CD19
FLWTBNK
10^9/L [2]
CD19 Event Counts from Plasma/Transitional Panels
CD19 Event (Plasma 
B cell panel)
CD19E
CD19 Number of 
Events
FLWPLSM
EVENTS
CD19 Event 
(Transitional B cell 
panel)
CD19E
CD19 Number of 
Events
FLWTRANS
EVENTS
Rare B Cell Events
Activated
CDX141E
CD20+CD69+ 
Number of Events
FLWPLSM
EVENTS
Plasmacytoid
CDX145E
CD20+CD138+ 
Number of Events
FLWPLSM
EVENTS
Plasma
CDX143E
CD20-CD138+ 
Number of Events
FLWPLSM
EVENTS
Short-lived plasma
CDX154E
CD27+bCD20-
Number of Events
FLWPLSM
EVENTS
SLE subset
CDX156E
CD27+CD38+CD19+ 
Number of Events
FLWPLSM
EVENTS
Transitional
CDX199E
CD19+ CD24b+ 
CD38b+ CD27-
Number of Events
FLWTRANS
EVENTS
[1] FLWPLSM=FLOW CYTOMETRY - PLASMA B CELLS PANEL; FLWTRANS= FLOW CYTOMETRY -
TRANSITIONAL B CELLS PANEL, and LWTBNK=FLOW CYTOMETRY - TRUCOUNT TBNK (BD MULTITEST) 
PANEL.
[2] Source data require conversion from GI/L (=109/L) to /L.
9.4.12.
Proteinuria
For analysis, urine protein in g/24-hour will be approximated by the urine 
protein:creatine ratio (uPCR) in mg/mg which is stored in the variable for the original 
unit in the SI dataset. The SI dataset standard unit is reported in mg/mmol and is used for 
scoring the BILAG only.
9.4.13.
Average Daily Prednisone Equivalent

For steroid use analyses, all steroid dosages are converted to a prednisone equivalent 
in milligrams; therefore, analyses refer to average daily prednisone dose instead of 
average daily steroid dose.  See Appendix 2 for instructions on converting steroids to 
prednisone equivalents.  


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
This document will be updated throughout the course of the study to include all 
corticosteroids taken by subjects and will be finalized prior to the first database lock 
and unblinding.

The average daily prednisone dose takes account of all steroids taken intravenously 
(IV), intramuscularly (IM), SC, intradermally, and orally for both SLE and non-SLE 
reasons. 

Please note: the prednisone visit slotting is based on the earliest date of (exposure 
dose date at the visit, primary efficacy assessment date [BILAG, PGA, SLEDAI]), if 
these are missing then use target visit date.
9.4.13.1.
Baseline Prednisone Dose
At baseline, the average daily prednisone dose is the sum of all prednisone doses over 7 
consecutive days up to, but not including Day 1, divided by 7.  This baseline is used for 
comparison to post baseline average dose between visits and average dose at the visit.
9.4.13.2.
Average Daily Prednisone Dose Between Visits
The average daily prednisone dose between visits will be calculated for each scheduled 
post-baseline visit by summing all prednisone doses since the previous visit (previous 
visit date +1) up to and including the current visit and then dividing by the number of 
days in this period (Date of current visit – Date of previous scheduled visit).  Days on 
which a subject does not have prednisone use recorded will be considered as 0 mg for the 
day in the calculation of average daily prednisone dose.
For subjects who withdraw from the study or are deemed treatment failures prior to a 
scheduled visit, the average dose will be calculated as the average of all prednisone doses 
since the previous visit up to and including the date of withdrawal or date of treatment 
failure, whichever is earlier. For a subject who withdrew/treatment failed at baseline then 
the average dose will be the baseline value.
9.4.13.3.
Average Daily Prednisone Dose at the Visit
While on treatment, the average daily prednisone dose at the visit is the sum of all 
prednisone doses over 7 consecutive days up to and including the day of interest, divided 
by 7, unless otherwise specified. Days on which a subject does not have prednisone use 
recorded will be considered as 0 mg for the day in the calculation of average daily 
prednisone dose.
The average daily prednisone equivalent dose will be calculated for each scheduled visit.  
For subjects who withdraw from the study or are treatment failures prior to a scheduled 
visit, the average dose will be calculated at the date of withdrawal or date of treatment 
failure, whichever is earlier. For a subject who withdrew/treatment failed at baseline then 
the average dose will be the baseline value.
Note: for the treatment failure adjudication, an intermediate dataset containing the rolling 
7-day average daily prednisone for each study day will be used to capture treatment 
failures occurring between visits.


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9.4.13.4.
Average Daily Prednisone Dose during Weeks 40 to 52
DO/TF
While on treatment, the average daily prednisone dose during Weeks 40 to 52 is the 
average of all prednisone doses starting the day after the Week 40 visit date up to but not 
including the Week 52 visit date.  
For subjects who withdraw or are treatment failures on or before the Week 40 visit date, 
the average daily prednisone dose during Weeks 40 to 52 will be missing.  For subjects 
who withdraw or are treatment failures after the Week 40 visit date, the average daily 
dose will be calculated as the average of all prednisone doses from the day after the Week 
40 visit date up to and including the date of withdrawal or date of treatment failure, 
whichever is earlier. 
Observed
A sensitivity analysis may be performed using all observed data.  The average daily 
prednisone dose during Weeks 40 to 52 is the average of all prednisone doses starting the 
day following the Week 40 visit date up to but not including the Week 52 visit date.  All 
data in the interval is used irrespective of drop out (IP withdrawal) or treatment failure. 
9.4.13.5.
Prednisone Increase by 50% from Baseline by a Minimum 5 mg/day
Subjects are considered to have a prednisone increase by 50% and a minimum of 
5mg/day if the percent change from baseline in daily prednisone dose is 50% AND the 
change from baseline in daily prednisone dose is 5mg/day.  For subjects with no 
prednisone use at baseline, a subject meets the definition if the change from baseline in 
prednisone use is 5mg/day; percent change from baseline cannot be calculated when 
there is no baseline prednisone use due to division by zero.
9.4.13.6.
Prednisone Reduction by 50% from Baseline
Subjects are considered to have a prednisone reduction if the prednisone percent change 
from baseline is ≤ -50%.  To have a reduction subjects must have a baseline average daily 
prednisone dose >0. 
9.4.13.7.
Any Increase from Baseline
Subjects are considered to have ‘any increase’ from baseline when the change from 
baseline in average daily prednisone dose is >0.
9.4.14.
SLICC/ACR Scoring

The SLICC/ACR Damage Index (Appendix 5) 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 


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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.  

Worsening is defined as an increase from baseline in SLICC/ACR Damage Index
score [(post-baseline visit score – baseline score)] >0.    

No worsening is defined as no increase from baseline in SLICC/ACR Damage Index
score [(post-baseline visit score – baseline score) = 0].
9.4.15.
SELENA SLEDAI and SLEDAI-S2K scoring
SELENA SLEDAI and SLEDAI-S2K Total and Organ System Domain Scores
SELENA SLEDAI assessments consist of 24 individual items 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 
(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 below.  
SELENA SLEDAI
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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to the Vascular organ system and the Constitutional organ system will be eliminated and its one component, fever, 
will be moved to the hematologic organ system.
SS-S2K- differs from SS [Gladman, 2002] in that it also reflects persistent disease activity in certain 
descriptors (listed below) whereas the SS only reflects new or recurrent disease activity.
Descriptors
Original SELENA SLEDAI
SELENA SLEDAI-S2K
Alopecia, 
Mucous Membrane
Lesions, Rash
Items are only scored if they are 
new or recurrent.
Items are scored if they are 
present, regardless of history.
Proteinuria 
Scored if it is a new onset or a 
recent increase of more than 
0.5g/24hr.*
Scored if it was new, recurrent or 
persistent (i.e., any result 
>0.5g/24hr*).  
*Urine protein:creatinine ratio of 0.5 mg/mg is considered equivalent to 0.5 g/24 hours for urine 
protein.  
In this study, proteinuria is evaluated using spot-urine protein [represented as protein-creatinine ratio or PC 
Ratio (see Section 9.4.12) in the laboratory dataset] in lieu of the 24-hour urine collection. 
For reporting, SS-S2K will be approximated by adjusting only the proteinuria descriptor of SELENA SLEDAI. 
If the laboratory PC ratio value exceeds 0.5 mg/mg the proteinuria item of the SLEDAI is given a positive 
score (4-point weight) creating an approximation to the SS-S2K assessment.
If the PC 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 SS score.  For the SS-S2K
score, the lab data will be assessed and if the PC ratio is >0.5 mg/mg for the visit then the proteinuria item 
will be scored as 4 points, otherwise it will receive a score of 0.  If the PC ratio is missing, the proteinuria item 
from the previous SS-S2K will be carried forward.   
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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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.  In such instances where an item is ticked unknown, LOCF 
will be used
Missing items on the SS and SS-S2K will be managed per Section 9.3.4.
9.4.15.1.
SLEDAI 4-point reduction
The SS 4-point reduction and SS-S2K 4-point reduction are defined below.
Endpoint
Criterion
Result
SS 4-point reduction
SS post-baseline – SS baseline - 4 (negative 4)
Y
SS post-baseline – SS baseline > - 4 (negative 4)
N
SS post-baseline = missing  
See Section 
9.3
SS baseline = missing 
Missing
SS-S2K 4-point 
reduction
SS-S2K post-baseline – SS-S2K baseline - 4
(negative 4)  
Y
SS-S2K post-baseline – SS-S2K baseline > -  4
(negative 4)  
N
SS-S2K post-baseline = missing  
See Section 
9.3
SS-S2K baseline = missing 
Missing
9.4.15.2.
SLEDAI Organ System Improvement and Worsening
For both the SS and SS-S2K, each organ system (as defined in Section 9.4.15) will be 
evaluated for improvement and worsening as defined below:
Endpoint
Criterion
Result
Improvement
Organ score post-baseline – baseline organ score<0
Y
Organ score post-baseline – baseline organ score 0
N
Organ score post-baseline = missing  
See
Section
9.3
Organ score baseline = missing 
Missing
Worsening
Organ score post-baseline – baseline Organ score ≤0
N
Organ score post-baseline – baseline Organ score > 0
Y
Organ score post-baseline = missing  
See 
Section 
9.3
Organ score baseline = missing 
Missing


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9.4.16.
BILAG Scoring
BILAG
BILAG Score

The British Isles Lupus Assessment Group (BILAG) score is an assessment of current lupus 
disease activity, as well as an indicator of historical disease activity in subjects with SLE. The 
Classic BILAG index was used in this study.

Eight systems are given scores ranging from A to E where:

A = Active disease sufficient to require disease-modifying treatment (prednisolone >20mg 
or immunosuppressants)

B = Mild reversible problems requiring only symptomatic therapy (anti-malarials, NSAIDs, 
or prednisolone <20mg/day)

C = Stable, mild disease

D = Previous disease but currently inactive

E = Never active; no history  

If a subject meets the requirements for more than one letter score (A-E, with A being the 
highest), then the highest score met will be assigned for the organ system.

Scoring of the BILAG is based on three publications including Hay, 1993; Isenberg, 2000, and a 
doctoral thesis written by Yee, 2008.    

The item numbers referred to below are CRF item numbers. 


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BILAG
BILAG Index Assessment (Scheduled Visits)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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BILAG System
Computationa
l References 
Used
Source / Derivation / Comments
Variables named by BILAG item number (e.g. BILAG01 is item 1).
General
(Items 1-5)
Modified HGS 
BILAG Scoring 
using Hay 
First Assessment:
= 'A' if Pyrexia (BILAG01)>0 AND 2 of the other scores (BILAG02-BILAG05)>0
= 'B' if Pyrexia (BILAG01)>0 OR 2 of the other scores (BILAG02-BILAG05)>0
= 'C' if any of BILAG02-BILAG05 are >0
= 'E' if no involvement
Subsequent Assessments:
= 'A' if Pyrexia (BILAG01)>1 AND 2 of the other scores (BILAG02-BILAG05)>1
= 'B' if Pyrexia (BILAG01)>1 OR 2 of the other scores (BILAG02-BILAG05)>1
= 'C’ if any of BILAG01-BILAG05 are >0
= 'D' if any previous value was in (A,B,C,D)
= 'E' if at least one non-missing item score and no previous assessments were 
       above E.
Mucocutaneous
(Items 6-23)
Modified HGS 
BILAG Scoring 
using Hay for 
first 
assessments 
and Yee for 
subsequent 
assessments
First Assessment:
= 'A' if any of BILAG06, BILAG08, BILAG13, or BILAG14 are >0 
= 'B' if any one of BILAG16, BILAG07, BILAG12, BILAG09, BILAG10, 
        BILAG17, or BILAG18 are >0 
= 'C' if any one of BILAG19, BILAG20, BILAG21, BILAG22, BILAG23, 
        BILAG11, or BILAG15 are >0 for 0-4 items or Yes for Yes/No items
= 'E' if no involvement
Subsequent Assessments:
= 'A' if any of BILAG06, BILAG08, BILAG13, or BILAG14 are >1
= 'B' if any one of BILAG16, BILAG07, BILAG12, BILAG09, BILAG10, 
       BILAG17, or BILAG18 are >1
= 'C' if (any one of BILAG19, BILAG20, BILAG21, BILAG22, BILAG23, 
        BILAG11, or BILAG15 are >0 for 0-4 items or Yes for Yes/No items) 
        or 
        (any of BILAG06, BILAG08, BILAG13, BILAG14, BILAG16, BILAG07,
        BILAG12, BILAG09, BILAG10, BILAG17, or BILAG18 are =1)
= 'D' if any previous value was in (A,B,C,D)
= 'E' if at least one non-missing item score & no previous assessments were
      above E.
Neurological
(Items 24-38)
Modified HGS 
BILAG Scoring 
using Yee
All Assessments:
= 'A' if any of BILAG24, BILAG25, BILAG26, BILAG27, BILAG28, 
        BILAG29, BILAG30, BILAG31, BILAG33, BILAG34 are in (3,4)
= 'B' if (any of BILAG35, BILAG36, BILAG37, or BILAG32 are in (3, 4)) OR 
        ((if any of BILAG24, BILAG25, BILAG26 are in (1,2))
= 'C' if BILAG38>0 OR (if any of BILAG27, BILAG28, BILAG29, BILAG30,   
        BILAG31, BILAG33, BILAG34, BILAG35, BILAG36, BILAG37, or 
        BILAG32 are in (1, 2))
= 'D' if any previous value was in (A,B,C,D)
= 'E' if at least one non-missing item score & no previous assessments were
       above E.


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BILAG System
Computationa
l References 
Used
Source / Derivation / Comments
Variables named by BILAG item number (e.g. BILAG01 is item 1).
Musculoskeletal
(Items 39-47)
Modified HGS 
BILAG Scoring 
using Hay for 
first 
assessments 
and Yee for 
subsequent 
assessments
First Assessment:
= 'A' if at least one of BILAG39 or BILAG40 is >0
= 'B' if at least one of BILAG41 or BILAG42 is >0
= 'C' if at least one of BILAG44, BILAG45, BILAG46, BILAG47, or BILAG43 is 
         >0 for 0-4 items or Yes for Yes/No items
= 'E' if no involvement
Subsequent Assessments:
= 'A' if at least one of BILAG39 or BILAG40 is >1
= 'B' if at least one of BILAG41 or BILAG42 is >1
= 'C' if (at least one of BILAG44, BILAG45, BILAG46, BILAG47, or BILAG43 is
        >0 for 0-4 items or Yes for Yes/No items) OR (one of BILAG39, 
        BILAG40, BILAG41, BILAG42 is =1)
= 'D' if any previous value was in (A, B, C, D)
= 'E' if at least one non-missing item score and no previous assessments were
       above E.
Cardiovascular 
and Respiratory
(Items 48-59)
Modified HGS 
BILAG Scoring 
using Hay for 
first 
assessments 
and Yee for 
subsequent 
assessments
First Assessment:
= 'A' if 4 of the following are >0 for 0-4 items or Yes for Yes/No items:
        BILAG48, BILAG49, BILAG51, BILAG54, BILAG55, BILAG56,  
        BILAG57, BILAG58, BILAG59 
       OR
        BILAG50>0 AND 2 of BILAG48, BILAG49, BILAG51, BILAG54, 
        BILAG55, BILAG56, BILAG57, BILAG58, BILAG59 are >0 for 0-4 items
        or Yes for Yes/No items
       OR
        BILAG52>0 AND 2 of BILAG48, BILAG49, BILAG51, BILAG54, 
        BILAG55, BILAG56, BILAG57, BILAG58, BILAG59 are >0 for 0-4 items
       or Yes for Yes/No items
= 'B' if 2 of BILAG48, BILAG49, BILAG51, BILAG54, BILAG55, 
        BILAG56, BILAG57, BILAG58, BILAG59, BILAG50, BILAG52     
        Are >0 for 0-4 items or Yes for Yes/No items
= 'C' if any of BILAG53, BILAG50, BILAG52, BILAG48, BILAG49, 
        BILAG51, BILAG54, BILAG55, BILAG56, BILAG57, BILAG58, or 
        BILAG59 are >0 for 0-4 items or Yes for Yes/No items
= 'E' if no involvement
Subsequent Assessments:
='A' if 4 of the following are >1 for 0-4 items or Yes for Yes/No items:
       BILAG48, BILAG49, BILAG51, BILAG54, BILAG55, BILAG56, 
       BILAG57, BILAG58, BILAG59
       OR
       BILAG50>1 AND 2 of BILAG48, BILAG49, BILAG51, BILAG54, 
       BILAG55, BILAG56, BILAG57, BILAG58, BILAG59 are >1 for 0-4 items or
      Yes for Yes/No items
       OR
       BILAG52>1 AND 2 of BILAG48, BILAG49, BILAG51, BILAG54, 
       BILAG55, BILAG56, BILAG57, BILAG58, BILAG59 are >1 for 0-4 items or
      Yes for Yes/No items
= 'B' if 2 of BILAG48, BILAG49, BILAG51, BILAG54, BILAG55, 
        BILAG56, BILAG57, BILAG58, BILAG59, BILAG50, BILAG52 


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BILAG System
Computationa
l References 
Used
Source / Derivation / Comments
Variables named by BILAG item number (e.g. BILAG01 is item 1).
       Are >1 for 0-4 items or Yes for Yes/No items
= 'C' if any of BILAG53, BILAG50, BILAG52, BILAG48, BILAG49,   
        BILAG51, BILAG54, BILAG55, BILAG56, BILAG57, BILAG58, or 
        BILAG59 are >0 for 0-4 items or Yes for Yes/No items
= 'D' if any previous value was in (A,B,C,D)
= 'E' if at least one non-missing item score and no previous assessments were
       above E.
Vasculitis
(Items 60-67)
Modified HGS 
BILAG Scoring 
using Hay for 
first 
assessment 
and Yee for 
subsequent 
assessments
First Assessment:
='A' if at least one of BILAG60, BILAG61, or BILAG62 is >0
='B' if at least one of BILAG66, BILAG65, or BILAG67 is >0 for 0-4 items or
      Yes for Yes/No item
='C' if at least one of BILAG63 or BILAG64 is >0
='E' if no involvement
Subsequent Assessments:
='A' if at least one of BILAG60, BILAG61, or BILAG62 is >1
='B' if at least one of BILAG66, BILAG65, or BILAG67 is >1 for 0-4 items or 
       Yes for Yes/No item
='C' if (at least one of BILAG63 or BILAG64 is >0) 
       OR
       (at least one of BILAG60, BILAG61, BILAG62, BILAG65, BILAG66, or
       BILAG67 = 1 for 0-4 items or Yes for Yes/No item)
='D' if any previous value was in (A,B,C,D)
='E' if at least one non-missing item score and no previous assessments were 
       above E.
Renal
(Items 68-78)
All Assessments: 
For items 72 and 
73, use item b 
recorded as urine 
protein-creatinine 
ratio (mg/mmol). 
Data requested 
per item a (24-
hour urinary 
protein recorded in 
g/24 hours). was 
not collected per 
protocol
Modified HGS 
BILAG Scoring 
using Isenberg 
and memo to 
file regarding 
items 72 and 
73.  Item 74 
added to 
category D but 
no reference.
Note:  Typo in 
Isenberg
(2000) paper 
where A3c 
creatinine 
clearance >50 
ml/min and last 
time was 
>50/ml, in Yee 
this is <50 
ml/min and last 
time >50 
ml/min
All Assessments: For items 72 and 73, use item b recorded as urine protein-
creatinine ratio (mg/mmol). Data requested per item a (24-hour urinary protein 
recorded in g/24 hours). was not collected per protocol
Define Proteinuria as:
(BILAG71 has a change from previous BILAG71 record >=2) OR (previous 
BILAG72B<0.2*100 mg/mmol and current BILAG72B>1*100 mg/mmol) OR 
(BILAG72B>1*100 mg/mmol and percentage change from previous BILAG72B 
value >=100%) or BILAG73B=1/yes and corresponding SLE relationship box 
has been checked for the criterion met
Define Deteriorating Renal Function as follows:
(BILAG75*88.4>130 mg/dl and percentage change from previous 
BILAG75>130%) OR (BILAG76<67% of previous BILAG76 value) OR
(BILAG76<50 ml/min and previous BILAG76 value was >50 ml/min) and 
corresponding SLE relationship box has been checked for the criterion met
='A' if (two or more of the following occur: Proteinuria, BILAG70=1/yes, 
       Deteriorating renal function, BILAG77=1/yes, BILAG78=1/yes) 
       AND
       at least one of the two or more is Proteinuria, BILAG77, or BILAG78, and
      the corresponding SLE relationship has been checked for the criterion
       met. 
='B' if (one or more of the following occur: Proteinuria, BILAG70=1/yes, 
       Deteriorating renal function, BILAG77=1/yes, BILAG78=1/yes) 


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BILAG System
Computationa
l References 
Used
Source / Derivation / Comments
Variables named by BILAG item number (e.g. BILAG01 is item 1).
      OR 
       (BILAG71>=2 and has risen from previous assessment by 1 or more) 
       OR 
       (BILAG72B has risen by >1*100 mg/mmol from previous BILAG72B 
       record and increased by >50% but <100%) or (BILAG75*88.4>130 mg/dl 
       and percentage change from previous record was >115%) and 
       corresponding SLE relationship box has been checked for the criterion
       met.
='C' if (BILAG72B>0.25*100 mg/mmol) or (BILAG71>=1) 
       OR 
       (BILAG68>140 mm/Hg and change from previous BILAG68 >=30 mm/Hg
      and 
       BILAG69>90 mm/Hg and change from previous BILAG69>=15 mm/Hg)
='D' if any previous value was in ('A', 'B', 'C', 'D') or BILAG74=1/yes and SLE 
       related is checked
='E' if no involvement
Hematology
(Items 79-86)
Modified HGS 
BILAG Scoring 
(all the same 
scoring 
algorithm), 
plus additional 
criterion for D 
from "See 
email from 
MChevrier 
dated 
01Sep05 re 
neutrophils."
All Assessments (Note: 10^9/L=GI/L):
='A' if BILAG80<1.0x10^9/L or BILAG83<25 x10^9/L or BILAG79<8 g/dL and 
       the corresponding SLE related box is checked
='B' if BILAG80<2.5x10^9/L or BILAG83<100 x10^9/L or BILAG79<11 g/dL or 
         (BILAG84=YES and BILAG85=YES) and the corresponding SLE related 
         box is checked (there is no checkbox for BILAG85)
='C' BILAG80<4.0x10^9/L or BILAG83<150 x10^9/L or BILAG82<1.5x10^9/L
      or (BILAG85=YES and BILAG84^=YES) or BILAG86=YES and the 
       corresponding SLE related box is checked (no checkbox for 
       BILAG85 or BILAG86)
='D' if any previous value was in (A,B,C,D) or (.z<BILAG81 <0.5 x10^9/L and 
       SLE related checkbox is checked)
='E' if at least one non-missing item score and no previous assessments were 
       above E.
NB: COMB’ S Test  Only done with evidence of hemolysis. So if #84 is yes, is 
evidence of hemolysis #84 no, #85 yes query
9.4.16.1.
BILAG Improvement
BILAG improvement is limited to improvement from an A or B score, therefore within 
each organ domain, only subjects with an A or B score at baseline will be included. 
Subjects who have an A at baseline and change to a B, C, or D will be considered to have 
improvement.  Similarly, subjects with a B at baseline who change to a C or D will be 
considered to have improvement.  
9.4.16.2.
BILAG Worsening
BILAG worsening is limited to worsening to an A or B score.  Subjects who have a B at 
baseline and change to an A will be considered to have worsening.  Similarly, subjects 
who have a C, D, or E at baseline and change to an A or B will be considered to have 
worsening. Subjects with an A at baseline are excluded since they cannot worsen.  


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9.4.16.3.
BILAG No New 1A/2B
This responder endpoint (responder, non-responder) is a component of the SRI endpoint.  
A new A score is defined as any organ domain with an A score at a post-baseline visit 
that was not an A score at baseline.  Similarly, a new B score is any organ domain with a 
B score post-baseline that was not an A or B at baseline (i.e., constitutes a worsening in 
the domain).  To be a responder for this endpoint a subject cannot have any new A scores 
and no more than 1 new B score (i.e., not 2 new B scores). 
9.4.16.4.
BILAG No 1A/2B
This responder endpoint (responder, non-responder) is a component of the EMA SRI-
S2K endpoint.  To be a responder for this endpoint a subject cannot have any A scores 
and no more than 1 B score.  This differs from the BILAG No New 1A/2B in that any 
subject with an A or more than one B score, even if they existed at baseline and are not 
‘new’, will be considered a non-responder.  
9.4.17.
PGA Scoring
The PGA is collected on a 10cm visual analogue scale (VAS).  
The standard scoring range for the PGA is 0 to 3, therefore the score will be rescaled for 
standard reporting by multiplying the collected score on the centimeter scale by 3/10.This 
rescaling will be within the SDTM datasets.
9.4.17.1.
PGA No Worsening
PGA No Worsening is defined as (Post-baseline PGA – Baseline PGA) <0.3 using the re-
scaled score (0-3 scale).
9.4.17.2.
PGA Improvement
PGA Improvement is defined as (Post-baseline PGA – Baseline PGA) ≤ -0.3 using the re-
scaled score (0-3 scale).
9.4.18.
SRI-S2K
The primary endpoint is the systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K (S2K) scoring for proteinuria at Week 52. 
This S2K rule scores proteinuria as 4 points anytime the value is >0.5 g/24hr. This 
endpoint will be referred to as the SRI-S2K for reporting and is defined as: 

4-point reduction from baseline in SELENA SLEDAI score using the 
SLEDAI-2K proteinuria scoring [SS-S2K 4pt], 
AND 

No worsening (increase of <0.3 points from baseline) in Physician’s Global 
Assessment (PGA) [PGA No Worsening], 
AND 


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
No new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ 
domain score or 2 new BILAG B organ domain scores compared with baseline 
at the time of assessment (i.e., at Week 52 visit) [BILAG No new 1A/2B]. 
The percentage of subjects achieving an SRI-S2K response at Week 52 will be presented 
for belimumab and placebo.  
9.4.19.
SRI using SELENA SLEDAI proteinuria scoring
The SRI will also be derived as described in Section 9.4.18 requiring a 4-point reduction 
using the SELENA SLEDAI proteinuria scoring as was originally recorded on the 
SELENA SLEDAI disease activity scale.  
9.4.20.
European Medicines Agency (EMA) modified SRI response at 
week 52 (EMA SRI-S2K)
The EMA modified SRI response rate with the modified SLEDAI-2K (S2K) scoring for 
proteinuria (EMA SRI-S2K) at Week 52 is defined as: 

4-point reduction from baseline in SELENA SLEDAI - S2K score, 
AND 

No worsening (increase of <0.30 points from baseline) in PGA, 
AND 

No BILAG A organ domain scores or 2 BILAG B organ domain scores at the 
time of assessment (i.e., at Week 52).
This endpoint differs from the SRI-S2K in the BILAG component.  The SRI-S2K 
requires no new BILAG 1A/2B scores whereas the EMA SRI-S2K requires no BILAG A 
and no more than one BILAG B score (No BILAG 1A/2B).
9.4.21.
Date of SRI-S2K Response
SRI-S2K response is derived from three assessments (SELENA SLEDAI - S2K, PGA 
and BILAG) which were scheduled to be assessed on the same calendar date.  At any 
visit, if the dates for the three assessments differ, then the date of SRI-S2K response will 
be determined from the observed dates (rather than any imputed dates).  If there are 
multiple observed dates, the latest of these dates will be taken as the date of SRI-S2K
response. Please see Section 6.1 for LOCF date details.
9.4.22.
SRI-S2K Durable Response from Week 44 through Week 52
A durable SRI-S2K response is defined as a sustained SRI-S2K response from Week 44 
through Week 52.  Specifically, a subject has a durable response if the subject is an SRI-
S2K responder at Weeks 44, 48, and 52.  


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9.4.23.
SRI-S2K Duration of Longest Response
The duration of longest SRI-S2K response among subjects with at least 1 SRI-S2K 
response is defined as the entire duration of a response that first occurs at or before Week 
52 to the last visit in which a subject responds consecutively.  It will be calculated by: 1 + 
number of days from the first visit to the last visit in which a subject responds 
consecutively. 
Last consecutive response date – first consecutive response date +1
For subjects without an SRI-S2K response, the duration will be set to zero (0).
For a SRI-S2K response starting on Week 52, the duration will be set to one (1) day.
9.4.24.
SRI-S2K Duration of Week 52 Response
For subjects with a SRI-S2K response at Week 52, the duration is defined as: 
[Date of Week 52 Assessment – Date of the first post-baseline visit where the subject is a 
responder and remains a responder at all following visits up to Week 52] + 1
For subjects without any response at Week 52, the duration of response will be set to zero
(0) days.  If a subject misses a visit between two scheduled visits at which the subject has 
a response, the subject will be defined as having a response at the missing visit.  


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9.4.25.
SLE Flare Index (SFI) Scoring
SLE Flare Index
CRF Information
Derivations

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; otherwise the flare will not be counted.


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
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, 
then the flare will not be counted.
9.4.26.
Time to First SFI Flare, Censoring and Disposition Rules
The rules described in this section apply to SLE Flares and SLE Severe Flares. 
Up to 52 Weeks
Time to first modified severe SLE flare is defined as the number of days from first 
exposure until the subject meets an event (event date – first exposure date + 1). The 
disposition of subjects is defined as follows in Table 5. 
Only post-baseline flares are included in the analysis, therefore flares (not subjects) 
occurring on the treatment start date should be removed from the analysis set prior to 
determining the first flare. In the rare situation that a treatment failure occurs on the 
treatment start date, the treatment failure will be counted as a flare as the assessment of 
treatment failure is performed post-dose.
For the Double-Blind phase, time to first flare over 52 weeks is calculated as:
Time to first flare (days)
=
Date of first flare  – treatment start date +1.
From Week 24 to Week 52
For the time to first flare from Week 24 to Week 52, flares (not subjects) occurring on the 
Week 24 visit date should be removed from the analysis set prior to determining the first 
flare. Time to first flare from Week 24 to Week 52 is calculated as:
Time to first flare (days)
=
Date of first flare – Week 24 visit date + 1.
Table 5
Subject Disposition Rules for SLE Flares (Double-Blind Phase)
Subject Disposition
Event Met
Event Date
Subject has a flare or is a treatment failure, whichever occurs first
Subject has a flare [1]
Yes
Date of first flare
Subject is a treatment failure [1] 
Yes
Treatment failure date
Subject does not have a flare and is not a treatment failure
Subject withdraws
No
Censored at last flare 
assessment date
Subject dies
No
Censored at date of death
Subject completes 
No
Censored at last flare 
assessment date
[1] If a subject has a flare and is a treatment failure then the event date is the earliest of the first 
flare date and the date of treatment failure.


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9.4.27.
Severe SFI flare rate per subject-year over 52 weeks
Within a treatment group, the unadjusted severe flare rate per subject-year from Day 1 
through Week 52 (not including baseline flares) will be calculated as:
Unadjusted Rate per subject-year
=
total number of severe flares
total number of years subjects are on study
The follow-up time (years) for each subject will be calculated as (date of last available 
study visit (or date of first treatment failure) – treatment start date + 1) / 365.25. 
If a subject is a treatment failure, the subject will be considered having a severe SFI flare 
at the time of treatment failure.  If the subject dies or withdraws from the study without 
experiencing a severe flare or treatment failure, the subject will be considered as not 
having a severe flare. If a subject is a treatment failure prior to Day 29, the subject will be 
excluded from the analysis.  Similarly, subjects whose last visit is the Day 1 or Day 15 
visit will be excluded from the analysis.  No flares will be assigned for missing visits 
before the exit/treatment failure date.
9.4.28.
Renal Flare
The protocol definition of renal flare [Alarcón-Segovia, 2003] consists of the 
development of one or more of the following 3 factors: increased proteinuria, impaired 
renal function, and hematuria.  Since the protocol was written, there is new evidence 
indicating that the hematuria criterion introduces more variability into the definition 
making it harder to identify a true renal flare. Therefore, the protocol definition has been 
modified to remove the hematuria criterion. Renal flare is defined as follows:

Increased Proteinuria (using spot urine)
A reproducible increase in 24-hour urine protein levels (as measured in uPCR) to:
>1g if the baseline value was <0.2g  
OR
>2g if the baseline value was between 0.2g and 1g
OR
More than twice the value at baseline if the baseline value was >1g

Impaired Renal Function
A reproducible decrease in GFR of >20%, accompanied by proteinuria (>1), and/or 
cellular (RBC and WBC) casts.
The protocol definition (protocol Section 8.5.4) expresses proteinuria in mg/24-hour.  
The definition above converts mg/24-hours to g/24-hours by dividing by 1000.  


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Proteinuria is assessed using the urine protein:creatinine ratio (uPCR) as a 1:1 equivalent 
for urine protein in g/24-hours.  For example, 1000 mg/24-hours = 1 g/24-hours. 
GFR is estimated by the Cockcroft-Gault equation for creatinine clearance in mL/min.
Cockcroft-Gault Equation [Cockcroft, 1976]
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 and the 8 week FU visit.
Table 6 identifies the lab parameters to be used to evaluate the criteria in the renal flare 
definition above.  
Table 6
Lab Parameters used in Renal Flare Definition
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
RBC cellular casts
RBC cellular casts
RBCSTM_URQ
WBC cellular casts
WBC cellular casts
WBCSTM_URQ
9.4.29.
Time to First Renal Flare, Censoring and Disposition Rules
Time to first renal flare is defined as the number of days from first exposure until the 
subject meets an event (event date – first exposure date + 1). The disposition of subjects 
is defined as follows in Table 7. 
Renal flares are defined as reproducible results comparative to Baseline values, so can 
only occur post-Baseline.
Time to first renal flare over 52 weeks is calculated as:
Time to first flare (days)
=
Date of first flare – treatment start date +1
NB: Patients who withdraw or are lost to follow up without a renal flare assessment will 
be censored at zero days.  Patients who withdraw or are lost to follow up with only one 
renal flare assessment (which therefore cannot be reproduced) will be censored at their 


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flare assessment date. It is possible for a renal flare to occur at the Week 52 visit as it 
could be reproduced at an unscheduled visit or the 8 week follow up visit.
Table 7
Subject Disposition Rules for Renal Flares (Double-Blind Phase)
Subject Disposition
Event Met
Event Date
Subject has a flare
Subject has a renal flare
Yes
Date of first renal flare which 
has been reproduced by a later 
assessment
Subject does not have a flare
Subject withdraws
No
Censored at last flare 
assessment date
Subject dies
No
Censored at last flare 
assessment date
Subject is a treatment failure 
No
Censored at last flare 
assessment date prior to 
treatment failure date
Subject completes 
No
Censored at last flare 
assessment date


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9.4.30.
FACIT Fatigue Scale Scoring and MCID indicator
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


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MCID 4
An additional indicator variable will be created by visit to identify subjects who have met 
or exceeded the Minimum Clinically Important Difference of greater than or equal to 4-
point increase from baseline in FACIT-Fatigue score.  Missing data will be imputed using 
the DO/TF=NR responder rule. 
9.4.31.
Date of Last Double-Blind Treatment Phase
For subjects continuing in the open-label phase, the last date in the double-blind 
treatment phase will be the first dose date of Open Label medication.  For subjects not 
continuing in the open-label phase, the last date in the double-blind treatment phase will 
be the latest of the 8-week follow-up visit date, the early termination date or the Week 
52/Exit visit date.  
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


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9.4.32.
Date of Last Double-Blind Treatment Period
The end of the double-blind treatment period is defined as follows:
For subjects continuing in the open-label phase the end of the double-blind treatment 
period will be in a hierarchical fashion:

The earliest of the Week 52 visit date and first dose date of Open Label 
medication.  

The earliest of the death date or early termination date 

Subjects’ last treatment date of Double Blind medication
For subjects not continuing in the open-label phase the end of the double-blind treatment 
period will be (rules will be applied in a hierarchical order):

Week 52/Exit visit date

Earliest of death date or early termination date 

subjects’ last treatment date in the double-blind phase will be used.
NB: Exit visits for subjects, in the double-blind phase, that withdrew early will be slotted 
to the closest visit based on planned visit day. All other visits used the CRF visit and 
were not slotted based on planned visit day. The general rule for the primary (Double-
blind) reporting, is that it will include all records where the assessment date is less than or 
equals to the Open label period start date (AP02SDT). For Pharmacokinetic 
Concentration and Laboratory datasets, include all records where assessment date/time is 
less than or equals to Open label period start date/time. For Adverse Events include all 
records where AE start date is less than or equal to AP02SDT. For Concomitant 
Medications include all records where imputed start date is less than or equals to 
AP02SDT. Note that Adverse Events and Concomitant Medications on the first Open 
label treatment start date will be included for both the primary (Double-blind) and final 
(Open-label) reporting.
9.4.33.
Extent of Exposure
Only complete dates will be used when calculating duration of exposure. First and last 
infusion dates will be used, regardless of any missed doses.
Duration of exposure in days for each subject will be calculated in the double-blind phase 
as:
Last infusion date in double-blind - first infusion date in double-blind + 28.
9.4.34.
Treatment-Emergent AEs and AE Duration
Only treatment-emergent AEs will be summarized, unless otherwise stated.  A treatment-
emergent AE is an adverse event that emerges on or after the first treatment dose, having 


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been absent pre-treatment, or that worsens relative to the pre-treatment state.  AEs with 
missing start and/or stop dates will be assumed to be treatment-emergent.  
The duration of the AE will be calculated as follows:
Duration of AE (days) = Date of AE resolution – AE start date + 1.
If the AE is ongoing the duration will be left blank and no imputation will be done.
9.4.35.
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 12.4, 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)
9.4.36.
Laboratory Assessments
If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is missing, 
but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or 
greater than x in the comment field) is present, the number of decimal places in the 
observed values will be used to determine how much to add or subtract in order to impute 
the corresponding numeric value. 

Example 1: 2 Decimal Places = ‘< x‘ becomes x – 0.01

Example 2: 1 Decimal Place   = ‘> x’ becomes x + 0.1

Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
    
9.4.36.1.
Clinical Laboratory Toxicity Grades
Toxicity grades are assigned by the central laboratory according to the Adverse Event 
Grading Tables in Appendix 11.  Four analytes (electrolytes: calcium, potassium, and 
sodium; chemistry: glucose) have toxicities in both the high (hyper) and low (hypo) 
directions. Both directions will be presented in toxicity displays by the name of the 
toxicity.  For example, calcium will have two toxicity sections, one for hypocalcaemia 
and one for hypercalcaemia. The hyper/hypo direction was set based on the following:
If laboratory value (AVAL) > (normal range low [ANRLO] + normal range high 
[ANRHI]) /2, then set as Hyper (toxicity grade=original toxicity grade);


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If laboratory value(AVAL) < (normal range low [ANRLO] + normal range high 
[ANRHI]) /2, then set as Hypo (toxicity grade =original toxicity grade).
9.4.36.2.
Laboratory Toxicity Worsening of at Least 2 Grades
Laboratory toxicity worsening of at least 2 grades will be reported for all possible shift 
categories even if no observed shifts occur in some of the categories, as follows:
 Grade 0 to 2
 Grade 0 to 3
 Grade 0 to 4
 Grade 1 to 3
 Grade 1 to 4
 Grade 2 to 4
For the four analytes (electrolytes: calcium, potassium, and sodium; chemistry: glucose) 
that have toxicity grade worsening in both high and low directions, 2 grade worsening 
will also include shifts from Hypo to Hyper and Hyper to Hypo with Grade 0 being 
considered a grade. Only observed shifts will be presented for shifts from Hyper to Hypo 
and Hypo to Hyper.  An example is presented below. 
 Grade 0 to 2
 Grade 0 to 3
 Grade 0 to 4
 Grade 1 to 3
 Grade 1 to 4
 Grade 2 to 4
 Hyper 1 to Hypo 1
 Hyper 1 to Hypo 2
9.4.36.3.
C3 and C4 Unit Conversions
The biomarkers C3 and C4 need to be converted from G/L to mg/dL for reporting to be 
consistent with the Benlysta reporting standard.  The formula for the unit conversion is:
mg/dL
=
g/L x 100


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10.
STUDY POPULATION
The mITT population will be used to summarize the study population data and data will 
be presented by treatment and for all subjects combined, unless otherwise specified.  
10.1.
Disposition of Subjects
The number and percentage of subjects randomized by Country and Site ID will be 
summarized overall and by treatment group for the randomized population.
Using the Randomized population, the number of subjects in each population 
(Randomized, Safety, mITT, Per Protocol, Completers, As-Treated and PK) will be 
summarized overall and by treatment group
If there are any subjects who are randomized but do not receive any study drug, they will 
be included in the Randomized population, but not the Safety or mITT populations.  
For the mITT population, the subject’s completion status will be assessed to evaluate 
percentages of dropouts by treatment group as well as the reasons for dropout.  The 
number and percentage of subjects who completed through Week 52 and who withdrew, 
including their Primary reason for withdrawal, will be displayed by treatment group and 
overall for the double-blind phase. Additionally, the cumulative number and percentage 
of subjects who withdrew by study visit will be displayed by treatment group and overall.
These summaries will be repeated for the safety population.
Additionally, a Kaplan Meier (KM) plot of time to withdrawal will be generated to 
evaluate the pattern of dropouts over time.  Subjects who complete through Week 52 will 
be censored at 52 weeks.  To aid stage 3 review of the Kaplan Meier plot, the SAS 
LIFETEST output will be provided. This will not be a reported output.
A listing of subject disposition will be provided showing their completion status and 
whether they are included in each population.  A listing of subjects who withdrew from 
the study, including reason for and study day of withdrawal will also be provided.
A listing of subjects that deviated from the inclusion or exclusion criteria will be 
provided. 
10.2.
Protocol Deviations
Please refer to the Protocol Deviation Management Plan (PDMP): Dated:  6Jun2017 
(Version 2.0) for full details describing important deviations and important deviations 
which result in exclusion from the PP population. 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized by treatment group.  


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A summary of protocol deviations leading to exclusion from the Per Protocol population 
will be displayed.  The summary will include the number of subjects excluded, category 
of the reason for exclusion, and the reason for exclusion.  
Important protocol deviations and deviations which result in exclusion from the PP 
population will be listed. (See Appendix 8 for details of important protocol deviations 
and deviations leading to exclusion from PP population). 
A subject listing of the criteria which lead to exclusion, the category and coded term for 
the criteria will be produced.  The display will include columns to indicate from which 
analysis population the subject was excluded.
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 database release to ensure 
all important deviations and deviations which may lead to exclusion from the analysis are 
captured and categorized on the eCRF and protocol deviations dataset. This dataset will 
be the basis for the summaries and listings of protocol deviations.
10.3.
Demographic and Baseline Characteristics
Continuous parameters will be summarized using descriptive statistics (mean, standard 
deviation, median, 25th percentile, 75th percentile, minimum, and maximum).  Categorical 
parameters will be summarized using counts and percentages.
In addition to the overall mITT population, the summaries of demographic 
characteristics, baseline characteristics and allowable SLE medications at baseline will be 
repeated for the overall safety population and the following subgroups (using the mITT 
population):

Baseline SS-S2K score (9 vs. 10)

Complement level (At least one C3/C4 Low vs. No C3/C4 Low)

Region (US/Canada, other)

Baseline C3/C4 levels & anti-dsDNA (At least one C3/C4 low and anti-dsDNA 
>=30 IU/mL vs. Not (At least one C3/C4 low and anti-dsDNA >=30 IU/mL)

Age Group (<65, ≥ 65 years)
NB: Gender summaries will not be performed due to the low number of male subjects.
Demographic and baseline characteristics will be listed for all patients by treatment 
group. A listing of stratifications factors used in the randomization will also be listed 
(using the information recorded in the IVRS) for all patients by treatment group.
A listing of medical history data will be provided by treatment group.


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The following Demographic and baseline disease activity indicators will be summarized:
PARAMETER
SUMMARY TYPE
Medical History
Medical History by Body System and Term
Categorical: presented if current or past 
medical history is present
Stratification Factors at Screening and as Randomized
SELENA SLEDAI (SS)
Categorical: <=9, >=10
Complement Level
Categorical:
- At least one C3/C4 Low
-No C3/C4 Low
Region
Categorical: US/Canada, Rest of World
Demographic
Age (years)
Continuous
Categorical:
< 65 years
>= 65 years
<=45 years, 
>45 – <65 years
>=65 – <75 years 
>=75 years  
18 - 64
65 - 84
>= 85
Height (cm)
Continuous
Weight (kg)
Continuous
Body Mass Index (BMI) (kg/m2) 
Continuous
Region
Categorical: US/Canada vs. RoW
Sex
Categorical: Female, Male
Race
Categorical:
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Multiple
Hispanic or Latino origin 
Categorical: Yes, No
Baseline Disease Activity
ACR classification criteria by symptom
Categorical: items answered ‘Yes’
Categorical: total criteria met (integers from 4 to 
11)
SELENA SLEDAI-S2K score
Continuous
Categorical: <=9, 10-11, >=12
SELENA SLEDAI score
Continuous
Categorical: <=9, 10-11, >=12


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PARAMETER
SUMMARY TYPE
Shift Table of differences between SS-S2K and 
SS
Categorical: <=9, >=10
BILAG organ domain scores at baseline
Categorical: 
-at least 1A or 2B 
-at least 1A
-at least 1B 
-no A or B
*subjects may be included in more than one 
category
SLE Flare Index
Categorical:
-at least one flare
-at least one severe flare
PGA score
Continuous
Categorical: 0-1, >1 – 2.5, >2.5
SLICC/ACR Damage Index score
Continuous
Categorical: 0, 1, >1
Proteinuria
Continuous
Categorical: <=0.5, >0.5-<1, 1-<2, >=2
SLE disease duration (years)
Continuous
SELENA SLEDAI by organ domain and item at 
baseline
Categorical: presented if Yes
BILAG grade by organ domain at baseline
Categorical: A, B, C, D, and E scores
Baseline immunoglobulin levels (g/L): 
IgG, IgA, and IgM
Continuous value
Categorical:
- below the lower limit of normal (LLN) (IgG < 
6.94 g/L, IgA < 0.81 g/L, and IgM
< 0.48 g/L)
- above upper limit of normal (ULN) (IgG > 
16.18 g/L, IgA > 4.63 g/L, and IgM > 2.71 g/L).


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PARAMETER
SUMMARY TYPE
Baseline autoantibody levels
anti-dsDNA [IU/mL]
Continuous
Categorical:
-positive (30 IU/mL)
-negative (<30 IU/mL)
ANA [Titer]
Continuous
Categorical:
-positive (1:80 Titer)
-negative (<1:80 Titer)
anti-cardiolipin (aCL)
Continuous
Categorical:
-positive (if any of the three isotypes IgG, IgA or 
IgM are above the upper limit of normal (ULN))
-negative (if at least one is non-missing and 
none of the isotypes above the upper limit of 
normal)
-missing (all three isotypes are missing)
anti-dsDNA and/or ANA positive 
Categorical: Yes, No
Beta-2-glycoprotein [U/mL] for isotypes IgG, IgA, 
and IgM
Continuous
Categorical: Positive (>=21 U/mL), Negative
Lupus anticoagulant
Continuous
Complement Levels and BLyS at Baseline
Baseline levels of complement:
C3 [mg/dL]
Continuous
Categorical: high (>180 mg/dL), normal (90 -
180 mg/dL), low (<90 mg/dL)
Baseline levels of complement: 
C4 [mg/dL]
Continuous
Categorical: high (>40 mg/dL), normal (10 -40 
mg/dL), low (<10 mg/dL) 
Complement Level
Categorical: At least one C3/C4 Low; 
No C3/C4 Low
Complement Level and anti-dsDNA Level
Categorical: At least one C3/C4 Low and anti-
dsDNA >=30 IU/mL; Not (At least one C3/C4 
Low and anti-dsDNA >=30 IU/mL)
BLyS [ng/mL]
Continuous
Categorical: below limit of quantification [LOQ] 
(<0.02048 ng/mL), above LOQ


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PARAMETER
SUMMARY TYPE
B cells at Baseline
CD19+
CD20+
CD20+/27+ memory
CD20+/27+ memory (%CD19)
CD20+/27– naïve
CD20+/27– naïve (%CD19)
CD20+/69+ activated
CD20+/138+ plasmacytoid
CD19+/27BRIGHT/38BRIGHT SLE subset
CD19+/CD24HIGH/CD38HIGH transitional
CD20-/138+ plasma
CD27+BRIGHT/CD20– Short-lived plasma
Continuous
Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline
C-SSRS responses by behavior and ideation 
components for lifetime and over the last two 
months
Note: C-SSRS summaries use Safety 
Population.
Categorical:
-Ideation: categories 1-5 with corresponding 
text
-Behavior: categories 6-10 with corresponding 
text
FACIT Fatigue
Baseline FACIT-Fatigue scale score
Continuous
Categorical: (<20, 20-<35, 35)
Allowable SLE Medication Usage at Baseline
Allowable SLE medications by class and drug
Categorical:
Steroids, Anti-malarials, Immunosuppressants, 
Aspirin, NSAIDs
Average daily prednisone dose (mg/day) at
baseline
Continuous
Categorical: (0, >0 - 7.5, >7.5)
Steroid, Anti-malarial and Immunosuppressant 
Use at Baseline
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


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10.4.
Concomitant Medications
Concomitant medications will be coded according to drug name as defined in the GSK 
Drug Dictionary, and classified according to the GSK-Drug ATC classification level 1 
and ATC level 4.  Concomitant medications are defined as medications that start on or 
before the first dose date of study treatment and end on or after the first dose date of 
study treatment, or medications that start on or after the first dose date of study treatment.  
Note that 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.
A summary of the number and percentage of subjects with concomitant medications by 
ATC level 1 term and ATC level 4 term will be displayed.  A further summary of 
concomitant medications by ATC level 4 term and preferred term will be provided.  
A listing of all concomitant medication data will be displayed by treatment and subject. 
First protocol-prohibited medication and allowable medication that results in treatment 
failure designation (see Section 5.5 of the protocol) will be summarized by treatment 
group and overall.  A similar summary will be produced with subjects appearing in 
multiple protocol-prohibited medication and allowable medication treatment failure 
categories.  
A listing of protocol-prohibited medication and allowable medication that result in 
treatment failure designation will be displayed by treatment and subject. 
Concomitant medications will be summarized for the mITT and safety populations.
10.5.
Extent of Exposure
The extent of exposure to study treatment through Week 52 will be assessed by 
examining the duration of exposure to belimumab/placebo in days and the total number 
of infusions a subject receives.  Duration of exposure in days will be calculated as:
Duration of exposure (days) = (Last infusion date – First infusion date + 28).  
Only complete dates will be used when calculating duration of exposure.  First and last 
infusion dates will be used, regardless of any missed doses. 
The duration of exposure and the total number of infusions will be summarized using 
descriptive statistics for the double-blind phase.  The total number of infusions will also 
be summarized using counts and percentages using the following categories: 1 – 5 doses, 
6 – 10 doses, 11 – 14 doses and ≥15 doses.  
Exposure data will be summarized for the mITT and safety populations. 


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Exposure data will be listed for all subjects by treatment group and subject.  A listing of 
study agent administration will also be produced for all subjects by treatment group and 
subject.
10.6.
Subjects for Whom the Treatment Blind was Broken
A listing will be produced of subjects for whom the treatment blind was broken during 
the study.


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11.
EFFICACY ANALYSES
The efficacy analyses will be performed for the mITT population as defined in Section 6
unless otherwise stated.  The data will be presented by treatment group. 
Treatment failures and handling of missing data, for all efficacy analyses, will be 
managed as described in Section 9.  
For the analysis of steroid use, all steroid dosages are converted to a prednisone 
equivalent in milligrams (see Section 9.4.13 for further details); therefore, analyses refer 
to average daily prednisone dose instead of average daily steroid dose.
Where efficacy endpoints are expected to be Normally distributed, ANCOVA is planned 
to be performed.  However, if the normality assumptions are violated, or there are 
influential outliers in the dataset, then other methods of analysis will be investigated.  The 
first alternative to be investigated will be the non-parametric Wilcoxon Rank Sum Test.  
In the case that a non-parametric analysis is more appropriate, then the analysis will be 
adapted and relevant statistics for the new analysis will be presented in the output tables.  
If analyses are changed to be non-parametric due to the distribution of the data, then 
Figures presenting the data will switch from presenting means (± SE) to medians (± 
quartiles).
Listings will be provided by treatment group for the following data:

SRI-S2K Results

SELENA SLEDAI and SS-S2K Results

PGA Results

BILAG Results

Daily Prednisone Dose

SFI Flares

SLICC/ACR Damage Index Results
11.1.
Primary Efficacy Analysis
SRI-S2K
A logistic regression model will be used to estimate the odds of an SRI-S2K response for 
belimumab vs. placebo.  The independent variables in the model will include 

treatment group, 

baseline SS-S2K score (9 vs. 10), 

baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 


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
region (US/Canada vs. rest of the world). 
NB: due to the change in the primary endpoint, the SS-S2K will be used as the 
independent variable in the model instead of the SELENA SLEDAI to be consistent with 
the SLEDAI component of the primary endpoint for the primary analysis. A secondary 
analysis will be performed using the original endpoint SELENA SLEDAI scoring (SRI) 
with SS (9 vs. 10) as the independent variable in the model (Section 11.2.1).
Additionally, for the primary analysis and key secondary analyses the covariate 
adjustment will not occur for any of these baseline randomization factors that has <10
responders or <10 non-responders in a stratification level [Peduzzi, 1996].
The table will display the number and percentage of subjects achieving a response by 
treatment group and standard error for the percentage, the treatment difference versus 
placebo, the odds ratio, and 95% confidence interval (CI) versus placebo and a p-value 
for the odds ratio. 
A table showing the details from the logistic regression will also be presented; including 
the parameter estimate, standard error and p-value for the intercept and the parameter 
estimate, standard error, odds ratio and 95% CI and p-value for treatment group and each 
covariate in the model.
The percentage of SRI-S2K responders (± SE) at Week 52 will be displayed in a bar 
chart, by treatment group. 
NB; In the event a patient has a baseline SS-S2K<4 they will be excluded from the 
analysis.  
11.1.1.
Supportive Summaries of the Primary Efficacy Endpoint
11.1.1.1.
Components of Primary Endpoint
In support of the primary endpoint, the number and percentage of subjects meeting each 
of the three components of the primary endpoint will be presented at Week 52 with the 
SRI-S2K.  If any subject has missing data that excludes them from the SRI-S2K analysis, 
they will also be excluded from each of the component analyses in this table.
Additionally, each component will also be summarized individually by visit, with the 
analysis presented at Week 52. The percentage of subjects meeting each component 
criteria (± SE) will be displayed by treatment group in a line plot over the double-blind
treatment period. 
Logistic regression models will be used to estimate the odds of a response in each 
component for belimumab vs. placebo at Week 52.  The independent variables in the 
models will include treatment group, baseline SS-S2K score (9 vs. 10), baseline 
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world).  Baseline PGA score will also be included as a covariate in the 
model for the PGA No Worsening component.  Similarly, baseline BILAG organ domain 
involvement (at least 1A/2B vs. at most 1B) will also be included as a covariate in the 
model for the BILAG No new 1A/2B component. 


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The tables will display the number and percentage of subjects achieving a response in 
each component by treatment group, the SE for the percentage of responders, the 
treatment difference vs. Placebo and also the odds ratios and 95% CIs versus placebo and 
p-values for the odds ratios at Week 52.
11.1.1.2.
Disposition of SRI-S2K Response
For the primary SRI-S2K endpoint, the disposition of factors contributing to response or 
non-response will be presented as the number and percentage of subjects falling into the 
following categories at Week 52 by treatment group:

SRI-S2K Responder

SRI-S2K Non- Responder
–
Dropout (without a treatment failure)
–
Treatment failure
–
SS-S2K <4-point reduction
–
SS-S2K 4-point reduction with the following:

PGA Worsening only

BILAG New 1A/2B only

Both PGA Worsening and BILAG new 1A/2B
A bar chart showing the percentage of subjects falling into each of the categories above at 
Week 52 in each treatment group will also be presented.
11.1.1.3.
Additional SRI-S2K Analyses
The following additional supportive analyses of the SRI-S2K primary endpoint will be 
performed using logistic regression at Week 52. 
Sensitivity Analysis
Dependent Variable
Independent Variables[1]
in Logistic Regression Model
Unadjusted
SRI-S2K
Treatment
LOCF
SRI-S2K
Treatment, SS-S2K, Complement, Region
Per Protocol
SRI-S2K
Treatment, SS-S2K, Complement, Region
Completers
SRI-S2K
Treatment, SS-S2K, Complement, Region
SS-S2K 5-point 
reduction
SRI5-S2K
Treatment, SS-S2K, Complement, Region
SS-S2K 6-point 
reduction
SRI6-S2K
Treatment, SS-S2K, Complement, Region
SS-S2K 7-point 
reduction
SRI7-S2K
Treatment, SS-S2K, Complement, Region
SS-S2K 8-point 
reduction
SRI8-S2K
Treatment, SS-S2K, Complement, Region
[1] Treatment=Belimumab vs. Placebo,
SS-S2K=baseline SS-S2K score (9 vs. 10), 


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Sensitivity Analysis
Dependent Variable
Independent Variables[1]
in Logistic Regression Model
Complement =baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low), and
Region =US/Canada vs. rest of the world.
NB; In the event a patient has a baseline SS-S2K<4, they will be excluded from the analysis.  
Additionally, patients who have baseline SS-S2K <5, <6, <7 or <8, they will be excluded from the 
SRI5-S2K - SRI8-S2K respectively
The tables will display the number and percentage of subjects achieving a response in 
each component by treatment group, the SE for the percentage of responders, the 
treatment difference vs. Placebo and also the odds ratios and 95% CIs versus placebo and 
p-values for the odds ratios at Week 52.
11.1.1.4.
SRI-S2K by subgroup
The primary efficacy analysis at Week 52 will also be repeated for each of the subgroups 
listed in Section 8.3.  

The logistic regression models will be used to estimate the odds of an SRI-S2K
response for belimumab vs. placebo in each subgroup category.  The model will be 
unadjusted. 

The tables will display the number and percentage (with standard error) of subjects 
achieving a response by each subgroup category and treatment group, the treatment 
difference versus placebo, the odds ratio and 95% CI versus placebo, a p-value for 
the odds ratio and a p-value for the treatment-by-subgroup interaction.  

In order to obtain the treatment by sub-group interaction term a model will be fitted 
which includes treatment group, subgroup and treatment-by subgroup term.

The odds ratios (and 95% CI) will be presented graphically for each category within 
each subgroup.
11.1.1.5.
SRI-S2K by visit
An analysis of the SRI-S2K will performed by visit. The analysis will be performed as 
described in Section 11.1.
The percentage of responders (± SE) will be presented in a line graph over the Double-
Blind treatment period.
11.1.1.6.
EMA Modified SRI-S2K Response
An analysis of the EMA Modified SRI-S2K Response will performed at Week 52. The 
analysis will be performed as described in Section 11.1.


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11.2.
Secondary Efficacy Analyses
11.2.1.
SRI response rate with the SELENA SLEDAI scoring of 
proteinuria by visit (SRI)
An analysis of the SRI using the SELENA SLEDAI scoring for proteinuria will 
performed by visit and the percentage of responders (± SE) will be presented in a line 
graph over the Double-Blind treatment period. The analysis will be performed as 
described in Section 11.1 (using the Baseline SELENA-SLEDAI subgroups instead of the 
Baseline SS-S2K subgroups as a covariate in the model).
In addition, the SRI analysis at Week 52 will be repeated for the Baseline C3/C4 levels & 
anti-dsDNA subgroups, the Baseline SELENA-SLEDAI subgroups and the Baseline 
C3/C4 level subgroups.
11.2.2.
Time to first severe SFI flare over 52 weeks
Analysis of severe SFI flare will be performed on the modified SELENA SLEDAI SLE 
flare index in which the modification excludes severe flares that were triggered only by 
an increase in SELENA SLEDAI score to >12 (since this may only represent a modest 
increase in disease activity).  Only post-baseline severe flares will be considered in these 
analyses.  
The time to the first severe SFI flare over 52 weeks will be compared between 
belimumab and placebo using a Cox proportional hazards model, adjusting for baseline 
SS-S2K score (9 vs. 10), baseline complement levels (At least one C3/C4 Low vs. No 
C3/C4 Low) and region (US/Canada vs. rest of the world). Ties will be handled using 
approximate likelihood (EFRON).
The rules for counting events and censoring are described in Section 9.4.26.  
The table will display the number and percentage of subjects with a severe SFI flare over 
52 weeks, the median, 25th, and 75th percentile of days to first severe flare, the hazard 
ratio (and 95% CI) versus placebo and the p-value from the Cox proportional hazards 
model. For subjects who experience a severe flare, the study day of the flare will be 
summarized and the table will display the median, 25th and 75th percentiles and minimum 
and maximum. A Kaplan Meier plot will be produced to show the probability of 
experiencing a severe SFI flare over 52 weeks.
In addition, the Cox proportional hazards analysis will be repeated for the Baseline 
C3/C4 levels & anti-dsDNA subgroup using the SS.
11.2.3.
Percent of subjects with prednisone reduction by 25% from 
baseline to 7.5 mg/day during week 40 through week 52
(DO/TF=NR)
For this analysis, only subjects with a baseline average daily prednisone dose >7.5mg/day 
will be included in the analysis.  Average daily prednisone dose during Weeks 40 through 
52 is defined in Section 9.4.13.4.  The percent of subjects whose average prednisone dose 


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has been reduced by 25% from baseline to 7.5 mg/day during Weeks 40 through 52 
will be compared between belimumab and placebo using a logistic regression model.  
Independent variables in the model will include treatment group, baseline prednisone 
dose, baseline SS-S2K score (9 vs. 10), baseline complement levels (At least one 
C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world).
Any subject who withdraws from the study prior to the Week 52 visit or is deemed a 
treatment failure prior to the Week 52 visit will be considered a non-responder for this 
analysis (DO/TF=NR).
The table will display the number and percentage of subjects who are responders by 
treatment group, the SE for the percentage of responders, the treatment difference versus 
placebo, the odds ratio and 95% CI versus placebo, and a p-value for the odds ratio.
This analysis will be repeated for the Baseline C3/C4 levels & anti-dsDNA subgroups.
11.2.4.
Estimand Definition
This study was designed prior to the publication of the draft ICH E9 Addendum. Table 8
below shows how the primary and major secondary analyses can be aligned with the 
expected terminology.
Table 8
Alignment with Estimand Definition Terminology
SRI-S2K 4-point 
responder
SRI 4-point
responders
Time to first 
Severe Flare
Prednisone reduction 
responder
Population 
mITT
mITT
mITT
mITT taking >7.5mg 
prednisone at baseline
Variable
Composite of 
following
1.
4-point 
reduction 
from baseline 
in SELENA 
SLEDAI 
score with the 
modified 
SLEDAI-2K 
scoring for 
proteinuria
2.
No worsening 
(increase of 
<0.30 points 
from 
baseline) in 
Physician’s 
Global 
Assessment 
(PGA)
Composite of 
following
1.
4-point 
reduction 
from 
baseline in 
SELENA 
SLEDAI
2.
No 
worsening 
(increase of 
<0.30 
points from 
baseline) in 
Physician’s 
Global 
Assessment 
(PGA)
3.
No new 
Composite of 
following
1.
Subject 
experiences 
Severe 
Flare
2.
Subject 
meets 
treatment 
failure 
definition 
Composite of following 
1.
prednisone 
reduction by 
25% from 
baseline to 
7.5 mg/day 
during week 
40 through 
week 52
2.
Subject does 
not drop out 
before week 52 
(28 days)
3.
Subject does 
not meet 
treatment 
failure 
definition 


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SRI-S2K 4-point 
responder
SRI 4-point
responders
Time to first 
Severe Flare
Prednisone reduction 
responder
3.
No new 
British Isles 
Lupus 
Assessment 
Group of SLE 
Clinics 
(BILAG) A 
organ domain 
score or 2 
new BILAG 
B organ
domain scores 
compared 
with baseline 
at the time of 
assessment 
(i.e., at Week 
52).
4.
Subject does 
not drop out 
before week 
52 (28 
days)
5.
Subject does 
not meet 
treatment 
failure criteria
British 
Isles Lupus 
Assessment 
Group of 
SLE 
Clinics 
(BILAG) A 
organ 
domain 
score or 2 
new 
BILAG B 
organ 
domain 
scores 
compared 
with 
baseline at 
the time of 
assessment 
(i.e., at 
Week 52).
4.
Subject 
does not 
drop out 
before 
week 52 (
28 days)
5.
Subject 
does not 
meet 
treatment 
failure 
criteria
Intercurrent 
event 
Subject drops out 
or meets treatment
failure definition; 
incorporated in the 
composite 
endpoint as a non-
responder
Subject drops out or 
meets treatment 
failure definition; 
incorporated in the 
composite endpoint 
as a non-responder
Subject meets 
treatment failure 
definition; 
incorporated in the 
composite endpoint
Subject drops out: 
subject is censored 
at last available visit
Subject dies: Subject 
is censored at the 
date of death
Subject drops out or 
meets treatment failure 
definition; incorporated 
in the composite 
endpoint as a non-
responder
Measure 
Adjusted odds 
ratio; see Section 
11.1
Adjusted odds ratio; 
see Section 11.2.1
Adjusted hazard 
ratio; see Section 
11.2.2
Adjusted odds ratio; see 
Section 11.2.3


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11.3.
Other Efficacy Analyses
Formal statistical analysis of the other efficacy endpoints will be performed at week 52 
only. Other study visits will be limited to descriptive summaries. 
11.3.1.
Disease Activity
11.3.1.1.
Durable SRI-S2K Response from Week 44 - Week 52
The percentage of subjects achieving a durable SRI-S2K response from Week 44 through 
Week 52 will be presented for belimumab and placebo. A logistic regression model will 
be used to estimate the odds of an SRI-S2K response for belimumab vs. placebo.  The 
independent variables in the model will include treatment group, baseline SS-S2K score
(9 vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) 
and region (US/Canada vs. rest of the world). 
The table will display the number and percentage of subjects achieving a response by 
treatment group, the SE of the percentage of responders, the treatment difference versus 
placebo, the odds ratio and 95% CI versus placebo and a p-value for the odds ratio. 
11.3.1.2.
Time to first SRI-S2K response that is maintained through week 52
The time to the first SRI-S2K response that is maintained through Week 52 will be 
compared between belimumab and placebo using a Cox proportional hazards model, 
adjusting for baseline SS-S2K score (9 vs. 10), baseline complement levels (At least 
one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world). Ties 
will be handled using approximate likelihood (EFRON).
The table will display the number and percentage of subjects with a SRI-S2K response 
that is maintained through Week 52, the median, 25th, and 75th percentile of days to first 
SRI response, the hazard ratio (and 95% CI) versus placebo and the p-value from the Cox 
proportional hazards model. A Kaplan Meier plot for time to first SRI response that is 
maintained through Week 52 will also be produced.
11.3.1.3.
Duration of longest SRI-S2K response 
The duration of longest SRI-S2K response among subjects with at least one SRI-S2K 
response will be compared between belimumab and placebo using an analysis of 
covariance (ANCOVA) model.  The covariates in the model will include treatment group, 
baseline SS-S2K score (9 vs. 10), baseline complement levels (At least one C3/C4 
Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world). The table will 
display the number of responders, the mean, standard deviation and SE of the mean, 
median, minimum, maximum, 25th and 75th percentiles, least squares (LS) mean and 
associated standard error, treatment difference versus placebo, 95% CI for the treatment 
difference, and p-value from the ANCOVA model.  
In addition, another table will display the number and percentage of subjects with a SRI-
S2K response, the median, 25th, and 75th percentile, the hazard ratio (and 95% CI) 
versus placebo and the p-value from the Cox proportional hazards model.


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11.3.1.4.
Duration of week 52 SRI-S2K response by month
The duration of the primary response evident at Week 52 will be grouped into monthly 
(where a month is defined as 30 days) intervals.
The table will display the number and percentage of subjects falling into each duration of 
response category (1 day, 1 month, 2 months, etc.).  Subjects will be presented in 
multiple categories, e.g. if their duration of response is 2.5 months, they will be presented 
in the first 3 categories.
11.3.1.5.
SLICC/ACR Damage Index change from baseline at Week 52/Exit Visit 
(Observed Case, Corrected)
The change from baseline in SLICC/ACR Damage Index score at Week 52/Exit visit will 
be compared between belimumab and placebo using the Exact Wilcoxon Rank Sum test
with continuity correction.  Only subjects with a baseline and post-baseline assessment 
will be included in the analysis.
The table will display the summary statistics for the SLICC/ACR Damage Index score at 
baseline and at Week 52/Exit visit.  The table will also display the mean change from 
baseline, standard deviation and SE of the mean, median, minimum, maximum, 25th and 
75th percentiles, plus the p-value from the Wilcoxon Rank Sum Test. 
This analysis will be repeated by baseline SLICC score (0, ≥1). 
11.3.1.6.
SLICC/ACR Damage Index Worsening at Week 52 (WOCF)
The number and percentage subjects with worsening in their SLICC/ACR Damage Index 
score compared with baseline at Week 52 will be presented.  Worsening is defined as a 
change in score >0, i.e. (Week 52/Exit visit minus Baseline) >0.  
The percentage of subjects with worsening in their SLICC/ACR Damage Index score at 
Week 52 will be compared between belimumab and placebo using a logistic regression 
model. The independent variables in the model will include treatment group, baseline 
SLICC/ACR Damage Index score, baseline SS-S2K score (9 vs. 10), baseline 
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world).
Missing data will be imputed using WOCF (NB: in the instance of SLICC/ACR this 
would mean baseline).  The table will display the number and percentage of subjects with 
worsening in their SLICC/ACR Damage Index score by treatment group, the SE of the 
percentage of subjects, the treatment difference versus placebo, the odds ratio and 95% 
CI versus placebo, and a p-value for the odds ratio.
This analysis will be repeated by baseline SLICC score (0, ≥1). 


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11.3.1.7.
SELENA SLEDAI Organ System Improvement by Organ System and 
Visit among Subjects with Organ System Involvement at Baseline 
(DO/TF=NR)
Details of the grouping of the SELENA SLEDAI organ systems can be found in Section 
9.4.15.2. 
The number and percentage of subjects with an improvement in their SELENA SLEDAI 
score compared to baseline by each organ system will be presented for each visit.  Within 
each organ domain, only subjects with organ system involvement (i.e. SELENA SLEDAI 
organ system score >0) at baseline will be included.  The renal domain will use the 
SLEDAI-2K proteinuria scoring as the primary method.  An improvement is defined as a 
decrease (compared to baseline) in the SELENA SLEDAI S2K organ system score within 
the same organ system at a post-baseline visit.
For each organ system and visit, the table will display the number and percentage of 
subjects with an improvement in their SELENA SLEDAI score by treatment group and 
the treatment difference vs. Placebo.  
11.3.1.8.
SELENA SLEDAI Organ System Worsening by Organ System and Visit 
among Subjects with No Organ System Involvement at Baseline (LOCF)
The number and percentage of subjects with worsening in their SELENA SLEDAI score 
compared to baseline by each organ system and visit will be presented.  Within each 
organ domain, only subjects with no organ system involvement (i.e. SELENA SLEDAI 
domain score = 0) at baseline will be included. The renal domain will use the SLEDAI-
2K proteinuria scoring. Worsening is defined as an increase (compared to baseline) in the 
SELENA SLEDAI S2K score within the same organ system at a post-baseline visit.
Missing data due to treatment failure or study withdrawal will be imputed using LOCF.  
For each organ system and visit, the table will display the number and percentage of 
subjects with worsening in their SELENA SLEDAI score by treatment group and the 
treatment difference versus placebo.
11.3.1.9.
SS-S2K Percent Change from Baseline by Visit (LOCF)
The percent change from baseline in SS-S2K score at each visit will be calculated as the 
visit score minus the baseline score divided by the baseline score then multiplied by 100.  
Subjects with a baseline score of zero will be excluded from the analysis due to division 
by zero. Belimumab and placebo will be compared using an ANCOVA model with 
treatment group, baseline SS-S2K score (9 vs. 10), baseline complement levels (At 
least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world) as 
covariates.  The LOCF method will be employed for subjects with missing data on SS-
S2K score at each visit, see Section 9.3.4 for further details.  
For the baseline visit, the tables will display the mean SS-S2K score, standard deviation 
and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At each 
post-baseline visit, the tables will display the mean percent change from baseline, 
standard deviation and SE of the mean, median, 25th and 75th percentiles, minimum and 


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maximum.  At week 52 the table will also include the LS mean and associated standard 
error, treatment difference versus placebo in LS means, 95% CI for the LS means 
treatment difference, and p-value from the ANCOVA model.
The mean percent change from baseline in SS-S2K score (± SE) at each visit will be 
presented graphically using a line graph by treatment group.
This analysis will also be performed on the SELENA SLEDAI for comparison to other 
trials.  
11.3.1.10. SS-S2K Change from Baseline by Visit (LOCF)
The change from baseline in SS-S2K score at each visit will be calculated as the visit 
score minus the baseline score. Belimumab and placebo will be compared using an 
ANCOVA model with treatment group, baseline SS-S2K score (9 vs. 10), baseline
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world) as covariates.  The LOCF method will be employed for subjects 
with missing data on SS-S2K score at each visit, see Section 9.3.4 for further details.  
For the baseline visit, the tables will display the mean SS-S2K score, standard deviation 
and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At each 
post-baseline visit, the tables will display the mean change from baseline, standard 
deviation and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  
At week 52 the table will also include the LS mean and associated standard error, 
treatment difference versus placebo in LS means, 95% CI for the LS means treatment 
difference, and p-value from the ANCOVA model.
The mean change from baseline in SS-S2K score at each visit (± SE) will be presented 
graphically using a line graph by treatment group.
This analysis will also be performed on the SELENA SLEDAI for comparison to other 
trials.  
11.3.1.11. PGA Percent Change from Baseline by Visit (LOCF) 
The percent change from baseline in PGA at each visit will be calculated as the visit 
score minus the baseline score divided by the baseline score then multiplied by 100.  
Subjects with a baseline score of zero will be excluded from the analysis due to division 
by zero. Belimumab and placebo will be compared at Week 52 using an ANCOVA 
model with treatment group, baseline PGA score, baseline SS-S2K score (9 vs. 10), 
baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region 
(US/Canada vs. rest of the world) as covariates. The LOCF method will be employed for 
subjects with missing data on PGA score at each visit, see Section 9.3.6 for further 
details.
For the baseline visit, the table will display the mean PGA score, standard deviation and 
SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At each 
post-baseline visit, the tables will display the mean percent change from baseline, 
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maximum.  At week 52 the table will also include the LS mean and associated standard 
error, treatment difference versus placebo in LS means, 95% CI for the LS means 
treatment difference, and p-value from the ANCOVA model.
The mean percent change from baseline in PGA score at each visit (± SE) will be 
presented graphically using a line graph by treatment group.
11.3.1.12. PGA change from baseline by visit (LOCF)
The change from baseline in PGA score at each visit will be calculated as the visit score 
minus the baseline score. Belimumab and placebo will be compared at Week 52 using an 
ANCOVA model with treatment group, baseline PGA score, baseline SS-S2K score (9 
vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world) as covariates.  The LOCF method will be 
employed for subjects with missing data on PGA score at each visit, see Section 9.3.6 for 
further details.  
For the baseline visit, the tables will display the mean PGA score, standard deviation and 
SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At each 
post-baseline visit, the tables will display the mean change from baseline, standard 
deviation and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  
At week 52 the table will also include the LS mean and associated standard error, 
treatment difference versus placebo in LS means, 95% CI for the LS means treatment 
difference, and p-value from the ANCOVA model.
The mean change from baseline in PGA score at each visit (± SE) will be presented 
graphically using a line graph by treatment group.
11.3.1.13. PGA percent of subjects with 0.3 point improvement from baseline by 
visit (DO/TF=NR)
The percent of subjects with 0.30 points improvement (i.e. reduction) from baseline in 
PGA will be compared at Week 52 between belimumab and placebo using a logistic 
regression model.  The independent variables in the model will include treatment group, 
baseline PGA score, baseline SS-S2K score (9 vs. 10), baseline complement levels (At 
least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world). 
Treatment failures and handling of missing data will be managed as described in Section
9.1, Section 9.2 and Section 9.3.  Subjects with baseline PGA score <0.3 will be treated 
as having no improvement.
At each visit, the table will display the number and percentage of subjects with 0.30 
points improvement in their PGA score by treatment group, the SE for the percentage and 
the treatment difference versus Placebo.  At week 52 the table will also include the odds 
ratio and 95% CI versus placebo, and a p-value for the odds ratio.
The percentage of subjects with 0.30 points improvement in their PGA score at each 
visit (± SE) will be presented graphically using a line graph by treatment group.


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11.3.1.14. BILAG no 1A/2B organ domain scores by visit (supportive of EMA SRI-
S2K)
The percent of subjects with no BILAG 1A/2B organ domain scores will be compared at 
Week 52 between belimumab and placebo using a logistic regression model.  The 
independent variables in the model will include treatment group, baseline BILAG organ 
domain involvement (at least 1A/2B vs. at most 1B), baseline SS-S2K score (≤9 vs. ≥10), 
baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region 
(US/Canada vs. rest of the world).  Treatment failures and handling of missing data will 
be managed as described in Section 9.1, Section 9.2 and Section 9.3. 
At each visit, the table will display the number and percentage of subjects with no 
BILAG 1A/2B organ domain scores by treatment group, the SE for the percentage and 
the treatment difference versus Placebo.  At week 52 the table will also include the odds 
ratio and 95% CI versus placebo and a p-value for the odds ratio.
The percentage of subjects with no BILAG 1A/2B organ domain scores at each visit (± 
SE) will be presented graphically using a line graph by treatment group.
11.3.1.15. BILAG improvement by organ domain and visit in subjects with an A or 
B domain score at baseline (DO/TF=NR)
The number and percentage of subjects with an improvement in their BILAG score 
compared to baseline will be summarized for each organ domain and visit.  Only subjects 
with an A or B domain score at Baseline will be included.
If a subject withdraws early or is deemed a treatment failure, the subject will be 
considered as having no improvement.  
For each organ domain and visit, the table will display the number and percentage of 
subjects with an improvement in their BILAG score by treatment group and the treatment 
difference versus placebo.  
11.3.1.16. BILAG worsening by organ domain and visit among subjects with no A 
domain score at baseline (LOCF)
The number and percentage of subjects with worsening in their BILAG score compared 
to baseline by each organ system domain and visit will be presented.  Only subjects with 
no A domain score at Baseline will be included.
Missing data due to treatment failure or study withdrawal will be imputed using LOCF.  
For each organ domain and visit, the table will display the number and percentage of 
subjects with worsening in their BILAG score by treatment group and the treatment 
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11.3.2.
Flares
11.3.2.1.
Time to first severe SFI flare over 52 weeks
See Section 11.2.2 for details of the time to first severe SFI flare analyses.
11.3.2.2.
Time to first severe SFI flare from week 24 to week 52
The time to first severe SFI flare after 24 weeks is defined in Section 9.4.26. The 
analysis of time to first severe SFI flare after 24 weeks will be identical to Section 11.2.2.
This analysis will be performed on subjects who have at least 1 visit after the Week 24 
visit. Data observed at or prior to Week 24 visit will not be included in this analysis.
11.3.2.3.
Time to first SFI flare over 52 weeks
The time to first SFI flare (defined as mild, moderate, or severe) analyses will be 
performed using SELENA SLEDAI.  The analysis of time to first SFI flare will be 
identical to Section 11.2.2.
A Kaplan Meier plot will be produced to show the probability of experiencing a SFI flare 
over 52 weeks.
11.3.2.4.
Time to first SFI flare from week 24 to week 52
The time to first SFI flare (defined as mild, moderate, or severe) after 24 weeks is defined 
in Section 9.4.26. The analysis of time to first SFI flare after 24 weeks will be identical to 
Section 11.2.2.
This analysis will be performed on subjects who have at least 1 visit after Week 24 visit. 
Data observed at or prior to Week 24 visit will not be included in this analysis.
11.3.2.5.
Severe SFI flare rate per subject-year over 52 weeks
Severe SFI flare rate per subject year is defined in Section 9.4.27.
The rate of severe flares per subject-year over 52 Weeks will be compared between 
treatment groups using a negative binomial regression with the number of severe flares as 
the dependent variable and adjusting for baseline SS-S2K score (9 vs. 10), baseline 
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world). Adjustment will also be made for the subject's follow-up time by 
including log follow-up time (years) as an offset variable in the model.  The tables will 
display the total number of severe flares and total subject-years of study follow-up in the 
time interval by treatment group, the unadjusted rate per subject-year, the adjusted rate 
per subject-year, and the adjusted rate ratio (95% CI) and p-value vs. placebo (the 
adjusted rates and ratio, along with the 95% CI, are a back-transformation of the values 
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11.3.2.6.
SFI flare rate per subject-year over 52 weeks
Analyses of SFI flare rate (defined as mild, moderate, or severe) will be performed as 
defined in Section 11.3.2.5 for the severe SFI flare rate. 
11.3.3.
Organ-specific Measures
11.3.3.1.
Time to first renal flare over 52 weeks
A SLE renal flare is defined in Section 9.4.28.  Time to first renal flare is defined in 
Section 9.4.29.
The time to the first renal flare over 52 weeks will be compared between belimumab and 
placebo using a Cox proportional hazards model, adjusting for baseline SS-S2K score (9 
vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world). Ties will be handled using approximate 
likelihood (EFRON).
The table will display the number and percentage of subjects with a flare in the interval, 
the median days to first flare, the 25th and 75th percentile of days to first flare, and the 
hazard ratio and 95% CI versus placebo and the p-value from the Cox proportional 
hazards model. For subjects who experience a renal flare, the study day of the flare will 
be summarized and the table will display the median, 25th and 75th percentiles and 
minimum and maximum.  A Kaplan Meier plot of time to first renal flare over 52 weeks 
will also be produced.
The analysis for time to first renal flare over 52 weeks will be repeated for subjects with 
baseline proteinuria >0.5 g/24hr.  A Kaplan Meier plot will be produced to show the 
probability of experiencing a renal flare for subjects with baseline proteinuria >0.5 g/24hr 
over 52 weeks.
11.3.3.2.
Proteinuria percent change from Baseline by visit among subjects with 
baseline proteinuria >0.5 g/24hr (Observed)
The percent change from baseline in proteinuria at each visit among subjects with 
baseline proteinuria >0.5 g/24hr will be calculated as the visit value minus the baseline 
value divided by the baseline value then multiplied by 100.  The analysis will be 
performed based on the observed data in subjects with proteinuria >0.5 g/24 hour at 
baseline.  Belimumab and placebo will be compared at Week 52 using a Wilcoxon rank 
sum test with continuity correction. No imputation will be done for missing data.
For the baseline visit, the tables will display the mean proteinuria, standard deviation and 
SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At each 
post-baseline visit, the tables will display the mean percent change from baseline, 
standard deviation and SE of the mean, median, 25th and 75th percentiles, minimum and 
maximum.  At week 52 the table will also include the p-value from the Wilcoxon rank 
sum test.
A line graph for the median percent change from baseline (± quartiles) in proteinuria at 
each visit will be presented by treatment group.


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11.3.3.3.
Proteinuria change from baseline by visit (Observed)
The change from baseline in proteinuria will be analyzed by treatment group at Week 52.  
Belimumab and placebo will be compared using a Wilcoxon rank sum test with 
continuity correction.  This analysis will be performed based on the observed data.  No 
imputation will be done for missing data.
For the baseline visit, the table will display the mean proteinuria, standard deviation and 
SE of the mean, median, 25th and 75th percentiles, minimum and maximum. At each 
post-baseline visit, the tables will display the mean change from baseline, standard 
deviation and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  
At week 52 the table will also include the p-value from the Wilcoxon rank sum test.
A line graph for the median change from baseline (± quartiles) in proteinuria at each visit 
will be presented by treatment group.
11.3.3.4.
Proteinuria shifts from Baseline by visit (Observed)
Baseline proteinuria data will be summarized as the number and percent of subjects who 
are normal (0.5 g/24 hour) or high (>0.5 g/24 hour).  For each post-baseline visit the 
data will be summarized by baseline status defined as normal or high.  Among subjects 
normal at baseline the shifts presented will be ‘No change’ or ‘Normal to High’.  Among 
subjects high at baseline, the shifts presented will be ‘No change’ or ‘High to Normal’. 
Additionally, the proteinuria values will be summarized based on shifts occurring any 
time while on treatment.  Among subjects with normal proteinuria at baseline, the 
percentage of subjects with at least one high post-baseline value will be presented as 
‘Normal to High’; subjects who never experience a high proteinuria value post-baseline 
will be presented as ‘No change’.  Among subjects with high baseline proteinuria, 
subjects with at least one normal post-baseline value will be presented as ‘High to 
Normal’; subjects who never experience a normal post-baseline value will be presented 
as ‘No change’.  No statistical tests will be performed.  
11.3.3.5.
Percent of subjects with doubling from baseline of serum creatinine by 
visit (Observed)
The percent of subjects with doubling of serum creatinine from baseline to each 
scheduled visit will be presented by treatment group, and will, at week 52, be compared 
between belimumab and placebo using a logistic regression model.  The independent 
variables in the model will include treatment group, serum creatinine level at baseline, 
baseline SS-S2K score (9 vs. 10), baseline complement levels (At least one C3/C4 
Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world). This analysis will 
be performed based on the observed data only.  No imputation will be done for missing 
data.
For each visit, the table will display the number and percentage of subjects with doubling 
of serum creatinine by treatment group, the SE of the percentage and the treatment 
difference versus Placebo.  At week 52 the table will also include the odds ratio and 95% 
CI versus placebo, and a p-value for the odds ratio.


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11.3.4.
Prednisone
For analyses, all corticosteroids are converted to a prednisone equivalent average daily 
dose (mg/day), therefore analyses refer to average daily prednisone dose instead of 
average daily steroid dose.  The definition and derivation of this can be found in Section
9.4.13. For these analyses (except cumulative dose), average daily prednisone dose is 
based on the 7–day average prednisone dose.  This represents a departure from the 
protocol which indicates the prednisone analyses will be conducted using dosing on all 
days between visits.  The departure is to be consistent with the reporting of prior studies 
for comparison purposes.  
11.3.4.1.
Cumulative Prednisone dose
Cumulative prednisone dose (area under the curve [AUC]) is defined as the sum of daily
prednisone equivalent dose from Day 1 to Day 365 (Week 52) Visit.
The daily prednisone equivalent dose after the last visit day or the day of treatment
failure, if prior to Day 365 (Week 52) Visit, will be imputed using the average of the last 
28 daily prednisone equivalent doses prior to the day of last visit/treatment failure (i.e., 
not including day of visit/treatment failure).
For subjects who drop out or have treatment failure before Day 28, the daily prednisone
equivalent dose after early dropout or treatment failure will be imputed using the average
post-baseline daily doses available prior to dropout/treatment failure.
The AUC will be compared between Belimumab and placebo using a rank ANCOVA 
model. The covariates in the model will include treatment group, baseline prednisone 
dose, baseline SS-S2K score (≤ 9 vs. ≥10), baseline complement levels (At least one 
C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world). 
The table will display the unadjusted mean, standard deviation and SE of the mean, 
median, 25th and 75th percentiles, minimum and maximum of AUC and p-value from the 
rank ANCOVA.  
11.3.4.2.
Prednisone Change from Baseline by Visit (Observed)
The change from baseline in average daily prednisone dose will be summarized by 
treatment group and visit.  At week 52 Belimumab and placebo will be compared using 
an ANCOVA model with treatment group, baseline prednisone dose, baseline SS-S2K 
score (9 vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 
Low) and region (US/Canada vs. rest of the world) as covariates.  This analysis will be 
performed based on the observed data.  No imputation will be done for missing data.
For the baseline visit, the table will display the mean, standard deviation and SE of the 
mean, median, 25th and 75th percentiles, minimum and maximum. At each post-baseline 
visit, the tables will display the mean change from baseline, standard deviation and SE of 
the mean, median, 25th and 75th percentiles, minimum and maximum.  At week 52 the 
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versus placebo in LS means, 95% CI for the LS means treatment difference, and p-value 
from the ANCOVA model.
A line graph for the mean change from baseline (± SE) in average daily prednisone dose 
will be presented by treatment group.
11.3.4.3.
Prednisone Reduction by 50% from Baseline by Visit among subjects 
using Prednisone at Baseline (DO/TF=NR)
The percent of subjects with 50% reduction in daily prednisone dose compared to 
baseline will be presented by treatment group and by visit. At week 52, belimumab and 
placebo will be compared using a logistic regression model. Independent variables in the 
model will include treatment group, baseline prednisone dose, baseline SS-S2K score (9 
vs. 10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world). A responder is defined as having 50% 
reduction in prednisone compared to baseline. All subjects who use prednisone (dose>0)
at baseline will be included in the analysis.
If a subject withdraws from the study and/or is a treatment failure prior to a scheduled 
visit, the subject will be considered a non-responder (i.e. no decrease in prednisone) for 
that and subsequent visits (DO/TF=NR).
For each visit, the table will display the number and percentage of subjects achieving a 
response by treatment group, the SE for the percentage and the treatment difference 
versus placebo.  At week 52 the table will also include the odds ratio and 95% CI versus 
placebo and a p-value for the odds ratio.  
A line graph will present the percentage of responders (± SE) at each visit.
11.3.4.4.
Prednisone Increase by 50% from Baseline and by a Minimum of 5 
mg/day by Visit (LOCF)
The percent of subjects with 50% increase in daily prednisone dose compared to 
baseline and by a minimum of 5 mg/ day will be presented by treatment group and by 
visit. At week 52, belimumab and placebo will be compared using a logistic regression 
model.  Independent variables in the model will include treatment group, baseline 
prednisone dose, baseline SS-S2K score (9 vs. 10), baseline complement levels (At 
least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world).   
Missing data due to treatment failure or study withdrawal will be imputed using LOCF. 
Subjects who are not on prednisone at baseline (dose=0) are considered to have an 
increase if their average daily dose increases by at least 5 mg/day. 
For each visit, the table will display the number and percentage of subjects with an 
increase in prednisone by treatment group, the SE for the percentage and the treatment 
difference versus Placebo. At week 52 the table will also include the odds ratio and 95% 
CI versus placebo and a p-value for the odds ratio.  


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A line graph will present the percentage of subjects with 50% increase in prednisone
from Baseline and by a minimum of ≥5 mg/day (± SE) at each visit in each treatment 
group.
11.3.4.5.
Prednisone Any Increase from Baseline by Visit (LOCF)
The percent of subjects with any increase in daily prednisone dose compared to baseline 
will be presented by treatment group and by visit.  At week 52, belimumab and placebo 
will be compared using a logistic regression model.  Independent variables in the model 
will include treatment group, baseline prednisone dose, baseline SS-S2K score (9 vs. 
10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world).   
Missing data due to treatment failure or study withdrawal will be imputed using LOCF. 
For each visit, the table will display the number and percentage of subjects with an 
increase in prednisone by treatment group, the SE for the percentage and the treatment 
difference versus placebo.  At week 52 the table will also include the odds ratio and 95% 
CI versus placebo and a p-value for the odds ratio.  
A line graph will present the percentage of subjects with any increase in prednisone (± 
SE) at each visit in each treatment group.
11.3.4.6.
Percent of Subjects with Daily Prednisone Dose Reduced to 7.5 
mg/day from >7.5 mg/day at Baseline by Visit (DO/TF=NR)
The percent of subjects with daily prednisone dose reduced to 7.5 mg/day from >7.5 
mg/day at baseline will be presented by treatment group and by visit.  At week 52, 
belimumab and placebo will be compared using a logistic regression model.  Independent 
variables in the model will include treatment group, baseline prednisone dose, baseline 
SS-S2K score (9 vs. 10), baseline complement levels (At least one C3/C4 Low vs. No 
C3/C4 Low) and region (US/Canada vs. rest of the world). A responder is defined as 
subject who decreased their daily prednisone dose to 7.5 mg/day from a baseline dose 
>7.5 mg/day.  This analysis will be performed on subjects who used prednisone >7.5 
mg/day at baseline. 
If a subject withdraws from the study and/or receives a protocol-prohibited medication or 
a dose of allowable (but protocol-restricted) medication that results in treatment failure 
designation prior to a scheduled visit, the subject will be considered a non-responder (i.e. 
no reduction in prednisone) for that and subsequent visits (DO/TF=NR).  
For each visit, the table will display the number and percentage of subjects achieving a 
response by treatment group, the SE for the percentage and the treatment difference 
versus placebo.  At week 52 the table will also include the odds ratio and 95% CI versus 
placebo and a p-value for the odds ratio.  
A line graph will present the percentage of responders (± SE) at each visit in each 
treatment group.


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11.3.4.7.
Percent of Subjects with Daily Prednisone Dose Increased to >7.5 
mg/day from 7.5 mg/day at Baseline by Visit (LOCF)
The percent of subjects with average daily prednisone dose increased to >7.5 mg/day at 
each visit from 7.5 mg/day at baseline will be presented by treatment group and by visit.  
At week 52, belimumab and placebo will be compared using a logistic regression model.  
Independent variables in the model will include treatment group, baseline prednisone 
dose, baseline SS-S2K score (9 vs. 10), baseline complement levels (At least one 
C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world).  This 
analysis will be performed on subjects who had a prednisone dose ≤7.5mg/day at 
Baseline.
Missing data due to treatment failure or study withdrawal will be imputed using LOCF.
For each visit, the table will display the number and percentage of subjects with an 
increase by treatment group, the SE for the percentage and the treatment difference 
versus placebo.  At week 52 the table will also include the odds ratio and 95% CI versus 
placebo and a p-value for the odds ratio.  
11.4.
Missing Data Sensitivity Analyses 
The following analyses will be performed if pre-specified criteria are met. As these 
analyses are contingent on the study results they are not considered part of the Statistical 
Analysis Complete (SAC) delivery but will be delivered within 2 weeks of SAC.
Within this study LOCF imputation is restricted to missing visit (but not 
withdrawn/treatment failure) and item level imputation within the primary and major 
secondary analyses (Section 9.3) and endpoint imputation for some of the other 
endpoints. Within the primary and major secondary responder analyses, study drop outs 
and treatment failures are imputed using DO/TF=NR.  It is not expected that a subject, 
who has not been withdrawn, will be missing a week 52 (± 28 days) assessment for the 
primary endpoint.  Therefore, no further sensitivity analyses are planned for the other 
secondary analyses. This is consistent with previously reported Benlysta studies.
11.4.1.
Observed Case Analyses
This study was not designed to collect off treatment efficacy data. Per protocol subjects 
who became treatment failures should have been withdrawn from the study. However, it 
is likely that a small number of subjects who became treatment failures remained in the 
study. If more than 5% of subjects contribute off-treatment efficacy data the primary and 
three major secondary analyses will be repeated using the observed data (i.e., subject’s 
response status will be assessed using their week 52 observed data, without regard to 
their treatment failure status).  In this analysis subjects who drop out from the study will 
be imputed as non-responders. These analyses will only be performed for statistically 
significant primary and key secondary endpoints.


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11.4.2.
Tipping Point Analyses
If the primary analysis is statistically significant (P<0.05) then tipping point analysis will 
be performed for the SRI-S2K week 52 responder analysis.  Additionally, tipping point 
analysis will be performed for each of the key secondary endpoints if it is plausible that 
missing data could alter the conclusions of the analysis. Plausible is defined as the p-
value for the key secondary endpoint being ≤ 0.05 and > 0.001. Tipping point will only 
be performed for secondary endpoints considered to be statistically significant according 
to the prespecified testing hierarchy. All tipping point analysis will be unadjusted.
11.4.2.1.
Tipping Point Methodology for Responder Endpoints
The methodology specified in this section will be applied to the following endpoints:
Primary and Key Secondary Responder Endpoints

SRI -S2K Responder Analysis

SRI Responder Analysis

Percent of subjects whose average prednisone dose has been reduced by 25% 
from baseline to 7.5 mg/day during Weeks 40 through 52, in subjects receiving 
greater than 7.5 mg/day at baseline.
In the DO/TF=NR endpoint analyses, withdrawals who did not have an assessment 
within 28 days of week 52 or received prohibited medications will be considered non-
responders. Tipping Point sensitivity analyses will be conducted to investigate the impact 
of the above assumptions on the study conclusions. 
Additional analyses will be conducted on the response at Week 52 using an ‘observed’ 
dataset. This dataset will include all subjects who complete the Week 52 visit (including 
subjects who withdraw at day 365 assessment 28 days) without applying any 
imputation for subjects with completely missing data at Week 52. However, if 
components of the endpoint are missing, those items will have LOCF applied. Unlike the 
primary analysis, treatment failures will not be imputed as non-responders, but will be 
categorized as responder or non-responder if the subject has a Week 52 visit, or 
categorized as a dropout if the subject withdraws prior to the Week 52 visit window. 
Subjects who withdrew from the study and did not have an observed value in the Week 
52 window will be excluded from this analysis.
As no covariates will be used in the tipping point analysis it is possible to enumerate all 
possible combinations of responder/non-responder status for dropouts on each arm. For 
both treatment groups the response rate will be incrementally increased by one subject
(with a corresponding reduction in non-response rate), up to a maximum extreme
whereby all dropouts were assumed to be responders. The statistical significance of 
treatment difference will be assessed by the Mantel-Hantzel chi-square test.  A listing of 
all combinations of placebo and belimumab response rates for dropouts up to the 
maximum of all dropouts as responders, along with p-values will be produced, Results 
will be displayed graphically in a heatmap for each endpoint with the percentage of 
additional placebo responders on the Y-axis and belimumab responders on the X-axis. 


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A plausible assumption is that the response rate for dropouts in both the belimumab and 
placebo groups is the same as the observed response rate in the placebo group. This 
provides an anchor point to aid interpretation of the results of the tipping point analyses.
11.4.2.2.
Tipping Point Methodology for Time to First Severe Flare endpoint
To assess the sensitivity to the censoring-at-random assumption, the missing event times 
for subjects who dropped out or died will be imputed under the censoring-not-at-random 
assumption implemented using a range of values for the true event rate for these subjects 
[Jackson, 2014; Zhao, 2014]. 
The following methods and assumptions will be applied:
The assumed event rates for censored subjects will be varied independently for each
treatment group, and range from assuming that all prematurely censored subjects on a
particular treatment arm experienced a severe flare at the time of censoring (worst case
scenario corresponding to an infinite event rate for subjects who dropped out/died) to
assuming that all prematurely censored subjects on a particular treatment arm had
completed the study without experiencing a severe flare (best case scenario
corresponding to zero event rate for subjects who dropped out/died). Assumed event rates
for each arm will be varied incrementally between these two extreme scenarios.
A multiple imputation approach will be used to account for uncertainty about imputed 
event times. The multiple imputation process will follow Jackson et al [Jackson, 2014]. 
For a particular assumption about the post-censoring step-change in the event rate for 
censored subjects on each arm, this will involve the following steps:
1.
Bootstrap (i.e. sample with replacement the subjects in the original dataset). This
accounts for uncertainty in the estimated baseline hazard function used to impute the
event times for censored subjects. The seed to be used for the bootstrap will be
115471. The number of replications will be at least 50.
2.
Fit a Cox proportional hazards model (unadjusted for covariates) to the bootstrapped 
dataset. To inform on the validity of the adjusted Cox proportional hazards model, 
the proportional hazards assumption will be assessed by plotting the logarithm of the 
negative logarithm of the estimated survivor function against the logarithm of time, 
for each treatment group.  If the hazards are proportional, the lines should be 
approximately parallel. With the fitted model

Extract the baseline cumulative hazard function.

Predict the hazard risk for subjects who discontinued prematurely.

Increase or decrease the predicted hazard of the subject by the pre-specified
step-change amount relative to those in the same arm who stay longer in the
trial. The hazard rate of subjects will be increased/decreased multiplicatively 
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3.
Impute time-to-event for subjects who dropped out or died. For a given subject, if the
imputed time was below the maximum follow-up time (taken here to be 365 days),
the subject will be considered to have experienced a severe SFI flare at the imputed
event time. Otherwise the subject was administratively censored at 365 days (i.e., 
assumed to have completed the study event-free). The resulting imputed dataset
assumes that all subjects have been followed until the end of the study.
4.
Repeat steps 1 to 3 m times to obtain m imputed datasets.
5.
Fit a Cox proportional hazards model to each imputed dataset to estimate the hazard
ratio for severe SFI flare for belimumab versus placebo. The proportional hazards 
assumption will be assessed for a random subset of the fitted models. The analysis 
will allude to an average hazard ratio for interpretation of result if appropriate.
6.
Combine the results of the m imputed datasets using Rubin’s rules [Rubin, 1987].
These analyses assume a step change in the hazard even though there could be a more 
gradual change after dropout. The sensitivity analyses will not distinguish between 
reasons for dropout, i.e., they assume dropouts for any reason have the same step change 
in the event rate.
The results will be displayed in a heat map.


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12.
SAFETY ANALYSES
Safety will be evaluated by adverse events (AEs), changes in laboratory parameters, vital 
signs and immunogenicity. Safety analyses will be performed on the safety population.  
However, if there are more than 5% of subjects who receive a study treatment that is 
different from the randomized treatment through the entire study, safety analyses will be 
performed on the As-Treated population.
12.1.
Adverse Events

All subjects will be followed for safety through at least 8 weeks post-treatment 
(unless continuing treatment in the open label extension). 

A table summarizing AEs that occurred prior to treatment start date will be 
presented, for each system organ class (SOC) and preferred term (PT) by treatment 
group.

All AEs will be classified using the standard GSK Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary, and grouped by SOC and PT, unless 
otherwise stated. The investigator will evaluate all AEs with respect to seriousness, 
severity, and causality. The severity of an AE is to be evaluated according to the 
Adverse Event Severity Grading Tables in Appendix 12 and Section 7.7 of the 
Protocol, if a grade is defined for the AE of interest.  

All treatment-emergent AEs will be summarized for the double-blind phase.

An overall summary of AEs will be presented showing the number and percent of 
subjects with at least one: AE, related AE, serious AE (SAE), severe AE, Serious 
and/or severe AE, AE resulting in study agent discontinuation, and deaths.

The number and percentage of subjects experiencing an AE and the total number of 
AEs will be summarized for each of the following AE categories:

All AEs (by SOC; by SOC and PT; by PT only)

Serious AEs (by SOC; by SOC and PT; by PT only)

Severe AEs (by SOC and PT)

Related AEs (by SOC and PT; by PT only)

AEs leading to permanent discontinuation of study agent (by SOC and PT)

Deaths (by Category and PT)

Common Non-Serious AEs (by SOC and PT)

Common related SAEs (by SOC and PT)

Related Serious AEs (by SOC and PT)

Fatal Serious AEs (by SOC and PT)

The tabular summary for each category of AE listed above will include the number 
of events, number of subjects who reported at least one event, and percentage of 
subjects who reported at least one AE (incidence) by treatment group for each SOC 
(where applicable), each PT, and overall. By default, adverse events will be sorted by 
MedDRA SOCs, in descending order from the SOC with the highest total incidence 
(i.e., summed across all treatment groups) for any adverse event within the class, to 


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the SOC with the lowest total incidence. If the total incidence for any two or more 
adverse events is equal, the events will be presented in alphabetical order. Only 
SOCs with observed AE PTs will be presented.  Repeat sort order for MedDRA PTs 
within each SOC.

Common AEs will be defined as 5% incidence in any treatment group.

The table for all AEs by SOC and PT will be repeated for age group (<65, ≥65).

A summary of AEs by SOC and severity will also be provided by treatment group.  
For this display, 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.

A summary of AEs by SOC, PT and severity will also be provided by treatment 
group.  The number and percentage of subjects will be summarized as mild, 
moderate, or severe, based on the maximum severity observed within each PT, and 
within each SOC.

The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text will 
be displayed in a table for all AEs.

A listing of all AEs will be presented, including duration and study day of 
onset/resolution.  

A listing that displays which subjects reported each AE will also be produced. AEs 
will be grouped and sorted by SOC and PT.
12.2.
Deaths, Serious Adverse Events, and Survival Status
In addition to the tabular summaries of AEs described in Section 12.1, listings for all 
SAEs and all deaths will be produced.  The categorization of the cause of death will be 
adjudicated by GSK.
Survival status will also be summarized at Week 52. The number and percentage of 
subjects will be summarized for each of the following categories:

Alive (‘date last known alive’ is >= study day 351 or entered open label extension)

Unknown (Including subjects where the ‘date last known alive’ was < study day 351 
(Week 50))

Lost to Follow-up

All Deaths

Fatal SAEs that started during the Double-Blind phase although death occurred 
in a later study phase (i.e. alive at Week 52)

Based on stop date of Fatal SAE (i.e. date of death) being in the double-blind
phase.
A listing of survival status at Week 52 will also be presented.


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12.3.
Adverse Events Leading to Discontinuation of 
Investigational Product
In addition to the tabular summaries described in Section 12.1, a listing of all AEs 
leading to permanent discontinuation of study treatment will be produced.   
12.4.
Adverse Events of Special Interest
The Benlysta Program Safety Analysis Plan (PSAP) has been developed to include an 
adverse event of special interest (AESI) analysis for consistent reporting across 
belimumab studies.  Categorizations for the AESIs will be defined in the PSAP and 
reporting of AESIs for these analyses is defined in Attachment 3.  An overall summary of 
AESIs 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 of the following AESI will be provided. 
A listing of AESI will be produced by treatment group and Special Interest category.
The following AESIs will be identified using the list of preferred terms in Attachment 3
and adjudicated by GSK.
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
–
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


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Adverse Events
Adverse Events of Special Interest (AESI)

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 Behavior

Completed Suicide
–
Suicidal Ideation
–
Self-injurious Behavior without Suicidal Intent

Deaths
For malignant neoplasms events identified as “tumours of unspecified malignancy” will 
be reviewed for classification as malignant per GSK adjudication.
Post-infusion systemic reactions will be presented using nine different definitions as 
indicated above. These will also be presented by category and PT.   
Post-infusion systemic reactions per Anaphylactic Reaction CMQ narrow search are 
defined as at least one event from the list of preferred terms in Category A as listed in 
Attachment 3.  
Post-infusion systemic reactions per Anaphylactic Reaction CMQ broad search are 
defined as at least one event from the list of preferred terms in either Category A, B, C or 
D as listed in Attachment 3.  The SAEs that are identified by the Anaphylactic Reaction 
CMQ broad search will be reviewed further for potential classification as serious post-
infusion systemic reactions per GSK adjudication.
For CSR reporting, all post-infusion/injection 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 9.4.35 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/injection systemic reactions or hypersensitivity reactions per 
the criteria in Section 9.4.35 Adverse events with partial or missing start dates will be 
included unless there is evidence through comparison of partial dates to suggest 
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Possible cases of serious anaphylaxis per Sampson criteria will be identified as defined in 
Attachment 3.
Infection AESIs will also be presented by category and PT. Infections AESI leading to 
discontinuation will be presented by category and PT. 
Depression, Suicide and Self-injury Adverse Events of Special Interest will be presented 
by Category and PT. Depression, suicide and self-injury are defined using terms from the 
‘Depression (excluding suicide and self injury)’ CMQ plus additional terms added by 
MAH and ‘Suicide/self-injury’ CMQ.  
12.4.1.
Post-infusion systemic reactions by infusion
Summaries of post-infusion systemic reactions that occur on the day of an infusion or 
within 3 days after an infusion will be presented by the first six infusions and PT for the 
following:  

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

Post-Infusion Systemic Reactions Adverse Events of Special Interest by 
Category and PT

Serious Post-Infusion Systemic Reactions Adverse Events of Special Interest by 
Category and PT
12.5.
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality assessments are completed at every visit during the double-blind phase, but 
not completed during the open-label phase.  Assessments are done using the C-SSRS.  If 
a “yes” response is given to any suicidal behavior or a “yes” response to suicidal ideation 
questions 3, 4 or 5 on the C-SSRS, the investigator will be prompted to complete the 
Possible Suicidality Related Questionnaire (PSRQ).  A listing of the PSRQ will be 
presented.
Listings will be generated for the following:

Suicidal ideation and behavior data for subjects who have any suicidal ideation 
or behavior recorded at any point on the study (including screening) 

Behavior details for subjects who have any suicidal behavior recorded at any 
point on the study (including screening) 


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
The most severe suicidal ideation details for subjects who have any suicidal 
ideation recorded at any point on the study (including screening).
12.5.1.
C-SSRS suicidal ideation or behavior during treatment
The number and percentage of subjects with each category of suicidal ideation or 
behavior during treatment (including all assessments post Day 1) will be presented for the 
double-blind phase, selecting the worst record a subject has for each category.  The 
categories of suicidal ideation and behavior are presented in increasing order of severity 
from 1 to 10.  For the rows pertaining to suicidal behavior, the number of subjects who 
have the specified behavior at least once during treatment is presented.  For the rows 
pertaining to suicidal ideation, the number of subjects whose maximum ideation at any 
on-treatment assessment is the specified ideation is presented.  Within each category, 
subjects may have more than one type of suicidal ideation and behavior.
12.5.2.
C-SSRS suicidal ideation or behavior relative to pre-treatment 
The number and percentage of subjects with treatment-emergent suicidal ideation or 
behavior during treatment (including all assessment post Day 1) will be presented.  A 
subject must have at least one pre-treatment assessment and at least one on-treatment 
assessment in order to be included in this display. Any assessments performed on Day 1 
will be considered pre-treatment. A subject may have more than one treatment-emergent 
suicidal ideation and/or behavior.
12.5.3.
C-SSRS shift changes in categories from pre-treatment to on-
treatment
A summary of the shift from maximum pre-treatment C-SSRS (Day 1 or before) category 
to maximum on-treatment (up to and including Week 52) category will be produced.  The 
pre-treatment period is based on the lifetime evaluation up to and including Day 1.  A 
subject must have at least one pre-treatment assessment and at least one on-treatment 
assessment in order to be included in this display.  The table will display the number and 
percentage of subjects within the specific shift categories: No suicidal ideation or 
behavior, suicidal ideation, and suicidal behavior.  
12.6.
Clinical Laboratory Evaluations
For laboratory analyses, only analytes with a numeric normal range will be analyzed and 
summaries and analyses will be performed based on the observed data.  No imputation 
will be done for missing data.  Baseline is defined as described in Section 9.4.1.  See
Appendix 10 of the Protocol for a list of laboratory parameters.
Listings will be generated for all laboratory results and for Grade 3 or Grade 4 laboratory 
toxicity results, by laboratory category (hematology, liver function, electrolytes, other 
chemistries, urinalysis and immunoglobulins) and treatment group.


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12.6.1.
Laboratory descriptive statistics by visit
Descriptive statistics for each analyte will be displayed by treatment group for each visit.
The tables will display the mean value, standard error, standard deviation, median, 25th
and 75th percentiles, minimum and maximum. No statistical tests will be performed.
A line graph will be produced for each analyte which displays the mean value (±SE) by 
visit and treatment group.
12.6.2.
Worst laboratory toxicity grade post-baseline
Laboratory toxicity will be graded using Adverse Event and Laboratory Toxicity Grading 
Tables (Section 18.11) when possible. The worst laboratory toxicity grade post-baseline
for each laboratory parameter within each laboratory category (hematology, liver 
function, electrolytes, other chemistries, urinalysis and immunoglobulins) will be 
presented. Data for both scheduled and unscheduled visits will be included throughout
the double-blind phase of the study (including follow-up).
12.6.3.
Laboratory toxicity 2 grade shift post-baseline
Toxicity grade shifts from baseline of 2 grades will be summarized for each laboratory 
parameter within each laboratory category (hematology, liver function, electrolytes, other 
chemistries, urinalysis and immunoglobulins). The table will display the number and 
percentage of subjects with at least one 2 grade shift as well as the specific shift 
categories: Grade 0 to 2, Grade 0 to 3, Grade 0 to 4, Grade 1 to 3, Grade 1 to 4, Grade 2 
to 4 and hyper to hypo Laboratory reference range shifts from baseline.  Data for both 
scheduled and unscheduled visits will be included throughout the double-blind phase.
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 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 will be displayed using the categories:  no shift to high 
and normal/low to high.  No statistical tests will be performed.  
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.
12.6.4.
Immunoglobulin reference range shifts from baseline by visit
For immunoglobulins (IgG, IgA, and IgM) reference range shifts will be summarized 
across all visits based on the baseline normal range category.  For subjects with 
immunoglobulin values below the LLN, the number and percentage of subjects who 
‘remained low’ or went ‘to normal/high’ post-baseline will be summarized.  Similarly, 
for subjects with immunoglobulin values within the normal range or above the ULN, the 
number and percentage of subjects who ‘remained normal/high’ or went ‘to low’ post-
baseline will be summarized. 


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12.6.5.
Immunoglobulin below LLN by visit
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) 
below the LLN at each visit will also be presented for all subjects and then repeated for 
subjects LLN at baseline. No statistical tests will be performed.
12.6.6.
Immunoglobulin above LLN by visit
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) 
above the LLN at each visit will also be presented for all subjects and then repeated for 
subjects <LLN at baseline. No statistical tests will be performed.
12.6.7.
Immunogenicity
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.
For the incidence of patients with positive binding antibody, two tables will be produced 
summarizing results for the binding antibody assay by (i) treatment group and visit and 
(ii) a shift table. The table will include the number and proportion of subjects in each 
results category for each visit (including early withdrawal visit). Binding confirmatory 
assay results will be categorized as negative, persistent positive (defined as a positive 
immunogenic response on at least 2 consecutive assessments or a single result at the final 
assessment) or transient positive (defined as a single positive immunogenic response that 
does not occur at the final assessment).  
A listing of titer values will be produced for anyone who was positive at any time during 
the study.


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12.7.
Other Safety Measures
12.7.1.
Vital Signs
A summary of change from baseline of vital signs will be presented by visit and by 
treatment group. The tables will display the mean change from baseline, standard 
deviation, median, 25th and 75th percentiles, minimum and maximum.
A listing of all subjects’ vital signs will be presented by treatment group.
12.7.2.
Concomitant Procedures/Surgery
A listing of all concomitant procedures/surgery will be presented.


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13.
HEALTH OUTCOMES ANALYSES
13.1.
FACIT-Fatigue Scale score change from baseline by visit 
(LOCF)
A composite fatigue score will be created from the FACIT-Fatigue questionnaires 
(http://www.facit.org). The change from baseline in FACIT-Fatigue Scale score at each 
visit will be calculated as the visit score minus the baseline score. Belimumab and 
placebo will be compared, at week 52, using an ANCOVA model with treatment group, 
baseline FACIT-Fatigue Scale score, baseline SS-S2K score (9 vs. 10), baseline
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region 
(U.S./Canada vs Rest of World).  The LOCF method will be employed for subjects with 
missing data on FACIT-Fatigue Scale score at each visit, see Section 9.4.29 and Section 
6.1 (LOCF) for further details.  
For the baseline visit, the tables will display the mean FACIT-Fatigue Scale score, 
standard deviation, SE of the mean, median, 25th and 75th percentiles, minimum and 
maximum.  At each post-baseline visit, the tables will display the mean change from 
baseline, standard deviation, SE of the mean, median, 25th and 75th percentiles, minimum 
and maximum, and at Week 52 LS mean and associated standard error, treatment 
difference versus placebo in LS means, 95% CI for the LS means treatment difference, 
and p-value from the ANCOVA model.
A listing of all subjects’ FACIT-Fatigue scale scores will be presented.
The mean change from baseline in FACIT-Fatigue Scale score (±SE) at each visit will be 
presented graphically using a line graph by treatment group.
13.2.
FACIT-Fatigue Scale Score Improvement exceeding the 
MCID (4 points) by visit (DO/TF=NR)
A composite fatigue score will be created from the FACIT-Fatigue questionnaires 
(http://www.facit.org).  The percent of subjects with 4 points improvement (i.e. 
increase) from baseline in FACIT-Fatigue Scale score will be presented by treatment 
group and by visit, and will be compared, at week 52, between belimumab and placebo 
using a logistic regression model.  The independent variables in the model will include 
treatment group, baseline FACIT-Fatigue Scale score, baseline SS-S2K score (9 vs. 
10), baseline complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and 
region (US/Canada vs. rest of the world). Treatment failures and handling of missing 
data will be managed as described in Section 9.1, Section 9.2 and Section 9.3.  Subjects 
with baseline FACIT-Fatigue Scale score >48 will be treated as having no improvement.
At each visit, the table will display the number and percentage of subjects with 4 points
improvement in their FACIT-Fatigue Scale score by treatment group, and the treatment 
difference versus placebo.  At week 52, the table will also display the odds ratio and 95% 
CI versus placebo, and a p-value for the odds ratio.The percentage of subjects with 4 
points improvement in their FACIT-Fatigue Scale score (±SE) at each visit will be 
presented graphically using a line graph by treatment group.


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14.
CLINICAL PHARMACOLOGY DATA ANALYSES
14.1.
Pharmacokinetic Analyses
The PK summaries will be performed using the PK population, defined in Section 6.
Descriptive statistics for serum belimumab concentrations will be displayed for each visit 
for the double-blind phase. Summary statistics will be calculated including mean,
geometric mean,  as well as SD,  %CV, median, 25th and 75th percentiles, minimum, 
maximum and 95% confidence intervals for mean and geometric means. No statistical
tests will be performed.
A line graph will be produced which displays the median value along with 25th and 75th
percentiles by visit for the double-blind phase. 
To assess the effect of body size and immunogenicity on belimumab exposure the table 
and line graph described above will also be repeated for the subgroups of baseline BMI 
category and baseline body weight quartiles and may be repeated for immunogenicity 
status (persistent positive vs. transient persistent vs. negative) if the number of subjects 
with a positive status warrant it.  
A listing of serum belimumab PK concentration-time data will be presented.


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15.
BIOMARKER DATA ANALYSIS
The biomarker analyses will be performed for the mITT population as defined in Section 
6 unless otherwise stated.  
For the duration of the study, biomarker data (serum immunoglobulin isotypes IgA and 
IgM and B cell results) that have the potential to unblind the study team will not be 
transferred to the blinded study team.  Instead, blinded datasets will be required which 
contain dummy results. These blinded datasets will be exact models of the real datasets 
which will be received following unblinding. This will ensure that programs written 
using blinded data will still run on the real treatment codes and real unblinded data 
following the first database lock.
A listing of Biomarker data will be presented.
The intention is to analyze the Biomarker data using ANCOVA.  However, if the 
normality assumptions are violated, or there are a significant proportion of outliers in the 
dataset, then other methods of analysis will be investigated The first alternative to be 
investigated will be the non-parametric Wilcoxon Rank Sum Test.  If a non-parametric 
analysis is more appropriate, then the analysis will be updated and the relevant statistics 
will be presented in the output tables.  If analyses are changed to non-parametric due to 
the distribution of the data, then Figures presenting the data will switch from presenting 
means (± SE) to medians (± quartiles).
15.1.
Immunoglobulins, Autoantibodies, and Complement
Immunoglobulin isotypes (IgG, IgA, and IgM), autoantibodies (anti-dsDNA, ANA, aCL 
(IgA, IgG, IgM), lupus anticoagulant, beta-2-glycoprotein, anti-sm, anti-RNP, anti-SS-A, 
anti-SS-B, anti-ribosomal P) and complement (C3 and C4) will be assessed.
15.1.1.
Percent change from baseline in immunoglobulins, 
autoantibodies, and complement by visit (Observed)
The percent change from baseline for immunoglobulins, autoantibodies, and complement 
will be summarized by treatment group and visit. Belimumab and placebo will be 
compared, at week 52, using an ANCOVA model with treatment group, baseline 
biomarker value, baseline SS-S2K score (9 vs. 10), baseline complement levels (At 
least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world) as 
covariates. These analyses will be performed based on the observed data.  No imputation 
will be done for missing data.
For the baseline visit, the table will display the mean, standard deviation and SE of the 
mean, median, 25th and 75th percentiles, minimum and maximum. At each post-baseline 
visit, the tables will display the mean percent change from baseline, standard deviation 
and SE of the mean, median, 25th and 75th percentiles, minimum and maximum. At week 
52 the table will also display the LS mean and associated standard error, treatment 
difference versus placebo in LS means, 95% CI for the LS means treatment difference, 
and p-value from the ANCOVA model.


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A line graph for the mean percent change from baseline (±SE) in each of these 
biomarkers will be presented by treatment group.
Additionally, for autoantibodies (anti-dsDNA, ANA), analyses will be performed on 
subjects who were positive at baseline (anti-dsDNA 30 IU /mL, ANA index 0.80).  For 
complement (C3 and C4), analyses will be performed on subjects with low values at 
baseline (C3 <90 mg/dL and C4 <10 mg/dL).
A line graph for the mean percent change from baseline (±SE) in each of these 
biomarkers in these subgroups will be presented by treatment group.
15.1.2.
Change from baseline in immunoglobulins, autoantibodies, and 
complement by visit (Observed)
The change from baseline for immunoglobulins, autoantibodies, and complement will be
summarized by treatment group and visit.  Belimumab and placebo will be compared, at 
week 52, using an ANCOVA model with treatment group, baseline biomarker value, 
baseline SS-S2K score (9 vs. 10), baseline complement levels (At least one C3/C4 
Low vs. No C3/C4 Low) and region (US/Canada vs. rest of the world) as covariates. 
These analyses will be performed based on the observed data.  No imputation will be 
done for missing data.
For the baseline visit, the table will display the mean, standard deviation and SE of the 
mean, median, 25th and 75th percentiles, minimum and maximum. At each post-baseline 
visit, the tables will display the mean change from baseline, standard deviation and SE of 
the mean, median, 25th and 75th percentiles, minimum and maximum, At Week 52 the 
table will also display LS mean and associated standard error, treatment difference versus 
placebo in LS means, 95% CI for the LS means treatment difference, and p-value from 
the ANCOVA model.
A line graph for the observed mean percent change from baseline (±SE) in each of these 
biomarkers will be presented by treatment group.
Additionally, for autoantibodies (anti-dsDNA, ANA), analyses will be performed on 
subjects who were positive at baseline (anti-dsDNA 30 IU /mL, ANA index 0.80).  For 
complement (C3 and C4), analyses will be performed on subjects with low values at 
baseline (C3 <90 mg/dL and C4 <10 mg/dL).
A line graph for the mean percent change from baseline (±SE) in each of these 
biomarkers in these subgroups will be presented by treatment group.
15.1.3.
Shifts in immunoglobulins, autoantibodies, and complement by 
visit
Shift tables will be used to summarize the changes in immunoglobulins, autoantibodies, 
and complement by visit.
For IgG, IgA, and IgM baseline data will be summarized as the number and percent of 
subjects who are low or normal/high at baseline.  For post-baseline visits the data will be 


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summarized by baseline status defined as low (IgG <6.94 g/L, IgA <0.81 g/L, and IgM 
<0.48 g/L) or normal/high (IgG 6.94 g/L, IgA 0.81 g/L, and IgM 0.48 g/L).  Among 
subjects low at baseline the shifts presented will be low to normal/high and low to low. 
Among subjects normal/high at baseline, the shifts presented will be normal/high to 
normal/high and normal/high to low.  At Week 52 the shifts will be evaluated using 
Fisher’s exact test within each baseline category.
For anti-dsDNA, baseline data will be summarized as the number and percent of subjects 
who are positive and negative at baseline.  For post-baseline visits the data will be 
summarized by baseline status defined as positive (30 IU/mL) or negative (<30 IU/mL).  
Among subjects positive at baseline the shifts presented will be positive to negative and 
positive to positive.  Among subjects negative at baseline, the shifts presented will be 
negative to negative and negative to positive.  At week 52, the shifts will be evaluated 
using Fisher’s exact test within each baseline category.
For C3 and C4, baseline data will be summarized as the number and percent of subjects 
who are low or normal/high at baseline.  For post-baseline visits the data will be 
summarized by baseline status defined as low (C3 <90 mg/dL, C4 <10 mg/dL) or 
normal/high (C3 90 mg/dL, C4 10 mg/dL).  Among subjects low at baseline the shifts 
presented will be low to normal/high and low to low. Among subjects normal/high at 
baseline, the shifts presented will be normal/high to normal/high, and normal/high to low.  
At week 52 the shifts will be evaluated using Fisher’s exact test within each baseline 
category.  
15.2.
B cell Analyses
A listing of B cell results will be presented.
15.2.1.
B cell percent change from baseline by visit (Observed)
The following biomarkers will be summarized by treatment group and visit: 

Percent change in absolute B cell subsets (CD19+, CD20+, CD20+/27+ memory, 
CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, CD27+
BRIGHT/CD20– Short-lived plasma cells, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH/CD38HIGH transitional and CD20-/138+ plasma cells) at each visit.
Belimumab and placebo will be compared, at week 52, using an ANCOVA model with 
treatment group, baseline B cell value, baseline SS-S2K score (9 vs. 10), baseline 
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world) as covariates.  These analyses will be performed based on the 
observed data.  No imputation will be done for missing data.
For the baseline visit, the table will display the mean, standard deviation and SE of the 
mean, median, 25th and 75th percentiles, minimum and maximum.  At each post-baseline 
visit, the tables will display the mean percent change from baseline, standard deviation 
and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At week 
52 the table will also display the LS mean and associated standard error, treatment 


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difference versus placebo in LS means, 95% CI for the LS means treatment difference, 
and p-value from the ANCOVA model.
A line graph for the mean percent change from baseline (±SE) in each of these B cells 
will be presented by treatment group.
15.2.2.
B cell change from baseline by visit (Observed)
The following biomarkers will be summarized by treatment group and visit: 

Change in absolute B cell subsets (CD19+, CD20+, CD20+/27+ memory, 
CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ plasmacytoid, CD27+
BRIGHT/CD20– Short-lived plasma cells, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH/CD38HIGH transitional and CD20-/138+ plasma cells) at each visit.

Change in CD20+/27– naïve and CD20+/27+ memory B cell subsets expressed as a 
percentage of CD19
Belimumab and placebo will be compared, at week 52, using an ANCOVA model with 
treatment group, baseline B cell value, baseline SS-S2K score (9 vs. 10), baseline 
complement levels (At least one C3/C4 Low vs. No C3/C4 Low) and region (US/Canada 
vs. rest of the world) as covariates.  These analyses will be performed based on the 
observed data. No imputation will be done for missing data.
For the baseline visit, the table will display the mean, standard deviation and SE of the 
mean, median, 25th and 75th percentiles, minimum and maximum.  At each post-baseline 
visit, the tables will display the mean percent change from baseline, standard deviation 
and SE of the mean, median, 25th and 75th percentiles, minimum and maximum.  At week 
52 the table will also display the LS mean and associated standard error, treatment 
difference versus placebo in LS means, 95% CI for the LS means treatment difference, 
and p-value from the ANCOVA model.
A line graph for the mean percent change from baseline (±SE) in each of these B cells 
will be presented by treatment group.


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16.
PHARMACOGENETIC DATA ANALYSES
Any pharmacogenetic analyses will be described in a separate pharmacogenetic analysis 
plan and will be reported separately from the main clinical study report.


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17.
REFERENCES
Alarcón-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare 
in patients with systemic lupus erythematosus. Arthritis Rheum 2003;48(2):442–54.
Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone 
hormone replacement therapy on disease activity in systemic lupus erythematosus: A 
randomized trial. Ann Intern Med 2005;142(12 Pt 1):953-62.
Cockcroft DW and Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41.
Cohen J. 1960. A coefficient of Agreement for Nominal Scales Educational and 
Psychology.
Fleiss JL, Cohen J, Everitt B.S. 1969. Large Sample Standard Errors of Kappa and 
Weighted Kappa Psychological Bulletin 72,323-327.
Fleiss JL, Cohen J. 1973. The Equivalence of Weighted Kappa and Intraclass Correlation.
Gladman DD, Ibanez D, Urowitz MB. Systemic lupus Erythematosus disease activity 
index 2000. J Rheumatol 2002;29(2):288-91.
Gladman EM, Ginzler E, Goldsmith C et al. SLICC/ACR damage index for SLE. 
Arthritis Rheum. 1996a;39(3):363-9.
Hay EM, Bacon PA, Gordon C, et al. The BILAG index: a reliable and valid instrument 
for measuring clinical disease activity is systemic lupus erythematosus. Q J Med 
1993;86:447-58.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the 
classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
Isenberg DA, Gordon C. From BILAG to BLIPS--disease activity assessment in lupus 
past, present and future. Lupus 2000;9(9):651-4.
Jackson D, White IR, Seemain S, et al. Relaxing the independent censoring assumptions 
in the Cox proportional hazards model using multiple imputation. Stat Med. 
2014;33:4681-94.
Neergard. Reducing the risk of blood thinners. Associated press, September 2006.
Peduzzi P, Concato J et al. A simulation of the number of events per variable in logistic 
regression analysis, J Clin Epidemiol. 1996 Dec;49(12):1373-9.
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, et al. Combined oral contraceptives in women with 
systemic lupus erythematosus. N Engl J Med 2005;353(24):2550-8.


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Rubin DB. Multiple Imputations for Nonresponse in Surveys. John Wiley & Sons. 1987.
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of 
systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271-7.
Yee CS, Development and Validation of the BILAG 2004 Index for the Assessment of 
Disease Activity in Systemic Lupus Erythematosus.  Doctoral Thesis submitted to the 
University of Birmingham, Rheumatology Research Group, Division of Infection and 
Immunology, School of Medicine, February 2008. 
Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group 2004 
index is valid for assessment of disease activity in systemic lupus erythematosus. 
Arthritis Rheum. 2007;56(12):4113-9.
Yee CS, Isenberg DA, Prabu A, et al. BILAG-2004 index captures systemic lupus 
erythematosus disease activity better than SLEDAI-2000. Ann Rheum Dis. 
2008;67(6):873-6.
Zhao Y, Herring AH, Zhou H, et al. A multiple imputation method for sensitivity 
analyses of time-to-event data with possibly informative censoring. J Biopharm Stat. 
2014;24:229-53.


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18.
APPENDICES
18.1.
Appendix 1 Allowable Medication Categories
Medication Category
Rule
Anti-malarials
Set to "ANTIMALARIALS" if the preferred term begins with "QUINACRINE", 
"QUININE", "HYDROXYCHLOROQUINE", "MEPACRINE", or CHLOROQUINE" 
AND
the route of administration is not 'TOPICAL', 'VAGINAL', 'CONJUNCTIVAL', 
'INTRANASAL', 'INHALATION', 'INTRA-OCULAR', 'INTRATRACHEAL', 
'EPIDURAL', 'INTRA-ARTICULAR', or 'OTHER'.
Steroids
Set to ‘STEROIDS’ if at least one associated ATC code (ATCCD1 – ATCCD6) 
begins with ‘H02’ 
AND
Route of administration is 
"INTRADERMAL", "INTRAMUSCULAR",
"INTRAVENOUS", "ORAL", "SUBCUTANEOUS", or "INTRA-ARTICULAR".
Immunosuppressants
Set to ‘IMMUNOSUPPRESSANTS’ if at least one associated ATC code 
(ATCCD1 – ATCCD6) begins with ‘L04A’ or the preferred term begins with 
“CYCLOPHOSPHAMIDE” (oral and parenteral routes) or 
“MERCAPTOPURINE” (oral route) or “METHOTREXATE”
AND 
route of administration is not “TOPICAL” or “CONJUCTIVAL”.
NSAIDs
Set to NSAIDs if at least one associated ATC code (ATCCD1 – ATCCD6) 
begins with ‘M01A’.
Aspirin
Set to "ASPIRIN" if preferred term contains "ACETYLSALICYLIC ACID" or 
"ACETYLSALICYLATE LYSINE".
Prohibited
Set to "PROHIBITED" if any of the following conditions are met, 
if preferred term equals "INVESTIGATIONAL DRUG", "IMMUNOGLOBULIN",
"ADALIMUMAB", “BELIMUMAB”, "ETANERCEPT", "INFLIXIMAB", 
"RITUXIMAB", "ABATACEPT", "ANAKINRA", "GOLIMUMAB", 
"CERTOLIZUMAB", "PLASMAPHERESIS", “TOCILIZUMAB” or 
“CYCLOPHOSPHAMIDE” (IV route).
NOTE: Plasmapheresis in the ‘Prohibited’ category would be recorded in the Surgery/Procedures form, not 
the concomitant medication form.


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18.2.
Appendix 2 Prednisone Equivalent Conversion

A concomitant medication is identified as a steroid if at least one associated ATC 
code (ATCCD1 – ATCCD6) begins with ‘H02.’ Mineralocorticords are included in 
the group of ATC codes beginning with ‘H02’ but do not have sufficient anti-
inflammatory properties to be considered as a prednisone equivalent.  For this reason, 
the conversion factor has been set to 0.

The following routes are considered to provide systemic exposure: oral, 
subcutaneous, intramuscular, intradermal, and intravenous.  Although not systemic, 
intra-articular steroids are also identified for treatment failure rules.  Topical routes 
of administration are excluded (e.g., topical, conjunctival, intranasal).  

At data base release, all preferred terms identified with an ATC code beginning with 
‘H02’ will be reviewed to ensure a conversion factor exists for all terms with a 
systemic route of administration. 

Similarly, all routes of administration for preferred terms with an ATC code 
beginning with ‘H02’will be reviewed to ensure all systemic routes have been 
identified in the list above.  

In order to be converted the frequency and dose of the steroid must be present with 
the unit dose in milligrams (mg) or grams (g).  Doses recorded in grams will be 
converted to milligrams by multiplying the dose in grams by 1000 prior to applying 
the conversion factor.

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
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
8.3333
CORTISONE
0.2
CORTISONE ACETATE
0.2
CRONOLEVEL
8.3333
DEFLAZACORT
0.8333
DEPO-MEDROL MED LIDOKAIN
1.25
DEXAMETHASONE
6.6667


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Prednisone Conversion Factors (mg)
Preferred term
Conversion factor for converting to a 
prednisone-equivalent dose
DEXAMETHASONE ACETATE
6.6667
DEXAMETHASONE SODIUM PHOSPHATE
6.6667
FLUDROCORTISONE
0
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
Combination Products:  Prednisone Conversion Factors (mg) 
Preferred term
Ingredients
Conversion factor for 
converting to a 
prednisone-equivalent 
dose
CELESTONA BIFAS
Betamethasone acetate + 
Betamethasone sodium phosphate
8.3333
DEPO-MEDROL MED 
LIDOKAIN
Methylprednisolone + Lidocaine
1.25
CELESTAMINE
Betamethasone + Dexchlorpheniramine 
maleate
8.3333
SYNBETAMINE
Betamethasone + Dexchlorpheniramine 
maleate
8.3333


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Frequency Factors
Frequency
Factor
BID
2
BIW
2/7
HS
1
OAM
1/30
ONCE
1
PRN
null
Q2H
12
Q2W
1/14
Q3D
1/3
Q3H
8
Q3MO
1/84
Q3W
1/21
Q4D
1/4
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


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18.3.
Appendix 3 Treatment Failure Rules
General Conventions

Assessment of dose is based on analysis dose. Analysis dose is daily dose adjusted 
for dosing frequency, and in the case of steroid is converted to prednisone 
equivalents. Exception is intra-articular dose where analysis dose is not populated.

In the event there are multiple visit dates within a visit window, the date for 
determining Treatment Failure, will be the earliest date at which efficacy data (from 
PGA, BILAG, SLEDAI and SLE Flare) is recorded. This may be different than the 
earliest visit within that window

If a critical visit (Day 113 [Week 16], 169 [Week 24], 309 [Week 44]) is missing 
from efficacy data (from PGA, BILAG, SLEDAI and SLE Flare) then the date is 
imputed e.g., date of Day 169 visit is imputed as the target day for Day 169 (Week 
24). 

Actual visit date, not target visit date, is used to assess treatment failures. For 
example, the Day 169 (Week 24) visit can occur on study day 169 7 days.  If the 
subject’s Day 169 (Week 24) study visit occurs on Day 171, the date for Day 171 is 
used when applying the treatment failure rules. 

Prohibited medications/dosages started on the day the subject completes the double-
blind treatment phase do not result in TF designation. 

Prohibited medications/dosages started on the date of early withdrawal are 
considered a TF (see clarification below for steroids).  If the prohibited 
medication/dose starts after the date of withdrawal it will not be part of the TF 
assessment.

Generally, only the first instance of each unique TF rule violation type is output 
programmatically. If this instance is adjudicated as a not being a TF then the clinical 
adjudicators will review the entirety of the relevant concomitant medication records 
to assess if the subject subsequently became a TF for the same violation type (e.g., 
steroid dose does not return to within 25% or 5mg, whichever is higher, above 
baseline dose by Day 169 [Week 24] visit).

Clinical may amend the date of TF during adjudication if, for instance, a subject did 
not meet the criterion on the date identified by the program (as may be the case if 
their steroid usage was short term and not SLE-related) but did meet it later. 
Steroids

SLE-related steroids are steroids where medication type is marked as ‘Systemic 
Lupus Erythematosus (SLE)’ (CMTYPCD=156), regardless of reason for medication 
(CMREAS).

Total steroids include steroids for SLE and non-SLE reasons.

Baseline dose is the 7-day average based on the 7 days prior to, but not including, 
treatment start date.


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
The Day 309 (Week 44) steroid dose is the sum of steroid dose over 7 consecutive 
days leading to and including the Day 309 (Week 44) visit, divided by 7. The Day 
309 steroid dose is used to determine if there is a new increase in steroids above the 
baseline (Day 1) or Week 44 (Day 309) visit within 8 weeks of the Day 365 (Week 
52) visit.  Within 8 weeks of the Day 365 (Week 52) visit is defined as occurring in 
the window starting the day after the Week 44 (Day 309) visit through the Week 52 
(Day 365) visit. Note there is no check that the Day 309 (Week 44) and Day 365 
(Week 52) visits are within 8 weeks of each other. 

In all instances in which the protocol states that a subject’s steroid dose must return 
to a specified level (e.g., within 5 mg or 25% of baseline whichever is higher) by a 
specific visit day (e.g., Day 169 [Week 24] visit), the calculation of the 7-day 
average steroid dose to determine whether a subject is a treatment failure will begin 
on the day after the visit.  This does not apply to the calculation of the Day 309 
(Week 44) visit dose (see above).

When assessing dose at critical visits the average dose is based on the 7 days after 
the visit e.g., Day 169 (Week 24) 7-day average dose is the average of day 170 -176 
(if Day 169 occurred on the actual target date; or 7 days after the date of the Day 169 
[Week 24] visit otherwise). 

The final week interval for subjects who complete the double-blind treatment period 
will be 7 days prior to the exit visit date; [exit visit -7 days] to [exit visit -1 day]. The 
day of the exit visit will not be included.

The final interval for subjects who withdraw early from the double-blind phase will 
be the 7 days up to and including the exit visit date; [exit visit/early withdrawal date 
-6] to [exit visit/ early withdrawal date]. The day of withdrawal will be included. 

If a subject meets the criterion for TF based on a 7-day average, the date of TF will 
be the last day of the 7-day interval. 

The above rules may miss a subject who starts/increases a steroid close to the day of 
withdrawal. In this situation it is possible that the subject may have withdrawn prior 
to the end of the interval for computing their 7-day average exceeding the TF 
threshold. Hence all subjects whose dose of steroid increased within 7 days 
(including day of withdrawal) of withdrawal, and have not already crossed the dose 
threshold for TF based on the 7-day average rule, will be output for clinical 
adjudication. If clinical adjudication determines these to be treatment failures the 
date of treatment failure will be set to the date of withdrawal.

A subject who is receiving 0mg of steroid at baseline will be allowed to take 5mg 
of steroid at critical assessments without being considered a treatment failure.

Intra-articular steroids are not included in average steroid dose calculations.

All assessments relating to within 8 weeks of Day 365 (Week 52) are based off the 
interval from Day 309 (Week 44) visit date to the Day 365 (Week 52) visit date; not 
Day 365 (Week 52) visit date – 64 days.

QOD dosing regimens (and regimens with frequency <once/day) will be reviewed to 
ensure the analysis dose is calculated correctly.  Consider an example of a subject 
taking 5mg QOD and 7.5mg QOD. To calculate an analysis average daily dose for a 


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QOD (every other day) regimen, half of the dose is attributed to each day in the 
dosing interval.  In this example, 2.5mg would be assigned as the analysis dose for 
each day of the 5mg QOD dosing interval and 3.75mg would be the analysis dose for 
each day of the 7.5mg QOD dosing interval.  The analysis dose for a given day is the 
sum of all steroid doses for the day. If the 5mg QOD dose is recorded as starting one 
day prior to the 7.5mg QOD dose and no other steroids were taken on that day, then 
the analysis dose for the first day of the 5mg QOD will be 2.5mg; for subsequent 
days when the 5mg and 7.5mg dosing intervals overlap, the analysis dose will be 
2.5mg + 3.75mg = 6.25mg. 
Systemic Steroids for SLE-related Disease Activity

A subject who fails to return to within 25% or 5 mg over the baseline (Day 1) dose, 
whichever is higher, by the Day 169 (Week 24) visit will be considered a treatment 
failure.

After the Day 169 (Week 24) visit, an increase >25% or >5 mg over the baseline 
(Day 1) dose, whichever is higher, for SLE activity will deem the subject a 
treatment failure.

Within 8 weeks before the Day 365 (Week 52) visit, no new increase over the 
baseline (Day 1) or Day 309 (Week 44) visit dose, whichever is higher, is allowed. A 
new increase would deem the subject a treatment failure.
Intra-articular (IA) injections

Subjects may receive intra-articular injections between baseline (Day 1) and the Day
309 (Week 44) visit. Intra-articular (IA) injections after the Day 309 (Week 44) visit 
and before the Day 365 (Week 52) visit will result in treatment failure.
Steroids for Reasons Other Than SLE Disease Activity
From Day 1 to the Day 169 (Week 24) Visit:

Steroids may be given for reasons other than SLE disease activity (such as asthma, 
contact dermatitis) as clinically indicated until Day 169 (Week 24) visit.
From Days 169 to 309 (Weeks 24 to 44) Visits:

Steroids may be given for reasons other than SLE disease activity from the Day 169 
(Week 24) visit until the Day 309 (Week 44) visit at any dose/duration that does not 
result in a total steroid dose (for SLE and non-SLE reasons) >25% or >5 mg, 
whichever is higher, over the baseline dose. The total baseline steroid dose will be 
calculated from steroids given for both SLE and non-SLE reasons. Any total steroid 
dose exceeding this rule will deem the subject a treatment failure. 

In addition, steroids for non-SLE reasons may be given short term at higher doses 
according to the following guidelines:

Up to 750 mg (prednisone) for 1 day,
and/or


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
Up to 100 mg/day (prednisone) for 2-3 days,
and/or

Up to 40 mg/day (prednisone) for 4-7 days.
The duration of high dose steroid use for reasons other than SLE must not exceed 7 
days, after which time, tapering should begin. The total steroid dose must be tapered 
to within 25% or 5 mg over the baseline dose, whichever is higher, within 30 days of 
the 1st dose of a course of steroids. In addition, the steroid dose must be tapered to 
within 25% or 5 mg over the baseline dose, whichever is higher, by the Day 309 
(Week 44) visit. Otherwise the subject will be deemed a treatment failure.
From the Day 309 to 365 (Week 44 to 52) Visits:
After the Day 309 (Week 44) visit through the Day 365 (Week 52) visit, no new steroids 
are allowed for reasons other than SLE activity that result in a total daily steroid dose 
>25% or >5 mg, whichever is higher, over the baseline total steroid dose. A subject will 
be considered a treatment failure for any steroid use 8 weeks before the Day 365 (Week 
52) visit that does not meet this criterion.
Anti-Malarials

Dose of anti-malarial at baseline is the dose the subject received on the treatment 
start date. If a patient is receiving an anti-malarial at baseline it will be assumed that 
dose is stable and not a loading dose

Dose of anti-malarial at Day 113 is the dose of received on the Day 113 (Week 16)
visit date.

Treatment failure date will be the anti-malarial start date that resulted in treatment 
failure. 

Clinical loading dose is permitted for initiation or replacement. Whether or not the 
dose was a loading dose will be assessed by clinical adjudication. 

A new anti-malarial (e.g., hydroxychloroquine, chloroquine, quinacrine) may be 
started between Day 1 and the Day 113 (Week 16) visit.

The dose of an anti-malarial may be reduced during the course of the study. The dose 
of an anti-malarial may be increased as clinically required, up to the Day 113 (Week 
16) visit.

After the Day 113 (Week 16) visit, any increase in dose of an anti-malarial over the 
baseline (Day 1) or Day 113 (Week 16) visit dose, whichever is higher, will declare 
the subject a treatment failure.

Starting any new anti-malarial treatment after the Day 113 (Week 16) visit will 
declare the subject a treatment failure.

An anti-malarial treatment will be considered new if the subject did not receive an 
anti-malarial at any time during the Day 1 to Day 113 (Week 16) treatment interval.


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
An anti-malarial may be replaced by another anti-malarial due to documented 
toxicity or lack of availability at any time during the study. Replacement due to 
toxicity/lack of availability will be assessed during clinical adjudication.
Immunosuppressant/Immunomodulatory agents

Baseline dose is the dose received on the treatment start date.

Whether the dose was a loading dose will be assessed by clinical adjudication. 

Replacement due to toxicity/lack of availability will be assessed during clinical 
adjudication.

No check is made for medications not listed in protocol which required medical 
monitor approval. Conjunctival agents will not be considered in treatment failure 
assessment
NSAIDs and Aspirin

NSAIDs may be given as clinically indicated until the Day 309 (Week 44) visit.

For subjects who never received an NSAID between the Day 1 and Day 309 (Week 
44) visit, starting a new NSAID after the Day 309 (Week 44) visit will declare the 
subject a treatment failure unless the NSAID is given for <1 week. The 
programming algorithm will need to check if an NSAID was taken between the Day 
1 and Day 309 (Week 44) visit.

An NSAID may be replaced with another NSAID due to documented toxicity or lack 
of availability. Replacement due to toxicity/lack of availability will be assessed 
during clinical adjudication; therefore, programming should identify first unique 
NSAID terms that were taken post-baseline that were not present at baseline.

Daily doses of aspirin up to 1000 mg/day are allowed at any time during the study.

Daily doses of aspirin above 1000 mg/day may be initiated at any time up to Day 
309 (Week 44) visit and may continue through the end of the study.

For subjects who never received an aspirin regimen at a dose >1000 mg/day between 
the Day 1 and Day 309 (Week 44) visit, starting a new aspirin regimen at a dose 
>1000 mg/day after the Day 309 (Week 44) visit will declare the subject a treatment 
failure unless the aspirin is given for <1 week. The programming algorithm will 
need to check if an aspirin was received at a dose >1000 mg/day between the Day 1 
and Day 309 (Week 44) visit.

Baseline is defined as the NSAID/aspirin received on the treatment start date.  
Program to checks if subject received NSAID from Baseline to day 309.If so, they 
are not output for adjudication.

Treatment failure date will be the date the medication/dose was started resulting in 
treatment failure designation.
Prohibited medications/non-Drug Therapies

Date of treatment failure is date subject started Prohibited medications/non-Drug 
Therapy.


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
The following medications and therapies are forbidden 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. [No 
check for investigational agents not approved for sale in country is being made.]

Co-enrollment into another study of an investigational agent or another study 
that may interfere with the conduct of this protocol. [No check available for this 
criterion.]

Anti-TNF therapy (e.g., adalimumab, certolizumab pegol, etanercept, 
golimumab, infliximab).

Other biologics (e.g., rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra], tocilizumab).

Intravenous immunoglobulin (IVIG).

IV cyclophosphamide.

Plasmapheresis 
Live Vaccines

Receiving a live vaccine is prohibited due to safety reasons but is not a treatment 
failure criterion.


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18.4.
Appendix 4 ACR Criteria at Baseline
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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18.5.
Appendix 5 SLICC/ACR Damage Index
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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18.6.
Appendix 6 BILAG Assessment
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices,
which are protected by third party copyright laws and therefore have been excluded.


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18.7.
Appendix 7: SLE Flare Index
Mild-moderate flare
Severe flare
Change in SELENA SLEDAI instrument 
score of 3 points or more (but not to more 
than 12), or
Change in SELENA SLEDAI instrument 
score to greater than 12a,  or
New/worse:
   Discoid, photosensitive, profundus,
       cutaneous vasculitis, bullous lupus
   Nasopharyngeal ulcers
   Pleuritis
   Pericarditis
   Arthritis
   Fever (SLE)
Or
New/worse:
   CNS-SLE
   Vasculitis
   Nephritis
   Myositis
   Plt<60,000
   Hemolytic anemia with Hb<70g/L or 
decrease in Hb>3g/L 
Requiring:  double prednisone, or prednisone 
increase to >0.5mg/kg/day, or hospitalization, 
or
Increase in prednisone, but not to 
>0.5mg/kg/day, or
Increase in prednisone to >0.5mg/kg/day, 
or
Added NSAID or hydroxychloroquine for SLE 
activity, or
New cyclophosphamide, azathioprine, 
methotrexate, or mycophenolate for SLE 
activity, or
1.0 Increase in PGA score, but not to more 
than 2.5
Hospitalization for SLE activity, or
Increase in a PGA score to 2.5
a.
The modified SLE Flare index excludes severe flares that are triggered only by an increase is SLEDAI Score to 
greater than 12.
(Adapted from [Buyon, 2005; Petri, 2005; Neergard, 2006. Petri, 1999])


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18.8.
Appendix 8 Important Protocol Deviations
A summary of important protocol deviations is given below. Further detail is given in the 
Protocol Deviation Management Plan (PDMP): Dated: 25Feb2018 (Version 3.0).
Category
GSK Important Deviations 
ICF Process
Subject never signed ICF or amendment 
ICF signed after study procedure done
Eligibility Criteria
Any "no" response to inclusion criteria and/or 
any "yes" response to exclusion criteria and 
subject was subsequently randomized and 
dosed 
Study drug ADMINISTERED at Day 0 PRIOR 
to confirmation that subject meets all eligibility 
criteria AND subject subsequently determined 
to be ineligible
IP assignment in IXRS
Study drug assigned in IXRS prior to confirming 
subject meets eligibility on Day 0; then 
determined not to be eligible and subject 
NEVER dosed
Misstratification 
Subject misstratified in IXRS
IP Infusion Time
Less than 50 minutes
Study Procedures Not Done
Missing Screening AND Day 0 SRI components 
(includes SS or BILAG or PGA)
Missing Laboratory Values at Randomization
Subjects randomized without results available 
for review and, upon availability of lab results, 
subject ineligible for inclusion 
Not Withdrawn from Study after developing 
Protocol Specific Withdrawal Criteria 
Subject developed withdrawal criteria specified 
in the protocol but were not withdrawn and 
continued dosing/study
**Note: Determine if GSK medical monitor 
allowed patient to continue if this criterion was 
met after patient completed Week 48 of IP
dosing.  If GSK medical monitor granted 
permission, then NOT Important
Prohibited Medication
Subject used prohibited medication(s) and/or 
therapies at any time during the study.
Incorrect IP or IP dose administered 
Site administered wrong IP to subject
Dose of >=20mg/kg/day given at more than 2 
consecutive visits


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Category
GSK Important Deviations 
Failure to report SAE 
SAE discovered as never reported
Liver Stopping Criteria
Patient met liver stopping criteria and not 
reported to GSK
OR 
Liver stopping criteria reported but patient
received additional doses of IP without GSK 
approval
Blinding and Unblinding
An event that led to improper unblinding to 
Sponsor, CRO, site and/or subject 


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18.9.
Appendix 9 Per Protocol Population Exclusions
According to the RAP and the PDMP, if a subject meets the following major study 
criteria, then they will be excluded from the Per Protocol population:

Received an incorrect treatment most of the time (>50% of the time).

Did not self-identify as black race (Inclusion Criterion 2).

Did not have a clinical diagnosis of SLE according to the American College of 
Rheumatology (ACR) criteria (Inclusion Criterion 3)

Did not have active SLE disease defined as a SELENA SLEDAI score >= 8 at 
screening (Inclusion Criterion 4)

Did not have unequivocally positive anti-nuclear antibody (ANA) test results 
from 2 independent time points as defined in the inclusion criteria (Inclusion 
Criterion 5)

Was not on a stable SLE treatment regimen at baseline as defined in the protocol 
(Inclusion Criterion 6)

Received an excluded medication prior to Day 0 (Exclusion Criteria 1-6)

Missed 3 or more consecutive study agent infusions

Study blind/unblind procedures   Investigator/site staff/GSK Clinical team did 
not remain blinded to treatment assignment through Week 52/Exit visit efficacy 
evaluation

Other, a deviation that does not satisfy the above criteria, however, in the 
judgment of the clinical team, including the medical monitor, constitutes an 
exclusion from the Per Protocol population
Specific Adjudications: All violations will be discussed and adjudicated as important or 
not important and for exclusion from the Per Protocol population.


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18.10.
Appendix 10 Laboratory Parameters
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count
Differential:
Absolute Neutrophils 
o Segmented Neutrophils
o Band Neutrophils
o Myelocytes 
o Metamyelocytes 
o 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:

AST

ALT

Alkaline Phosphatase

GGT

LDH
Other:

Creatinine

Blood urea nitrogen

BUN/creatinine ratio

Bilirubin, total

Protein, total

Albumin

Uric acid

Glucose

Estimated Creatinine 
Clearance/GFR 
(Cockcroft-Gault) 
Biological Markers
Autoantibodies
FACS of peripheral lymphocytes: 
B lymphocytes
CD19+
CD20+ 
CD20+/27+memory
CD20+/27+ memory (%CD19)
CD20+/27– naïve
CD20+/27– naïve (%CD19)
CD20+/69+ activated
CD20+/138+plasmacytoid
CD27+BRIGHT/CD20– Short-
lived plasma cells
CD19+/27BRIGHT/38BRIGHT SLE 
subset 
CD19+/CD24HIGH /CD38HIGH
regulatory B cell
CD20-/138+plasma cells
Complement
C3 
C4 
BLyS Protein
ANA
Anti-dsDNA
aCL
Lupus anti-coagulant
±beta-2-glycoprotein-1**
ENAs**
Immunoglobulins
PK/Immunogenicity
Serum immunoglobulin isotypes:
IgG, IgM, IgA
PK assessment
Immunogenicity assessment


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18.11.
Appendix 11 Adverse Event and Laboratory Toxicity
Grading Tables


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18.12.
Appendix 12 Adverse Events of Special Interest
Prior to RAP finalization this section will be updated to reflect the latest version of 
the Benlysta PSAP. 
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 version of MedDRA can be found in Attachment 3.    
Malignant neoplasms
Malignant neoplasms are identified using the sub-SMQs of Malignant or unspecified 
tumours (20000091) and Malignancy related conditions (20000092) 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 
(Attachment 3).  In addition, the following customizations have been made:

The term “Paraneoplastic glomerulonephritis” has been removed from the SMQ as it 
is a complication of malignancy. 

The term “Mismatch repair cancer syndrome” has not been assigned a tumor type.

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” is added as a tumour of unspecified malignancy.
Non-melanoma skin cancer (NMSC) will be categorized using a CMQ developed by the 
Marketing authorization holder (MAH) (Attachment 3).
Post-infusion/injection systemic reactions
Post-infusion/injection 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 Category A. Category A has been 
modified to include the following additional terms: “Infusion-related reaction,” “Drug 


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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 
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/injection 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/injection 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 9.4.35 or 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/injection systemic reactions or hypersensitivity reactions per 
the criteria in Section 9.4.35. Adverse events with partial or missing start dates will be 
included unless there is evidence through comparison of partial dates to suggest 
otherwise.


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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 Injection-related Reaction per Anaphylactic Reaction SMQ broad 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 injection.
Infections
The infections of special interest are described below.
Opportunistic Infections
Opportunistic infections will be identified using a broad CMQ developed by the MAH 
(Attachment 3). 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 PSAP Appendix 7: Potential Opportunistic Infections.  
Mycobacterium Tuberculosis
Tuberculosis events will be identified using a CMQ developed by the MAH (Attachment 
3). 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 PSAP 
(PSAP Appendix 7: Potential Opportunistic Infections).
Herpes Zoster
Herpes Zoster events will be identified using a CMQ developed by the MAH 
(Attachment 3). Additional manual adjudication by GSK prior to database release will 
identify events that are recurrent or disseminated (PSAP Appendix 7: Herpes Zoster).


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Pneumonia
Pneumonia events will be identified using a CMQ developed by the MAH (Attachment 
3).  Pneumonia events will not be reported separately, but are being flagged in the event 
further evaluation is necessary.
Sepsis
Sepsis events will be identified using a CMQ developed by the MAH (Attachment 3).
Depression/suicide/self-injury
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 (Attachment 3).
Suicide and Self-Injury
Suicide and self-injury events will be identified using the SMQ (20000035) preferred 
terms (Attachment 3).
Fatalities
All fatalities will be identified in the clinical database and subsequently adjudicated by 
the GSK SRT into a general category of death (PSAP Appendix 7: Fatalities).
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.
GSK SRT Adjudication of Adverse Events of Special Interest
Adverse events of special interest (AESI) are identified per the preferred terms 
(Attachment 3) and other criteria described in PSAP Appendix 6.  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 ongoingly 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).


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Malignancies
All malignancies identified via the terms in Attachment 3 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 per the terms in Attachment 3, 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 
malignant; tumor types with higher likelihood for malignancy would be assumed to be 
malignant).
Serious Hypersensitivity and Post-Infusion/Injection Systemic Reactions
Before the data base is released, GSK SRT will review all serious cases identified from 
the Broad Anaphylaxis SMQ as described in PSAP Appendix 6 and Attachment 3, 
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, descriptions of associated symptoms are taken into account for 
this categorization. In studies where subjects are receiving weekly injections, any 
delayed, non-acute reactions will typically occur in the interval 4-7 days later, but may 
occur up to 21 days later following a missed injection or after the last injection.
In addition, possible cases of serious anaphylaxis per Sampson criteria will be identified 
per the criteria in PSAP Appendix 6. 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.
Potential Opportunistic Infections
Opportunistic infections (OIs) will be identified using a list of preferred terms 
(Attachment 3), 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 


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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)

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 listed in Attachment 3, 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)


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Herpes Zoster 
Herpes Zoster events will be identified per terms in Attachment 3. Adjudication by GSK 
prior to database release 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 nor disseminated.
Mycobacterium Tuberculosis
Tuberculosis (TB) cases are reviewed clinically by the GSK SRT before data base release 
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.
Suicide/self-injury
Suicide and self-injury SAEs will be identified using the preferred terms identified in 
Attachment 3 and subsequently adjudicated into the following categories:
Adjudicated Category
Suicidal Behavior
      Completed Suicide
Suicidal Ideation
Self-Injurious Behavior without Suicidal Intent
In addition, GSK SRT will review all SAEs, including those coded under preferred terms 
not listed in Attachment 3, and utilizing the supplemental/narrative information, will 
adjudicate the SAEs as suicide/self-injury if warranted based on medical judgment. 
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


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Adjudicated Category of Death
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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18.13.
Appendix 13 B Cells
B Cell Panel
(BIMETHCD)
Biomarker 
Category Code
[BICATCD]
Biomarker 
Category
[BICAT]
Lab Test 
Code
(LBTESTCD)
Lab Test Code
(LBTEST)
Units of 
Measurement
(BIORRESU/
LBORRESU)
FLWTBNK
CD19
CD19
CD19LY
CD19/Lymphocyte
s
%
FLWTBNK
CD19
CD19
CD19
CD19
GI/L
FLWPLSM
CD19
CD19
CD19E
CD19 Number of 
Events
EVENTS
FLWTRANS
CD19
CD19
CD19E
CD19 Number of 
Events
EVENTS
FLWPLSM
CD20
CD20
CD20CD19
CD20/CD19+
%
FLWPLSM
CD20
CD20
CD20
CD20 Number of 
Events 
EVENTS
FLWPLSM
CD20
CD20
CD20E
CD20
GI/L
FLWPLSM
CDX136
CD20+ CD27-
CDX13619
CD20+ CD27-
/CD19+
%
FLWPLSM
CDX136
CD20+ CD27-
CDX136E
CD20+ CD27-
Number of Events
EVENTS
FLWPLSM
CDX136
CD20+ CD27-
CDX136
CD20+ CD27-
GI/L
FLWPLSM
CDX137
CD20+ CD27+
CDX13719
CD20+ 
CD27+/CD19+
%
FLWPLSM
CDX137
CD20+ CD27+
CDX137E
CD20+ CD27+
Number of Events
EVENTS
FLWPLSM
CDX137
CD20+ CD27+
CDX137
CD20+ CD27+
GI/L
FLWPLSM
CDX141
CD20+ CD69+
CDX14119
CD20+ 
CD69+/CD19+
%
FLWPLSM
CDX141
CD20+ CD69+
CDX141
CD20+ CD69+
GI/L
FLWPLSM
CDX141
CD19+CD20+
CD69+
CDX141E
CD20+CD69+_Nu
mber of events
EVENTS
FLWPLSM
CDX143
CD20-
CD138+
CDX14319
CD20-
CD138+/CD19+
%
FLWPLSM
CDX143
CD20-
CD138+
CDX143E
CD20- CD138+
Number of Events
EVENTS
FLWPLSM
CDX143
CD20-
CD138+
CDX143
CD20- CD138+
GI/L
FLWPLSM
CDX145
CD20+ 
CD138+
CDX14519
CD20+ 
CD138+/CD19+
%
FLWPLSM
CDX145
CD20+ 
CD138+
CDX145E
CD20+ CD138+
Number of Events
EVENTS
FLWPLSM
CDX145
CD20+ 
CD138+
CDX145
CD20+ CD138+
GI/L
FLWPLSM
CDX154
CD27+b 
CD20-
CDX15419
CD27+b CD20-
/CD19+
%
FLWPLSM
CDX154
CD27+b 
CD20-
CDX154E
CD27+b CD20-
Number of Events
EVENTS
FLWPLSM
CDX154
CD27+b 
CDX154
CD27+b CD20-
GI/L


CONFIDENTIAL
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148
B Cell Panel
(BIMETHCD)
Biomarker 
Category Code
[BICATCD]
Biomarker 
Category
[BICAT]
Lab Test 
Code
(LBTESTCD)
Lab Test Code
(LBTEST)
Units of 
Measurement
(BIORRESU/
LBORRESU)
CD20-
FLWPLSM
CDX156
CD27+CD38+
CD19+
CDX15619
CD27+CD38+CD1
9+/CD19+
%
FLWPLSM
CDX156
CD27+CD38+
CD19+
CDX156E
CD27+CD38+CD1
9+ Number of 
Events
EVENTS
FLWPLSM
CDX156
CD27+CD38+
CD19+
CDX156
CD27+CD38+CD1
9+
GI/L
FLWTRANS
CDX199
CD19+ 
CD24b+ 
CD38b+ CD27
CDX19919
CD19+ CD24b+ 
CD38b+ 
CD27/CD19+
%
FLWTRANS
CDX199
CD19+ 
CD24b+ 
CD38b+ CD27
CDX199
CD19+ CD24b+ 
CD38b+ CD27
CELLS/CUM
M
FLWTRANS
CDX199
CD19+ 
CD24b+ 
CD38b+ CD27
CDX199E
CD19+ CD24b+ 
CD38b+ CD27
Number of Events
EVENTS
FLWTRANS
CDX200
CD19+CD24b
+CD38b+
CD27-IgD+ 
CD10+
CDX20019
CD19+CD24b+CD
38b+CD27-
IgD+CD10+/CD19
+
%
FLWTRANS
CDX200
CD19+CD24b
+CD38b+
CD27-IgD+ 
CD10+
CDX200
CD19+CD24b+CD
38b+CD27-
IgD+CD10+
CELLS/CUM
M
FLWTRANS
CDX200
CD19+CD24b
+CD38b+
CD27-IgD+ 
CD10+
CDX200E
CD19+24b+38b+2
7-IgD+10+ Num of 
Events
EVENTS


CONFIDENTIAL
BEL115471
149
B cell subsets to be reported:
Lab Test Code (LBTESTCD)
Lab Test (LBTEST)
Units of Measurement1
(LBORRESU)
Display Label for B cell
Common B cells
CD19
CD19
GI/L
CD19 (/uL)
CD20
CD20
GI/L
CD20 (/uL)
CDX136
CD20+ CD27-
GI/L
Naive CD19+CD20+CD27- (/uL)
CDX13619
CD20+ CD27-/CD19+
%
Naive CD19+CD20+CD27- (%CD19)
CDX137
CD20+ CD27+
GI/L
Memory CD19+CD20+CD27+ (/uL)
CDX13719
CD20+ CD27+/CD19+
%
Memory CD19+CD20+CD27+ (%CD19)
Rare B cells2
CDX141N
CD20+ CD69+
GI/L
Activated CD19+CD20+CD69+ Normalised (COUNT/mL)
CDX143N
CD20- CD138+
GI/L
Plasma CD19+CD20-CD138+ Normalised (COUNT/mL)
CDX145N
CD20+ CD138+
GI/L
Plasmacytoid CD19+CD20+CD138+ Normalised (COUNT/mL)
CDX154N
CD27+b CD20-
GI/L
Short-lived Plasma CD19+CD20-CD27b+ Normalised (COUNT/mL)
CDX156N
CD27+CD38+CD19+
GI/L
SLE Subset CD19+CD38b+CD27b+Lymph Normalised (COUNT/mL)
CDX199N
CD19+ CD24b+ CD38b+ CD27-
GI/L
Transitional CD19+CD24b+CD38b+CD27- Normalised (COUNT/mL)
1GI/L=109/L
2The lab test code for the new record containing the normalized value will be the same as the corresponding absolute B cell concentration record prior to 
normalization, suffixed with N. The display label corresponds to the normalized value that is to be reported in the displays.


CONFIDENTIAL
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150
18.14.
Appendix 14 Headline Results
The following tables will be included as headline results:
Table numbers will be populated when numbering is finalized.
1.02
Populations (Double-Blind Phase) (randomized)
1.03
Summary of Subject Disposition for the Double-Blind Subject 
Conclusion Record (mITT)
1.08
Summary of Demographic Characteristics (Double-blind phase) 
(mITT)
1.13
Baseline Disease Activity (Double-blind phase) (mITT)
2.01
SRI-S2K Response at Week 52 (Double-blind phase) (mITT)
2.02
Logistic Regression Analysis of SRI-S2K Response at Week 52 
(Double-blind phase) (mITT)
2.03
SRI-S2K Response at Week 52 and the 3 Components (Double-blind 
phase) (mITT)
2.09
SRI-S2K Response by Visit (Double-blind phase) (mITT)
2.21
SRI response by visit using SELENA SLEDAI (Double-blind phase) 
(mITT)
2.25
Time to First Severe SFI Flare over 52 Weeks (Double-blind phase) 
(mITT)
2.27
Prednisone Reduction by >= 25% from Baseline to <= 7.5 mg/day 
during Week 40 through Week 52 (DO/TF=NR) (Double-blind 
phase) (mITT)
3.15
Serious Adverse Events by SOC and PT (Double-Blind phase) 
(Safety)
3.19
Adverse Events Resulting in Study Agent Discontinuation (Double-
Blind phase) (Safety)
3.23
Adverse Events of Special Interest by Category (Double-Blind phase) 
(Safety)
3.59
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Immunoglobulins (Double-Blind phase) (Safety)


CONFIDENTIAL
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151
19.
ATTACHMENTS
19.1.
Attachment 1: Table of Contents for Data Display 
Specifications
See separate TFL document.
19.2.
Attachment 2: Data Display Specifications
See separate TFL document.
19.3.
Attachment 3: AESI Preferred Term Definitions under 
MedDRA v20.1
The AESI definitions are stored at the project level for GSK1550188.

Prot_000.pdf: 
CLINICAL PROTOCOL HGS1006-C1112
Protocol Amendment: 02
Date: 09 February 2017
EudraCT Number: 2011-005672-42
TITLE OF STUDY:
A Phase 3/4, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-
Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Adult 
Subjects of Black Race with Systemic Lupus Erythematosus (SLE) 
STUDY SPONSOR:
Human Genome Sciences, Inc.
9910 Belward Campus Drive
Rockville, Maryland 20850
U.S.A.
Confidentiality
This document contains proprietary and confidential information of Human 
Genome Sciences, Inc. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or 
disclosed without prior written approval from Human Genome Sciences, Inc., 
except that this document may be disclosed to study personnel under your 
supervision who need to know the contents for conducting the study and 
appropriate Institutional Review Boards/Independent Ethics Committees under 
the condition that they are requested to keep it confidential. The foregoing shall 
not apply to disclosure required by governmental regulations or laws, however, 
Human Genome Sciences, Inc. must be promptly informed of any such 
disclosure.


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Revision Chronology for HGS1006-C1112 (BEL115471)
Date
Document*
Global
21 November 2011
Original
Global
20 June 2012
Amendment No 01
Local
2014N219219_00
02 February 2015
Local Amendment No 01 for France
Global
2014N199062_00
09 February 2017
Amendment No 02
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.


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Investigator Agreement
I will provide copies of the protocol, any subsequent amendments and access to all 
information furnished by the sponsor to study personnel under my supervision. I will 
discuss this material with them to ensure that they are fully informed about the 
investigational study agent and the study protocol. I agree to conduct this clinical trial 
according to the protocol described herein, except when mutually agreed to in writing 
with the sponsor. I also agree to conduct this study in compliance with Good Clinical 
Practice (GCP) standards as defined by the International Conference on Harmonisation 
(ICH) Guideline for Good Clinical Practice, all applicable national, state, and local 
regulations, as well as the requirements of the appropriate Institutional Review 
Board/Independent 
Ethics 
Committee 
(IRB/IEC) 
and 
any 
other 
institutional 
requirements.
Principal Investigator:
Signature
Date (dd mmm yy)
Name (please type or print)
Institution
Address


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STUDY SYNOPSIS
Study Number: HGS1006-C1112
Title of the Study: A Phase 3/4, Multi-Center, Randomized, Double-Blind, 
Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab 
(HGS1006) in Adult Subjects of Black Race with Systemic Lupus Erythematosus (SLE).
Clinical Development Phase: 3/4
Objectives:
•
To evaluate the efficacy of belimumab in adult SLE subjects of black race.
•
To evaluate the safety and tolerability of belimumab in adult SLE subjects of black 
race.
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria:
1. Are at least 18 years of age.
2. Are of self-identified black race.
3. Have a clinical diagnosis of SLE according to the American College of 
Rheumatology (ACR) criteria (See Appendix 1). 
4. Have active SLE disease defined as a SELENA SLEDAI score ≥ 8 at screening (refer 
to Appendix 5 and Section 6.8.1.1 Scoring for Proteinuria for Eligibility at 
Screening). 
5. Have 2 unequivocally positive autoantibody test results defined as a positive
antinuclear antibody (ANA) test [ie, a titer ≥ 1:80 by HEp-2 immunofluorescence 
assay (IFA) and/or positive enzyme immunoassay (EIA)] and/or a positive anti-
dsDNA (≥ 30 IU/mL) serum antibody test as follows: 
•
from 2 independent time points within the study screening period. Screening 
results must be based on the study’s central laboratory results.
OR
•
One positive historical test result and 1 positive test result during the screening 
period.  
-
Historical documentation of a positive ANA test (eg, HEp-2 IFA or EIA) or 
anti-dsDNA (eg, anti-dsDNA by any validated commercial assay) must 
include the date and type of the test, the name of the testing laboratory, 
numerical reference range, and a key that explains values provided as positive 
vs negative OR negative, equivocal/borderline positive). Only unequivocally 
positive values as defined in the laboratory’s reference range are acceptable; 
borderline values will not be accepted.
6. Are on a stable SLE treatment regimen consisting of any of the following medications 
(alone or in combination) for a period of at least 30 days prior to Day 0 (ie, day of 1st
dose of study agent) [Refer to Section 5.5.1 for allowable medications and maximum 
dose]: 


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•
Corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day):
-
For subjects on SLE combination therapy, their stable steroid dose must be 
fixed within the range of 0 to 40 mg/day (prednisone or prednisone 
equivalent).
-
For subjects whose only SLE treatment is steroids, their stable steroid dose 
must be fixed within the range of 7.5 to 40 mg/day (prednisone or prednisone 
equivalent).  
-
For those subjects on alternating day doses of steroids, use the average of 2 
daily doses to calculate the average daily steroid dose.
•
Other immunosuppressive or immunomodulatory agents including methotrexate, 
azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, 
mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin 
inhibitors (eg, tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-
mercaptopurine, mizoribine, or thalidomide.
•
Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
•
Non-steroidal anti-inflammatory drugs (NSAIDs).
NOTE: 
•
Pre-existing SLE medications must be stable for at least 30 days prior to Day 0.
•
Corticosteroids may be added as new medication or their doses adjusted only up 
to 30 days prior to Day 0 (see Exclusion Criterion #6).
•
New SLE therapy other than corticosteroids must not be added within 60 days of 
Day 0 (see Exclusion Criterion #5).
7. A female subject is eligible to enter the study if she is:  
•
Not pregnant or nursing; 
•
Of non-childbearing potential defined as
•
pre-menopausal females with a documented tubal ligation, hysterectomy, 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, or documented bilateral 
oophorectomy or
•
postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile [eg, > 45 years, in the absence of hormone 
replacement therapy or other cause for amenorrhea]; in questionable cases 
obtain a blood sample for follicle stimulating hormone (FSH) and estradiol 
simultaneously to confirm. Diagnostic levels for FSH and estradiol vary by 
specific laboratories/assays; 
•
OR is of child-bearing potential with negative pregnancy test as determined by 
serum human chorionic gonadotrophin (hCG) test at screening and urine hCG test 
prior to dosing AND
•
Agrees to use one of the contraception methods listed in the protocol (see 
Section 4.3) for 2 weeks prior to the day of dosing to sufficiently minimize the 


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risk of pregnancy at that point.  Female subjects must agree to use
contraception until 16 weeks following the last dose of study agent.
•
OR has only same-sex partners, when this is her preferred and usual lifestyle.
8. Have the ability to understand the requirements of the study, provide written 
informed consent (including consent for the use and disclosure of research-related 
health information), and comply with the study protocol procedures (including 
required study visits). 
Exclusion Criteria: Subjects will be excluded from participating in the study if they 
meet any of the following exclusion criteria:
1. Have received treatment with anti-BLyS [belimumab]) at any time. 
2. Have received any of the following within 364 days of Day 0:
•
Abatacept.
•
Other B cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 
[epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], 
TACI-Fc, or anti-BAFF (LY2127399).
•
A biologic investigational agent other than B cell targeted therapy (eg, abetimus 
sodium, anti-CD40L antibody [BG9588/IDEC-131]). (Investigational agent 
applies to any drug not approved for sale in the country in which it is being used.)
3. Have required 3 or more courses of systemic corticosteroids for concomitant 
conditions (eg, asthma, atopic dermatitis) within 364 days of Day 0. (Topical or 
inhaled steroids are permitted.)
4. Have received any of the following within 90 days of Day 0:  
•
Anti-TNF therapy (eg, adalimumab, certolizumab pegol, etanercept, golimumab, 
infliximab).
•
Intravenous (IV) cyclophosphamide.
•
Interleukin-1 receptor antagonist (anakinra).
•
Intravenous immunoglobulin (IVIG).
•
High dose prednisone or equivalent (> 100 mg/day).
•
Plasmapheresis.
5. Have received any of the following within 60 days of Day 0:
•
A non-biologic investigational agent. 
•
Any new immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID 
(see Inclusion Criterion #6).
-
Note: New inhaled and topical steroids and new topical immunosuppressive 
agents (eg, eye drops, topical creams) are allowed. Any NSAID use for < 1 
week is allowed.
•
Any steroid injection (eg, intramuscular, intraarticular, or intravenous).


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6. Have received any of the following within 30 days of Day 0:
•
A live vaccine. 
•
A change in dose of a corticosteroid, other 
immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID (see 
Inclusion Criterion #6).
7. Have severe lupus kidney disease (defined by proteinuria > 6 g/24 hour or equivalent 
using spot urine protein to creatinine ratio, or serum creatinine > 2.5 mg/dL), or have 
severe active nephritis requiring acute therapy not permitted by protocol (eg, IV 
cyclophosphamide within 90 days of Day 0), or have required hemodialysis or 
high-dose prednisone or equivalent (> 100 mg/day) within 90 days of Day 0. 
8. Have severe active central nervous system (CNS) lupus (including seizures, 
psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis, or 
CNS vasculitis) requiring therapeutic intervention within 60 days of Day 0.
9. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant.
10. Have clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, 
hepatic, renal, neurological, malignancy, or infectious diseases) which, in the opinion 
of the principal investigator, could confound the results of the study or put the subject 
at undue risk.
11. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
12. Have a history of malignant neoplasm within the last 5 years, except for adequately 
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine 
cervix.
13. Have required management of acute or chronic infections, as follows:
•
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical 
mycobacteria).
•
Hospitalization for treatment of infection within 60 days of Day 0.
•
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of Day 0. 
14. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) (refer to Appendix 3 for 
baseline/screening C-SSRS) in the last 2 months or who, in the investigator's opinion, 
pose a significant suicide risk.
15. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to Day 0. 
16. Have a historically positive test or test positive at screening for HIV antibody, 
hepatitis B surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C 
antibody.
17. Have an IgA deficiency (IgA level < 10 mg/dL).


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18. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event 
Severity Grading Tables (Appendix 12) except for the following that are allowed:
•
Stable Grade 3 prothrombin time (PT) secondary to anticoagulant, eg, warfarin,
treatment.
•
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and 
not related to liver disease or anti-coagulant therapy.
•
Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to 
creatinine ratio allowed).
•
Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver 
disease or malnutrition.
•
Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes, or viral 
hepatitis. If present, any abnormalities in ALT and/or AST must be ≤ Grade 2.
•
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. 
•
Stable Grade 3 hemoglobin reduction due to lupus.
19. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins, or monoclonal antibodies.
Study Design and Schedule: 
This is a Phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult 
subjects of black race with active SLE. Approximately 501 SLE subjects will be 
randomized with a target of at least 334 subjects receiving belimumab and 167 subjects 
receiving placebo.
In addition to receiving stable standard therapy, subjects will be randomized in a 2:1 ratio 
to treatment with either 10 mg/kg belimumab or placebo. At randomization, subjects will 
be stratified by their screening SELENA SLEDAI score (8-9 vs ≥ 10), complement level 
(C3 and/or C4 low vs other), and region (US/Canada vs rest of the world). Subjects will 
be dosed with study agent on Days 0, 14, 28, and then every 28 days through 48 weeks, 
with a final evaluation at Week 52 (4 weeks after the last dose). Study agent will be 
administered intravenously (IV) over no less than 1 hour. Subjects will remain under 
clinical supervision for 3 hours after completion of the first 2 infusions during the 52-
week double-blind phase and 6-month open-label extension.
All subjects will continue the stable standard therapy they were receiving during the 
screening period. Subjects who complete dosing up to 48 weeks will return for a Day 
364/Week 52 (final evaluation) visit. Subjects who successfully complete the initial 52 
week double-blind phase may enter into a 6-month open-label extension. The Day 
364/Week 52 visit will serve as the Day 0 visit for subjects entering the 6-month open-
label extension. Subjects on active drug or placebo will receive belimumab 10 mg/kg IV 
every 28 days for 6 months in the open-label extension. The 1st dose on the 6-month 
open-label extension will be given on Day 364 (Week 52) of the double-blind treatment 
phase following the completion of all Day 364 (Week 52) assessments. Subjects 
participating in the 6-month open-label extension will continue to be monitored for safety 


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and more latitude will be permitted for background medication changes as outlined in 
Section 5.5.
At the end of the 6-month open-label period, subjects who wish to continue treatment 
may do so by being prescribed commercially available product. If belimumab is not 
commercially available in a subject’s country of participation, subjects may continue to 
receive belimumab under a separate continuation protocol.  A separate informed consent 
will need to be provided for the continuation protocol. The 8-week follow up visit is not 
required for subjects entering the separate continuation protocol.  Subjects who complete 
the 52-week double-blind phase, but do not enter the 6-month open-label extension will 
be required to return for an additional follow up visit 8 weeks after the last dose of study 
agent. Subjects who withdraw early will be required to return for an Exit visit (4 weeks 
after the last dose of study agent) and a follow-up visit approximately 8 weeks after their 
last dose of study agent. In the event that a subject discontinues study agent at any time 
during the study or withdraws consent, an attempt will be made to ascertain survival 
status approximately 52 weeks after the first dose of study agent.
Belimumab and placebo will be supplied in open-label vials. The study agent will be 
reconstituted and diluted by the unblinded site pharmacist or unblinded designee. The 
unblinded site pharmacist or unblinded designee will also be the person responsible for 
receiving and dispensing study agent, but independent of all other study activities. Except 
for a limited number of safety oversight personnel, all other study site personnel, the 
subject, the sponsor, and the contract research organization (CRO) will remain blinded to 
the study agent received and to certain biomarkers and pharmacodynamic laboratory 
results. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study.
Efficacy Endpoints and Analysis:
The primary efficacy endpoint is the systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K scoring for proteinuria at Week 52.
A SRI response is defined as:
•
≥ 4 point reduction from baseline in SELENA SLEDAI score (with the modified 
SLEDAI-2K scoring for proteinuria), 
AND
•
No worsening (increase of < 0.30 points from baseline) in Physician’s Global 
Assessment (PGA), 
AND
•
No new BILAG A organ domain score or 2 new BILAG B organ domain scores 
compared with baseline at the time of assessment (ie, at Week 52).


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Major secondary efficacy endpoints: 
1. SRI response rate with the SELENA SLEDAI for scoring of proteinuria at Week 52.
2. Time to first severe flare (as measured by the modified SLE Flare Index; with 
SLEDAI-2K and SELENA SLEDAI as the SLEDAI criterion of the SFI).
3. Percent of subjects whose average prednisone dose has been reduced by ≥ 25% from 
baseline to ≤7.5 mg/day during Weeks 40 through 52, in subjects receiving greater 
than 7.5 mg/day at baseline.
Sample Size Calculation:
Approximately 501 subjects will be randomized and treated in the study, with a target of 
at least 334 subjects in the arm receiving belimumab and 167 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 15.55% absolute improvement in the SRI response 
rate with the modified SLEDAI-2K scoring for proteinuria for the 10 mg/kg belimumab 
group relative to the placebo group (assumed rate = 43.95%) at Week 52. This sample 
size is also sufficient to provide approximately 80% power at a 5% level of significance 
to detect a minimum of a 13.4% absolute improvement in the SRI response rate with the 
SELENA SLEDAI scoring for proteinuria for the 10 mg/kg belimumab group relative to 
the placebo group (assumed rate = 44.8%).
The selection of these assumed treatment differences is based on the observed SRI data 
from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 (Northeast 
Asia), which are two efficacy studies that concluded in 2015 and 2016, respectively, and 
have nearly identical eligibility criteria to study HGS1006-C1112 including requiring a 
screening SS score ≥8.
Analysis of Primary Efficacy Endpoint:
The proportion of subjects achieving a treatment response at Week 52 will be compared 
between the belimumab treatment group and placebo using a logistic regression model, 
adjusted for baseline randomization factors. The independent variables in the model will 
include treatment groups (ie, belimumab vs placebo), baseline SELENA SLEDAI score 
(≤9 vs ≥ 10), complement level (C3 and/or C4 low vs other), and region (US/Canada vs 
rest of the world). However, the adjustment will not occur for any of these baseline 
randomization factors that has < 10 responders or < 10 non-responders in a stratification 
level (Peduzzi et al, 1996). The analysis will be performed on an intention-to-treat (ITT) 
population, defined as all subjects who are randomized and treated with at least 1 dose of 
study agent. The ITT analysis will be performed according to the treatment that a subject 
was randomized to receive, regardless of the actual treatment received. 
Any subject who withdraws from the study prior to the Day 364 (Week 52) visit, misses 
the Day 364 (Week 52) visit (± 28 day window allowed), and/or starts a prohibited 
medication or dose prior to the Day 364 (Week 52) visit will be considered a non-
responder for the Week 52 primary efficacy analysis.  


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Analysis of Major Secondary Efficacy Endpoints:
The SRI response rate with the SELENA SLEDAI scoring for proteinuria at Week 52 
will be compared between the belimumab treatment group and the placebo group using 
the same analysis methods as described for the primary endpoint.
The time to the 1st severe SLE flare over 52 weeks will be compared between the 
belimumab treatment group and the placebo group using the Cox proportional hazard 
model. The independent variables in the model will include treatment groups (ie, 
belimumab vs placebo), baseline SELENA SLEDAI score (≤ 9 vs ≥ 10), complement 
level (C3 and/or C4 low vs other), and region (US/Canada vs rest of the world). 
However, this adjustment will not occur for any of these baseline randomization factors
that has < 10 events (severe flares) or < 10 non-events in a stratification level. If a subject 
withdraws from the study or completes the study up to the Day 364 (Week 52) visit 
without any severe SLE flare, time to the 1st severe SLE flare will be censored at the 
time of the last observation. If a subject receives a dose of protocol prohibited/restricted 
medication that results in treatment failure designation up to the Week 52 visit, the 
subject will be considered as having a severe SLE flare at the time the medication is 
started.
The percent of subjects with average prednisone dose that has been reduced by ≥ 25% 
from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 will be compared between the 
belimumab treatment and the placebo groups using a logistic regression model. The 
independent variables in the model will include treatment groups (ie, belimumab vs 
placebo), baseline SELENA SLEDAI score (≤ 9 vs ≥ 10), complement level (C3 and/or 
C4 low vs other), and region (US/Canada vs rest of the world). However, the adjustment 
will not occur for any of these baseline randomization factors that has < 10 events (ie, 
having a prednisone reduction by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 
through 52) or < 10 non-events in a stratification level. The analysis will be performed on 
subjects who used prednisone > 7.5 mg/day at baseline. Any subject who withdraws from 
the study prior to the Day 364 (Week 52) visit, misses the Day 364 (Week 52) visit, 
and/or receives a dose of protocol prohibited/restricted medication that results in 
treatment failure designation prior to the Day 364 (Week 52) visit will be considered as 
without any prednisone reduction for the analysis.  
Other efficacy endpoints are described in Section 8.5.4.
Safety Endpoints and Analysis:
Descriptive statistics will be used to summarize adverse events (AEs), changes in 
laboratory parameters, and immunogenicity. The frequency and rate of laboratory 
abnormalities will be tabulated by treatment group. The frequency and rate of adverse 
events will be tabulated by MedDRA system organ class (SOC) and preferred term and 
compared between placebo and belimumab treatment groups.
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this study on an ongoing basis until the data are locked and analyzed through Week 
52. The IDMC will include at least 3 physicians, and a statistician, none of whom are 


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affiliated with the sponsor. Events to be monitored during the safety review will include 
at a minimum all serious adverse events (including deaths, serious psychiatric events, and 
serious infections), Grade 3 and Grade 4 laboratory abnormalities, opportunistic 
infections (serious and nonserious), malignancies, and hypersensitivity/anaphylactic 
reactions.  The 1st IDMC data review meeting will occur after the first 100 subjects have 
been treated through Day 56 or within 6 months of the treatment of the 1st subject, 
whichever is earlier. After the initial review, the committee will review the data 
approximately every 6
months.
Investigators and Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), as appropriate, will be notified of the 
outcome of each IDMC meeting.
PK Endpoints and Analysis:
Blood samples will be collected during the study and analyzed to determine serum 
belimumab concentrations. Serum belimumab concentration data will be used in a 
population PK analysis, which will be reported separately.
Immunogenicity:
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent on Days 0, 56 (Week 8), 
168 (Week 24), 364/Exit (Week 52), and at the 8-week follow-up visit. 
Biological Markers and Autoantibodies:
The following biological markers will be measured at baseline (Day 0) and at multiple 
time points thereafter: 
•
Autoantibodies: anti-dsDNA, anti-phospholipid antibodies (aCL, lupus anticoagulant, 
± beta-2-glycoprotein-1), and extractable nuclear antigens (ENAs).
•
ANA (baseline).
•
Serum immunoglobulin isotypes: IgG, IgM, IgA.
•
Serum complement (C3, C4).
•
BLyS protein (baseline).
In geographies where feasible, the following biological markers will be measured at 
baseline (Day 0) and at multiple time points thereafter:
•
FACS of peripheral lymphocytes: 
-
B lymphocytes (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+
activated, CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/24HIGH/38HIGH regulatory B cells, and CD20-/138+ plasma cells).
Study Calendar:
See Section 6 and Table 6-1 and Table 6-2 for a calendar of study visits and assessments.
Study Schematic:
See Figure 0-1.


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Figure 0-1
Study schematic
a
The last dose of study agent is given on the Day 336 (Week 48) visit to subjects NOT participating in the 6-month open-label extension.
b
Subjects participating in the 6-month open-label extension phase of the study are dosed on the Day 364/Week 52 visit of the double-blind period after the 
completion of all Day 364/Week 52 assessments. This Day 364/Week 52 represents the first dose (ie, Day 0) of the 6-month open-label extension. For 
subjects not participating in the 6-month open-label extension, the Day 364/Week 52 visit serves as the Exit visit, with follow-up visit occurring 8 weeks after 
the last dose of study agent.
c
The primary treatment period includes 48 weeks of study agent administration (Day 0 to the Day 336 visit) and a final visit for the primary endpoint 
assessment at Week 52 which is 4 weeks after the last dose of the study agent.
d
An Exit visit (1-4 weeks after the last dose of study agent) and a follow-up visit 8 weeks after the last dose of study agent will be performed for subjects 
withdrawing at any time during the study. The 8-week follow-up visit is not required in subjects entering the separate continuation protocol.
e
At the end of the 6-month extension period, subjects who wish to continue treatment may do so by being prescribed the commercially available IV belimumab. 
If IV belimumab is not commercially available in a subject’s country of participation, subjects may continue to receive belimumab administered IV every 4 
weeks under a separate continuation protocol.


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Table of Contents
Study Synopsis.....................................................................................................................4
Table of Contents...............................................................................................................14
List of Tables .....................................................................................................................17
List of Figures....................................................................................................................18
List of Abbreviations .........................................................................................................19
1.
Background............................................................................................................22
1.1.
Disease Background.........................................................................................22
1.2.
Belimumab.......................................................................................................23
1.2.1.
Mechanism of Action.............................................................................23
1.2.2.
Clinical Experience with Belimumab Administered Intraveneously.....23
1.3.
Rationale for the Study ....................................................................................25
1.3.1.
General Rationale...................................................................................25
1.3.2.
Choice of Target Patient Population......................................................26
1.3.3.
Rationale for Choice of Primary Endpoint for Efficacy........................27
1.3.4.
Rationale for Dose and Schedule...........................................................27
1.4.
Benefit-Risk Assessment .................................................................................27
1.4.1.
Risk Assessment ....................................................................................27
1.4.2.
Benefit Assessment................................................................................33
1.4.3.
Overall Benefit:Risk Conclusion...........................................................33
2.
Study Objectives ....................................................................................................33
3.
Study Design..........................................................................................................33
4.
Inclusion and Exclusion Criteria............................................................................34
4.1.
Inclusion Criteria .............................................................................................34
4.2.
Exclusion Criteria ............................................................................................36
4.3.
Contraception Requirements for Female Subjects...........................................38
5.
Study Treatment Regimen .....................................................................................39
5.1.
Study Agent Name and Formulation ...............................................................39
5.2.
Packaging, Labeling, Preparation, and Storage ...............................................40
5.3.
Dose, Route of Administration, and Schedule.................................................41
5.4.
Alteration of Dose/Schedule Due to Toxicity..................................................42
5.5.
Concurrent Medications...................................................................................42
5.5.1.
Allowable Medications ..........................................................................43
5.5.2.
Prohibited Medications and Therapies...................................................48
5.5.3.
Live Vaccines.........................................................................................49
6.
Study Procedures ...................................................................................................49
6.1.
Screening Procedures (Day -35 to Day 0) .......................................................49
6.2.
Study Enrollment Procedures ..........................................................................50


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6.3.
Double-Blind Treatment Period.......................................................................51
6.4.
6-Month Open-Label Extension ......................................................................56
6.5.
Exit Visit..........................................................................................................58
6.6.
8-Week Follow-up Visit ..................................................................................58
6.7.
Unscheduled Visits ..........................................................................................58
6.8.
Laboratory Tests ..............................................................................................58
6.8.1.
Guidelines for Scoring Proteinuria for SELENA SLEDAI...................59
6.8.2.
Pharmacokinetics...................................................................................60
6.8.3.
Liver Stopping Criteria ..........................................................................61
6.8.4.
Immunogenicity.....................................................................................62
6.9.
Withdrawal of Subjects from Treatment..........................................................63
6.10.
Subject Unblinding ..........................................................................................63
7.
Adverse Event Reporting.......................................................................................64
7.1.
Definitions........................................................................................................64
7.2.
Reporting Adverse Events to the Sponsor .......................................................66
7.3.
Laboratory Abnormalities as Adverse Events .................................................66
7.4.
Progressive Multifocal Leukoencephalopathy.................................................67
7.5.
Suicidality Assessment ....................................................................................67
7.5.1.
Possible Suicidality Related Questionnaire (PSRQ)..............................68
7.6.
Reporting a Pregnancy.....................................................................................68
7.7.
Investigator Evaluation of Adverse Events......................................................68
7.8.
Follow-Up of Adverse Events .........................................................................69
7.9.
Disease Related Events....................................................................................70
7.10.
Regulatory Reporting Requirements for SAEs................................................70
8.
Endpoints and Statistical Analysis.........................................................................72
8.1.
General Statistical Considerations...................................................................72
8.2.
Randomization Procedure and Assignment to Treatment Groups...................72
8.3.
Independent Data Monitoring Committee (IDMC).........................................72
8.4.
Sample Size Rationale .....................................................................................73
8.5.
Efficacy............................................................................................................74
8.5.1.
Primary Efficacy Endpoint ....................................................................74
8.5.2.
Primary Efficacy Analysis.....................................................................74
8.5.3.
Secondary Efficacy Endpoints...............................................................75
8.5.4.
Other Efficacy Endpoints.......................................................................75
8.5.5.
Secondary Efficacy Analyses ................................................................78
8.5.6.
Other Efficacy Analyses ........................................................................79
8.6.
Safety ...............................................................................................................79
8.6.1.
Definition of Safety Variables ...............................................................79
8.6.2.
Analysis of Safety Variables..................................................................79


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8.7.
Pharmacokinetics.............................................................................................80
8.7.1.
Definition of Pharmacokinetic Evaluation.............................................80
8.7.2.
Analysis of Pharmacokinetics................................................................80
9.
Pharmacogenetics (PGx)........................................................................................80
10.
Study Administration.............................................................................................80
10.1.
Informed Consent.............................................................................................81
10.2.
Institutional Review Board Review/Independent Ethics Committee 
Review and Approval ......................................................................................81
10.3.
Protocol Compliance........................................................................................81
10.4.
Protocol Revisions ...........................................................................................81
10.5.
Data Collection and Management....................................................................82
10.6.
Study Monitoring.............................................................................................82
10.7.
Drug Accountability.........................................................................................83
10.8.
Retention of Records........................................................................................83
10.9.
Financial Disclosure.........................................................................................83
10.10. Publication Policy............................................................................................83
10.11. Study or Study Site Termination......................................................................84
11.
References..............................................................................................................85
List of Appendices.............................................................................................................90


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List of Tables
Table 1-1
Safety in black subgroup vs all other races............................................26
Table 1-2
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk...29
Table 5-1
Algorithm for reducing dose of prednisone ...........................................46
Table 5-2
Recommended, standardized initial steroid dosing and steroid 
tapering algorithm for treatment of an SLE flare...................................47
Table 6-1
Study calendar- On-treatment evaluations.............................................52
Table 6-2
Study calendar 6-month open-label extension .......................................57
Table 6-3 
PK visit days and sample times..............................................................61
Table 8-1
SRI Results From Studies BEL112341 and BEL113750.......................73
Table 11-1 
Major SLE presentations where steroids would be used......................129
Table 11-2 
Recommended, standardized initial steroid dosing and steroid 
tapering.................................................................................................130


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List of Figures
Figure 1-1 
Treatment effect in black subgroup in Phase 3 vs Phase 2 (SRI at 
Week 52) ................................................................................................25


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List of Abbreviations
aCL
anticardiolipin
ACR
American College of Rheumatology
AE
adverse event
ANA
anti-nuclear antibody 
ANCOVA
analysis of covariance
Anti-dsDNA
anti-double-stranded DNA
Anti-TNF
anti-tumor necrosis factor
ARB
angiotensin receptor blocker
AUC
area under the serum drug concentration-time curve
BAFF
B-cell activating factor
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BLyS
B lymphocyte stimulator
BR3
BLyS-receptor fusion protein
BUN
blood urea nitrogen
ºC
degrees Celsius
CD
cluster of differentiation
Clcr
creatinine clearance
CNS
central nervous system
COX
cyclooxygenase
CrCl
creatinine clearance
CRF
case report form
CRO
Contract Research Organization
CRP
C-reactive protein
C-SSRS  
Columbia-Suicide Severity Rating Scale
CVA
cerebrovascular accident
DI
damage index
dL
deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DO=F
dropout = failure
dsDNA
double stranded DNA
DSM
Diagnostic and Statistical Manual
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data capture
EIA
Enzyme immunoassay
ELISA
enzyme linked immunosorbent assay
ENA
extractable nuclear antigens
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FACS
florescence activated cell sorting
Fc 
immunoglobulin constant region (fragment crystallizable)
FDA
United States Food and Drug Administration
g
gram
GCP
Good Clinical Practice


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GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLP
Good Laboratory Practice
HB
Hepatitis B
HBsAg
Hepatitis B surface antigen
hCG
human chorionic gonadotrophin
HEp-2
human epithelial cell line 2
HGS
Human Genome Sciences, Inc.
HIV
human immunodeficiency virus
HLA
human leukocyte antigen 
Hpf
high power field
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFA
immunofluorescence assay
Ig
immunoglobulin
IM
intramuscular
IRB
Institutional Review Board
ITT
intention to treat
IUD
intrauterine device
IV
intravenous
IVIG
intravenous immunoglobulin
IVRS
interactive voice response system
IWRS
interactive web response system
JVC
John Cunningham virus
kg
kilogram
LDH
lactic dehydrogenase
LOCF
last observation carried forward
MCID
minimal clinically important difference
MDD 
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MITT
modified intention to treat
MMF
mycophenolate mofetil
μg
microgram
mg
milligram
μL
microliter
mL
milliliter
NS0
mouse myeloma cell line
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NSAIDs
non-steroidal anti-inflammatory drugs
NWHIC
National Women’s Health Information Center
OD
optical density
OMHRC
Office of Minority Health Resource Center
PASS
Power Analysis and Sample Size
PGA
Physician’s Global Disease Assessment


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PGx
pharmacogenetics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PO
per os (by mouth)
PSRQ
possible suicidality related questionnaire
PSRHQ
possible suicidality related history questionnaire
PT
prothrombin time
PTT
partial thromboplastin time
QOL
quality of life
RA
rheumatoid arthritis
RBC
red blood cell
SAE
serious adverse event
SC
subcutaneous
scFv
single chain antibody
SD
standard deviation
SELENA
Safety of Estrogen in Lupus National Assessment trial
SFI
SELENA flare index
SLE 
systemic lupus erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SOC
system organ class
SRI
Systemic Lupus Erythematosus responder index
SWFI
sterile water for injection
t1/2,term
terminal half-life 
TNF
tumor necrosis factor
ULN
upper limits of normal
US
United States of America
USAN/INN
United States adopted name/international nonproprietary name
WBC
white blood cell


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1.
BACKGROUND
1.1.
Disease Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by 
autoantibody production and abnormal B lymphocyte function (Pisetsky, 2001). The 
etiology of SLE is unknown, although genetics, sex hormones, and environmental 
conditions are thought to play a role (Kotzin, 1996; Pisetsky, 1998; Sobel et al, 1999). 
This disease is more common in women (~90% of patients) than men (NWHIC, 2003) 
and more prevalent in African-Americans than Caucasians (OMHRC, 2001; NWHIC, 
2003). In the United States (US) the reported prevalence is 100,000 to 500,000 patients 
with some estimates of 1 million as the incidence increased 2-3 fold between 1950 and 
1979. In the European Union (EU), prevalence rates have been reported ranging from 25 
to 39 cases per 100,000 persons (Jiménez et al, 2003). The disease onset is generally 
between the ages of 20 and 40 years. 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 (Houssiau et al, 2004).
SLE can lead to arthritis, kidney failure, heart and lung inflammation, central nervous 
system (CNS) changes, vasculitis, severe skin rash, and blood dyscrasias such as anemia, 
leukopenia, and thrombocytopenia. The manifestations of SLE vary from patient to 
patient and it may take many years to render the proper diagnosis. The American College 
of Rheumatology (ACR) criteria that define a diagnosis of this heterogeneous disease 
require 4 of 11 criteria that include SLE-associated signs or symptoms, lab abnormalities, 
and the presence of specific anti-nuclear autoantibodies (Tan et al, 1982).
The current paradigm of the pathogenesis of SLE begins with a genetic predisposition 
(multi-factorial as > 10 chromosomal regions have been identified) that leads to the 
production of pathogenic autoantibodies, cytokine abnormalities, and autoreactive 
effector B and T lymphocytes (Harley et al, 1998; Lipsky, 2001; Schur, 1995). B 
lymphocyte abnormalities include an altered state of B lymphocyte differentiation, 
indicated by increased numbers of plasma cells secreting immunoglobulin (Ig), especially 
during times of increased clinical activity (Grammer and Lipsky, 2003). B lymphocytes 
isolated from SLE patients often have dysregulated expression of cell surface molecules, 
such as B7 and CD40, suggesting an enhanced state of B lymphocyte activation 
(Yazdany and Davis, 2004). 
The behavior of laboratory biomarkers in SLE is under active investigation (Illei et al, 
2004a; Illei, 2004b; Schiffenbauer et al, 2004). As yet, no clear surrogate endpoints have 
been widely accepted that clearly define clinical outcomes for the multi-organ system 
manifestations of SLE. As such, it is important to evaluate multiple markers of disease 
activity which may be clinically meaningful. Autoantibodies have been shown to be 
important early markers of specific disease processes or severity in SLE (Hahn, 1998; 
Leslie
et al, 2001; Ravirajan
et al, 2001) and are associated with disease 
activity (Villarreal et al, 1997). Autoantibodies can be directly involved in the disease 
process by binding to their target antigen and initiating immune injury by triggering a 
cascade of cellular and cytokine responses or indirectly, through immune complex 


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formation (Kotzin, 1996; Macchi et al, 1997). Many of the specific autoantibodies 
associated with autoimmune diseases appear to be antigen selected and require 
T lymphocyte help associated with conventional B lymphocyte antibody responses (Ando
et al, 1987; Hahn, 1998). Patients with active general or organ-specific SLE may have 
distinct autoantibody profiles (Villarreal et al, 1997). The mechanism for initiation of 
these autoantibody responses is unclear. However, prolonged survival of B lymphocytes, 
molecular mimicry, altered tolerance to self-antigens, and abnormal apoptosis have been 
proposed as potential triggering mechanisms (Hutloff et al, 2004).
Standard therapies for SLE include corticosteroids (the mainstay of therapy), anti-
malarial agents (eg, hydroxychloroquine), non-steroidal anti-inflammatory drugs 
(NSAIDs), 
cytotoxic 
agents 
like 
cyclophosphamide, 
and 
immunosuppressive/immunomodulatory agents used in cancer or transplantation (eg, 
azathioprine, cyclosporine, mycophenolate mofetil (MMF), methotrexate, leflunomide, 
thalidomide, 6-mercaptopurine). (Brocard et al, 2005; Chatham and Kimberly, 2001; 
Ginzler et al, 2005; Houssiau et al, 2004; Petri, 2001; Reveille, 2001; Ruiz-Irastorza et al, 
2001; Wallace, 2002). These therapies can be associated with significant toxicity. Long-
term use of high-dose corticosteroids can cause significant morbidity including 
osteoporosis, osteonecrosis, metabolic disorders (including exacerbation of diabetes), 
increased infection risk, edema, weight gain, and hyperlipidemia (Chatham and 
Kimberly, 2001). Cytotoxic agents like cyclophosphamide are immunosuppressive, 
resulting in increased risk of serious infections and certain cancers. Belimumab (also 
known as BENLYSTATM) is also approved in the United States (US), Canada, and the 
EU for the treatment of adult patients with active autoantibody-positive SLE who are 
receiving standard therapy; patients with severe active lupus nephritis and severe active 
CNS lupus were excluded, as were patients receiving other biologics and IV 
cyclophosphamide (refer to specific country labeling for additional information regarding
the approved indication). Approval of belimumab for SLE is being sought in other 
regions of the world.
1.2.
Belimumab
1.2.1.
Mechanism of Action
Belimumab (also known as LymphoStat-B; BENLYSTATM) is a B lymphocyte 
stimulator (BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B cell 
survival factor, to its receptors 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.  
Nonclinical pharmacologic, pharmacokinetic (PK), and toxicologic data generated with 
belimumab are provided in the Investigator’s Brochure (IB).
1.2.2.
Clinical Experience with Belimumab Administered Intraveneously
Belimumab administered as an IV infusion in SLE patients has been studied in 1 Phase 1 
trial (LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial (LBSL02),


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and 2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 (HGS1006-
C1057) and BLISS 76 (HGS1006-C1056)], and in rheumatoid arthritis (RA) patients in a 
Phase 2 double-blind, placebo-controlled trial (LBRA01). Belimumab administered by 
subcutaneous injection is also being evaluated in clinical trials.
Phase 3 studies of belimumab administered IV in SLE were completed in 2009 and 2010 
and formed the basis of the approval of belimumab in the US, Canada, and the EU. The 
Phase 3 trials included 1,684 subjects where belimumab 10 mg/kg plus standard therapy
demonstrated superiority over placebo plus standard therapy in reduction in disease 
activity as measured by the SLE responder index (SRI) with an acceptable safety profile.
The primary safety population supporting approval also included data from a Phase 2 
study in 449 subjects with SLE. Evidence of benefit in other clinical measures such as 
reductions in disease activity as measured by SELENA SLEDAI, severe flare, and 
reduced steroid use were also observed. Treatment with belimumab plus standard therapy
was generally well tolerated, with rates of adverse events (AEs), severe AEs, serious 
AEs, AEs leading to discontinuation, and serious/severe infections generally comparable 
to the rates observed in the placebo plus standard therapy group. Mortality rates in the 
controlled clinical trials were low, although numerically higher in the belimumab groups:
0.4% and 0.8% in the placebo and belimumab groups, respectively. Causes of death were 
as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as steroids and immunosuppressants, and included
infection, 
cardiovascular disease, and suicide. Serious infections were observed in 5.2% and 6.0% 
of subjects receiving placebo and belimumab, respectively. The rate of malignancy 
(excluding non-melanoma skin cancer) was the same between the placebo and 
belimumab groups at 0.4%; however, as with other immunomodulating agents, the 
mechanism of action of belimumab could increase the risk for the development of 
malignancies. Hypersensitivity and infusion reactions were observed. Anaphylaxis was 
also observed, though rare (< 1%). Depression-related events, common in patients with 
SLE, were observed more frequently with belimumab than with placebo; it is unknown if 
belimumab treatment is associated with an increased risk for these events. The most 
commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were 
nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, 
depression, migraine, and pharyngitis.
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests that prolonged treatment with belimumab remains generally well tolerated, with 
no apparent increase in the incidence rate of AEs or serious adverse events (SAEs) over 
time, including important events such as infections and malignancies. The prevalence rate 
of AEs and SAEs has also remained relatively stable over time. Long-term belimumab 
treatment through 6 years appears to provide sustained improvement in SLE disease 
activity. 
Results of the clinical trials of belimumab administered IV are described in further detail 
in the Investigator’s Brochure.  


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1.3.
Rationale for the Study
1.3.1.
General Rationale
Univariate and multivariate subgroup analyses of the primary efficacy endpoint (SRI at 
Week 52) were performed on the pooled Phase 3 study results. Although treatment-by-
race did not trigger an interaction p-value < 0.10 in these analyses, among black subjects 
[N = 148; 80% of whom participated in BLISS 76 (C1056)], response rates were higher 
in the placebo plus standard therapy group than they were in the belimumab plus standard 
therapy groups.
Belimumab had similar effects on biomarkers (autoantibodies, 
complement, and B cell subsets) in black subjects compared with other subjects.
While an apparent lack of benefit was observed in black subjects in Phase 3, the opposite 
was observed in the Phase 2 study, where black subjects (N = 106) had a better response 
to belimumab than non-black subjects. The treatment effect shown as odds ratios in the 
black and non-black subgroups in Phase 3 and Phase 2 is shown in Figure 1-1. The 
reasons for the different results in black subjects in Phase 3 vs Phase 2 are unknown. 
Baseline characteristics were similar in black subjects in Phase 2 and Phase 3. The 
numbers of black subjects in the Phase 2 and Phase 3 studies are too small to draw 
conclusions about observed treatment differences and therefore further study is needed.
Figure 1-1
Treatment effect in black subgroup in Phase 3 vs Phase 2 (SRI at 
Week 52)


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The univariate and multivariate analyses suggested that subjects with higher disease or 
serological activity, as measured by SELENA SLEDAI scores ≥ 10, greater steroid use 
and low complement appeared to benefit from belimumab treatment most. Consistent 
with this finding, black subjects with higher disease activity (SELENA SLEDAI scores 
of at least 10) appeared to derive greater benefit with belimumab treatment.
Importantly, the safety profile in black subjects receiving belimumab was similar to those 
receiving placebo. Although black subjects reported more serious and severe adverse 
events than non-black subjects, the rates were similar between the belimumab and 
placebo groups. There were more discontinuations due to an adverse event in the black 
subgroup than in other races, with a greater rate in the belimumab groups (Table 1-1).
Table 1-1
Safety in black subgroup vs all other races
Black/African American
All Others
Placebo 
N = 74 (%)
1 mg/kg 
N = 72 (%)
10 mg/kg 
N = 78 (%)
Placebo 
N = 601 (%)
1 mg/kg 
N = 601 (%)
10 mg/kg 
N = 596 (%)
At least 1 AE
93.2
97.2
93.6
92.3
92.5
92.6
Serious AE
28.4
19.4
24.4
14.3
18.5
16.4
Severe AE
27.0
19.4
21.8
14.0
15.0
14.4
Serious and/or 
Severe AE
33.8
26.4
29.5
20.0
22.6
21.6
Discontinuation 
due to AE
9.5
12.5
11.5
6.8
5.5
6.0
The small numbers of subjects, and conflicting results, do not allow conclusions to be 
drawn with respect to the efficacy of belimumab in subjects of black race. The available 
data suggests that belimumab has an acceptable safety profile in this population. Given 
that black subjects are disproportionately affected by SLE, both in terms of frequency and 
severity, it is important that the efficacy and safety of belimumab be fully evaluated in 
this population. This multi-center, randomized, double-blind, placebo-controlled, 52-
week study is intended to evaluate the efficacy and safety of IV administered belimumab 
in adult subjects of black race (self-identified) with active, autoantibody-positive, 
systemic lupus erythematosus who are receiving standard therapy.
1.3.2.
Choice of Target Patient Population
Black race is associated with higher prevalence rates of lupus disease, higher overall 
disease activity, increased overall end-organ damage, and higher mortality rates 
compared to Caucasians (Johnson et al, 2006; Uribe and Alarcon, 2003).
The target population to be enrolled in this trial will be adult subjects of self-identified 
black race with a clinical diagnosis of SLE according to the ACR criteria. These subjects 
must have active disease defined as a SELENA SLEDAI score ≥ 8 at screening, and be 
positive for autoantibodies, defined as a positive ANA test, and/or anti-dsDNA (≥ 30 
IU/mL) at 2 time points prior to randomization. A minimum SELENA SLEDAI score of 
8 and a positive diagnosis by the ACR criteria (at least 4 of 11 manifestations of SLE) 


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will ensure enrollment of an SLE population with active disease. Subjects in the Phase 3 
trials with SELENA SLEDAI scores ≥7 had higher response rates to belimumab.
1.3.3.
Rationale for Choice of Primary Endpoint for Efficacy
The primary efficacy endpoint is response by the SLE responder index (SRI) response 
rate with the modified SLEDAI-2K scoring for proteinuria at Week 52. It is evidence-
based and supported by the data from the Phase 2 (LBSL02) and Phase 3 (HGS1006-
C1056 and C1057) SLE trials. This was the primary efficacy endpoint in the Phase 3 
trials of belimumab IV. The SRI includes an objective measure of the reduction in global 
disease activity (reduction in SELENA SLEDAI score ≥4) and 2 measures to ensure that 
the improvement in disease activity is not offset by worsening of the subject’s condition 
overall (ie, no worsening in the PGA defined as an increase of < 0.3 points) or worsening 
in any specific organ system (ie, no new BILAG A or 2 new B organ domain scores).
1.3.4.
Rationale for Dose and Schedule
The dose and schedule to be studied is 10 mg/kg administered as an IV infusion over no 
less than 1 hour, at 2-week intervals for the first 3 doses and at 4-week intervals 
thereafter.
In the Phase 3 trials supporting approval of belimumab in the US, Canada, and EU, only 
the 10 mg/kg dose achieved the primary endpoint in both Phase 3 IV trials, although both 
1 mg/kg and 10 mg/kg belimumab were active. The SRI (including prespecified and post-
hoc sensitivity analyses), severe flare risk reduction, and normalization of complement all 
favored the 10 mg/kg dose. While reductions in steroid dose favored 1 mg/kg, fewer 
patients receiving 10 mg/kg belimumab required increases in steroid dose. Certain B cell 
subsets, 
including 
plasma 
cells, 
short-lived 
plasma 
cells, 
and 
CD19+/CD27BRIGHT/CD38BRIGHT B cells, also showed trends for a dose response favoring 
10 mg/kg. Importantly, there was no consistent pattern of dose-related adverse findings.
The totality of the data supported approval of the 10 mg/kg dose of belimumab in the US,
EU, and Canada, and approvals in other countries are being sought.
1.4.
Benefit-Risk Assessment
1.4.1.
Risk Assessment
Belimumab administered by IV infusion is indicated for reducing disease activity in adult 
patients with active autoantibody positive SLE who are receiving standard therapy. The 
benefit/risk profile of belimumab for SLE remains favorable.
Identified risks include hypersensitivity/infusion reactions and non opportunistic 
infections. Potential risks (ie, based on pharmacology but no association identified to 
date) include progressive multifocal leukoencephalopathy (PML);
malignancies; 
immunogenicity; effects on immunizations (including interactions with live vaccine); and
psychiatric events including depression and suicidality.


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The most common AEs reported in the primary safety population of adults with SLE 
were associated with hypersensitivity/infusion related reactions, infections, and 
symptoms consistent with SLE.  The majority of reports of infusion-related and 
hypersensitivity reactions were non-serious and include symptoms such as nausea, 
vomiting, diarrhea, chills, fever, rash, urticaria, pruritus, headache, dizziness, and 
dyspnoea.  However, infusion and hypersensitivity reactions can be severe and fatal.  
Most clinical trial and spontaneous cases of serious hypersensitivity occurred during or 
within the first hour after the completion of the infusion, although some cases report 
delayed acute onset (>4 hours but <4 days) or a delayed non-acute onset (4-21 days) 
hypersensitivity reactions.  
Infections have been reported with administration of belimumab and are also associated 
with both SLE and immunosuppressant medication used to treat SLE. The mechanism of 
action of belimumab may increase the potential risk for the development of infections.  In 
the phase 2 and 3 clinical trials, there was a slight increase in the overall rate of infections 
in the belimumab group compared with the placebo group. There was no difference in the 
rate of serious infections, infections leading to discontinuation, or infections of special 
interest. Out to 10 years in the Phase 2 and 3 continuation studies, the incidence rate of 
serious infections has remained stable or declined over time.
Table 1-2 provides a summary of key issues, their impact, and strategy to mitigate risk in 
this study.


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Table 1-2
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Post-injection 
systemic reactions 
and 
Hypersensitivity 
Administration of belimumab may result in 
infusion and hypersensitivity reactions, 
which can be severe and can be fatal.  
Non-serious infusion reactions and 
hypersensitivity reactions are common in 
SLE clinical trials with IV belimumab.  
Serious infusion and hypersensitivity 
reactions affected less than 1% of patients 
and included anaphylactic reaction, 
bradycardia, hypotension, angioedema, 
and dyspnea. Delays in the onset of 
hypersensitivity reactions have been 
observed. Infusion reactions following 
administration of belimumab occurred 
more frequently on the first 2 infusion days 
and tended to decrease with subsequent 
administrations. Delayed-type, non-acute 
hypersensitivity reactions have also been 
observed and included symptoms such as
rash, nausea, fatigue, myalgia, headache, 
and facial oedema.
Exclusion of subjects with a 
history of an anaphylactic reaction 
to parenteral administration of 
contrast agents, human or murine 
proteins or monoclonal antibodies.
Subjects should remain under clinical 
supervision for 3 hours after completion of the 
first 2 infusions. Should symptoms of acute 
hypersensitivity occur, an extended period of 
monitoring may be appropriate, based on 
clinical judgment. Otherwise, subjects will be 
monitored 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.  Subjects should be 
made aware of the potential risk, the signs 
and symptoms of such reactions, and the 
importance of immediately seeking medical 
attention.  Belimumab should be administered 
by a healthcare professional prepared to treat 
hypersensitivity reactions including 
anaphylaxis.
Infections
Infections occurred in a slightly greater 
proportion of subjects treated with 
belimumab compared with placebo. 
Infections occurring in at least 3% of 
patients receiving belimumab and at least 
1% more frequently than patients receiving 
Exclude patients with any of the 
following: currently on any 
suppressive therapy for a chronic 
infection; hospitalization for 
treatment of an infection within 60 
days of Day 0; use of IV or IM 
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
placebo were nasopharyngitis, bronchitis, 
pharyngitis, cystitis, and gastroenteritis 
viral.  Serious infections occurred in 5% of 
patients receiving either belimumab or 
placebo.
antibiotics within 60 days of Day 
0; a history of or positive test at 
screening for HIV, hepatatis B or 
hepatitis C; have Grade 3 or 4 
lymphopenia; or have Grade 3 or 
4 IgG or IgA deficiency
Progressive 
multifocal 
leukoencephalopa
thy (PML)
No association between belimumab and 
the risk of opportunistic infections, 
including PML, has been indentified to 
date, but data are limited. 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.
Malignancies
As with other immunomodulating agents, 
the mechanism of action of belimumab 
may increase the potential risk for the 
development of malignancies.
Exclude patients with a history of 
malignant neoplasm within the 
last 5 years, except for adequately 
treated basal or squamous cell 
cancers of the skin, or carcinoma 
in situ of the uterine cervix.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, 
request that patients report signs and 
symptoms.  Treat appropriately.
Immunogenecity
As with other monoclonal antibodies, 
treatment with belimumab could lead to the 
development of anti-drug antibodies 
Monitor anti-drug antibody laboratory values.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
(ADA). Among SLE subjects treated with 
belimumab, the proportion of subjects who 
developed persistently positive ADA was 
low and very few of the persistently 
positive antibodies were found to be 
neutralizing. Neither development of ADA 
nor persistent ADA was associated with 
infusion or hypersensitivity reactions. As 
expected, the proportions of subjects with 
persistent ADA increased slightly over time 
in belimumab-treated subjects but (there 
was no increase in the number of subjects 
with neutralizing antibodies or the number 
reporting infusion-related adverse events. 
Effects on 
immunizations 
including reactions 
with live vaccines
No data are available on the secondary 
transmission of infection from persons 
receiving live vaccines to patients receiving 
belimumab. Because of its mechanism of 
action, belimumab may interfere with the 
response to immunisations. The efficacy of 
concurrent vaccination in patients receiving 
belimumab is not known.  Limited data 
suggest that belimumab does not 
significantly affect the ability to maintain a 
protective immune response to 
immunisations received prior to 
administration of belimumab. 
Exclude patients who have 
received a live vaccine within 30 
days of Day 0.
Do not administer live vaccines concurrently.
Potential 
There have been reports of depression 
Exclude patients who have 
Monitor patients for signs and symptoms of 


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
psychiatric events 
- Depression and 
suicidality
and suicidality in patients receiving 
belimumab.  The estimated rates of 
suicidality for belimumab remain consistent 
with the rates of the background SLE 
population.  The background rate for 
completed suicide identified in the 
literature ranged from 0.02 to 2.18 per 100 
PY and varied by study type (clinical trial or 
observational study) [Li-Yu 2007; Cervera
2003; Cervera 2006; Cervera 2009]. The 
background rate for suicidal behavior 
(completed suicide and attempts) is 0.12 
(95% CI 0.05, 0.24)/100 patient years 
[Karassa 2003].
evidence of serious suicide risk 
including any history of suicidal 
behaviour in the last 6 months 
and/or any suicidal ideation of 
type 4 or 5 on the Columbia 
Suicide Severity Rating Scale 
[C-SSRS in the last 2 months or 
who in the investigator's 
judgment, pose a significant 
suicide risk.
psychiatric events including depression and 
suicidality, request that patients report signs 
and symptoms.  Treat appropriately


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Refer to Section 8.3 for information about the Independent Data Monitoring Committee 
(IDMC) being used in the study.
1.4.2.
Benefit Assessment
The primary data supporting efficacy of belimumab were the Phase 3 trials (C1056 and 
C1057) in which 1,684 subjects were treated for up to 52 weeks (C1057) or 76 weeks 
(C1056) 
(Belimumab 
IB, 
Section 
5.3.1.2). 
Belimumab 
produced 
significant 
improvements in the SLE Responder Index as well as in individual component SELENA-
SLEDAI score in both studies. Pooled analyses demonstrated steroid sparing, delay in 
median time to first flare, and decreased risk of severe flares over 52 weeks. Clinical trial 
data for belimumab since approval continue to show efficacy in the treatment of SLE 
through decreased SLE flares and decreased disease activity across multiple organ 
systems (Belimumab IB, Section 5.3.1.3).
1.4.3.
Overall Benefit:Risk Conclusion
The safety profile of belimumab remains consistent with that known at approval and is 
consistent with expected events based on the mechanism of action and the disease under 
study. Appropriate risk mitigation measures are in place; rare and long-term risks will be 
further evaluated via the large safety study and registry, ongoing and future studies, and 
routine pharmacovigilance. Review of safety data is conducted on a continual basis in 
order to identify new safety signals which may arise from clinical trial and/or post-
marketing reports. The benefit: risk profile of belimumab for SLE continues to be 
favorable.
2.
STUDY OBJECTIVES
•
To evaluate the efficacy of belimumab in adult SLE subjects of black race.
•
To evaluate the safety and tolerability of belimumab in adult SLE subjects of black
race.
3.
STUDY DESIGN
This is a Phase 3/4, multi-center, international, randomized, double-blind, placebo-
controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult black 
subjects with active SLE. Approximately 501 SLE subjects will be randomized with a 
target of at least 334 subjects treated with belimumab and 167 subjects receiving placebo.
In addition to receiving stable standard therapy, subjects will be randomized in a 2:1 ratio 
to treatment with either 10 mg/kg belimumab or placebo. At randomization, subjects will 
be stratified by their screening SELENA SLEDAI score (8-9 vs ≥ 10), complement level 
(C3 and/or C4 low vs other), and region (US/Canada vs rest of the world). Subjects will 
be dosed with study agent on Days 0, 14, 28, and then every 28 days through 48 weeks, 
with a final evaluation at Week 52 (4 weeks after the last dose). Study agent will be 
administered IV over no less than 1 hour. Subjects will remain under clinical supervision 


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for 3 hours after completion of the first 2 infusions during the 52-week double-blind 
phase and 6-month open-label extension.
All subjects will continue the stable standard therapy they were receiving during the 
screening period. Subjects who complete dosing up to 48 weeks will return for a 
Day 364/Week 52 (final evaluation) visit. Subjects who successfully complete the initial 
52 week double-blind phase may enter into a 6-month open-label extension. The 
Day 364/Week 52 visit will serve as the Day 0 visit for subjects entering the 6-month 
open-label extension. Subjects on active drug or placebo will receive belimumab 10 
mg/kg IV every 28 days for 6 months in the open-label extension. The 1st dose on the 6-
month open-label extension will be given on Day 364 (Week 52) of the double-blind 
treatment phase following the completion of all Day 364 (Week 52) assessments.
Subjects participating in the 6-month open-label extension will continue to be monitored 
for safety and more latitude will be permitted for background medication changes as 
outlined in Section 5.5. Subjects who complete the 52-week double-blind phase, but do 
not enter the 6-month open-label extension will be required to return for an additional 
follow up visit 8 weeks after the last dose of study agent. Subjects who withdraw early 
will be required to return for an Exit visit (4 weeks after the last dose of study agent) and 
a follow-up visit approximately 8 weeks after their last dose of study agent. The 8-week 
follow up visit is not required for subjects entering the separate continuation protocol. In 
the event that a subject discontinues study agent at any time during the study or 
withdraws consent, an attempt will be made to ascertain survival status approximately 52 
weeks after the first dose of study agent.
At the end of the 6-month open-label period, subjects who wish to continue treatment 
may do so by being prescribed commercially available product. If belimumab is not 
commercially available in a subject’s country of participation, subjects may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent 
will need to be provided for the continuation protocol.
4.
INCLUSION AND EXCLUSION CRITERIA
4.1.
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Are at least 18 years of age.
2. Are self-identified black race.
3. Have a clinical diagnosis of SLE according to the American College of 
Rheumatology (ACR) criteria (see Appendix 1). 
4. Have active SLE disease defined as a SELENA SLEDAI score ≥ 8 at screening (refer 
to Appendix 5 and Section 6.8.1.1 Scoring for Proteinuria for Eligibility at 
Screening). 
5. Have 2 unequivocally positive autoantibody test results defined as a positive 
antinuclear antibody (ANA) test [ie, titer ≥ 1:80 by HEp-2 immunofluorescence assay 
(IFA) and/or positive enzyme immunoassay (EIA)] and/or a positive anti-dsDNA (≥ 
30 IU/mL) serum antibody test as follows: 


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•
from 2 independent time points within the study screening period. Screening 
results must be based on the study’s central laboratory results.
OR
•
One positive historical test result and 1 positive test result during the screening 
period.
Historical documentation of a positive ANA test (eg, HEp-2 IFA or EIA) or anti-
dsDNA (eg, anti-dsDNA by any validated commercial assay) must include the 
date and type of the test, the name of the testing laboratory, numerical reference 
range, and a key that explains values provided as positive vs negative OR 
negative, equivocal/borderline positive). Only unequivocally positive values as 
defined in the laboratory’s reference range are acceptable; borderline values will 
not be accepted.
6. Are on a stable SLE treatment regimen consisting of any of the following medications 
(alone or in combination) for a period of at least 30 days prior to Day 0 (ie, day of 1st
dose of study agent) [Refer to Section 5.5.1 for allowable medications and maximum 
dose]: 
•
Corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day):
-
For subjects on SLE combination therapy, their stable steroid dose must be 
fixed within the range of 0 to 40 mg/day (prednisone or prednisone 
equivalent).
-
For subjects whose only SLE treatment is steroids, their stable steroid dose 
must be fixed within the range of 7.5 to 40 mg/day (prednisone or prednisone 
equivalent).  
-
For those subjects on alternating day doses of steroids, use the average of 2 
daily doses to calculate the average daily steroid dose.
•
Other immunosuppressive or immunomodulatory agents including methotrexate, 
azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, 
mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin 
inhibitors (eg, tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-
mercaptopurine, mizoribine, or thalidomide.
•
Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
•
Non-steroidal anti-inflammatory drugs (NSAIDs).
NOTE: 
•
Pre-existing SLE medications must be stable for at least 30 days prior to Day 0.
•
Corticosteroids may be added as new medication or their doses adjusted only up 
to 30 days prior to Day 0 (see Exclusion Criterion #6).
•
New SLE therapy other than corticosteroids must not be added within 60 days of 
Day 0 (see Exclusion Criterion #5).
7. A female subject is eligible to enter the study if she is:  
•
Not pregnant or nursing;
•
Of non-childbearing potential defined as


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•
pre-menopausal females with a documented tubal ligation, hysterectomy, 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, or documented bilateral 
oophorectomy or
•
postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile [eg, > 45 years, in the absence of hormone 
replacement therapy or other cause for amenorrhea]; in questionable cases 
obtain a blood sample for follicle stimulating hormone (FSH) and estradiol 
simultaneously to confirm. Diagnostic levels for FSH and estradiol vary by 
specific laboratories/assays; 
•
OR is of child-bearing potential with negative pregnancy test as determined by 
serum human chorionic gonadotrophin (hCG) test at screening and urine hCG test 
prior to dosing AND
•
Agrees to use one of the contraception methods listed in the protocol (see 
Section 4.3) for 2 weeks prior to the day of dosing to sufficiently minimize the 
risk of pregnancy at that point. Female subjects must agree to use 
contraception until 16 weeks following the last dose of study agent.
•
OR has only same-sex partners, when this is her preferred and usual lifestyle.
8. Have the ability to understand the requirements of the study, provide written 
informed consent (including consent for the use and disclosure of research-related 
health information), and comply with the study protocol procedures (including 
required study visits).
4.2.
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the 
following exclusion criteria:
1. Have received treatment with anti-BLyS [belimumab]) at any time. 
2. Have received any of the following within 364 days of Day 0:
•
Abatacept.
•
Other B cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 
[epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], 
TACI-Fc, or anti-BAFF (LY2127399).
•
A biologic investigational agent other than B cell targeted therapy (e.g., abetimus 
sodium, anti-CD40L antibody [BG9588/IDEC-131]). (Investigational agent 
applies to any drug not approved for sale in the country in which it is being used.)
3. Have required 3 or more courses of systemic corticosteroids for concomitant 
conditions (eg, asthma, atopic dermatitis) within 364 days of Day 0. (Topical or
inhaled steroids are permitted.)
4. Have received any of the following within 90 days of Day 0:
•
Anti-TNF therapy (eg, adalimumab, certolizumab pegol, etanercept, golimumab, 
infliximab).
•
Intravenous (IV) cyclophosphamide


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•
Interleukin-1 receptor antagonist (anakinra).
•
Intravenous immunoglobulin (IVIG).
•
High dose prednisone or equivalent (> 100 mg/day).
•
Plasmapheresis.
5. Have received any of the following within 60 days of Day 0:
•
A non-biologic investigational agent. 
•
Any new immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID 
(see Inclusion Criterion #6).
Note: New inhaled and topical steroids and new topical immunosuppressive agents 
(eg, eye drops, topical creams) are allowed. Any NSAID use for < 1 week is allowed.
•
Any steroid injection (eg, intramuscular, intraarticular, or intravenous).
6. Have received any of the following within 30 days of Day 0:
•
A live vaccine. 
•
A change in dose of a corticosteroid, other 
immunosuppressive/immunomodulatory agent, anti-malarial, or NSAID (see 
Inclusion Criterion #6).
7. Have severe lupus kidney disease (defined by proteinuria > 6 g/24 hour or equivalent 
using spot urine protein to creatinine ratio, or serum creatinine > 2.5 mg/dL), or have 
severe active nephritis requiring acute therapy not permitted by protocol (eg, IV 
cyclophosphamide within 90 days of Day 0), or have required hemodialysis or 
high-dose prednisone (> 100 mg/day) within 90 days of Day 0. 
8. Have severe active central nervous system (CNS) lupus (including seizures, 
psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis, or 
CNS vasculitis) requiring therapeutic intervention within 60 days of Day 0.
9. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant.
10. Have clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, 
hepatic, renal, neurological, malignancy, or infectious diseases) which, in the opinion 
of the principal investigator, could confound the results of the study or put the subject 
at undue risk.
11. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
12. Have a history of malignant neoplasm within the last 5 years, except for adequately 
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine 
cervix.  
13. Have required management of acute or chronic infections, as follows:
•
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical 
mycobacteria).
•
Hospitalization for treatment of infection within 60 days of Day 0.


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•
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of Day 0. 
14. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the 
screening Columbia-Suicide Severity Rating Scale (C-SSRS) (refer to Appendix 3 for 
baseline/screening C-SSRS) in the last 2 months or who, in the investigator's opinion, 
pose a significant suicide risk.
15. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to Day 0. 
16. Have a historically positive test or test positive at screening for HIV antibody, 
hepatitis B surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C 
antibody.
17. Have an IgA deficiency (IgA level < 10 mg/dL).
18. Have a Grade 3 or greater laboratory abnormality based on the  Adverse Event 
Severity Grading Tables (Appendix 12) except for the following that are allowed:
•
Stable Grade 3 prothrombin time (PT) secondary to anticoagulant, eg, warfarin,
treatment.
•
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and 
not related to liver disease or anti-coagulant therapy.
•
Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to 
creatinine ratio allowed).
•
Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver 
disease or malnutrition.
•
Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes, or viral 
hepatitis. If present, any abnormalities in ALT and/or AST must be ≤ Grade 2.
•
Stable Grade 3 hemoglobin reduction due to lupus.
•
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. 
19. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins, or monoclonal antibodies.
4.3.
Contraception Requirements for Female Subjects
Female subjects of childbearing potential must not become pregnant during the study and 
so must be sexually inactive by abstinence or use contraceptive methods with a failure 
rate of < 1%.  Female subjects of childbearing potential with same sex partners (when 
this is their preferred and usual lifestyle) are not required to be abstinent or to use 
contraception.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (eg calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 


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Contraceptive Methods with a Failure Rate of < 1%

Oral contraceptive, either combined or progestogen alone

Injectable progestogen

Implants of levonorgestrel or etonogestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) with  <1% failure rate as 
stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject.  For this definition, “documented” refers to the outcome of the 
investigator's/designee’s review of the subject's medical history for study eligibility, 
as obtained via a verbal interview with the subject or from the subject’s medical 
records.

Double barrier method:  condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository).
NOTE: MMF and other forms of mycophenolate affect the metabolism of oral 
contraceptives and may reduce their effectiveness. As such, women receiving 
mycophenolate who are using oral contraceptives for birth control should employ an 
additional method (eg, barrier method).
NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The investigator is 
responsible for ensuring that subjects understand how to properly use these methods of 
contraception.
5.
STUDY TREATMENT REGIMEN
5.1.
Study Agent Name and Formulation
The common name of the investigational product is BENLYSTATM. The generic 
(USAN/INN) name is belimumab.
Belimumab is a recombinant, human, IgG1λ monoclonal antibody specific for soluble 
human B lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13B). 
Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced 
by recombinant DNA technology in a mammalian cell expression system. 
Belimumab drug product is provided as a sterile, lyophilized product. Upon 
reconstitution with sterile water for injection (SWFI), each vial will contain 80 mg/mL 
belimumab in 0.16 mg/mL citric acid, 2.7 mg/mL sodium citrate, 80 mg/mL sucrose, 0.4 
mg/mL polysorbate 80, pH 6.5. Each lyophilized vial is single use.


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The placebo control is prepared as a sterile and lyophilized product. Upon reconstitution 
with 4.8 mL SWFI, each vial will contain 0.16 mg/mL citric acid, 2.7 mg/mL sodium 
citrate, 80 mg/mL sucrose, 0.4 mg/mL polysorbate 80, pH 6.5. Each lyophilized vial is 
single use.
5.2.
Packaging, Labeling, Preparation, and Storage
Belimumab will be supplied in a 20 mL vial containing 400 mg belimumab (deliverable).
Placebo control will be supplied in a 20 mL vial.
Lyophilized belimumab and placebo should be stored at 2-8°C. After reconstitution and 
dilution in normal saline, the material is stable for up to 8 hours at 2-8°C, or at room 
temperature. Refer to the Pharmacy Manual for detailed instructions on the preparation, 
administration, and storage of study agent.
The 400 mg single use vial of study agent will be reconstituted with 4.8 mL SWFI, to 
yield a final concentration of 80 mg/mL of belimumab. Placebo will be reconstituted with 
4.8 mL SWFI.
In addition to any country-specific requirements, the study agent label will contain, at a 
minimum, the following information:
•
Product name
•
Concentration
•
Lot number
•
Storage conditions
•
Investigational drug statement
•
Manufacturer’s name and address
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's current body weight in 
kilograms (kg) obtained at each visit prior to dosing. At sites where it is impractical to 
use the subject’s current body weight to calculate the dose, it is permissible for the Week 
2 visit onward to use the subject’s body weight from the previous visit (eg, the Day 0 
weight can be used to calculate the dose for the Week 2 visit). However, the subject’s 
body weight will be measured prior to dosing and if the previous visit weight and current 
visit weight vary by more than 10%, then the weight measured at the current visit must be 
used. The reconstituted study agent will be diluted in 250 mL normal saline for IV 
infusion. An amount of normal saline, equal to the calculated amount of product to be 
added (refer to the Pharmacy Manual), should be removed from the infusion bag prior to 
adding the product. After adding the reconstituted product, gently invert the bag to mix 
the solution.
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will 
be employed. The study agent will be reconstituted and diluted by the unblinded site 


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pharmacist or designee, independent of the study (person responsible for receiving and 
dispensing study agent). Except for a limited number of safety oversight personnel, all 
other site personnel, the subject, the sponsor, and contract research organization (CRO) 
will remain blinded to the study agent received and to certain biomarkers and 
pharmacodynamic laboratory results (see Section 6.8). Separate monitors will be 
responsible for the clinical (blinded monitor) and study agent (unblinded monitor) aspects 
of the study.
Study agent inventory/accountability forms will be examined and reconciled by the 
unblinded monitor or designee as long as the study is blinded. After the end of the study 
all used and unused study agent must be accounted for on a study agent accountability 
form provided to the investigator by the sponsor, or its designee.
Refer to the Pharmacy Manual for more details regarding storage, handling, and drug 
accountability.
5.3.
Dose, Route of Administration, and Schedule
The treatment groups consist of one active treatment arm (10 mg/kg belimumab) and a 
placebo arm, with both treatment groups receiving standard therapy. All study agent 
treatments will be administered IV over no less than 1 hour. Once randomized, subjects 
will be dosed with study agent on Days 0, 14, and 28 and every 28 days thereafter 
through 48 weeks of treatment. Subjects who complete the initial treatment period (48 
weeks of treatment with final assessment at Week 52) will be given the option to receive 
belimumab in the 6-month open-label extension phase.
Premedication including an antihistamine, with or without an antipyretic, may be 
administered before the infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) 
are also permitted.
Study agent should be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the 
risk of hypersensitivity reactions, which may present as infusion reactions, and monitor 
subjects closely. In the event of a serious reaction, study agent administration must be 
discontinued immediately and the appropriate medical therapy administered.
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity 
reactions has been observed. Subjects should remain under clinical supervision for 3 
hours after completion of the first 2 infusions in the double-blind treatment phase and the 
6-month open-label extension. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgment. This may 
include, but is not limited to, monitoring vital signs and observing any untoward 
reactions. In addition, delayed-type, non-acute hypersensitivity reaction have also been 
observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and 
facial edema. Beyond the first 2 infusions, subjects should be monitored during and for 
an appropriate period of time after infusion according to the study sites’ guidelines or 
standard operating procedure for IV infusions.


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Subjects should be made aware of the potential risk, the signs and symptoms of such 
reactions, and the importance of immediately seeking medical attention. For further 
information, see the belimumab IB.
5.4.
Alteration of Dose/Schedule Due to Toxicity
The dose of study agent administered may not be altered. The infusion rate may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or 
infusion-associated symptoms (see Section 5.3). At later visits, these subjects may 
continue to be infused over a longer infusion period at the investigator’s clinical 
discretion. 
If a subject experiences a clinically significant AE that the investigator believes may be 
possibly related to study agent and could potentially be exacerbated by the next dose, the 
investigator may delay the dose by up to 2 weeks or withhold 1 dose. If a similar concern 
is present at the time of the next scheduled dose, the investigator should contact the 
Medical Monitor to determine whether treatment with belimumab should be 
discontinued.  
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE 
that the investigator believes may be possibly related to study agent, then treatment with 
study agent will be discontinued. The subject should be withdrawn from the study agent 
and followed until resolution of the AE(s). The subject must also return for an Exit visit 4 
weeks after the last administration of study agent and a follow-up visit 8 weeks after the 
last administration of study agent. An attempt will be made to ascertain survival status 
approximately 52 weeks after the first dose of study agent. 
5.5.
Concurrent Medications
This section reviews the medications and the doses allowed and prohibited during the 
course of the study. Any time the concurrent medication requirements are not followed, 
subjects are considered treatment failures (refer to Appendix 2). Subjects who meet a 
treatment failure criterion prior to completing IP administration at Week 48 should be 
withdrawn from IP and not permitted to enter the 6-month open-label extension of the 
protocol.  The subject must return for an Exit visit 4 weeks after the last administration of 
study agent and a follow-up visit 8 weeks after the last administration of study agent. An 
attempt will be made to ascertain survival status approximately 52 weeks after the first 
dose of study agent. If a subject completes all IP dosing through Week 48 of the protocol, 
and at the Week 52 protocol visit it is determined that a subject has met a treatment 
failure criterion, the subject should complete the Week 52 assessments in the double-
blind period, and after consultation with the Medical Monitor, consideration may be 
given for the subject to enter into the 6-month open-label extension.  The subject will still 
be deemed a treatment failure from the date the criterion was met for analysis purposes.
Dose received for all systemic corticosteroids will be converted to oral prednisone 
equivalent. As such, when "prednisone" is used throughout this protocol, it refers to oral 
prednisone dose or equivalent.


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5.5.1.
Allowable Medications
Subjects must be on a stable SLE treatment regimen for at least 30 days prior to Day 0 
(see Section 4.1 and Section 4.2).
Once the subject is randomized and receives the 1st dose of study agent on Day 0, the 
investigator may adjust concurrent medications (add, eliminate, change dose 
level/frequency) as clinically required; however, changes in certain medications (as 
outlined below) may result in the subject being defined as a treatment failure and may 
require withdrawal from the study following consultation with the medical monitor (see 
Section 5.5). Starting a new protocol-prohibited or restricted medication on the day of the 
Day 364 (Week 52) visit will not be used to classify treatment failure status. A schematic
overview of the adjustments permitted is provided in Appendix 2.
During the 6-month open-label phase (from the Week 52 visit in the double-blind 
treatment period and beyond), the investigator may adjust concurrent medications (add, 
eliminate, change dose level/frequency) as clinically appropriate. Investigators are 
encouraged to consider the guidance provided in Section 5.5.1.2 regarding corticosteroid 
reduction during periods of stable SLE disease. The American College of Rheumatology 
(ACR) draft guidance regarding steroid dosing and tapering in response to SLE flare is 
provided in Appendix 6. Prohibited medications as outlined in Section 5.5.2 will still 
apply.
5.5.1.1.
Anti-malarials
•
A new anti-malarial (eg, hydroxychloroquine, chloroquine, quinacrine) may be 
started between Day 0 and the Day 112 (Week 16) visit.  
•
The dose of an anti-malarial may be reduced during the course of the study. The dose 
of an anti-malarial may be increased as clinically required, up to the Day 112 (Week 
16) visit.  
•
After the Day 112 (Week 16) visit, any increase in dose of an anti-malarial over the 
baseline (Day 0) or Day 112 (Week 16) visit dose, whichever is higher, will declare 
the subject a treatment failure.  
•
Starting any new anti-malarial treatment after the Day 112 (Week 16) visit will 
declare the subject a treatment failure.
-
An anti-malarial treatment will be considered new if the subject did not receive an 
anti-malarial at any time during the Day 0 to Day 112 (Week 16) treatment 
interval.
•
An anti-malarial may be replaced by another anti-malarial due to documented toxicity 
or lack of availability at any time during the study.
The allowable maximum doses of anti-malarial drugs* are:
•
Hydroxychloroquine – 400 mg/day.
•
Chloroquine – 500 mg/day.
•
Quinacrine – 100 mg/day.


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•
Compounded anti-malarials – no individual component may exceed the maximum 
dose above.
*Clinical loading dose is permitted for initiation or replacement.
NOTE: The use of anti-malarials for anti-malarial prophylaxis is permitted.
5.5.1.2.
Corticosteroids
In this section, total systemic steroid dose is defined as the average daily dose of all 
steroids taken SC, IV, IM, intradermally, and orally for both SLE and non-SLE reasons. 
At baseline, the average daily dose of steroids is the sum of steroid dose over 7 
consecutive days up to, but not including Day 0, divided by 7. While on treatment, the 
average daily dose of steroids is the sum of steroid dose over any 7 consecutive days 
divided by 7 in the respective time window.  
5.5.1.2.1.
Systemic Steroids for SLE-related Disease Activity
•
The total dose of systemic steroids as defined above may be increased as clinically 
required during the first 6 months of the trial (ie, until the Day 168 [Week 24] visit), 
but must return to within 25% or 5 mg over the baseline (Day 0) dose, whichever is 
higher, by the Day 168 (Week 24) visit.
•
A subject who fails to return to within 25% or 5 mg over the baseline (Day 0) dose, 
whichever is higher, by the Day 168 (Week 24) visit will be considered a treatment 
failure.  
•
After the Day 168 (Week 24) visit, an increase > 25% or > 5 mg over the baseline 
(Day 0) dose, whichever is higher, for SLE activity will deem the subject a treatment 
failure.
•
Within 8 weeks before the Day 364 (Week 52) visit, no new increase over the 
baseline (Day 0) or Day 308 (Week 44) visit dose, whichever is higher, is allowed. A 
new increase would deem the subject a treatment failure.
5.5.1.2.2.
Intraarticular Injections
•
Subjects may receive intraarticular injections between baseline (Day 0) and the Day 
308 (Week 44) visit.
•
A subject who receives any intraarticular injection(s) within 8 weeks before the Day 
364 (Week 52) visit will be defined as a treatment failure for analysis.  
5.5.1.2.3.
Steroids for Reasons Other Than SLE Disease Activity 
From Day 0 to the Day 168 (Week 24) Visit:
Steroids may be given for reasons other than SLE disease activity (such as asthma, 
contact dermatitis) as clinically indicated until Day 168 (Week 24) visit.


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From Days 168 to 308 (Weeks 24 to 44) Visits:
Steroids may be given for reasons other than SLE disease activity from the Day 168 
(Week 24) visit until the Day 308 (Week 44) visit at any dose/duration that does not 
result in a total steroid dose (for SLE and non-SLE reasons) > 25% or > 5 mg, whichever 
is higher, over the baseline dose. Any total steroid dose exceeding this rule will deem the 
subject a treatment failure. In addition, steroids for non-SLE reasons may be given short-
term at higher doses according to the following guidelines:
•
Up to 750 mg (prednisone) for 1 day, 
and/or
•
Up to 100 mg/day (prednisone) for 2-3 days ,
and/or
•
Up to 40 mg/day (prednisone) for 4-7 days.
The duration of high dose steroids use for reasons other than SLE must not exceed 7 
days, after which time, tapering should begin. The total steroid dose must be tapered to 
within 25% or 5 mg over the baseline dose, whichever is higher, within 30 days of the 1st
dose of a course of steroids. In addition, the steroid dose must be tapered to within 25% 
or 5 mg over the baseline dose, whichever is higher, by the Day 308 (Week 44) visit.  
Otherwise the subject will be deemed a treatment failure.
From the Day 308 to 364 (Week 44 to 52) Visits:
After the Day 308 (Week 44) visit through the Day 364 (Week 52) visit, no new steroids 
are allowed for reasons other than SLE activity that result in a total daily steroid dose > 
25% or > 5 mg, whichever is higher, over the baseline total steroid dose. A subject will 
be considered a treatment failure for any steroid use 8 weeks before the Day 364 (Week 
52) visit that does not meet this criterion.  
NOTE: Inhaled and topical steroids are allowed throughout the course of the study.
5.5.1.2.4.
Tapering or Restoration/Restart of Steroids
The primary objective of this trial is to evaluate the ability of belimumab to reduce SLE 
disease activity. Premature or rapid reduction in steroids may confound interpretation of 
study results and could induce a flare. However, it is understood that an important goal of 
therapy is to reduce steroids, given their associated morbidity. As such, subjects who 
have improving SLE disease activity for at least 8 weeks may, at the investigator’s 
discretion, reduce the steroid dose targeting a reduction to 7.5 mg/day or lower after the 
Day 168 (Week 24) visit. Investigators should consider the guidance provided in Table 5-
1 below. This table reflects the ACR draft guidance regarding steroid reduction during 
periods of stable SLE disease. If the subject continues to have stable or improving disease 
activity after 4 weeks on a reduced dose, then the investigator may consider reducing the 
dose again. During attempts to wean subjects from steroid use altogether, alternating 


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dosages (eg, alternating 6/3/6 mg/day) are permitted to help guard against Addisonian 
crises. Caution should be exercised when discontinuing steroids before the Day 364/Exit
(Week 52) visit, given the potential to induce a flare and thereby confound the study 
results.
If a subject has had worsening SLE disease activity, then a 12-week period of stable or 
improving disease activity should be observed before considering a clinically significant 
steroid dose reduction. (Note: The investigator may always apply their clinical judgment 
as to whether a dose reduction is appropriate.)
Subjects who have their prednisone or equivalent tapered may have their dose increased 
up to the maximum allowed as defined in Section 5.5.1.2.1 and Section 5.5.1.2.3 (see
Appendix 6).
Table 5-1
Algorithm for reducing dose of prednisone
Daily Dose (mg)
Dose Reduction (mg)
Up to 7.5 
1.0
> 7.5 to 15
2.5
> 15 to 30 
5.0
> 30 to 40
10.0
> 40
Taper at the investigator’s discretion using draft 
guidelines prepared for ACR (see Appendix 6)
5.5.1.2.5.
Treatment of SLE Flares with Steroids
If a subject has an SLE flare requiring an increase in steroid dose before the Day 168 
(Week 24) visit, the investigator should consider the draft guidelines prepared for the 
ACR (ACR Ad Hoc Working Group, 2004) for steroid dose/duration of induction therapy 
and recommended time for tapering the dose to baseline (Day 0) provided in Table 5-2
below. The subject must return to within 25% or 5 mg over the baseline (Day 0) steroid 
dose, whichever is higher, on or before the Day 168 (Week 24) visit or they will be 
considered a treatment failure. If a subject’s dose is increased > 25% or > 5 mg over the 
baseline dose, whichever is higher, any time after the Day 168 (Week 24) visit, they are 
also considered a treatment failure.


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Table 5-2
Recommended, standardized initial steroid dosing and steroid 
tapering algorithm for treatment of an SLE flare
Dose1
Induction 
(Median)
Range
Mean ± SD
Duration of 
Induction 
Therapy 
(Median)
Duration to Off 
Steroids 
(Median)
Severe SLE 
60 PO 
1000 bolus
40-100
40-1000
66.4 ± 15.5
766 ± 344
14 days
3 days
20 weeks
-
Moderately Severe 
SLE
35 PO
15-75
38.5 ± 13.4
7 days
15 weeks
Mild SLE
10 PO
0-30
14.5 ± 6.8
not determined
not determined
1
Prednisone dose in mg for a 70-kilogram person.
(From: Criteria for Steroid-Sparing Ability of Interventions in Systemic Lupus Erythematosus: Report of 
a Consensus Meeting; Arthritis & Rheumatism; Nov 2004).
5.5.1.3.
Other Immunosuppressive/Immunomodulatory Agents
The primary objective of this trial is to evaluate the ability of belimumab to reduce SLE 
disease activity. Premature or rapid reduction in immunosuppressant/immunomodulatory 
agents may confound interpretation of study results and could induce a flare. 
•
Starting any new immunosuppressive/immunomodulatory agent after Day 0 will 
cause the subject to be declared a treatment failure. 
•
The dose of existing immunosuppressive/immunomodulatory agents may be 
increased, as clinically required, up to the Day 112 (Week 16) visit. 
•
After the Day 112 (Week 16) visit, any increase in dose over the baseline (Day 0) or 
Day 112 (Week 16) visit dose, whichever is higher, will cause the subject to be 
declared a treatment failure. 
The allowable maximum doses for immunosuppressives at baseline (Day 0) and during 
the study are listed below:
•
Azathioprine – 300 mg/day.
•
6-mercaptopurine – 300 mg/day.
•
Mycophenolate mofetil (PO)/mycophenolate mofetil hydrochloride (IV) – 4 g/day.
•
Mycophenolate sodium (PO) – 2.88 g/day.
•
Methotrexate – 25 mg/week.
•
Oral cyclophosphamide – 2.5 mg/kg/day.
•
Cyclosporine – 4 mg/kg/day*.
•
Tacrolimus – 0.2 mg/kg/day*. 
•
Sirolimus – 2 mg/day*.
•
Thalidomide – 200 mg/day.
•
Leflunomide – 40 mg/day*.
•
Mizoribine – 150 mg/day.


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An immunosuppressive/immunomodulatory agent may be replaced with 1 of the agents 
above due to documented toxicity or lack of availability. For other immunosuppressive 
agents not listed above, the investigator must contact the Medical Monitor for approval. 
*Clinical 
loading 
dose 
is 
permitted 
when 
replacing 
immunosuppressive/immunomodulatory agents. Monitor blood levels as clinically 
indicated.
New topical immunosuppressive agents (eg, eye drops, topical creams) are allowed after 
Day 0.
5.5.1.4.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin
Since NSAIDs and aspirin may affect efficacy parameters (eg, arthritis) and may affect 
renal function (NSAID nephropathy), the use of these agents should be initiated and 
stabilized prior to entry into the trial.
•
NSAIDs may be given as clinically indicated until the Day 308 (Week 44) visit.
•
For subjects who never received an NSAID between the Day 0 and Day 308 (Week 
44) visit, starting a new NSAID after the Day 308 (Week 44) visit will declare the 
subject a treatment failure unless the NSAID is given for 1 week.
•
An NSAID may be replaced with another NSAID due to documented toxicity or lack 
of availability.
•
Daily doses of aspirin up to 1000 mg/day are allowed at any time during the study. 
•
Daily doses of aspirin above 1000 mg/day may be initiated at any time up to Day 308 
(Week 44) visit and may continue through the end of the study.
•
For subjects who never received an aspirin regimen at a dose > 1000 mg/day between 
the Day 0 and Day 308 (Week 44) visit, starting a new aspirin regimen at a dose 
> 1000 mg/day after the Day 308 (Week 44) visit will declare the subject a treatment 
failure unless the aspirin is given for < 1 week.
Acetaminophen (paracetamol) is primarily an analgesic and lacks the anti-inflammatory 
properties of other NSAIDs. The use of acetaminophen is recommended when possible to 
treat non-SLE related conditions, in the absence of a pre-existing hepatic function 
deficiency.
5.5.2.
Prohibited Medications and Therapies
Subjects who start prohibited medications or therapies at any time during the study will 
be considered treatment failures for analysis (ie, non-responders) and must be withdrawn 
from study agent and return for an Exit visit 4 weeks after the last administration of study 
agent and a follow-up visit 8 weeks after the last administration of study agent. In 
addition, an attempt will be made to ascertain survival status approximately 52 weeks 
after the first dose of study agent.


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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-enrollment into another study of an investigational agent or another study that 
may interfere with the conduct of this protocol. 
•
Anti-TNF therapy (eg, adalimumab, certolizumab pegol, etanercept, golimumab, 
infliximab).
•
Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra], tocilizumab).
•
Intravenous immunoglobulin (IVIG).
•
IV cyclophosphamide.
•
Plasmapheresis
5.5.3.
Live Vaccines
Live vaccines are not permitted in the study. Subjects who require a live vaccine during 
the study should have study agent discontinued prior to receiving the live vaccine.
6.
STUDY PROCEDURES
The nature of potential risks and benefits associated with participation in the study will be 
explained to all potential study subjects. Written informed consent (including consent for 
the use and disclosure of research-related health information) must be obtained before the 
subject can begin any screening procedures that are not considered part of standard 
patient care. 
Subjects participating in the pharmacogenetics (PGx) research portion of the protocol 
must sign the PGx informed consent prior to any PGx samples being drawn from the 
subject.
The FACIT-Fatigue Scale will only be completed by subjects for whom a survey exists in 
the subject’s language.
Refer to the Study Calendar (Table 6-1), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
6.1.
Screening Procedures (Day -35 to Day 0)
Subjects must be on appropriate stable standard therapy before entering the trial (see 
Inclusion Criteria Section 4.1 and Section 5.5.1). Investigators should consider this 
carefully before screening subjects that only recently came under their care. A 60-day 
observation period is suggested if previous SLE disease activity documentation is 
suboptimal. This period prior to screening allows the principal investigator to observe the 
subject and make any necessary medication adjustments, especially if a subject has been 
recently referred to the study site.


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The following assessments are required at screening:
•
Demographics (including self-identified race).
•
Medical history.
•
Weight
•
Complete physical examination.
•
Confirm diagnosis of SLE disease (based on ACR criteria) by reviewing previously 
documented clinical records (see Appendix 1).
•
Record concurrent medications
•
Blood samples for: (see Appendix 10 – Laboratory Tests)
-
Hematology.
-
Modified Chem 20 (non-fasting).
-
Serum pregnancy test - for all women with an intact uterus, unless exempted 
from pregnancy testing (ie, of non-childbearing potential - women who had a 
hysterectomy, are post-menopausal which is defined as 1 year without 
menses, have both ovaries surgically removed, or have current documented 
tubal ligation or any other permanent female sterilization procedure).
-
HIV antibody, HBsAg, HB core antibody, and hepatitis C antibody testing.
-
Biological markers (Complement C3, C4).
-
Serum immunoglobulin isotypes (IgG, IgM, IgA).
-
Autoantibodies (ANA and anti-dsDNA).
•
Urine sample for:
-
Routine urinalysis.
-
Alcohol and drug screen.
-
Spot urine for macroscopic/microscopic/proteinuria assessments.
•
Disease activity scales:
-
SELENA SLEDAI (see Appendix 5; refer to Section 6.8.1 Guidelines for 
Scoring Proteinuria).
○
Confirm SLE disease is active, defined as SELENA SLEDAI score ≥ 8 at 
screening.
-
Physician’s Global Assessment (PGA) (see Appendix 5).
-
SLE Flare Index (see Appendix 5).
-
BILAG (see Appendix 7).
•
Suicidality assessment by using the Columbia-Suicide Severity Rating Scale (C-
SSRS) Baseline/Screening assessment form (see Appendix 3 and Section 7.5) at 
screening.
•
Confirm subject meets study entry criteria.
6.2.
Study Enrollment Procedures
Subjects who have undergone all screening procedures and have met the entry criteria 
will be enrolled into the study and assigned to treatment by Interactive Web or Voice
Response System (IWRS/IVRS). Subjects will be randomized in a 2:1 ratio to treatment 
with either 10 mg/kg belimumab or placebo. At randomization, subjects will be stratified 


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by their screening SELENA SLEDAI score (8-9 vs ≥ 10), complement level (C3 and/or 
C4 low vs other), and region (US/Canada vs rest of the world).
6.3.
Double-Blind Treatment Period
Subjects will be evaluated at the study site during the scheduled study visits outlined in 
the Study Calendar in Table 6-1. On Day 0, the subject will be randomized and receive 
the 1st dose of study agent. After the 1st month of therapy, visits to the study site for 
clinical evaluation, disease activity assessment, and laboratory sampling will occur
approximately every 28 days (calculated from the Day 0 dose) for a total of 48 weeks of 
treatment. All efforts should be made to retain subjects on schedule, based on the date of 
their Day 0 dose.
The final efficacy evaluation will occur at Week 52 (ie, the Day 364/Exit visit, 
approximately 4 weeks after the last dose of study agent). 
Time windows are provided for each study visit after Day 0 in Table 6-1 to allow 
flexibility in site and subject scheduling.  All study visits should occur within the visit 
window of the scheduled study visit (see Table 6-1). 
All subjects who withdraw from treatment prior to Week 52 will be followed (eg phone 
contact) for survival approximately 52 weeks after the first dose of study agent. In the 
event that a subject withdraws consent, an attempt should be made at the time of consent 
withdrawal to obtain consent for survival status.
Subjects who complete the double-blind period through Day 364 (Week 52) will be given 
the option to receive belimumab in the 6-month open-label extension.  
•
Subjects who complete the 364 day (52-week) double-blind period, but do not enter 
the open-label extension, will not have study agent administered at Week 52. 
Assessments should be completed for the Day 364/Week 52 visit, and then the subject 
should return in 4 weeks for the 8-week Follow-up Visit.
•
Subjects who wish to continue in the open-label extension, will have study agent 
administered at the Day 364 (Week 52/Day 0 of open-label extension) visit after all 
Day 364 (Week 52) assessments are performed (refer to Table 6-1 below).


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This is an on-treatment Study Calendar. Please refer to Section 6.1 for a complete list of assessments required during screening.
Table 6-1
Study calendar- On-treatment evaluations
52-Week Double-Blind Treatment Period
Days 0-364 (Weeks 0-52)
Post-Treatment Follow-up 
Period
Study Day
Screening
Day 0 visit
Day 14 visit
3 days
Day 28 visit 
3 days
Day 56 visit
7 days
Day 84 visit 
7 days
Day 112 visit
7 days
Day 140 visit
7 days
Day 168 visit
7 days
Day 196 visit 
7 days
Day 224 visit
7 days
Day 252 visit
7 days
Day 280 visit
7 days
Day 308 visit
7 days
Day 336 visit 
7 days
Day 364/ EXIT 
(4-wks post 
dose) A, J
7 days
Post-txt f-up for 
non-completers 
± 7 days
8-week
Follow-up B
7 Days
Unscheduled
Visit L
Study Week
Wk
2
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
4 wks 
post 
last 
dose
Written Informed 
Consent
X
Demographics 
(including race)
X
Medical History and 
complete Physical 
Exam
X
SLE 
History/diagnosis
X
Eligibility Criteria
X
Clinical 
Assessments:
WeightD
X
X
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
X
C-SSRS 
Baseline/ScreeningI
X
C-SSRS Since Last 
VisitI
X
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
X
X
Record all current 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 6-1
Study calendar- On-treatment evaluations
52-Week Double-Blind Treatment Period
Days 0-364 (Weeks 0-52)
Post-Treatment Follow-up 
Period
Study Day
Screening
Day 0 visit
Day 14 visit
3 days
Day 28 visit 
3 days
Day 56 visit
7 days
Day 84 visit 
7 days
Day 112 visit
7 days
Day 140 visit
7 days
Day 168 visit
7 days
Day 196 visit 
7 days
Day 224 visit
7 days
Day 252 visit
7 days
Day 280 visit
7 days
Day 308 visit
7 days
Day 336 visit 
7 days
Day 364/ EXIT 
(4-wks post 
dose) A, J
7 days
Post-txt f-up for 
non-completers 
± 7 days
8-week
Follow-up B
7 Days
Unscheduled
Visit L
Study Week
Wk
2
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
4 wks 
post 
last 
dose
SLE Disease Activity 
ScalesK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR 
Damage Index
X
X
FACIT-Fatigue 
ScaleC
X
X
X
X
X
X
X
Survival 
assessmentN
X
Laboratory 
Assessments:
HIV, Hepatitis B and 
Hepatitis C serology
X
Alcohol and Drug 
Screen 
X
Labs: Hematology & 
Modified Chem 20 
(non-fasting)E
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/PTTE
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spot urine (protein 
to creatinine ratio)F
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy TestG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic 
SamplingH 
X
X
X
X
X
X


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Table 6-1
Study calendar- On-treatment evaluations
52-Week Double-Blind Treatment Period
Days 0-364 (Weeks 0-52)
Post-Treatment Follow-up 
Period
Study Day
Screening
Day 0 visit
Day 14 visit
3 days
Day 28 visit 
3 days
Day 56 visit
7 days
Day 84 visit 
7 days
Day 112 visit
7 days
Day 140 visit
7 days
Day 168 visit
7 days
Day 196 visit 
7 days
Day 224 visit
7 days
Day 252 visit
7 days
Day 280 visit
7 days
Day 308 visit
7 days
Day 336 visit 
7 days
Day 364/ EXIT 
(4-wks post 
dose) A, J
7 days
Post-txt f-up for 
non-completers 
± 7 days
8-week
Follow-up B
7 Days
Unscheduled
Visit L
Study Week
Wk
2
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
4 wks 
post 
last 
dose
ImmunogenicityM
X
X
X
X
X
B cells
X
X
X
X
Pharmacogenetic 
SamplingM
X
BLyS Protein
X
ANA
X
X
Complement 
(C3/C4) and anti-
dsDNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Extractable nuclear 
antigens (ENAs)O
X
X
X
X
Anti-phospholipid 
antibodies (aCL, 
lupus anticoagulant, 
±beta-2-
glycoprotein-1)O
X
X
X
X
X 
Serum IgA, IgM, IgG
X
X
X
X
X
X
X
X
X
IV Administration 
of Study AgentP
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 6-1
Study calendar - On-treatment evaluations (footnotes)
Refer to Section 6.1 for a list of assessments required for screening/eligibility.
A
The Exit (Day 364) visit will occur approximately 4 weeks after the last dose of study agent. For subjects completing all 48 weeks of treatment and continuing into the 6-month open-
label extension, this visit will also serve as their 1st (ie, Day 0) visit of the 6-month open-label extension (see Table 6-2). For subjects who discontinue study agent prior to Week 48, 
the Exit (Day 364) visit should be performed 4 weeks after the last administration of study agent and a follow-up visit 8 weeks after the last administration of study agent, and a survival 
assessment (eg, by phone contact) will take place approximately 52 weeks after the first dose of study agent (see Footnote N). 
B
The 8-week follow-up visit is to occur approximately 8 weeks after last dose of study agent for subjects withdrawing early and those subjects who do not continue into the 6-month 
open-label extension.  
C
Must be completed by the subject prior to any study-related discussion with the investigator or study coordinator. The FACIT-Fatigue Scale will only be completed by subjects for 
whom a survey exists in the subject’s language.
D
Weight should be obtained prior to dosing at each visit to calculate the dose to be administered. At sites where it is impractical to use the subject’s current body weight to calculate the 
dose, it is permissible to use the subject’s body weight from the previous visit. However, the subject’s body weight will be measured prior to dosing and if the previous visit weight and 
current visit weight vary by more than 10% then the weight measured at the current visit must be used. 
E
Refer to Appendix 10 for a listing of laboratory assessments to be completed.  PT/PTT will be assessed according to the separate line item for PT/PTT in this table.
F
A 24-hour urine may be done if clinically indicated (eg, renal flare).
G
Serum pregnancy test required at screening. Results of urine pregnancy test at subsequent visits, if required, must be available prior to dose. See Section 6.1 (Screening Procedures) 
for definition of those exempted from subsequent pregnancy testing.  Women of child-bearing potential must be reminded of the requirement to report any pregnancy that occurs 
through 16 weeks following the last dose of study agent (see Section 7.6).
H
Pharmacokinetic sampling: Before the start of infusion on Days 0, 56, and 364 (only if continuing into the 6-month open-label extension); 0-4 hours after the end of infusion on Days 14 
and 168; at any time during the visit during the 8-week follow-up visit.
I
C-SSRS Since Last Visit form (see Appendix 4) will be used at Day 0 and all subsequent visits. The C-SSRS Baseline/Screening form (see Appendix 3) is only used at Screening.
J
Study agent is to be administered only if the subject is continuing into the 6-month open-label extension, and this dose will be the 1st dose in the 6-month open-label extension. The 
dose should not be administered until the completion of all Day 364/Week 52 assessments. 
K
SLE Disease Activity Scales:  SELENA SLEDAI, SLE Flare Index, BILAG, and PGA.  Refer to Section 6.8.1 for guidelines for scoring proteinuria for SELENA SLEDAI evaluation.
L
Unscheduled Visits: Other assessments may be performed as clinically indicated.
M
Pharmacogenetic (PGx) sampling should be drawn at baseline (Day 0); however, the sample can be taken at any time point during the study.  Informed consent must be obtained prior 
to any blood being taken for PGx research. Samples should be drawn prior to dosing.
N
Subjects who discontinue study agent treatment at any time during the study will have a survival assessment (eg, by phone contact) approximately 52 weeks after the first dose of 
study agent. In the event that a subject withdraws consent, an attempt should be made at the time of consent withdrawal to obtain consent for survival status at Week 52.
O
Will be measured in all subjects at Day 0 and samples will be collected at the time points specified; however, the assay will be run only on subjects with elevated titers of these 
antibodies.
P
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 study agent infusions.  Should symptoms of acute hypersensitivity occur, an extended 
period of monitoring may be appropriate, based on clinical judgment.
(concluded)


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6.4.
6-Month Open-Label Extension
Subjects who complete the initial 52-week double-blind treatment period may choose to 
enter into a 6-month open-label extension. The Day 364/Week 52 visit from the 52-week 
double-blind treatment period will serve as the Day 0 visit for subjects entering the 6-
month open-label extension. Subjects on active drug or placebo will receive belimumab 
10 mg/kg IV approximately every 28 days for 6 months in the open-label extension. The
1st dose on the 6-month open-label extension will be given on Day 364 (Week 52) of the 
double-blind treatment period after the completion of Day 364 (Week 52 assessments) 
(see Table 6-2 for schedule of evaluations). All subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions. Should symptoms of 
acute hypersensitivity occur, an extended period of monitoring may be appropriate, based 
on clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-2).
During the 6-month open-label extension, the investigator may adjust concurrent 
medications (add, eliminate, change dose level/frequency) as clinically appropriate.
Investigators are encouraged to consider the guidance provided in Section 5.5.1.2
regarding corticosteroid reduction during periods of stable SLE disease. The American 
College of Rheumatology (ACR) draft guidance regarding steroid dosing and tapering in 
response to SLE flare is provided in Appendix 6. The reason for altering any 
immunosuppressant therapy (eg, toxicity associated with the medication, fluctuations in 
disease activity, etc) must be recorded in the source documentation. Prohibited 
medications as outlined in Section 5.5.2 will still apply.
All subjects will return for an Exit visit approximately 4 weeks after their last dose of 
study agent as well as a follow-up visit approximately 8 weeks after the last dose of study 
agent.  These visits apply to subjects who have completed as well as those who have 
withdrawn early from the open-label extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment 
may do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue 
to receive belimumab under a separate continuation protocol. A separate informed 
consent will need to be provided for the continuation protocol. The 8-week follow-up 
visit is not required for subjects entering the continuation protocol.


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Table 6-2
Study calendar 6-month open-label extension
Study Day
Day 0 visit 
(Week 52/Exit 
Visit On-
Treatment 
Phase)a
Day 28 visit 
7 days
Day 56 visit
7 days
Day 84 visit 
7 days
Day 112 visit
7 days
Day 140 visit
7 days
Day 168 visit
7 days
Day 196/EXIT 
(4 weeks post 
last dose) 
7 daysb 
8-week
Follow-up 
(8 wks post 
last dose)
+ 7 Daysf
Study Week
Day 0
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
IV administration of study 
agenth
X
X
X
X
X
X
X
Clinical Assessments:
Weightd
See Day 364/Exit visit in Week 52 
Treatment Period
X
X
X
X
X
X
Symptom-driven Physical 
Exam
C-SSRS Since Last Visit
Assess/Record Adverse 
Events
X
X
X
X
X
X
X
X
Record all current 
medications
X
X
X
X
X
X
X
X
SLE Disease Activity Scales
X
Xe
SLICC/ACR Damage Index
X
FACIT-Fatigue Scaleg
X
Laboratory Assessments:
Labs: Hematology & 
Modified Chem 20 
(non-fasting)  
See Day 364/Exit visit in Week 52 Treatment Period
X
Xe
X
PT/PTT
X
Urinalysis
X
Xe
X
Spot urine (protein to 
creatinine ratio)
X
Xe
Urine Pregnancy Testc
X
X
X
X
X
X
X
X
Pharmacokinetic Sampling 
Immunogenicityf
X
Xe
X
B cells
X
Xe
Complement (C3/C4) and 
anti-dsDNA
X
Xe
Extractable nuclear antigens 
(ENAs)
Anti-phospholipid antibodies 
(aCL, lupus anticoagulant, 
±beta-2-glycoprotein-1)
Serum Immunoglobulin IgG, 
IgA, IgM
X
X
Xe
a
Day 0 of the 6-month open-label extension is the Day 364/Week 52/Exit study visit from the On-Treatment phase of 
the study (see Table 6-1) and represents the first belimumab administration for those subjects continuing in the 6-
month open-label extension.
b
All subjects, including subjects who have discontinued study agent prior to Day 196, will return for an Exit visit 
approximately 4 weeks after their last dose of study agent as well as a follow-up visit approximately 8 weeks after the 
last dose of study agent.  
c
Urine pregnancy test, as required, with results available prior to dosing. Women of child-bearing potential must be 
reminded of the requirement to report any pregnancy that occurs through 16 weeks following the last dose of study 
agent (see Section 7.6).
d
The weight at the current visit will be used for calculating the dose. At sites where it is impractical to use the subject’s 
current body weight to calculate the dose, it is permissible to use the subject’s body weight from the previous visit.  
However, the subject’s body weight will be measured prior to dosing and if the previous visit weight and current visit 
weight vary by more than 10%, then the weight measured at the current visit must be used.


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e
Assessment to be performed only if assessment was not done at Day 168/Week 24.
f
The 8-week follow up visit is not required for subjects entering the separate continuation protocol.
g
Must be completed by the subject prior to any study-related discussion with the investigator or study coordinator.  
The FACIT-Fatigue Scale will only be completed by subjects for whom a survey exists in the subject’s language.
h
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 infusions.  Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be appropriate, based on clinical 
judgment.
6.5.
Exit Visit
Subjects who drop out and do not complete the study will return for an Exit visit 4 weeks 
after the final dose of study agent.  
During the double-blind treatment period, the assessments for the Week 52 visit will be 
performed for the Exit visit. During the 6-month open-label extension, the assessments 
for the Week 28 visit will be performed for the Exit visit.
Refer to the Study Calendar (Table 6-1 and Table 6-2) for a list of procedures required at 
this visit.
6.6.
8-Week Follow-up Visit
All subjects, except those entering the separate continuation protocol, must return for a 
follow-up visit approximately 8 weeks after the last dose of study agent. 
Refer to the Study Calendar (Table 6-1 and Table 6-2) for a list of procedures required at 
this visit.
6.7.
Unscheduled Visits
Unscheduled visits may be necessary during the course of the study to capture a subject’s 
status between regularly scheduled visits. Examples include, but are not limited to, a 
worsening of SLE symptoms, AE reporting, or follow-up to a previously reported AE.
Refer to the Study Calendar (Table 6-1) for a list of procedures required at these visits. 
Other assessments as clinically indicated should be performed. 
6.8.
Laboratory Tests
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1 and Table 6-2).
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after Day 0: aCL (IgM, IgG, IgA isotypes),
ENAs (such as anti-Sm, 
anti-ribonucleoprotein (anti-RNP), anti-Sjögren Syndrome A (anti-SS-A), anti-Sjögren 
Syndrome B (anti-SS-B), and anti-ribosomal P), serum immunoglobulin isotypes 
IgM/IgA, and FACS of peripheral lymphocytes.
It has been demonstrated that there is a strong correlation between the protein content of 
a 24-hour urine collection and the urinary protein:urinary creatinine ratio in a single urine 


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sample (Ginsberg et al, 1983; Ruggenenti et al, 1998; K/DOQI Clinical Practice 
Guidelines for Chronic Kidney Disease, 2002a; Price et al, 2005). Given this information, 
spot urinary protein:urinary creatinine ratio will be used for determining proteinuria in 
this study for both the SELENA SLEDAI and BILAG 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 (K/DOQI Clinical Practice Guidelines for 
Chronic Kidney Disease, 2002b). Therefore, GFR estimated by the Cockcroft-Gault 
formula will be used in the BILAG disease activity index, as was done in the Phase 2 and 
Phase 3 trials of belimumab.
Cockcroft-Gault Equation (Cockcroft, 1976)
Clcr (mL/min) =
(140-age (yrs)) x weight (kg)
x 0.85 if female
72 x serum creatinine (mg/dL)
Additional instructions regarding collection procedures are provided in the Study 
Procedures Manual and Central Laboratory Manual.  
6.8.1.
Guidelines for Scoring Proteinuria for SELENA SLEDAI
The following guidelines should be followed for scoring for proteinuria in the SELENA 
SLEDAI disease activity index.
6.8.1.1.
Scoring for Proteinuria for Eligibility at Screening
In order to be assigned 4 points for proteinuria at screening, the screening spot urine 
proteinuria assessment must show:
•
Proteinuria > 1 g/24 hour equivalent (irrespective of previous value).
OR
•
New onset or recurrent proteinuria > 0.5 g/24 hour equivalent or a > 0.5 g/24 hour 
equivalent increase above the previously documented 24-hour proteinuria or 
equivalent value obtained within 26 weeks of the screening value. If the screening 
value is ≤ 1 g/24 hour equivalent and there are no previous assessments of 24-hour 
proteinuria or spot urinary protein to urinary creatinine ratio available within 26 
weeks for a given subject, 4 points cannot be given for proteinuria on the SELENA 
SLEDAI index, unless a 2nd assessment is done during the screening period of the 
study (ie, before Day 0).


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6.8.1.2.
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 (ie, baseline), the 
subject, by default, will have an improving SELENA SLEDAI score prior to treatment. 
Two assessments of 24-hour proteinuria (by spot urinary protein to urinary creatinine 
ratio) obtained in a 2 to 3 week period are unlikely to show a > 0.5 g/24 hour equivalent 
increase except in acute renal flare. 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:
6.8.1.2.1.
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 (ie, 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.
6.8.1.2.2.
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 urinary protein to urinary 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. 
6.8.2.
Pharmacokinetics
All randomized subjects will be sampled for serum belimumab levels during the double-
blind treatment period. A blood sample for pharmacokinetic analysis will be drawn
according to the time schedule below.


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Table 6-3
PK visit days and sample times
Day (Week)
Time (Related to Dosing of Study Agent)
0
Before the start of infusion
14 (Week 2)
0 - 4 hours after the end of infusion
56 (Week 8)
Before the start of infusion
168 (Week 24)
0 - 4 hours after the end of infusion
364/Exit (Week 52) 
Any time during visit (or prior to dosing if going into 
the open-label extension)
8-week follow-up 
(8 weeks after last dose)
Any time during visit
(if not going into the 6-month open-label extension)
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.  
6.8.3.
Liver Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
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 
Appendix 13.


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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 
Appendix 13.
6.8.3.1.
Study Agent Restart
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
Refer to Appendix 14 for full guidance
6.8.4.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent on Days 0, 56 (Week 8), 
168 (Week 24), 364 (Week 52), and at the 8-week follow-up visit (if applicable). 


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6.9.
Withdrawal of Subjects from Treatment
In addition to the reasons for withdrawal detailed below, subjects are free to withdraw 
from treatment or from the study at any time, for any reason, or may be 
withdrawn/removed, if necessary, to protect their health. It is understood by all concerned 
that an excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. Subjects who withdraw from the 
study after receiving at least 1 dose of study agent will not be replaced. 
Subjects should be withdrawn for any of the following reasons:
•
Missing 3 or more consecutive doses of study agent.
•
Prohibited concurrent medication or therapy or prohibited dose of concurrent 
medication or therapy resulting in treatment failure (see Section 5.5).
•
Unacceptable toxicity (See Section 5.4 and Section 6.8.3).
•
Withdrawal of consent (including use and disclosure of research-related health 
information).
•
Pregnancy.
•
Prior to the administration of live vaccine
•
At the discretion of the Sponsor, conditions that may warrant termination of a subject 
include but are not limited to safety concerns, subject significant non-compliance 
with protocol visits and procedures.
Subjects who discontinue treatment must complete the Exit visit (4 weeks after the last 
dose of study agent) and a follow up visit 8 weeks after the last dose of study agent. An 
attempt will be made to contact all discontinued subjects to determine survival status (eg, 
by phone contact) approximately 52 weeks after the first dose of study agent.
6.10.
Subject Unblinding
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will 
be employed. The study agent will be reconstituted and diluted by the unblinded site 
pharmacist or designee, independent of the study (person responsible for receiving and 
dispensing study agent). Except for a limited number of safety oversight personnel, all 
other study site personnel, the subject, the sponsor, and the Contract Research 
Organization (CRO) will remain blinded to the study agent received and to the results of 
certain biomarker and pharmacodynamic laboratory results. Separate monitors will be 
responsible for the clinical (blinded monitor) and study agent (unblinded monitor) aspects 
of the study.
In the case of a medical emergency when knowledge of the study treatment is essential 
for the appropriate clinical management or welfare of the subject, the study blind may be 
broken for the specific subject. Whenever possible, the investigator should discuss 
options with the Medical Monitor prior to unblinding any subject. If this is impractical, 
the investigator must notify the Medical Monitor as soon as possible of any broken blind, 
but without revealing the treatment assignment of the unblinded subject, unless that 


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information is important for the safety of other subjects currently in the study. Any 
broken blind will be clearly justified and explained by a comment in the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
7.
ADVERSE EVENT REPORTING
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.
Definitions
ADVERSE EVENT - 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 (ie, 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 (eg, 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
SERIOUS ADVERSE EVENT – A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
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
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 hospitalisation 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
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 


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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.
7.2.
Reporting Adverse Events to the Sponsor
All adverse events (AEs) that are identified from the start of study agent administration 
(Day 0) through 8 weeks following administration of the last dose of study agent will be 
recorded on the Adverse Event Case Report Form (AE eCRF). All data fields on the AE 
eCRF must be completed. 
Serious Adverse Events (SAEs) must be recorded on the SAE eCRF within 24 hours of 
site personnel becoming aware of a SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
SAE eCRF within 24 hours of site personnel becoming aware of the follow-up 
information as described in the Study Procedure Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an 
SAE from the time a subject consents to participate in the study.
SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study 
agent) that are assessed by the investigator as possibly related to study agent must be 
reported to the Sponsor as outlined in the Study Procedures Manual.
7.3.
Laboratory Abnormalities as Adverse Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, 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.


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If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality 
(eg, elevated creatinine, urine RBC increased).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 12. If a particular lab test is not listed in the Appendix, the lab test should be 
graded mild, moderate, or severe as specified in Section 7.7.
7.4.
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.
7.5.
Suicidality Assessment
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation 
(Bachen et al, 2009; Stenager et al, 1992; Timonen et al, 2003). In order to objectively 
assess suicidality in belimumab clinical programs the C-SSRS (Appendix 3 and 
Appendix 4) will be utilized to collect information on suicidal behavior and ideation. SLE 
patients have an increased prevalence of mood and anxiety disorders compared with the 
general population and disease activity may contribute to this higher risk. The incidence 
of major depressive disorder (MDD) among SLE patients has been reported to be as high 
as 47% (Bachen et al, 2009). Since active SLE and MDD may increase the risk of 
suicidal ideation or behavior before or during clinical studies, subjects participating in 
this study will be assessed for suicidality at every visit during the double-blind portion of 
the study.  
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation 
questions 4 or 5 on the C-SSRS should be referred to appropriate psychiatric care and 
prompts the completion of an SAE worksheet. The medical monitor should be notified 
when these events occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal 
ideation questions 3, 4 or 5 on the C-SSRS prompts the completion of a Possible 
Suicidality Related History Questionnaire (PSRHQ, only the first time this condition is 
met) eCRF and a Possible Suicidality Related Questionnaire (PSRQ) eCRF (at all times 
this condition is met).
Baseline/Screening and during treatment assessment of suicidality will be performed 
during the double-blinded portion of this study using C-SSRS (refer to Appendix 3 and 
Appendix 4 for C-SSRS). The C-SSRS is a brief measure which is designed to assess 


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severity and change of suicidality by integrating both behavior and ideation (Posner et al,
2007). The C-SSRS is administered by a qualified clinician and is designed to address the 
need for a summary measure to track change in the severity/density of suicidality across 
both clinical settings and treatment trials. It assesses intensity of ideation (a potentially 
important marker of severity) by specifically asking about frequency, duration, 
intrusiveness, controllability, and deterrents. In addition, it captures both the modal and 
most severe forms of ideation. The C-SSRS is to be completed by the investigator or 
his/her qualified designee at every visit during the double-blind portion of this study.
Although assessment of suicidality using the C-SSRS will take place only during the 
double-blinded portion of the study, investigators are reminded of the importance to 
clinically assess for suicidality at every visit given that SLE patients are at increased risk 
of suicidal behavior and/or ideation.
7.5.1.
Possible Suicidality Related Questionnaire (PSRQ)
The investigator will be prompted to complete the PSRQ (in addition to the AE, SAE 
pages, and PSRHQ as appropriate) if a “yes” response is given to any suicidal behavior or 
a “yes” response to suicidal ideation questions 3, 4 or 5 on the C-SSRS. If the adverse 
event meets the definition of an SAE, which includes a “yes” answer to any suicidal 
behavior or a “yes” to suicidal ideation questions 4 or 5 on the C-SSRS, the site must 
ensure that there are no significant discrepancies between the PSRQ and SAE.  
7.6.
Reporting a Pregnancy
Any pregnancy that occurs during study participation and up to 16 weeks post dose must 
be reported using a clinical trial pregnancy form. To ensure subject safety, each 
pregnancy must be reported to the Sponsor within 2 weeks of learning of its occurrence. 
The pregnancy must be followed to delivery to determine outcome (including premature 
termination) and status of mother and child. To gain additional information on pregnancy 
outcomes, the subject will be requested to complete a 1 year infant questionnaire.
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 the Sponsor.
7.7.
Investigator Evaluation of Adverse Events
The Investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to 
study agent). The investigator will make an assessment of intensity based on the Division 
of Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading 
Tables (see Appendix 12) where possible:


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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 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 
or 4 DMID).
Not applicable
Those event(s) where intensity is meaningless or 
impossible to determine (ie, blindness and coma).
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.
CAUSALITY
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out. The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated. The investigator will also consult the 
IB and/or Product Information, for marketed products, in the determination of his/her 
assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.  The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
7.8.
Follow-Up of Adverse Events
Serious and nonserious adverse events that occur from the start of study agent 
administration through 8 weeks after the date of last administration of study agent are 
reported.


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After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up. This applies to 
all subjects, including those withdrawn prematurely.
7.9.
Disease Related Events
Disease related events (DREs) can occur in the study population regardless of belimumab 
exposure and are not reported as AEs or SAEs, unless judged by the investigator to be 
more severe than expected for the subject’s condition.
The following DREs (preferred terms; MedDRA v. 14.0) are common in subjects with 
SLE and can be serious/life-threatening:
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis
Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
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 7.2. 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).
7.10. Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  The 
Sponsor 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 the Sponsor’s policy and are 
forwarded to investigators as necessary.


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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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8.
ENDPOINTS AND STATISTICAL ANALYSIS
8.1.
General Statistical Considerations
Unless otherwise specified, all analyses will be performed on the ITT population defined 
as all subjects who are randomized and received at least 1 dose of study agent. The ITT 
analysis will be performed according to the treatment that a subject was randomized to 
receive, regardless of the actual treatment received.
The database will be locked for primary analysis after the data through the Day 364 
(Week 52) visit for all subjects have been collected, verified, and validated. All subjects 
and study site personnel will remain blinded until the final database lock and the primary 
efficacy results become public. 
All statistical tests will be 2-sided and performed at an overall significance level of 0.05.
8.2.
Randomization Procedure and Assignment to Treatment 
Groups
This is a Phase 3/4, multi-center, randomized, double-blind, placebo-controlled study. 
Once subjects have consented, have undergone all screening procedures, and have been 
determined to be eligible for the study, they will return for the Day 0 visit to be randomly 
assigned (via an interactive voice or web response system [IVRS/IWRS]) to 1 of 2 
treatment groups (belimumab or placebo control) in a 2:1 ratio. The randomization will 
be stratified by screening SELENA SLEDAI score (8-9 vs ≥ 10), complement level (C3 
and/or C4 low vs other), and region (US/Canada vs rest of the world).
8.3.
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this Phase 3/4 study on an ongoing basis until the data are locked and analyzed
through Week 52. The IDMC will include at least 3 physicians, and a statistician, none of 
whom are affiliated with the sponsor. Events to be monitored during the safety review 
include, at a minimum, all serious adverse events (including deaths, serious psychiatric 
events, and serious infections), Grade 3 and Grade 4 laboratory abnormalities, 
opportunistic infections (serious and nonserious), malignancies, and hypersensitivity/ 
anaphylactic reactions.  The 1st IDMC data review meeting will occur after the first 100 
subjects have been treated through Day 56, or within 6 months of the treatment of the 1st
subject, whichever is earlier. After the initial review, the committee will review the data 
approximately every 6 months. At all times the sites and sponsor will remain blinded to 
treatment allocation. Investigators and IRBs/IECs, as appropriate, will be notified of the 
outcome of each IDMC meeting.
The IDMC will receive information within 72 hours of the sponsor or designee receiving 
notification of all SAEs that are life threatening or result in death. Other SAEs will be 
provided monthly to the IDMC.
After Week 52, the monitoring may be assumed by an internal GSK/HGS committee.


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8.4.
Sample Size Rationale
Approximately 501 subjects will be randomized and treated in the study, with a target of 
at least 334 subjects in the arm receiving belimumab and 167 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 15.55% absolute improvement in the SRI response 
rate with the modified SLEDAI-2K scoring for proteinuria for the 10 mg/kg belimumab 
group relative to the placebo group (assumed rate =43.95%) at Week 52. This sample size 
is also sufficient to provide approximately 80% power at a 5% level of significance to 
detect a minimum of a 13.4% absolute improvement in the SRI response rate with the 
SELENA SLEDAI scoring for proteinuria for the 10 mg/kg belimumab group relative to 
the placebo group (assumed rate = 44.8%).
The selection of the assumed treatment differences is based on the observed SRI data 
from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 (Northeast 
Asia), which are two efficacy studies that concluded in 2015 and 2016, respectively, and 
have nearly identical eligibility criteria to study HGS1006-C1112 including requiring a 
screening SS score ≥8. SRI results, calculated using the SS results and calculated using a 
modification to the proteinuria scoring based on SLEDAI-2K rules, are shown in Table 8-
1.
Table 8-1
SRI Results From Studies BEL112341 and BEL113750
SRI
Calculated Using the SS Results
as Collected
SRI
Calculated Using SS Results with the 
Modified SLEDAI-2K Proteinuria 
Scoring
Dataset
Placebo
Belimumab
Δ
Placebo
Belimumab
Δ
BEL112341*
48.4%
61.4%
12.98%
46.6%
61.7%
15.14%
BEL113750**
40.1%
54.3%
14.17%
40.2%
56.3%
16.16%
Pooled 
BEL112341 and 
BEL113750
44.8%
(222/496)
58.2%
(582/1000)
13.44%
43.95%
(218/496)
59.50%
(595/1000)
15.55%
* Inclusion criterion SS≥8, 200 mg SC dose used.
**Inclusion criterion SS≥8, 10 mg/kg IV dose used. 
All sample size calculations were performed using Power Analysis and Sample Size 
software (PASS 2012).


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8.5.
Efficacy
8.5.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K scoring for proteinuria at Week 52.
A SRI response is defined as:
•
≥ 4 point reduction from baseline in SELENA SLEDAI score (with the modified 
SLEDAI-2K scoring for proteinuria), 
AND
•
No worsening (increase of < 0.30 points from baseline) in Physician’s Global 
Assessment (PGA), 
AND
•
No new BILAG A organ domain score or 2 new BILAG B organ domain scores 
compared with baseline at the time of assessment (ie, at Week 52).
8.5.2.
Primary Efficacy Analysis
The proportion of subjects achieving a treatment response at Week 52 will be compared 
between the belimumab treatment group and placebo using a logistic regression model. 
The independent variables in the model will include treatment groups (ie, belimumab vs 
placebo), baseline SELENA SLEDAI score (≤9 vs ≥ 10), baseline complement level (C3 
and/or C4 low vs other), and region (US/Canada vs rest of the world). However, the 
adjustment will not occur for any of these baseline randomization factors that has < 10 
responders or < 10 non-responders in a stratification level (Peduzzi et al, 1996). The
analysis will be performed on the intention-to-treat (ITT) population, defined as all 
subjects who are randomized and treated with at least 1 dose of study agent. The ITT 
analysis will be performed according to the treatment that a subject was randomized to 
receive, regardless of the actual treatment received. 
Any subject who withdraws from the study prior to the Day 364 (Week 52) visit, misses 
the Day 364 (Week 52) visit (± 28 day window allowed), and/or starts a prohibited 
medication or dose (see Section 5.5.2) prior to the Day 364 (Week 52) visit will be 
considered a nonresponder for the Week 52 primary efficacy analysis.  


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8.5.2.1.
Subgroup Analysis
Subgroup analysis, of SRI only, will be performed in the following subgroups:
•
Baseline SELENA SLEDAI score (≤ 9 vs ≥10).
•
Baseline anti-dsDNA (≥ 30 IU/mL vs < 30 IU/mL).
•
Baseline prednisone dose level (≤ 7.5 mg/day vs > 7.5 mg/day).
•
Baseline complement levels (C3 and/or C4 low vs other).
•
Baseline complement and anti-dsDNA (C3 and/or C4 low AND anti-dsDNA ≥ 30
IU/mL vs other)*.
•
Region (US/Canada vs other).
A multivariate analysis will also be performed to evaluate how response to belimumab 
relative to placebo varied across different categories within relevant baseline 
demographic or disease characteristics. The details will be described in the analysis plan.
*Additional efficacy endpoint analyses in this subgroup will be performed and will be 
described in the analytical plan.
8.5.3.
Secondary Efficacy Endpoints
The major secondary efficacy endpoints include:
1. SRI response rate with the SELENA SLEDAI for scoring of proteinuria at Week 52.
2. Time to first severe flare (as measured by the modified SLE Flare Index; with 
SLEDAI-2K and SELENA SLEDAI as the SLEDAI criterion of the SFI).
3. Percent of subjects whose average prednisone dose has been reduced by ≥ 25% from 
baseline to ≤7.5 mg/day during Weeks 40 through 52, in subjects receiving greater 
than 7.5 mg/day at baseline.
8.5.4.
Other Efficacy Endpoints
Endpoints Supporting Primary Efficacy Endpoint (SRI where SELENA SLEDAI 
score is modified to use the SLEDAI-2K scoring for proteinuria):
1. SRI by visit.
2. Percent of subjects with a ≥ 4 point reduction from baseline in SELENA SLEDAI
(modified to use the SLEDAI-2K scoring for proteinuria) at Week 52 and by visit.
3. Percent of subjects with no new BILAG A organ domain score or 2 new BILAG B 
organ domain scores compared with baseline at Week 52 and by visit.
4. Percent of subjects without PGA worsening (increase of < 0.30 points from baseline) 
at Week 52 and by visit.
5. Percent of subjects with durable SRI from Week 44-52.
6. Time to the 1st SRI that is maintained through Week 52.
7. Duration of longest response among subjects with at least 1 SRI response.
8. SRI 5-8 at Week 52 and by visit. 


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The SRI 5-8 are defined identically to the SRI except for using higher thresholds of 
improvement for SELENA SLEDAI (modified to use the SLEDAI-2K scoring for 
proteinuria) reduction for a patient to be declared a responder (eg, SELENA SLEDAI ≥ 5 
point reduction for SRI5).
Disease activity:
1. Mean percent change and mean change in PGA by visit.
2. Mean percent change and mean change in SELENA SLEDAI with the modified 
SLEDAI-2K scoring for proteinuria score by visit. 
Organ Specific:
1. Percent of subjects with organ improvement by SELENA SLEDAI by visit. The renal 
domain will use the SLEDAI-2K proteinuria scoring as the primary method with the 
SELENA SLEDAI proteinuria scoring as a sensitivity analysis.
2. Percent of subjects with organ worsening by SELENA SLEDAI by visit. The renal 
domain will use the SLEDAI-2K proteinuria scoring as the primary method with the 
SELENA SLEDAI proteinuria scoring as a sensitivity analysis.
3. Percent of subjects with organ improvement by BILAG by visit. 
4. Percent of subjects with organ worsening by BILAG by visit. 
5. Mean/median percent (in patients with proteinuria at baseline) and mean/median 
absolute (in all patients) change in proteinuria by visit.
6. Time to renal flare over 52 weeks (see definition below).
7. Percent of patients developing at least 1 renal flare (see definition below) over 52 
weeks.
8. Percent of subjects with doubling of serum creatinine (the proportion of patients 
whose serum creatinine attains a level double that of the baseline value and is 
confirmed with a second measurement at least 3 weeks later). 
SFI Flare (SFI where SELENA SLEDAI score is modified to use the SLEDAI-2K 
scoring for proteinuria):
1. Time to flare over 52 weeks.
2. Time to flare after Week 24.
3. Time to severe flare after Week 24. 
4. Rate of flare per 100 subject years.
5. Rate of severe flare per 100 subject years.
Steroids (based on average steroid dose between visits):
1. Percent of subjects with daily prednisone dose reduced to ≤ 7.5 mg/day from > 7.5 
mg/day at baseline by visit (DO=F).
2. Percent of subjects with daily prednisone dose increased to > 7.5 mg/day from 
≤7.5 mg/day at baseline by visit (LOCF).
3. Percent of subjects with any increase in steroid use by visit (all patients, LOCF).


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4. Percent of subjects with a 50% decrease in steroid dose by visit (DO=F; in patients 
receiving steroids at baseline).
5. Percent of subjects with a 50% increase in steroid dose by a minimum ≥ 5 mg/day by 
visit (LOCF; in all patients).
6. Mean/median changes in steroid dose (mg/day) by visit.
SLICC Damage Index (DI):
1. Mean change from baseline in SLICC DI at Week 52.
2. Percent of patients with any SLICC DI worsening (change > 0) at Week 52 compared 
with baseline.
Patient Reported Outcome:
1. Mean change in FACIT-fatigue score at Week 52 and by visit.
2. Percent of patients with improvement in FACIT-fatigue score exceeding the MCID (≥ 
4) by visit.
Biological Markers:
1. Median/mean percent change and median/mean absolute change from baseline in 
absolute B cell subsets (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+
activated, CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH/CD38HIGH regulatory B cell, and CD20-/138+ plasma cells) by visit. 
Only in regions/countries where assessment of B cells is feasible. 
2. Median/mean percent change and median/mean absolute change from baseline by 
visit
-
Total serum immunoglobulin (IgG and other isotypes: IgM and IgA).
-
Autoantibodies* (anti-dsDNA, ANA, anti-phospholipid antibodies [aCL, 
lupus anticoagulant, ±beta-2-glycoprotein-1], and extractable nuclear antigens 
[ENAs]).
-
Complement (C3, C4) levels.
3. Percent of patients with normalized serological activity at Week 52 and by visit
-
IgG, IgM and IgA (high to normal/low).
-
Autoantibodies* (anti-dsDNA, ANA, anti-phospholipid antibodies [aCL, 
lupus anticoagulant, ±beta-2-glycoprotein-1], and extractable nuclear antigens 
[ENAs]) present to absent.
-
Complement (C3, C4, and C3 AND C4) levels low to normal/high.
*Anti-dsDNA will be collected monthly throughout the study for SELENA SLEDAI 
scoring modified to use the SLEDAI-2K scoring for proteinuria. ANA will be collected at 
screening and baseline only. Other autoantibodies will be collected from all patients at 
baseline, then at regular intervals in patients positive at baseline. 
Renal Flare Definition:
The following is the definition of renal flare (Alarcón-Segovia et al, 2003) consisting of 
the development of one or more of the following 3 factors:


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•
Increased Proteinuria (using spot urine)
A reproducible increase in 24-hour urine protein levels to: 
> 1,000 mg if the baseline value was < 200 mg 
OR 
> 2,000 mg if the baseline value was between 200 and 1000 mg 
OR 
More than twice the value at baseline if the baseline value was > 1000 mg 
•
Impaired Renal Function 
A reproducible decrease in GFR of > 20%, accompanied by proteinuria (> 1000 
mg/24 hours), hematuria (≥ 4 RBCs/hpf or above the reference range for the 
laboratory), and/or cellular (RBC and WBC) casts.
•
New Hematuria 
New, reproducible hematuria (≥ 11 to 20 RBCs/hpf) or a reproducible increase in 
hematuria by 2 grades compared with baseline, associated with > 25% dysmorphic 
RBCs, glomerular in origin, exclusive of menses, accompanied by either an 800 mg 
increase in 24-hour urinary protein levels or new RBC casts. 
8.5.5.
Secondary Efficacy Analyses
The SRI response rate with the SELENA SLEDAI scoring for proteinuria at Week 52 
will be compared between the belimumab treatment group and the placebo group using 
the same analysis methods as described for the primary endpoint in Section 8.5.2. 
The time to the 1st severe SLE flare over 52 weeks will be compared between the 
belimumab treatment group and the placebo group using the Cox proportional hazard 
model. The independent variables in the model will include treatment groups (ie, 
belimumab vs placebo), baseline SELENA SLEDAI score (≤ 9 vs ≥ 10), complement 
level (C3 and/or C4 low vs other), and region (US/Canada vs rest of the world).
However, the adjustment will not occur for any of these baseline randomization factors
that has < 10 events (ie, severe flares) or < 10 non-events in a stratification level. If a 
subject withdraws from the study or completes the study up to the Day 364 (Week 52) 
visit without any severe SLE flare, time to the 1st severe SLE flare will be censored at the 
time of the last observation. If a subject receives a dose of protocol prohibited/restricted 
medication that results in treatment failure designation up to the Week 52 visit, the 
subject will be considered as having a severe SLE flare at the time the medication is 
started.
The percent of subjects with average prednisone dose that has been reduced by ≥ 25% 
from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 will be compared between the 
belimumab treatment and the placebo groups using a logistic regression model. The 
independent variables in the model will include treatment groups (ie, belimumab vs 
placebo), baseline SELENA SLEDAI score (≤ 9 vs ≥ 10), complement level (C3 and/or 
C4 low vs other), and region (US/Canada vs rest of the world). However, the adjustment 


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will not occur for any of these baseline randomization factors that has < 10 events (ie, 
having a prednisone reduction by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 
through 52) or < 10 non-events in a stratification level. The analysis will be performed on
subjects who used prednisone > 7.5 mg/day at baseline. Any subject who withdraws from 
the study prior to the Day 364 (Week 52) visit, misses the Day 364 (Week 52) visit, 
and/or receives a dose of protocol prohibited/restricted medication that results in 
treatment failure designation prior to the Day 364 (Week 52) visit will be considered as 
without any prednisone reduction for the analysis.
8.5.6.
Other Efficacy Analyses
The analysis of all other efficacy endpoints will be described in the statistical analysis 
plan.
8.6.
Safety
8.6.1.
Definition of Safety Variables
Safety will be evaluated by adverse events, changes in laboratory parameters, and 
immunogenicity.
8.6.2.
Analysis of Safety Variables
AEs will graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 12) or the grades in Section 7.7, as appropriate. The frequency of AEs 
will be tabulated by MedDRA system organ class (SOC) and preferred term. Additional 
analysis may be performed based on event rates adjusting for subject-years on study 
agent if the dropout rates are unbalanced across treatment groups. AEs will also be 
summarized by MedDRA SOC and preferred terms for those that are considered to be 
severe (Grade 3 and Grade 4) and those that are considered serious. Discontinuations due 
to AEs will be summarized. 
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 4 laboratory abnormalities 
will be summarized.
Safety Endpoints of Special Interest
•
All cause mortality 
•
Serious and/or severe infections 
•
Opportunistic infections 
•
Malignant neoplasms
•
Selected serious psychiatric events 
•
Suicidality assessment (see Appendix 3 and Appendix 4)


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•
Infusion/hypersensitivity reactions
•
Immunogenicity
The analyses of these safety endpoints will be described in the statistical analysis plan.
8.7.
Pharmacokinetics
8.7.1.
Definition of Pharmacokinetic Evaluation
All randomized subjects will be sampled for serum belimumab levels. Serum belimumab 
concentration data will be used in a population PK analysis. Assessment of belimumab 
concentrations will be performed at the timepoints indicated in Table 6-1.
8.7.2.
Analysis of Pharmacokinetics
Serum belimumab concentration will be determined by an electrochemiluminescence 
(ECL)-based assay. Results for this study will be presented using appropriate graphic and 
tabular summaries. Serum belimumab concentration data obtained from this study will be 
used in a population PK analysis, which will be reported separately. Potential effects of 
demographic and disease characteristics, concurrent medications, or renal function on 
belimumab PK will be evaluated.
9.
PHARMACOGENETICS (PGX)
In consenting subjects, a blood sample for PGx research will be drawn predose, 
preferably on Day 0, but samples may be drawn at any time while the subject is 
participating in the study, to better characterize genetic variability (eg, HLA typing) that 
may affect efficacy or safety endpoints. Information regarding PGx research is included 
in Appendix 11.
The IEC/IRB and, where required, the applicable regulatory agency must approve the 
PGx assessments before these can be conducted at the study site. The approval(s) must be 
in writing and clearly specify approval of the PGx assessments (ie, approval of Appendix 
11). In some cases, approval of the PGx assessments can occur after approval is obtained 
for the rest of the study. If so, then the written approval will clearly indicate that approval 
of the PGx assessments is being deferred and the study, except for PGx assessments, can 
be initiated. When PGx assessments are not approved, then approval for the rest of the 
study will clearly indicate this and that PGx assessments will not be conducted.
10. STUDY ADMINISTRATION
Belimumab is under joint development by Human Genome Sciences, Inc. and 
GlaxoSmith Kline Pharmaceuticals. Human Genome Sciences, Inc. is the sponsor of this 
study.


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10.1.
Informed Consent
A copy of the proposed informed consent document must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The 
consent form must be approved by the IRB/IEC and contain all elements required by 
national, state, local, and institutional regulations or requirements.
It is the responsibility of the investigator to provide each subject with full and adequate 
verbal and written information using the IRB/IEC approved informed consent 
document(s), including the objective and procedures of the study and the possible risks 
involved before inclusion in the study. Each subject must voluntarily provide written 
informed consent (including consent for the use and disclosure of research-related health 
information). The consent must be obtained prior to performing any study-related 
procedures that are not part of normal patient care, including screening and changes in 
medications including any washout of medications. A copy of the signed informed 
consent must be given to the study subject.
10.2.
Institutional Review Board Review/Independent Ethics
Committee Review and Approval
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with the ICH Guideline for Good Clinical Practice 
(GCP), will provide initial and continuing review of the study.
Prior to shipment of the study agent and enrollment of study subjects, documented 
IRB/IEC approval of the protocol, informed consent form, and any advertisement for 
subject recruitment must be obtained and provided to the sponsor or designee.
The IRB/IEC must also be informed of all protocol amendments prior to implementation.
The investigator must provide reports of any change in research activity (ie, the 
completion, termination, or discontinuation of a study) to the IRB/IEC.
10.3.
Protocol Compliance
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC.
10.4.
Protocol Revisions
Protocol amendments will be prepared and approved by the sponsor. All protocol 
amendments will be signed by the investigator and submitted to the IRB/IEC for review 
prior to implementation. Documentation of IRB/IEC approval must be forwarded to the 
sponsor or designee. If an amendment significantly alters the study design, increases 
potential risk to the subject or otherwise affects statements in the informed consent form, 
the informed consent form must be revised accordingly and submitted to the IRB/IEC for 
review and approval. The approved consent form must be used to obtain informed 


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consent from new subjects prior to enrollment and must be used to obtain informed 
consent from subjects already enrolled if they are affected by the amendment.
10.5.
Data Collection and Management
The investigator is responsible for maintaining accurate, complete, and up-to-date records 
for each subject. The investigator is also responsible for maintaining any source 
documentation related to the study, including any films, tracings, computer discs, or 
tapes.
The anonymity of participating subjects must be maintained. For data collection and 
management purposes, subjects are to be identified by a subject number only. Documents 
that identify the subject beyond subject number will not be submitted to the sponsor (eg, 
the signed informed consent document; subject initials) and must be maintained in strict 
confidence by the investigator, except to the extent necessary to allow auditing by the 
regulatory authorities, study monitor, or sponsor representatives.
Site personnel record all data for each study subject through electronic case report forms 
(eCRFs) using an Electronic Data Capture (EDC) system provided and approved by the 
sponsor. Refer to the Study Procedures Manual for additional information regarding 
eCRFs that will be used as source documentation. Sites must complete the eCRFs in a 
timely manner and the investigator must promptly review the completed eCRFs for each 
subject. As the person ultimately responsible for the accuracy of all eCRF data, the 
investigator must sign the Investigator's Statement in each subject's eCRF.
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system, so as to ensure accuracy, quality, consistency, and 
completeness of the database. Manual queries resulting from review by monitors, medical 
coders, and other Data Management staff are also generated from within the EDC system, 
where they are tracked. Sites resolve the queries and correct the entered data when 
necessary. Every change to data is captured in the EDC system audit trail. 
Upon completion of the study, or after reaching a pre-specified point in the study, Data 
Management will lock the database and generate the SAS datasets necessary for data 
analysis and reporting. Upon completion of the study, each site will be provided with a 
compact disk containing the eCRFs for each of their subjects.
10.6.
Study Monitoring
The study sponsor, Human Genome Sciences, Inc., or designee, will monitor the study.
Study monitors representing the sponsor will visit study sites routinely throughout the 
trial. The sponsor will review CRFs and compare them with source documents to verify 
accurate and complete collection of data and confirm that the study is being conducted 
according to the protocol. Auditors representing the sponsor may also similarly evaluate 
the study and its monitors. For these purposes, the investigator will make CRFs and 
source documents available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 


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promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority.
10.7.
Drug Accountability
Upon receipt, the designated unblinded pharmacy personnel at the study site is 
responsible for taking an inventory of the study agent, including any buffers or diluents. 
A record of this inventory must be kept and usage must be documented on study agent 
inventory forms provided by the sponsor.
Study agent inventory forms will be examined and reconciled by a sponsor’s unblinded 
monitor, or designee. At the end of the study, all used and unused study agent must be 
accounted for on a study agent accountability form provided to the investigator by the 
sponsor or its designee.
10.8.
Retention of Records
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the 
longer of the maximum period required by the country and institution in which the study 
is conducted, or the period specified by the sponsor at the time the study is completed, 
terminated, or discontinued.
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall 
be documented in writing and provided to the sponsor.
10.9.
Financial Disclosure
The investigator and all sub-investigators will provide HGS sufficient and accurate 
information on financial interests (proprietary or equity interests, payments exclusive of 
clinical trial costs) to allow complete disclosure to regulatory authorities. The investigator 
shall promptly update this information if any relevant changes occur during the course of 
the investigation and for a period of 1 year following study completion.
10.10.
Publication Policy
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The 
investigator acknowledges that an independent, joint publication is anticipated to be 
authored by the investigators of the multi-center study and sponsor’s representatives. 
Neither institution nor principal investigator shall independently publish or present the 
results of the study prior to the publication of the multi-center study publication. The 
investigator agrees that the sponsor will be the coordinator and arbitrator of all multi-
center study publications. For multi-center trials, no investigator will be authorized to 
publish study results from an individual center until the earlier of the multi-center trial 
results are published or 12 months after the end or termination of the multi-center trial at 
all sites.


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The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until all of 
the sponsor’s comments on the proposed publication or presentation have been 
considered and any information determined by sponsor to be confidential information has 
been removed. If requested in writing by the sponsor, the investigator shall withhold 
material from submission for publication or presentation for an additional 60 days to 
allow for the filing of a patent application or the taking of other measures to establish and 
preserve the sponsor’s proprietary rights.
10.11.
Study or Study Site Termination
If HGS, the investigator, IRB/IEC, or a regulatory authority discovers conditions arising 
during the study that indicate that the study should be halted or that the study center 
should be terminated, this action may be taken after appropriate consultation between 
HGS and the investigator. Conditions that may warrant termination of the study include, 
but are not limited to, the following:
•
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.
•
A decision on the part of HGS to suspend or discontinue testing, evaluation, or 
development of the product.
The study site may warrant termination under the following conditions:
•
Failure of the investigator to enroll subjects into the study at an acceptable rate.
•
Failure of the investigator to comply with pertinent regulatory authority regulations.
•
Submission of knowingly false information from the research facility to HGS, study 
monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.


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List of Appendices
Appendix 1
American College of Rheumatology (ACR) Criteria for SLE...............91
Appendix 2
Concurrent Medications.........................................................................93
Appendix 3
Columbia Suicide-Severity Rating Scale (C-SSRS) 
Baseline/Screening.................................................................................97
Appendix 4
Columbia Suicide-Severity Rating Scale (C-SSRS) Since Last Visit..113
Appendix 5
SELENA SLEDAI Disease Assessment Scales...................................125
Appendix 6
Draft Recommendations for Steroid Dosing and Tapering..................129
Appendix 7
BILAG..................................................................................................131
Appendix 8
FACIT-Fatigue Scale (Version 4)........................................................133
Appendix 9
SLICC/ACR Damage Index.................................................................134
Appendix 10
Laboratory Tests...................................................................................136
Appendix 11
Pharmacogenetic Research...................................................................137
Appendix 12
Adverse Event Severity Grading Tables..............................................141
Appendix 13
Liver Safety Required Actions and Follow up Assessments ...............150
Appendix 14
Liver Safety – Study Treatment Restart Guidelines.............................153


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Appendix 1
American College of Rheumatology (ACR) Criteria 
for SLE
The ACR Criteria for the Classification of Systemic Lupus Erythematosus
(Tan, 1982; and Hochberg, 1997)
Criterion*
Definition
1. Malar "butterfly" rash 
Fixed erythema, flat or raised, over the malar eminences, tending to 
spare the nasolabial folds.
2. Discoid rash 
Erythematosus raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions.
3. Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation.
4. Oral ulcers 
Oral or nasopharyngeal ulceration usually painless, observed by 
physician.
5. Nonerosive Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints characterized 
by tenderness, swelling, or effusion.
6. Serositis 
a.
Pleuritis (convincing history or pleuritic pain or rub heard by 
physician or evidence of pleural effusion), OR
b.
Pericarditis (documented by ECG, rub, or evidence or pericardial 
effusion).
7. Renal disorder 
a.
Persistent proteinuria (> 0.5 grams/day or > 3 + if quantitation not 
performed) OR
b.
Cellular casts (may be red cell, hemoglobin, granular, tubular, or 
mixed).
8. Neurologic disorder 
a.
Seizures (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance) 
OR
b.
Psychosis (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance.
9. Hematologic disorder 
a.
Hemolytic anemia (with reticulocytosis)
OR
b.
Leukopenia (< 4000/mm3 total on 2 or more occasions), OR
c.
Lymphopenia (< 1500/mm3 on 2 or more occasions), OR
d.
Thrombocytopenia (< 100,000/mm3 in the absence of offending 
drugs).


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Criterion*
Definition
10. Immunologic disorder 
a.
Anti-DNA (antibody to native DNA in abnormal titer), OR
b.
Anti-Sm (presence of antibody to Sm nuclear antigen), OR
c.
Positive-finding of antiphospholipid antibodies based on 1) an 
abnormal serum level of IgG or IgM anticardiolipin antibodies, 2) a 
positive test result for lupus anticoagulant using a standard method, 
or 3) a false-positive serologic test for syphilis known to be positive 
for at least 6 months and confirmed by Treponema pallidum 
immobilization (TPI) or fluorescent treponemal antibody (FTA) 
absorption test.
11. Antinuclear antibody (ANA)
Abnormal titer of ANA by immunofluorescence or an equivalent assay at 
any point in time and in the absence of drugs known to be associated 
with "drug-induced lupus" syndrome.
*The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical 
studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are 
present, serially or simultaneously, during any interval or observation.


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Appendix 2
Concurrent Medications
Figure 2-1
Concurrent Medications


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Key to Figure 2-1:
Once the subject is randomized and receives the 1st dose of study agent on Day 0, the 
investigator may adjust concurrent medications (add, eliminate, change dose 
level/frequency) as clinically required; however, changes in certain medications (as 
outlined below) may result in the subject being defined as a treatment failure and will 
require withdrawal from the study.  
If background medications are adjusted that may affect entry criteria, a subject may need 
to be re-screened in order to ensure at least 30 days of stable therapy. 
a.
Stable SLE treatment regimen may consist any of the following (alone or in 
combination) for a period of at least 30 days prior to Day 0: 
•
Steroids (prednisone or prednisone equivalent, up to 40 mg/day).
•
Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
•
Non-steroidal anti-inflammatory drugs (NSAIDs).
•
Other immunosuppressive or immunomodulatory agents (eg, methotrexate, 
azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, 
mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin 
inhibitors (eg, tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 
6-mercaptopurine, mizoribine, thalidomide).
Pre-existing SLE medications must be stable for at least 30 days prior to Day 0. 
New SLE therapy other than corticosteroids must not be added within 60 days of 
Day 0. Corticosteroids may be added as new medication or their doses adjusted 
only up to 30 days prior to Day 0.
b. The total dose of systemic steroids may be increased as clinically required during the 
first 6 months of the trial (ie, until the Day 168 [Week 24] visit), but must return to 
within 25% or 5 mg over the baseline (Day 0) dose, whichever is higher, by the Day 
168 (Week 24) visit.
c.
A subject who fails to return to within 25% or 5 mg over the baseline (Day 0) dose of 
systemic steroids, whichever is higher, by the Day 168 (Week 24) visit will be 
considered a treatment failure.  
d. After the Day 168 (Week 24) visit, an increase > 25% or > 5 mg over the baseline 
(Day 0) dose(s) of systemic steroids, whichever is higher, for SLE activity will deem 
the subject a treatment failure. 
e.
Within 8 weeks before the Day 364 (Week 52) visit, no new increase of the systemic 
steroids over the baseline (Day 0) or Day 308 (Week 44) visit dose, whichever is 
higher, is allowed. 
f.
Steroids may be given for reasons other than SLE disease activity (such as asthma, 
contact dermatitis) as clinically indicated until the Day 168 (Week 24) visit.
g. GUIDELINE for Use of Steroids for reasons other than SLE:


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From Day 168 to 308 (Week 24 to 44) Visits:
Steroids may be given for reasons other than SLE disease activity from the Day 168 
(Week 24) visit until the Day 308 (Week 44) visit at any dose/duration that does not 
result in a total steroid dose (for SLE and non-SLE reasons) > 25% or > 5 mg, 
whichever is higher, over the baseline dose. In addition, steroids for non-SLE reasons 
may be given short-term at higher doses according to the following guidelines:
-
Up to 750 mg (prednisone) for 1 day; and/or
-
Up to 100 mg/day (prednisone) for 2-3 days; and/or
-
Up to 40 mg/day (prednisone) for 4-7 days.
The duration of high dose steroids use for reasons other than SLE must not exceed 7 
days, after which time, tapering should begin. The total steroid dose must be tapered 
to within 25% or 5 mg over the baseline dose, whichever is higher, within 30 days of 
the 1st dose of a course of steroids. In addition, the steroid dose must be tapered to 
within 25% or 5 mg over the baseline dose, whichever is higher, by the Day 308 
(Week 44) visit.  
h. From the Day 308 to 364 (Week 44 to 52) Visits:
After the Day 308 (Week 44) visit, no new steroids are allowed for reasons other than 
SLE activity that result in a total daily steroid dose > 25% or > 5 mg, whichever is 
higher, over the baseline total steroid dose. A subject will be considered a treatment 
failure for any steroid use 8 weeks before the Day 364 (Week 52) visit that does not 
meet this criterion.  
Note: Inhaled and topical steroids are allowed throughout the course of the study.
i.
Subjects may receive intraarticular steroid injections between baseline (Day 0) and 
the Day 308 (Week 44) visit.
j.
A subject who receives any intraarticular steroid injection(s) within 8 weeks before 
the Day 364 (Week 52) visit will be defined as a treatment failure.  
k. The dose of existing immunosuppressive/immunomodulatory agents may be 
increased, as clinically required, up to the Day 112 (Week 16) visit. 
l.
After the Day 112 (Week 16) visit, any increase in  
immunosuppressive/immunomodulatory agents dose above the baseline or Day 112 
(Week 16) visit dose, whichever is higher, will cause the subject to be declared a 
treatment failure.  
m. Starting any new immunosuppressive/immunomodulatory agent after Day 0 will 
cause the subject to be declared a treatment failure. 
n. NSAIDs may be given as clinically indicated until the Day 308 (Week 44) visit.
o. For subjects who never received an NSAID between the Day 0 and Day 308 (Week 
44) visit, starting a new NSAID after the Day 308 (Week 44) visit will declare the 
subject a treatment failure unless the NSAID is given for < 1 week.
p. Daily doses of aspirin up to 1000 mg/day are allowed at any time during the study. 


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q. For subjects who never received an aspirin regimen at a dose > 1000 mg/day between 
the Day 0 and Day 308 (Week 44) visit, starting a new aspirin regimen at a dose > 
1000 mg/day after the Day 308 (Week 44) visit will declare the subject a treatment 
failure unless the aspirin is given for < 1 week.
r.
Daily doses of aspirin above 1000 mg/day may be initiated at any time up to Day 308 
(Week 44) visit and may continue through the end of the study.
s.
A new anti-malarial (eg, hydroxychloroquine, chloroquine, quinacrine) may be 
started between Day 0 and the Day 112 (Week 16) visit. The dose may be increased 
as clinically required, up to the Day 112 (Week 16) visit, and may be reduced 
anytime during the study. 
t.
An antimalarial treatment will be considered NEW if the subject did not receive an 
antimalarial at any time during the Day 0 to Day 112 (Week 16) treatment interval.
u. After the Day 112 (Week 16) visit, any increase in dose of an anti-malarial above the 
baseline (Day 0) or Day 112 (Week 16) visit dose, whichever is higher, will declare 
the subject a treatment failure. Starting any new anti-malarial treatment after the Day 
112 (Week 16) visit will declare the subject a treatment failure.


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Appendix 3
Columbia Suicide-Severity Rating Scale (C-SSRS) 
Baseline/Screening
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which
are protected by third party copyright laws and therefore have been excluded.


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Appendix 4
Columbia Suicide-Severity Rating Scale (C-SSRS) 
Since Last Visit
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are
protected by third party copyright laws and therefore have been excluded.


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Appendix 5
SELENA SLEDAI Disease Assessment Scales
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


2 0 1 4 N 1 9 9 0 6 2 _ 0 0
H u ma n Ge n o me Scie nces, I nc.
C o nfi de ntial
Pa ge 1 2 7
Cli nical Pr ot oc ol H G S 1 0 0 6 -C 1 1 1 2 -0 2
Beli m u ma b
S L E Fl ar e I n d e x
Mil d o r M o d er at e Fl ar e
S e v er e Fl ar e
−
C h a n g e  i n S E L E N A  S L E D AI  i n str um e n t s c or e  of 3
p oi n t s or m or e ( b ut n ot t o m or e t h a n 1 2)
−  N e w/ w or s e:
Di s c oi d, p h ot o s e n siti v e, pr of u n d u s,
c u ta n e o u s v a s c uliti s, b ull o u s l u p u s
N a s o p h ar y n g e al ul c er s
Pl e uriti s
P eri c ar diti s
Art hrit i s
F e v er ( SL E)
−  I n cr ea s e  i n pr e d ni s o n e,  b ut  n ot  t o >  0. 5  m g/ k g/ d a y
−  A d d e d  N S AI D  or  h y dr o x y c hl or o q ui n e  f or S L E
A cti v it y
−  ≥ 1. 0  i n cr e a se  i n P G A  s c or e , b u t n o t t o m or e  t h an
2. 5
−
C h a n g e  i n S E L E N A  S L E D AI  i n stru m e nt  s c or e  t o 
gr e at er t h a n 1 2
−
N e w/ w or s e:
C N S -S L E
V a s c uliti s
N e p hr iti s
M y o siti s
Plt < 6 0, 0 0 0
H e m o l yti c a n e mi a: H b < 7 0 g/ L or d e cr e a s e i n
H b > 3 0 g/ L
R e q uiri n g : d o u bl e pr e d ni s o n e, or pr e d ni s o n e
i n cr e as e t o > 0 . 5 m g/ k g/ d a y, or h o s pit a li z ati o n
− I n cr e a s e i n pr e d ni s o n e  t o > 0 . 5 m g/ k g/ d a y
−
N e w  c y cl o p h o s p h a mi d e,  a z at h i o prin e,
m et h otr e x at e, or m y c o p h e n ol a t e for S L E a cti vit y
−
H o s pi t ali z ati o n f or S L E  a cti vi t y
−
I n cre a s e  i n P G A  s c or e  t o > 2. 5
A d a pt e d fr o m:  
P etri M, B u y o n J, Ki m M. Cl a s sifi c ati o n a n d d efi niti o n of m aj or fl ar e s i n S L E cli ni c al tri al s. L u p u s 1 9 9 9 ; 
8: 6 8 5 -6 9 1.
P etri M et al. C o m bi n e d Or al C o ntr a c e pti v e s i n Wo m e n wit h S y st e mi c L u p u s Er yt h e m at o s u s. N E n gl J M e d 
2 0 0 5; 3 5 3: 2 5 5 0 -8. 
B u y o n J P et al. T h e Eff e ct of C o m bi n e d E str o g e n a n d Pr o g e st er o n e H or m o n e R e pl a c e m e nt T h er a p y o n 
Di s e a s e A cti vit y i n S y st e mi c
L u p u s Er yt h e m at o s u s: A R a n d o mi z e d Tri al. A n n I nt er n al M e d 
2 0 0 5; 1 4 2 
( 1 2 Pt 1): 9 5 3 -6 2.


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Physician’s Global Disease Assessment
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


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Appendix 6
Draft Recommendations for Steroid Dosing and 
Tapering
Table 11-1 depicts the 2 main clinical groups of major SLE presentations where steroids 
would be used. Table 11-2 summarizes the recommended steroid dosing and tapering.
Table 11-1
Major SLE presentations where steroids would be used
SEVERE
MODERATELY SEVERE
Central Nervous System
cerebral vasculitis
encephalitis
psychosis
coma
transverse myelitis
chorea peripheral neuropathy
pseudotumor orbit
optic neuritis
retinitis
encephalopathy
autoimmune sensorineural hearing loss
mononeuritis multiplex
status epileliticus
demyelinating syndrome
lupoid
Cardiopulmonary
pneumonitis
pulmonary hemorrhage
cardiac tamponade
myocarditis
coronary arteritis
Pneumonitis
pulmonary effusion
shrinking lung
pericarditis
myocarditis
Cutaneous
thrombotic thrombocytopenia
purpura
severe discoid
severe oral ulcers
diffuse subacute cutaneous lupus
bullous skin disease
cutaneous vasculitis
Renal
Gastrointestinal
rapidly progressive
glomerulonephritis
mesenteric vasculitis
Glomerulonephritis
ureteral obstruction
pancreatitis
peritonitis
lupus colitis
severe hepatitis
protein losing enteropathy
Hematologic
idiopathic thrombocytopenia
(< 15,000 platelets/mm3)
Thrombocytopenia
(15-30,000 platelets/mm3)
hyperviscosity
hemophagocytic syndrome
lupus adenitis (a la kikochi)
hemolytic anemia


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SEVERE
MODERATELY SEVERE
Musculoskeletal
polychondritis
polyarthritis
Miscellaneous
fever
Table 11-2
Recommended, standardized initial steroid dosing and steroid 
tapering
Dose* Induction 
(Median)
Range
Mean ± SD
Duration of 
Induction 
Therapy 
(Median)
Duration to 
Off Steroids 
(Median)
Severe SLE 
60 PO
1000 bolus
40-100
40-1000
66.4 ± 15.5
766 ± 344
14 days
3 days
20 weeks
-
Moderately 
Severe SLE
35 PO
15-75
38.5 ± 13.4
7 days
15 weeks
Mild SLE
10 PO
0-30
14.5 ± 6.8
not detectable
not 
detectable
*Prednisone dose in mgs for a 70-kilogram person.
(From: Response Criteria for Systemic Lupus Erythematosus Clinical Trials: Steroid Sparing Ability of an 
Intervention-Working Draft; Prepared for The American College of Rheumatology; September 10, 2002). Not 
endorsed by ACR.


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Appendix 7
BILAG
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third
party copyright laws and therefore have been excluded.


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Appendix 8
FACIT-Fatigue Scale (Version 4)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


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Appendix 9
SLICC/ACR Damage Index
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party
copyright laws and therefore have been excluded.


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Appendix 10
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 eg, 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
Estimated Creatinine Clearance/ GFR 
(Cockcroft-Gault)
Other Screening Labs
HIV-1/2 antibody
Hepatitis C antibody
HBsAg and HB Core antibody
Serum pregnancy
Alcohol and Drug screen
PT / PTT
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
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
Biological Markers
FACS of peripheral lymphocytes: B lymphocytes (CD20+, 
CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, 
CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH /CD38HIGH regulatory B cell, and CD20-/138+ 
plasma cells)  
BLyS protein 
Serum complement (C3, C4) 
Immunoglobulins
Serum immunoglobulin isotypes:  IgG, IgM, IgA
PK and Immunogenicity
Belimumab pharmacokinetic assessment
Belimumab immunogenicity assessment
Autoantibodies
ANA titer and OD
Anti-dsDNA
aCL
Lupus anticoagulant
±beta-2-glycoprotein-1**
ENAs**
*Refer to Table 6-1 and Table 6-2 for assessment time points
**May be collected in selected sites/regions


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Appendix 11
Pharmacogenetic Research
Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in different populations. There is increasing evidence that an individual's genetic 
composition 
(ie, genotype) 
may 
impact 
pharmacokinetics, 
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).
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies. 
Research Rationale
Blood samples for pharmacogenetics will be drawn as described in Section 9. Collection 
of whole blood samples, even when no a priori hypothesis has been identified, may 
enable PGx analyses to be conducted if there is unexplained or unexpected variation in 
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 that may be attributable to genetic variations 
of subjects, the following objectives may be investigated: 
•
Relationship between genetic variants and the pharmacokinetics of belimumab.
•
Relationship between genetic variants and safety and/or tolerability of belimumab.
•
Relationship between genetic variants and efficacy of belimumab.
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives belimumab may take part in the 
PGx research. 
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
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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Study Assessments and Procedures
In addition to any blood samples drawn for the clinical study, a whole blood sample (~6 
to 8 mL) will be collected for the PGx research at baseline. The PGx sample is labeled (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 will be taken on a single occasion 
unless a duplicate sample is required due to inability to utilize the original sample. The 
blood samples should be drawn on Day 0 (baseline), provided informed consent for PGx 
research has been obtained from the subject, but the sample may be taken at any time 
while the subject is participating in the clinical study. 
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA will 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 set of studies) of 
belimumab has been completed and the study data reviewed. In some cases, the samples 
may not be studied. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or the sponsor may destroy the samples sooner. The sponsor or those 
working with the sponsor (for example, other researchers or a contract lab) will use 
samples collected from the study for the purpose stated in this protocol and in the subject 
informed consent form.
Subjects may request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:
1. The sample is retained for PGx research.
2. The sample is destroyed.
If a subject withdraws consent from the 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 the sponsor and maintain the 
documentation in the site study records. In either case, the sponsor will only use study 
information collected/generated up to that point.
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 


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investigator must complete the appropriate documentation to request sample destruction 
within the timeframe specified by the sponsor and maintain the documentation in the site 
study records.
Pharmacogenetic Analyses
Specific sections of DNA may be selected from areas of the genome (ie, candidate 
genes). The candidate genes could include the drug target, the drug target pathway, drug 
metabolizing enzymes, genes associated with mechanisms underlying adverse events, and 
genes associated with the study disease. 
In addition, a genome-wide scan or large scale sequencing of polymorphic markers 
located across the genome may be implemented. This approach is often employed when 
potential genetic effects are not well understood.
Other new technologies may be developed to help us better study and understand genetic 
variants associated with drug response.
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.
Components of the PGx analysis may include: 
•
Hardy-Weinberg Equilibrium testing
The genotypic frequencies of each polymorphism will be evaluated for conformity to 
those expected under normal conditions by employing Hardy-Weinberg Equilibrium 
testing.
•
Comparison of Demographic and Baseline Characteristics by Genotype
Differences in baseline clinical characteristics and potential contributing covariates 
may be summarized and compared among genotype (or haplotype) subgroups.
•
Evaluation of Genotypic Effects
Analyses may be carried out to evaluate the degree of association between subject’s 
genotype (or haplotype) and selected parameters (eg, pharmacokinetics, SLE disease 
activity and safety). Where such genotypic tests are inappropriate (eg, where the 
number of marker genotypes is too large and/or the frequency of individual genotypes 
too small), allelic tests may be conducted. Allelic tests evaluate whether the 
frequency of each marker allele is the same in responders and non-responders.
•
Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on 
the selected parameters, the possibility of a treatment group by genotype (haplotype 
or allele) interaction will also be explored. If appropriate, the joint effects of multiple 
markers (gene-gene interactions) may also be evaluated.


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•
Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the 2 sites are correlated 
(linkage disequilibrium) may also be evaluated. If the genotypes at 2 polymorphic 
sites within a gene are shown to be statistically associated with a response to 
investigational product, the degree of linkage disequilibrium will aid interpretation in 
that it will indicate the extent to which the 2 sites are exerting independent effects.
•
Multiple Comparisons and Multiplicity
Adjustment to observed p-values may be made to limit erroneous conclusions due to 
multiple tests when multiple markers are evaluated (especially in the case of a 
genome scan for association). 
•
Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site 
depends on the total number of subjects genotyped and the frequency distribution of 
the different genotypes. Consequently, genotyping analyses are plausible for those 
polymorphic sites where the number of subjects comprising the genotypic groups is 
sufficiently large; however, these frequencies will not be known until sufficient 
samples have been collected and genotyping is complete. These examples show that 
small sample sizes typically encountered in Phase 1 and Phase 2 studies may be 
sufficient to identify clinically relevant genetic associations.
•
Additional analyses may be conducted as necessary.
Provision of Study Results and Confidentiality of Subject’s PGx Data
The sponsor may summarize the cumulative PGx research results in the clinical study 
report or in a separate report. In general, the sponsor does not inform the investigator, 
subject or anyone else (eg, family members, study investigators, primary care physicians, 
insurers, or employers) of the PGx research results because the information generated 
from PGx studies is preliminary in nature, and the significance and scientific validity of 
the results are undetermined at such an early stage of research, under any circumstance 
unless required by law.


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Appendix 12
Adverse Event Severity Grading 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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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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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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CHEMISTRIES
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)
*(Goldfarb et al, 2001; Yamani et al, 2001; Eibl and Rosen, 1995).                                                                 Modified from DMID Adult Toxicity Tables, 2001


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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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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
(continued)


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URINALYSIS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Proteinuria:
Dipstick: 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
< 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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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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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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Appendix 13
Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 

Viral hepatitis serology4

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 antibody5

Blood sample for pharmacokinetic (PK) 
analysis, obtained within approximately 1 
to 2 weeks after the liver event 6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH)

Fractionate bilirubin, if total 


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granted (refer to Appendix 14)

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).   


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4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
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].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the study reference manual.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
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 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry
stopping criteria, proceed as described above

If 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.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  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):2363–2369. 


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Appendix 14
Liver Safety – Study Treatment Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study 
treatment is not granted, then subject must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments,
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (eg, 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 7.2.


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Protocol Number: HGS1006-C1112
Amendment 02, Date: 09 February 2017
Protocol Title: A Phase 3/4, Multi-Center, Randomized, Double-Blind, Placebo 
Controlled, 52 Week Study to Evaluate the Efficacy and Safety of Belimumab 
(HGS1006) in Adult Subjects of Black Race with Systemic Lupus Erythematosus 
(SLE)
Summary of Modifications and Rationale:
1. The sample size for this study has been reduced from 816 subjects to approximately 
501 subjects due to pragmatic considerations to address the study objectives for this
post marketing commitment trial within a reasonable timeframe and based on updated 
information from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 
(Northeast Asia) regarding the assumed treatment differences. This modification has 
been made in consultation with the US Food and Drug Administration and European 
Medicines Agency.
2. The following has been revised in the Synopsis and Section 8:

The primary efficacy endpoint has been changed to the SRI response rate with the 
SELENA SLEDAI modified for SLEDAI-2K scoring for proteinuria. The original 
endpoint of the SRI with the SELENA SLEDAI scoring for proteinuria will be a 
major secondary endpoint. (Note: the proteinuria scoring modification occurs 
programmatically and does not impact the current scoring for individual subjects 
by the site.)

For other efficacy endpoints, clarification regarding the use of modified SLEDAI-
2K scoring for proteinuria and SELENA SLEDAI scoring for proteinuria in the 
endpoint and its analysis has been added or modified accordingly.
3. The following selection criteria have been revised or clarified in the Synopsis and 
Section 4:

Revisions intended to allow more subjects to be considered for enrollment:

The inclusion criterion for having an unequivocally positive autoantibody test 
has been qualified to allow a HEp-2 immunofluorescence assay (IFA) and/or 
positive enzyme immunoassay (EIA) result as evidence and to allow a 
historically positive anti-dsDNA result to have confirmation by any validated 
commercial assay.

The exclusion criterion for prior B cell targeted therapies has been modified 
from a lifetime exclusion to allowance of a 1 year or more ago. Literature 
evidence supports that the majority of patients have largely recovered from 
immunosuppressive effects of B cell depletion within 1 year after treatment 
with B cell targeted therapy.

In the exclusion criterion for anti-TNF therapies, 2 other examples were added 
to the list.


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
In the exclusion criterion for Grade 3 lab AEs, the list of exceptions was
modified to allow subjects with stable Grade 3 prothrombin time (PT) 
secondary to anticoagulant treatment.

In the exclusion criterion for Grade 3 lab AEs, the list of exceptions was 
expanded to allow subjects with stable Grade 3 hemoglobin reduction due to 
lupus.

Modifications to be consistent with GSK standards:

The inclusion criterion for female subjects has been modified to be consistent 
with GSK standards. A separate section (Section 4.3) on contraception 
recommendations has been added.

The exclusion criterion for hepatitis B infection has been modified to be 
consistent with GSK standards to test for hepatitis B core antibody, in addition 
to hepatitis B surface antigen.
4. The following safety sections have been modified to be in alignment with the 
belimumab program standard text:

A benefit and risk assessment for belimumab has been added.

Information on non-acute delayed type hypersensitivity reaction and symptoms 
has been added.

The adverse events section has been modified throughout for consistency with AE 
and SAE, and pregnancy data collection procedures and forms.

Progressive multifocal leukoencephalopathy (PML) text has been updated. 

The section on liver safety evaluation has been replaced to be consistent with 
GSK standards.  Restart criteria and monitoring have been added. New associated 
appendices have been added and the Laboratory appendix was updated 
accordingly.
5. The following conduct sections have been modified or added:

The study agent infusion dosing time has been clarified from “over 1 hour” to 
“over no less than 1 hour”, which was the intent of the original protocol.

The concomitant medication section has been modified to clarify use of 
prohibited medications and treatment failures.

Missing 3 or more consecutive doses of study agent, before administration of live 
vaccine, and Sponsor discretion have been added to the list of reasons for 
treatment withdrawal.

Pragmatic flexibility has been added to the dosing visit and dosing schedule, to 
allow patients who are identified to have reached withdrawal criteria at 
completion of the double blind portion of the protocol (week 52) to enter the 
open-label phase of the study pending consultation with the medical monitor.

Pragmatic flexibility has been added to using the prior visit weight measurement 
in lieu of the same day weight measurement for dose calculation.  If the two 


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weights vary by more than 10% then the current visit weight measurement must 
be used.

The survival assessment language has been updated from determination at Week 
52 to determination at approximately 52 weeks after the first dose of study agent.

The communication process for an unblinding event has been clarified.

Collection of an immunogenicity sample has been removed at the 6 month follow-
up for subjects with positive response at 8-week follow-up.  Collection of the 
follow-up samples is no longer necessary based on current immunogenicity safety 
profile and anticipated low clinical utility. Thus, Section 6.8 1.1 Immunogenicity 
(6-Month Follow-Up) has been deleted which resulted in the renumbering of 
subsequent sections. These
renumbering changes are not shown in the 
Modifications section below, except for the renumbering change that affected 
Inclusion Criterion 4.

A urine pregnancy test has been added at the 8-week follow-up visit for all 
women of child bearing potential.  Also an instruction has been added that women 
of child-bearing potential must be reminded of the requirement to report any 
pregnancy that occurs through 16 weeks following the last dose of study agent. 
Sections of the protocol affected by this change have been modified accordingly.

The IDMC section has been edited for clarity regarding timing of the reviews.
6. Administrative updates have been made as follows:

The study sponsor street address has been updated on the cover page.

A page with the protocol’s revision chronology has been added.

Level 5 headings are now in bold type face. These minor changes are not shown 
in the Modifications section below.

The presentation of cross-referencing sections, e.g., “see Sections X.1 and Y.2” 
was changed to “see Section X.1 and Section Y.2”. These minor changes are not 
shown in the Modifications section below.
7. Administrative changes/corrections of typographical errors have been made as 
appropriate, including corrections to Appendix 1 (The ACR Criteria for the 
Classification of Systemic Lupus Erythematosus) and Appendix 11 (Pharmacogenetic 
Research).
Associated Protocol Modifications:
Strikethrough indicates deleted text; bold indicates new/replacement text when text has 
been modified. When a new section/text is preceded by “Added:” as all text is new, bold 
text indicates bolded text within the new section.


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Cover Page:
Formerly:
Protocol Amendment: 01
Date: 20 June 2012
STUDY SPONSOR, line 2: 14200 Shady Grove Road
Modified to:
Protocol Amendment: 02
Date: 09 February 2017
STUDY SPONSOR, line 2: 9910 Belward Campus Drive
Added:
REVISION CHRONOLOGY FOR HGS1006-C1112 (BEL115471)
Date
Document*
Global
21 November 2011
Original
Global
20 June 2012
Amendment No 01
Local
2014N219219_00
02 February 2015
Local Amendment 01 for France
Global
2014N199062_00
09 February 2017
Amendment No 02
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.
Synopsis Diagnosis & Inclusion Criteria and Section 4.1 Inclusion Criteria
Formerly:
4. Have active SLE disease defined as a SELENA SLEDAI score ≥ 8 at screening (refer 
to Appendix 5 and Section 6.9.1.1 Scoring for Proteinuria for Eligibility at Screening).
5. Have unequivocally positive autoantibody test results defined as an ANA titer ≥ 1:80
and/or a positive anti-dsDNA (≥30 IU/mL) serum antibody test from 2 independent 
time points as follows: 

Positive test results from 2 independent time points within the study screening 
period. Screening results must be based on the study’s central laboratory results.
OR


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
One positive historical test result and 1 positive test result during the screening 
period.

Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer ) or 
anti-dsDNA (eg, anti-dsDNA by Farr assay) must include the date and type of the 
test, the name of the testing laboratory, numerical reference range, and a key that 
explains values provided as positive vs negative OR negative, 
equivocal/borderline positive). Only unequivocally positive values as defined in 
the laboratory’s reference range are acceptable; borderline values will not be 
accepted.
7. A female subject is eligible to enter the study if she is:  

Not pregnant or nursing; 

Of non-childbearing potential (ie, women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed, or have current documented tubal ligation or any other 
permanent female sterilization procedure); or

Of childbearing potential (ie, 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 serum pregnancy test at screening, and agree to 1 of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or

Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 16 
weeks after the last dose of study agent:  

Implants of levonorgestrel or etonogestrel;

Ethinyl estradiol/Etonogestrel vaginal ring; 

Injectable progesterone; 

Any intrauterine device (IUD) with a documented failure rate of less than 
1% per year;

Oral contraceptives (either combined or progesterone only); 

Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; 

Transdermal 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 
mycophenolate who are using oral contraceptives for birth control should 
employ an additional method (eg, barrier method).


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Modified to:
4. Have active SLE disease defined as a SELENA SLEDAI score ≥ 8 at screening (refer 
to Appendix 5 and Section 6.8.1.1 Scoring for Proteinuria for Eligibility at Screening).
5. Have 2 unequivocally positive autoantibody test results defined as a positive 
antinuclear antibody (ANA) test [ie, a titer ≥ 1:80 by HEp-2 immunofluorescence 
assay (IFA) and/or positive enzyme immunoassay (EIA)] and/or a positive anti-
dsDNA (≥ 30 IU/mL) serum antibody test as follows: 

from 2 independent time points within the study screening period. Screening 
results must be based on the study’s central laboratory results.
OR

One positive historical test result and 1 positive test result during the screening 
period.  

Historical documentation of a positive ANA test (eg, HEp-2 IFA or EIA) or anti-
dsDNA (eg, anti-dsDNA by any validated commercial assay) must include the 
date and type of the test, the name of the testing laboratory, numerical reference 
range, and a key that explains values provided as positive vs negative OR 
negative, equivocal/borderline positive). Only unequivocally positive values as 
defined in the laboratory’s reference range are acceptable; borderline values will 
not be accepted.
7. A female subject is eligible to enter the study if she is:  

Not pregnant or nursing; 

Of non-childbearing potential defined as

pre-menopausal females with a documented tubal ligation, hysterectomy, 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, or documented bilateral 
oophorectomy or

postmenopausal defined as 12 months of spontaneous amenorrhea with 
an appropriate clinical profile [eg, > 45 years, in the absence of hormone 
replacement therapy or other cause for amenorrhea]; in questionable 
cases obtain a blood sample for follicle stimulating hormone (FSH) and 
estradiol simultaneously to confirm. Diagnostic levels for FSH and 
estradiol vary by specific laboratories/assays; 

OR is of child-bearing potential with negative pregnancy test as determined 
by serum human chorionic gonadotrophin (hCG) test at screening and urine 
hCG test prior to dosing AND

Agrees to use one of the contraception methods listed in the protocol (see 
Section 4.3) for 2 weeks prior to the day of dosing to sufficiently minimize 
the risk of pregnancy at that point.  Female subjects must agree to use 
contraception until 16 weeks following the last dose of study agent.

OR has only same-sex partners, when this is her preferred and usual 
lifestyle.


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Synopsis Diagnosis & Inclusion Criteria and Section 4.2 Exclusion Criteria
Formerly:
1. Have received treatment with any B cell targeted therapy (eg, rituximab, other anti-
CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor 
fusion protein [BR3], TACI-Fc, anti-BAFF (LY2127399), or anti-BLyS 
[belimumab]) at any time. 
2. Have received any of the following within 364 days of Day 0:

Abatacept.

A biologic investigational agent other than B cell targeted therapy (eg, abetimus 
sodium, anti-CD40L antibody [BG9588/IDEC-131]). (Investigational agent 
applies to any drug not approved for sale in the country in which it is being used.)
4. Have received any of the following within 90 days of Day 0:  

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).

Intravenous (IV) cyclophosphamide

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

High dose prednisone or equivalent (> 100 mg/day).

Plasmapheresis.
16. Have a historically positive test or test positive at screening for HIV antibody, 
hepatitis B surface antigen, or hepatitis C antibody.
18. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event 
Severity Grading Tables (Appendix 12) except for the following that are allowed:

Stable Grade 3 prothrombin time (PT) secondary to warfarin, treatment.

Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and 
not related to liver disease or anti-coagulant therapy.

Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to 
creatinine ratio allowed).

Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver 
disease or malnutrition.

Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes, or viral 
hepatitis. If present, any abnormalities in ALT and/or AST must be ≤ Grade 2.

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. 
Modified to:
1. Have received treatment with anti-BLyS [belimumab]) at any time.
2. Have received any of the following within 364 days of Day 0:


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
Abatacept.

Other B cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-
CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion 
protein [BR3], TACI-Fc, or anti-BAFF (LY2127399).

A biologic investigational agent other than B cell targeted therapy (eg, abetimus 
sodium, anti-CD40L antibody [BG9588/IDEC-131]). (Investigational agent 
applies to any drug not approved for sale in the country in which it is being used.)
4. Have received any of the following within 90 days of Day 0:  

Anti-TNF therapy (eg, adalimumab, certolizumab pegol, etanercept, 
golimumab, infliximab).

Intravenous (IV) cyclophosphamide.

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

High dose prednisone or equivalent (> 100 mg/day).

Plasmapheresis.
16. Have a historically positive test or test positive at screening for HIV antibody, 
hepatitis B surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C 
antibody.
18. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event 
Severity Grading Tables (Appendix 12) except for the following that are allowed:

Stable Grade 3 prothrombin time (PT) secondary to anticoagulant, eg, warfarin, 
treatment.

Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and 
not related to liver disease or anti-coagulant therapy.

Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to 
creatinine ratio allowed).

Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver 
disease or malnutrition.

Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes, or viral 
hepatitis. If present, any abnormalities in ALT and/or AST must be ≤ Grade 2.

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. 

Stable Grade 3 hemoglobin reduction due to lupus.
Synopsis – Study Design and Schedule and Section 3 Study Design, paragraph 1
Formerly:
Approximately 816 SLE subjects will be randomized with a target of about 544 subjects 
treated with belimumab and 272 subjects receiving placebo.


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Modified to:
Approximately 501 SLE subjects will be randomized with a target of at least
334 subjects treated with belimumab and 167 subjects receiving placebo.
Synopsis – Study Design and Schedule, Section 3 Study Design, paragraph 2
Formerly:
Study agent will be administered IV over 1 hour.
Modified to:
Study agent will be administered IV over no less than 1 hour.
Synopsis – Efficacy Endpoints and Analysis and Section 8.5.1 Primary Efficacy 
Endpoint
Formerly:
The primary efficacy endpoint is the systemic lupus erythematosus responder index (SRI) 
at Week 52.
A SRI response is defined as:

≥ 4 point reduction from baseline in SELENA SLEDAI score,
AND

No worsening (increase of < 0.30 points from baseline) in Physician’s Global 
Assessment (PGA), 
AND

No new BILAG A organ domain score or 2 new BILAG B organ domain scores 
compared with baseline at the time of assessment (ie, at Week 52).
Modified to:
The primary efficacy endpoint is the systemic lupus erythematosus responder index (SRI) 
response rate with the modified SLEDAI-2K scoring for proteinuria at Week 52.
A SRI response is defined as:

≥4 point reduction from baseline in SELENA SLEDAI score (with the modified 
SLEDAI-2K scoring for proteinuria), 
AND


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
No worsening (increase of < 0.30 points from baseline) in Physician’s Global 
Assessment (PGA), 
AND

No new BILAG A organ domain score or 2 new BILAG B organ domain scores 
compared with baseline at the time of assessment (ie, at Week 52).
Synopsis – Efficacy Endpoints and Analysis and Section 8.5.3 Secondary Efficacy 
Endpoints
Formerly:
1. Time to first severe flare (as measured by the modified SLE Flare Index).
2. Percent of subjects whose average prednisone dose has been reduced by ≥ 25% from 
baseline to ≤7.5 mg/day during Weeks 40 through 52, in subjects receiving greater 
than 7.5 mg/day at baseline.
Modified to:
1. SRI response rate with the SELENA SLEDAI for scoring of proteinuria at Week 
52.
2. Time to first severe flare (as measured by the modified SLE Flare Index); with 
SLEDAI-2K and SELENA SLEDAI as the SLEDAI criterion of the SFI.
3. Percent of subjects whose average prednisone dose has been reduced by ≥ 25% from 
baseline to ≤7.5 mg/day during Weeks 40 through 52, in subjects receiving greater 
than 7.5 mg/day at baseline.
Synopsis Sample Size Calculation
Formerly:
Approximately 816 subjects will be randomized and treated in the study, with a target of 
at least 544 subjects in the arm receiving belimumab and 272 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 12% absolute improvement in the response rate for 
the 10 mg/kg belimumab group (assumed rate = 56%) relative to the placebo group 
(assumed rate = 44%) at Week 52. The selection of the 12% absolute improvement is 
evidence-based and is based on the observed response rate in the Phase 3 studies [BLISS 
76 (HGS1006-C1056) and BLISS 52 (HGS1006-C1057)]. The sample size calculation 
uses the most conservative estimate for the standard deviation (SD) in the population (ie, 
population SD = 50%).
Modified to:
Approximately 501 subjects will be randomized and treated in the study, with a target of 
at least 334 subjects in the arm receiving belimumab and 167 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 15.55% absolute improvement in the SRI response 


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rate with the modified SLEDAI-2K scoring for proteinuria for the 10 mg/kg
belimumab group relative to the placebo group (assumed rate = 43.95%) at Week 52. 
This sample size is also sufficient to provide approximately 80% power at a 5% level 
of significance to detect a minimum of a 13.4% absolute improvement in the SRI 
response rate with the SELENA SLEDAI scoring for proteinuria for the 10 mg/kg 
belimumab group relative to the place group (assumed rate = 44.8%).
The selection of these assumed treatment differences is based on the observed SRI 
data from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 
(Northeast Asia), which are two efficacy studies that concluded in 2015 and 2016, 
respectively, and have nearly identical eligibility criteria to study HGS1006-C1112
including requiring a screening SS score ≥8.
Synopsis Analysis of Major Secondary Efficacy Endpoints
Added:
The SRI response rate with the SELENA SLEDAI scoring for proteinuria at Week 
52 will be compared between the belimumab treatment group and the placebo 
group using the same analysis methods as described for the primary endpoint.
Synopsis Safety Endpoints and Analysis 
Formerly:
An independent Data Monitoring Committee (DMC) will review unblinded safety data 
on an ongoing basis until data through Week 52 are locked and analyzed (after which 
monitoring may be assumed by an internal HGS committee). The DMC will include at 
least 3 physicians, and a statistician, none of whom are affiliated with the sponsor. The 1st
DMC data review meeting will occur after the first 100 subjects have been treated 
through Day 56 or approximately 6 months after the treatment of the 1st subject, 
whichever is earlier. After the initial review, the committee will review the data 
approximately every 6 months. Events to be monitored during the safety review will 
include at a minimum all serious adverse events (including deaths, serious psychiatric 
events, and serious infections), Grade 3 and Grade 4 laboratory abnormalities, 
opportunistic 
infections 
(serious 
and 
nonserious), 
malignancies, 
and 
hypersensitivity/anaphylactic reactions during the double-blind Week 52 and the 6-month 
open-label extension portion of the study. Investigators will be notified of the outcome of 
each DMC meeting.
Modified to:
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this study on an ongoing basis until the data are locked and analyzed through Week 
52. The IDMC will include at least 3 physicians, and a statistician, none of whom are 
affiliated with the sponsor. Events to be monitored during the safety review will 
include at a minimum all serious adverse events (including deaths, serious 


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psychiatric events, and serious infections), Grade 3 and Grade 4 laboratory 
abnormalities, opportunistic infections (serious and nonserious), malignancies, and 
hypersensitivity/anaphylactic reactions.  The 1st IDMC data review meeting will occur 
after the first 100 subjects have been treated through Day 56 or within 6 months of the 
treatment of the 1st subject, whichever is earlier. After the initial review, the committee 
will review the data approximately every 6 months. Investigators and Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), as appropriate, will 
be notified of the outcome of each IDMC meeting.
Synopsis Immunogenicity and Section 6.8.4 Immunogenicity
Formerly:
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent on Days 0, 56 (Week 8), 168 
(Week 24), 364/Exit (Week 52), and at the 8-week follow-up visit. For any subject who 
had a positive antibody response at the 8-week follow-up visit (or last study visit at which 
immunogenicity was assessed if 8-week follow-up immunogenicity sample is not 
available), an attempt will be made to obtain a serum sample for anti-belimumab 
antibodies at least 6 months after the last dose of study agent or after completion and/or 
unblinding of the study, whichever is later.
Modified to:
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent on Days 0, 56 (Week 8), 
168 (Week 24), 364/Exit (Week 52), and at the 8-week follow-up visit. 
List of Abbreviations
Added:
EIA
Enzyme immunoassay
HB
Hepatitis B
HBsAg
Hepatitis B surface antigen
hCG
human chorionic gonadotrophin
IDMC
Independent Data Monitoring Committee
JCV
John Cunningham virus
μL
microliter
PASS
Power Analysis and Sample Size


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Section 1.3.2 Choice of Target Patient Population
Formerly:
The target population to be enrolled in this trial will be adult subjects of self-identified 
black race with a clinical diagnosis of SLE according to the ACR criteria. These subjects 
must have active disease defined as a SELENA SLEDAI score ≥ 8 at screening, and be 
positive for autoantibodies, defined as ANA titer ≥ 1:80, and/or anti-dsDNA (≥ 30 
IU/mL) at 2 time points prior to randomization.
Modified to:
The target population to be enrolled in this trial will be adult subjects of self-identified 
black race with a clinical diagnosis of SLE according to the ACR criteria. These subjects 
must have active disease defined as a SELENA SLEDAI score ≥ 8 at screening, and be 
positive for autoantibodies, defined as a positive ANA test, and/or anti-dsDNA (≥ 30 
IU/mL) at 2 time points prior to randomization.
Section 1.3.3 Rationale of Choice of Primary Endpoint for Efficacy
Formerly:
The primary efficacy endpoint is response by the SLE responder index (SRI) at Week 52.
Modified to:
The primary efficacy endpoint is response by the SLE responder index (SRI) response 
rate with the modified SLEDAI-2K scoring for proteinuria at Week 52.
Section 1.3.4 Rationale for Dose and Schedule
Formerly:
The dose and schedule to be studied is 10 mg/kg administered as an IV infusion over a 
period of 1 hour, at 2-week intervals for the first 3 doses and at 4-week intervals 
thereafter.
Modified to:
The dose and schedule to be studied is 10 mg/kg administered as an IV infusion over no 
less than 1 hour, at 2-week intervals for the first 3 doses and at 4-week intervals 
thereafter.


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New Section for Benefit-Risk Assessment
Added:
Section 1.4 Benefit-Risk Assessment
Section 1.4.1 Risk Assessment
Belimumab administered by IV infusion is indicated for reducing disease activity in adult 
patients with active autoantibody positive SLE who are receiving standard therapy. The 
benefit/risk profile of belimumab for SLE remains favorable.
Identified risks include hypersensitivity/infusion reactions and non opportunistic 
infections. Potential risks (ie, based on pharmacology but no association identified to 
date) include progressive multifocal leukoencephalopathy (PML); malignancies; 
immunogenicity; effects on immunizations (including interactions with live vaccine); and 
psychiatric events including depression and suicidality.
The most common AEs reported in the primary safety population of adults with SLE 
were associated with hypersensitivity/infusion related reactions, infections, and 
symptoms consistent with SLE.  The majority of reports of infusion-related and 
hypersensitivity reactions were non-serious and include symptoms such as nausea, 
vomiting, diarrhea, chills, fever, rash, urticaria, pruritus, headache, dizziness, and 
dyspnoea.  However, infusion and hypersensitivity reactions can be severe and fatal.  
Most clinical trial and spontaneous cases of serious hypersensitivity occurred during or 
within the first hour after the completion of the infusion, although some cases report 
delayed acute onset (>4 hours but <4 days) or a delayed non-acute onset (4-21 days) 
hypersensitivity reactions.  
Infections have been reported with administration of belimumab and are also associated 
with both SLE and immunosuppressant medication used to treat SLE. The mechanism of 
action of belimumab may increase the potential risk for the development of infections.  In 
the phase 2 and 3 clinical trials, there was a slight increase in the overall rate of infections 
in the belimumab group compared with the placebo group. There was no difference in the 
rate of serious infections, infections leading to discontinuation, or infections of special 
interest. Out to 10 years in the Phase 2 and 3 continuation studies, the incidence rate of 
serious infections has remained stable or declined over time.
Table 1-2 provides a summary of key issues, their impact, and strategy to mitigate risk in 
this study.


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Table 1-2 Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Post-injection 
systemic reactions 
and 
Hypersensitivity 
Administration of belimumab may result in 
infusion and hypersensitivity reactions, 
which can be severe and can be fatal.  
Non-serious infusion reactions and 
hypersensitivity reactions are common in 
SLE clinical trials with IV belimumab.  
Serious infusion and hypersensitivity 
reactions affected less than 1% of patients 
and included anaphylactic reaction, 
bradycardia, hypotension, angioedema, 
and dyspnea. Delays in the onset of 
hypersensitivity reactions have been 
observed. Infusion reactions following 
administration of belimumab occurred 
more frequently on the first 2 infusion days 
and tended to decrease with subsequent 
administrations. Delayed-type, non-acute 
hypersensitivity reactions have also been 
observed and included symptoms such as
rash, nausea, fatigue, myalgia, headache, 
and facial oedema.
Exclusion of subjects with a 
history of an anaphylactic reaction 
to parenteral administration of 
contrast agents, human or murine 
proteins or monoclonal antibodies.
Subjects should remain under clinical 
supervision for 3 hours after completion of the 
first 2 infusions. Should symptoms of acute 
hypersensitivity occur, an extended period of 
monitoring may be appropriate, based on 
clinical judgment. Otherwise, subjects will be 
monitored 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.  Subjects should be 
made aware of the potential risk, the signs 
and symptoms of such reactions, and the 
importance of immediately seeking medical 
attention.  Belimumab should be administered 
by a healthcare professional prepared to treat 
hypersensitivity reactions including 
anaphylaxis.
Infections
Infections occurred in a slightly greater 
proportion of subjects treated with 
belimumab compared with placebo. 
Infections occurring in at least 3% of 
patients receiving belimumab and at least 
1% more frequently than patients receiving 
Exclude patients with any of the 
following: currently on any 
suppressive therapy for a chronic 
infection; hospitalization for 
treatment of an infection within 60 
days of Day 0; use of IV or IM 
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
placebo were nasopharyngitis, bronchitis, 
pharyngitis, cystitis, and gastroenteritis 
viral.  Serious infections occurred in 5% of 
patients receiving either belimumab or 
placebo.
antibiotics within 60 days of Day 
0; a history of or positive test at 
screening for HIV, hepatatis B or 
hepatitis C; have Grade 3 or 4 
lymphopenia; or have Grade 3 or 
4 IgG or IgA deficiency
Progressive 
multifocal 
leukoencephalopa
thy (PML)
No association between belimumab and 
the risk of opportunistic infections, 
including PML, has been indentified to 
date, but data are limited. 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.
Malignancies
As with other immunomodulating agents, 
the mechanism of action of belimumab 
may increase the potential risk for the 
development of malignancies.
Exclude patients with a history of 
malignant neoplasm within the 
last 5 years, except for adequately 
treated basal or squamous cell 
cancers of the skin, or carcinoma 
in situ of the uterine cervix.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, 
request that patients report signs and 
symptoms.  Treat appropriately.
Immunogenecity
As with other monoclonal antibodies, 
treatment with belimumab could lead to the 
development of anti-drug antibodies 
Monitor anti-drug antibody laboratory values.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
(ADA). Among SLE subjects treated with 
belimumab, the proportion of subjects who 
developed persistently positive ADA was 
low and very few of the persistently 
positive antibodies were found to be 
neutralizing. Neither development of ADA 
nor persistent ADA was associated with 
infusion or hypersensitivity reactions. As 
expected, the proportions of subjects with 
persistent ADA increased slightly over time 
in belimumab-treated subjects but (there 
was no increase in the number of subjects 
with neutralizing antibodies or the number 
reporting infusion-related adverse events. 
Effects on 
immunizations 
including reactions 
with live vaccines
No data are available on the secondary 
transmission of infection from persons 
receiving live vaccines to patients receiving 
belimumab. Because of its mechanism of 
action, belimumab may interfere with the 
response to immunisations. The efficacy of 
concurrent vaccination in patients receiving 
belimumab is not known.  Limited data 
suggest that belimumab does not 
significantly affect the ability to maintain a 
protective immune response to 
immunisations received prior to 
administration of belimumab. 
Exclude patients who have 
received a live vaccine within 30 
days of Day 0.
Do not administer live vaccines concurrently.
Potential 
There have been reports of depression 
Exclude patients who have 
Monitor patients for signs and symptoms of 


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
psychiatric events 
- Depression and 
suicidality
and suicidality in patients receiving 
belimumab.  The estimated rates of 
suicidality for belimumab remain consistent 
with the rates of the background SLE 
population.  The background rate for 
completed suicide identified in the 
literature ranged from 0.02 to 2.18 per 100 
PY and varied by study type (clinical trial or 
observational study) [Li-Yu 2007; Cervera 
2003; Cervera 2006; Cervera 2009]. The 
background rate for suicidal behavior 
(completed suicide and attempts) is 0.12 
(95% CI 0.05, 0.24)/100 patient years 
[Karassa 2003].
evidence of serious suicide risk 
including any history of suicidal 
behaviour in the last 6 months 
and/or any suicidal ideation of 
type 4 or 5 on the Columbia 
Suicide Severity Rating Scale 
[C-SSRS in the last 2 months or 
who in the investigator's 
judgment, pose a significant 
suicide risk.
psychiatric events including depression and 
suicidality, request that patients report signs 
and symptoms.  Treat appropriately


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Refer to Section 8.3 for information about the Independent Data Monitoring Committee 
(IDMC) being used in the study.
1.4.2 Benefit Assessment
The primary data supporting efficacy of belimumab were the Phase 3 trials (C1056 and 
C1057) in which 1,684 subjects were treated for up to 52 weeks (C1057) or 76 weeks 
(C1056)
(Belimumab 
IB, 
Section 
5.3.1.2). 
Belimumab 
produced 
significant 
improvements in the SLE Responder Index as well as in individual component SELENA-
SLEDAI score in both studies. Pooled analyses demonstrated steroid sparing, delay in 
median time to first flare, and decreased risk of severe flares over 52 weeks. Clinical trial 
data for belimumab since approval continue to show efficacy in the treatment of SLE 
through decreased SLE flares and decreased disease activity across multiple organ 
systems (Belimumab IB, Section 5.3.1.3).
1.4.3 Overall Benefit:Risk Conclusion
The safety profile of belimumab remains consistent with that known at approval and is 
consistent with expected events based on the mechanism of action and the disease under 
study. Appropriate risk mitigation measures are in place; rare and long-term risks will be 
further evaluated via the large safety study and registry, ongoing and future studies, and 
routine pharmacovigilance. Review of safety data is conducted on a continual basis in 
order to identify new safety signals which may arise from clinical trial and/or post-
marketing reports. The benefit: risk profile of belimumab for SLE continues to be 
favorable.
New Section 4.3
Added:
Section 4.3 Contraception Requirements for Female Subjects
Female subjects of childbearing potential must not become pregnant during the study and 
so must be sexually inactive by abstinence or use contraceptive methods with a failure 
rate of < 1%.  Female subjects of childbearing potential with same sex partners (when 
this is their preferred and usual lifestyle) are not required to be abstinent or to use 
contraception.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (eg calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of < 1%

Oral contraceptive, either combined or progestogen alone

Injectable progestogen


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
Implants of levonorgestrel or etonogestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) with  <1% failure rate as 
stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject.  For this definition, “documented” refers to the outcome of the 
investigator's/designee’s review of the subject's medical history for study eligibility, 
as obtained via a verbal interview with the subject or from the subject’s medical 
records.

Double barrier method:  condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository).
NOTE: MMF and other forms of mycophenolate affect the metabolism of oral 
contraceptives and may reduce their effectiveness. As such, women receiving 
mycophenolate who are using oral contraceptives for birth control should employ an 
additional method (eg, barrier method).
NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The investigator is 
responsible for ensuring that subjects understand how to properly use these methods of 
contraception.
Section 5.2 Packaging, Labeling, Preparation, and Storage, paragraph 6
Formerly:
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's current body weight in 
kilograms (kg) obtained at each visit prior to dosing.
Modified to:
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's current body weight in
kilograms (kg) obtained at each visit prior to dosing. At sites where it is impractical to 
use the subject’s current body weight to calculate the dose, it is permissible for the 
Week 2 visit onward to use the subject’s body weight from the previous visit (eg, the 
Day 0 weight can be used to calculate the dose for the Week 2 visit). However, the 
subject’s body weight will be measured prior to dosing and if the previous visit 
weight and current visit weight vary by more than 10% then the weight measured at 
the current visit must be used. 


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Belimumab
Section 5.3 Dose, Route of Administration, and Schedule, paragraph 1
Formerly:
All study agent treatments will be administered IV over 1 hour.
Modified to:
All study agent treatments will be administered IV over no less than 1 hour.
Section 5.3 Dose, Route of Administration, and Schedule, paragraph 4
Formerly:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity 
reactions has been observed. Subjects should remain under clinical supervision for 3 
hours after completion of the first 2 infusions in the double-blind treatment phase and the 
6-month open-label extension. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgment. This may 
include, but is not limited to, monitoring vital signs and observing any untoward 
reactions. Beyond the first 2 infusions, subjects should be monitored during and for an 
appropriate period of time after infusion according to the study sites’ guidelines or 
standard operating procedure for IV infusions.
Modified to:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity 
reactions has been observed. Subjects should remain under clinical supervision for 3 
hours after completion of the first 2 infusions in the double-blind treatment phase and the 
6-month open-label extension. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgment. This may 
include, but is not limited to, monitoring vital signs and observing any untoward 
reactions. In addition, delayed-type, non-acute hypersensitivity reaction have also 
been observed and included symptoms such as rash, nausea, fatigue, myalgia, 
headache, and facial edema. Beyond the first 2 infusions, subjects should be monitored 
during and for an appropriate period of time after infusion according to the study sites’ 
guidelines or standard operating procedure for IV infusions.
Section 5.4 Alteration of Dose/Schedule Due to Toxicity, paragraph 2
Formerly:
If a subject experiences a clinically significant AE that the investigator believes may be 
possibly, probably, or definitely related to study agent and could potentially be 
exacerbated by the next dose, the investigator may delay the dose by up to 2 weeks or 
withhold 1 dose.


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Modified to:
If a subject experiences a clinically significant AE that the investigator believes may be 
possibly related to study agent and could potentially be exacerbated by the next dose, the 
investigator may delay the dose by up to 2 weeks or withhold 1 dose.
Section 5.4 Alteration of Dose/Schedule Due to Toxicity, paragraph 3
Formerly:
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE 
that the investigator believes may be possibly, probably, or definitely related to study 
agent, then treatment with study agent will be discontinued. The subject should be 
withdrawn from the study agent, and followed at regularly scheduled study visits as 
specified by the protocol and also until resolution of the AE(s) (whichever is longer). The 
subject must also return for an Exit visit 4 weeks after the last administration of study 
agent and a follow-up visit 8 weeks after the last administration of study agent.
Modified to:
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE 
that the investigator believes may be possibly related to study agent, then treatment with 
study agent will be discontinued. The subject should be withdrawn from the study agent 
and followed until resolution of the AE(s). The subject must also return for an Exit visit 4 
weeks after the last administration of study agent and a follow-up visit 8 weeks after the 
last administration of study agent. An attempt will be made to ascertain survival status 
approximately 52 weeks after the first dose of study agent.
Section 5.5 Concurrent Medications
Formerly:
This section reviews the medications and the doses allowed and prohibited during the 
course of the study. Any time the concurrent medication guidelines are not followed, 
subjects are to be withdrawn from the study and will be considered treatment failures 
(refer to Appendix 2).
Received dose for all systemic corticosteroids will be converted to prednisone equivalent. 
As such, when "prednisone" is used throughout this protocol, it refers to prednisone dose 
or equivalent.
Modified to:
This section reviews the medications and the doses allowed and prohibited during the 
course of the study. Any time the concurrent medication requirements are not followed, 
subjects are considered treatment failures (refer to Appendix 2). Subjects who meet a 
treatment failure criterion prior to completing IP administration at Week 48 should 


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be withdrawn from IP and not permitted to enter the 6-month open-label extension 
of the protocol.  The subject must return for an Exit visit 4 weeks after the last 
administration of study agent and a follow-up visit 8 weeks after the last 
administration of study agent. An attempt will be made to ascertain survival status 
approximately 52 weeks after the first dose of study agent.  If a subject completes all 
IP dosing through Week 48 of the protocol, and at the Week 52 protocol visit it is 
determined that a subject has met a treatment failure criterion, the subject should 
complete the Week 52 assessments in the double-blind period, and after consultation 
with the Medical Monitor, consideration may be given for the subject to enter into 
the 6-month open-label extension.  The subject will still be deemed a treatment 
failure from the date the criterion was met for analysis purposes. 
Dose received for all systemic corticosteroids will be converted to oral prednisone 
equivalent. As such, when "prednisone" is used throughout this protocol, it refers to oral 
prednisone dose or equivalent.
Section 5.5.1 Allowable Medications, paragraph 2
Formerly:
Once the subject is randomized and receives the 1st dose of study agent on Day 0, the 
investigator may adjust concurrent medications (add, eliminate, change dose 
level/frequency) as clinically required; however, changes in certain medications (as 
outlined below) may result in the subject being defined as a treatment failure and will 
require withdrawal from the study.
Modified to:
Once the subject is randomized and receives the 1st dose of study agent on Day 0, the 
investigator may adjust concurrent medications (add, eliminate, change dose 
level/frequency) as clinically required; however, changes in certain medications (as 
outlined below) may result in the subject being defined as a treatment failure and may 
require withdrawal from the study following consultation with the medical monitor 
(see Section 5.5).
Section 5.5.1.2.1 Systemic Steroids for SLE-related Disease Activity, List Bullets 2, 3 
and 4
Formerly:

Within 8 weeks before the Day 364 (Week 52) visit, no new increase over the 
baseline (Day 0) or Day 308 (Week 44) visit dose, whichever is higher, is allowed. 


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Modified to:

Within 8 weeks before the Day 364 (Week 52) visit, no new increase over the 
baseline (Day 0) or Day 308 (Week 44) visit dose, whichever is higher, is allowed. A 
new increase would deem the subject a treatment failure.
Section 5.5.1.2.3 Steroids for Reasons Other Than SLE Disease Activity, From Days 
168 to 308 (Weeks 24 to 44) Visits:
Formerly:
Steroids may be given for reasons other than SLE disease activity from the Day 168 
(Week 24) visit until the Day 308 (Week 44) visit at any dose/duration that does not 
result in a total steroid dose (for SLE and non-SLE reasons) > 25% or > 5 mg, whichever 
is higher, over the baseline dose. In addition, steroids for non-SLE reasons may be given 
short-term at higher doses according to the following guidelines:

Up to 750 mg (prednisone) for 1 day, 
and/or

Up to 100 mg/day (prednisone) for 2-3 days ,
and/or

Up to 40 mg/day (prednisone) for 4-7 days.
The duration of high dose steroids use for reasons other than SLE must not exceed 7 
days, after which time, tapering should begin. The total steroid dose must be tapered to 
within 25% or 5 mg over the baseline dose, whichever is higher, within 30 days of the 1st
dose of a course of steroids. In addition, the steroid dose must be tapered to within 25% 
or 5 mg over the baseline dose, whichever is higher, by the Day 308 (Week 44) visit. 
Modified to:
Steroids may be given for reasons other than SLE disease activity from the Day 168 
(Week 24) visit until the Day 308 (Week 44) visit at any dose/duration that does not 
result in a total steroid dose (for SLE and non-SLE reasons) > 25% or > 5 mg, whichever 
is higher, over the baseline dose. Any total steroid dose exceeding this rule will deem 
the subject a treatment failure. In addition, steroids for non-SLE reasons may be given 
short-term at higher doses according to the following guidelines:

Up to 750 mg (prednisone) for 1 day, 
and/or

Up to 100 mg/day (prednisone) for 2-3 days ,
and/or

Up to 40 mg/day (prednisone) for 4-7 days.


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The duration of high dose steroids use for reasons other than SLE must not exceed 7 
days, after which time, tapering should begin. The total steroid dose must be tapered to 
within 25% or 5 mg over the baseline dose, whichever is higher, within 30 days of the 1st
dose of a course of steroids. In addition, the steroid dose must be tapered to within 25% 
or 5 mg over the baseline dose, whichever is higher, by the Day 308 (Week 44) visit. 
Otherwise the subject will be deemed a treatment failure.
Section 5.5.2 Prohibited Medications and Therapies, paragraph 1, List bullets 2, 3, 
and 4
Formerly:
Subjects who start prohibited medications or therapies at any time during the study will 
be considered treatment failures for analysis (ie, non-responders) and must be withdrawn 
from study agent and return for required exit and follow-up visits.The following 
medications and therapies are prohibited at any time during the study:

Co-enrollment into another study of an investigational agent or that may interfere 
with the conduct of this protocol. 

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).

Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra]).
Modified to:
Subjects who start prohibited medications or therapies at any time during the study will 
be considered treatment failures for analysis (ie, non-responders) and must be withdrawn 
from study agent and return for an Exit visit 4 weeks after the last administration of 
study agent and a follow-up visit 8 weeks after the last administration of study 
agent. In addition, an attempt will be made to ascertain survival status 
approximately 52 weeks after the first dose of study agent.

Co-enrollment into another study of an investigational agent or another study that 
may interfere with the conduct of this protocol. 

Anti-TNF therapy (eg, adalimumab, certolizumab pegol, etanercept, golimumab,
infliximab).

Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra], tocilizumab).
Section 6.1 Screening Procedures (Day -35 to Day 0), List Bullet 7
Formerly:
Blood samples for: (see Appendix 10 – Laboratory Tests)

HIV antibody, hepatitis B surface antigen, and hepatitis C antibody testing


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Modified to:
Blood samples for: (see Appendix 10 – Laboratory Tests)

HIV antibody, HBsAg, HB core antibody, and hepatitis C antibody testing.
Section 6.3 Double-blind Treatment Period, paragraphs 1 and 3
Formerly:
After the 1st month of therapy, visits to the study site for clinical evaluation, disease 
activity assessment, and laboratory sampling will occur every 28 days (calculated from 
the Day 0 dose) for a total of 48 weeks of treatment. 
All subjects who withdraw from treatment prior to Week 52 will be followed for survival 
at Week 52, unless consent is withdrawn. In the event that a subject discontinues study 
agent at any time during the study or withdraws consent, an attempt will be made to 
ascertain survival status at approximately 52 weeks after the first dose of study agent.
Modified to:
After the 1st month of therapy, visits to the study site for clinical evaluation, disease 
activity assessment, and laboratory sampling will occur approximately every 28 days 
(calculated from the Day 0 dose) for a total of 48 weeks of treatment.
All subjects who withdraw from treatment prior to Week 52 will be followed (eg, phone 
contact) for survival 52 weeks after the first dose of study agent. In the event that a 
subject withdraws consent, an attempt should be made at the time of consent 
withdrawal to obtain consent for survival status.
Section 6.3 Double-blind Treatment Period, last paragraph, List Bullet 2
Formerly:

Subjects who wish to continue in the open-label extension, will have study agent
administered at the Day 364 (Week 52) visit after all Day 364 (Week 52) assessments 
are performed (refer to Table 6-1 below).
Modified to:

Subjects who wish to continue in the open-label extension, will have study agent
administered at the Day 364 (Week 52/Day 0 of open-label extension) visit after all 
Day 364 (Week 52) assessments are performed (refer to Table 6-1 below).
Table 6-1 Study Calendar, On treatment evaluations, Post-Treatment Follow-up 
Period, Study Day and Study Week, 2nd Column


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Formerly:
Study Day: Day 364 for non-completers 7 days
Study Week: Wk 52
Modified to:
Study Day: Post txt f-up for non-completers 7 days
Study Week: 4 Wks post last dose
Table 6-1 Study Calendar, On treatment evaluations, Laboratory Assessments, 
HIV, Hepatitis B, C: Screening
Formerly:
HIV, HBsAg,and Hepatitis C antibody
Modified to:
HIV, Hepatitis B, and Hepatitis C serology
Table 6-1 Study Calendar, On treatment evaluations
Footnotes
Deleted: (Note: subsequent footnotes have been adjusted in the table and footnotes
accordingly – these changes are not shown below):
M
For subjects who had a positive anti-belimumab antibody response at the 8 week 
follow-up visit (or last study visit at which immunogenicity was assessed if 8 
week follow-up visit immunogenicity sample is not available), an attempt will be 
made to obtain a serum sample for anti belimumab antibodies at least 6 months 
after the last dose of study agent or after completion and/or unblinding of the 
study, whichever is later (see Section 6.8).
Formerly:
A
The Exit (Day 364) visit will occur approximately 4 weeks after the last dose of 
study agent. For subjects completing all 48 weeks of treatment and continuing 
into the 6-month open-label extension, this visit will also serve as their 1st (ie, 
Day 0) visit of the 6-month open-label extension (see Table 6-2).
D
Weight should be obtained prior to dosing at each visit to calculate the dose to be 
administered.
G
Serum pregnancy test required at screening. Results of urine pregnancy test at 
subsequent visits, if required, must be available prior to dose. See Section 6.1 


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(Screening Procedures) for definition of those exempted from subsequent 
pregnancy testing.
N
Subjects who discontinue study agent treatment at any time during the study will 
be followed at Week 52 for survival status. In the event that a subject withdraws 
consent, an attempt should be made at the time of consent withdrawal to obtain 
consent for survival status at Week 52.
Modified to:
A
The Exit (Day 364) visit will occur approximately 4 weeks after the last dose of 
study agent. For subjects completing all 48 weeks of treatment and continuing 
into the 6-month open-label extension, this visit will also serve as their 1st (ie, 
Day 0) visit of the 6-month open-label extension (see Table 6-2). For subjects
who discontinue study agent prior to Week 48, the Exit (Day 364) visit should 
be performed 4 weeks after the last administration of study agent and a 
follow-up visit 8 weeks after the last administration of study agent, and a
survival assessment (eg, by phone contact) will take place approximately 52 
weeks after the first dose of study agent (see Footnote N). 
D
Weight should be obtained prior to dosing at each visit to calculate the dose to be 
administered.  At sites where it is impractical to use the subject’s current body 
weight to calculate the dose, it is permissible to use the subject’s body weight 
from the previous visit. However, the subject’s body weight will be measured 
prior to dosing and if the previous visit weight and current visit weight vary 
by more than 10%, then the weight measured at the current visit must be 
used. 
G
Serum pregnancy test required at screening. Results of urine pregnancy test at 
subsequent visits, if required, must be available prior to dose. See Section 6.1 
(Screening Procedures) for definition of those exempted from subsequent 
pregnancy testing.  Women of child-bearing potential must be reminded of the 
requirement to report any pregnancy that occurs through 16 weeks following 
the last dose of study agent (see Section 7.6).
N
Subjects who discontinue study agent treatment at any time during the study will 
have a survival assessment (eg, by phone contact) approximately 52 weeks 
after the first dose of study agent. In the event that a subject withdraws consent, 
an attempt should be made at the time of consent withdrawal to obtain consent for 
survival status at Week 52.
Section 6.4 6-Month Open-Label Extension, paragraph 1
Formerly:
Subjects on active drug or placebo will receive belimumab 10 mg/kg IV every 28 days 
for 6 months in the open-label extension.


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Modified to:
Subjects on active drug or placebo will receive belimumab 10 mg/kg IV approximately 
every 28 days for 6 months in the open-label extension.
Section 6.4 6-Month Open-Label Extension, paragraph 3
Formerly:
The American College of Rheumatolog (ACR) draft guidance regarding steroid dosing 
and tapering in response to SLE flare is provided in Appendix 6. 
Modified to:
The American College of Rheumatology (ACR) draft guidance regarding steroid dosing 
and tapering in response to SLE flare is provided in Appendix 6. 
Table 6-1 Study Calendar, 6-month open-label extension
Formerly:
Study Day: Day 28 visit 3 days
Modified to:
Study Day: Day 28 visit 7 days
Table 6-3  Study Calendar, 6-month open-label extension
Urine pregnancy test: 8-week follow-up
Formerly:
Not listed.
Modified to:
Urine pregnancy test is marked “X” as required at this visit.
Table 6-1 Study Calendar, 6-month open-label extension, footnotes
Deleted: (Note: subsequent footnotes have been adjusted in the table and footnotes 
accordingly – these changes are not shown below):
f
For subjects not continuing to receive belimumab post-study who had a positive 
anti-belimumab antibody response at the 8 week follow-up visit (or last study visit 


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at which immunogenicity was assessed if 8 week follow up visit immunogenicity 
sample is not available), an attempt will be made to obtain a serum sample for 
anti-belimumab antibodies at least 6 months after the last dose, or upon 
completion and/or unblinding of the study, whichever is later.
Formerly:
b
Any visit in which the subject discontinues treatment will become the Exit visit. 
Study agent should not be administered and all Exit assessments must be 
completed
c
Urine pregnancy test, as required, with results available prior to dosing. 
d
The weight at the current visit will be used for calculating the dose.  
Modified to:
b
All subjects, including subjects who have discontinued study agent prior to 
Day 196, will return for an Exit visit approximately 4 weeks after their last 
dose of study agent as well as a follow-up visit approximately 8 weeks after 
the last dose of study agent.  
c
Urine pregnancy test, as required, with results available prior to dosing. Women 
of child-bearing potential must be reminded of the requirement to report any 
pregnancy that occurs through 16 weeks following the last dose of study 
agent (see Section 7.6).
d
The weight at the current visit will be used for calculating the dose. At sites 
where it is impractical to use the subject’s current body weight to calculate 
the dose, it is permissible to use the subject’s body weight from the previous 
visit.  However, the subject’s body weight will be measured prior to dosing 
and if the previous visit weight and current visit weight vary by more than 
10%, then the weight measured at the current visit must be used.
Section 6.8 Immunogenicity (6-Month Follow-Up)
Deleted:
6.8
Immunogenicity (6-Month Follow-Up)
For any subject who had a positive antibody response at the 8-week follow-up visit (or 
last study visit at which immunogenicity was assessed if 8-week follow-up 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent 
or after completion and/or unblinding of the study, whichever is later.


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New Section and Sub-section Added: Liver Stopping Criteria and Study Agent 
Restart 
Added:
6.8.3 Liver Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf


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Phase 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 
Appendix 13.
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*


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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 13.
6.8.3.1 Study Agent Restart 
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:
•
GSK Medical Governance approval is granted
•
Ethics and/or IRB approval is obtained, if required, and
•
Separate consent for treatment restart is signed by the subject
Refer to Appendix 14 for full guidance
Section 6.9 Withdrawal of Subjects from Treatment, Bulleted List and last 
paragraph
Formerly:
Subjects may be withdrawn for any of the following reasons:

Prohibited concurrent medication or therapy or prohibited dose of concurrent 
medication or therapy (see Section 5.5).

Unacceptable toxicity.

Withdrawal of consent (including use and disclosure of research-related health 
information).

Pregnancy.
Subjects who discontinue treatment must complete the Exit visit (4 weeks after the last 
dose of study agent) and a follow up visit 8 weeks after the last dose of study agent. An 
attempt will be made to contact all subjects at Week 52 to determine survival status.
Modified to:
Subjects should be withdrawn for any of the following reasons:

Missing 3 or more consecutive doses of study agent.

Prohibited concurrent medication or therapy or prohibited dose of concurrent 
medication or therapy resulting in treatment failure (see Section 5.5).

Unacceptable toxicity (See Section 5.4 and Section 6.8.3).

Withdrawal of consent (including use and disclosure of research-related health 
information).

Pregnancy.

Prior to the administration of live vaccine


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
At the discretion of the Sponsor, conditions that may warrant termination of a 
subject include but are not limited to safety concerns, subject significant non-
compliance with protocol visits and procedures.
Subjects who discontinue treatment must complete the Exit visit (4 weeks after the last 
dose of study agent) and a follow up visit 8 weeks after the last dose of study agent. An 
attempt will be made to contact all discontinued subjects to determine survival status 
(eg, by phone contact) approximately 52 weeks after the first dose of study agent.
Section 6.10 Subject Unblinding, paragraph 2
Formerly:
If a medical emergency occurs and a decision regarding the subject’s condition requires
knowledge of the treatment assignment, the study blind may be broken for the specific 
subject. Whenever possible, the investigator should consult with the medical monitor 
prior to unblinding any subject. Any broken blind will be clearly justified and explained 
by a comment in the eCRF. The investigator must notify the Medical Monitor of any 
broken blind, regardless of whether it was done for emergency or non-emergency 
reasons.
Modified to:
In the case of a medical emergency when knowledge of the study treatment is essential 
for the appropriate clinical management or welfare of the subject, the study blind 
may be broken for the specific subject. Whenever possible, the investigator should 
discuss options with the Medical Monitor prior to unblinding any subject. If this is 
impractical, the investigator must notify the Medical Monitor as soon as possible of 
any broken blind, but without revealing the treatment assignment of the unblinded 
subject, unless that information is important for the safety of other subjects 
currently in the study. Any broken blind will be clearly justified and explained by a 
comment in the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to clinical 
investigators in accordance with local regulations and/or GSK policy.


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Section 7 Adverse Event Reporting
Added:
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Section 7.1 Definitions
Formerly:
ADVERSE EVENT (EXPERIENCE): Any unfavorable or unintended sign, symptom, 
or disease that is temporally associated with the use of a study agent but is not necessarily 
caused by the study agent. This includes worsening (eg, increase in frequency or severity) 
of pre-existing conditions.
SERIOUS ADVERSE EVENT: an adverse event resulting in any of the following 
outcomes:

death

is life-threatening (ie, an immediate threat to life)

inpatient hospitalization*

prolongation of an existing hospitalization

persistent or significant disability / incapacity

congenital anomaly/birth defect

is medically important+
*An inpatient hospitalization is defined as an admission for any length of time. A 
hospitalization for administration of study agent, for routine or planned clinical 
procedures, or for “social” reasons (not the result of any adverse change in the subject’s 
condition) should not be considered an adverse event and should not be reported as a 
serious adverse event. If the subject experiences any adverse change in condition during 
hospitalization, the condition must be reported as an adverse event or serious adverse 
event according to the above definitions. 
+Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or result in hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed above. These should also usually be considered serious. (ICH guidelines, March 
1995)
UNEXPECTED ADVERSE EVENT: An adverse event, the nature or severity of which 
is not consistent with the applicable product information (eg, Investigator’s Brochure for 
an unapproved study agent or package insert/summary of product characteristics for an 
approved product). Expected means the event has previously been observed with the 
study agent and is identified and/or described in the applicable product information. It 


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does not mean that the event is expected with the underlying disease(s) or concomitant 
medications.
Modified to:
ADVERSE EVENT - 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 (ie, 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:

Medical or surgical procedure (eg, 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


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SERIOUS ADVERSE EVENT: A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
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
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
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg,
sprained ankle) which may interfere or prevent everyday life functions but do 
not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  These should 
also be considered serious.  Examples of such events are invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.
g. 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 


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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.   
Section 7.2 Reporting Adverse Events to the Sponsor, paragraphs 2, 3, and 4
Formerly:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent 
to the Drug Safety designee within 24 hours of site personnel becoming aware of the 
SAE, regardless of expectedness. All pages of the SAE Worksheet should be completed, 
but the SAE Worksheet should not be held until all information is available. Additional
information and corrections should be provided on subsequent SAE Worksheets as 
described in the Study Procedure Manual. SAE Worksheets should be sent by the EDC 
system (if EDC functionality is available) or by facsimile to the HGS Drug Safety 
designee using the toll free fax number listed on the SAE Worksheet.
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be recorded on the 
SAE worksheet and reported as described  above from the time a subject consents to 
participate in the study. Pre-treatment SAEs will not be documented on the AE eCRF.
SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study 
agent) that are assessed by the investigator as definitely, possibly, or probably related to 
study agent must be reported to the Drug Safety designee on the SAE worksheet. Post 
study SAEs will not be documented on the AE eCRF.
Modified to:
Serious Adverse Events (SAEs) must be recorded on the SAE eCRF within 24 hours of 
site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until 
all information is available. Follow-up information and corrections should be added to 
the SAE eCRF within 24 hours of site personnel becoming aware of the follow-up 
information as described in the Study Procedures Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an 
SAE from the time a subject consents to participate in the study.


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SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study 
agent) that are assessed by the investigator as possibly related to study agent must be 
reported to the Sponsor as outlined in the Study Procedures Manual.
Section 7.3 Laboratory Abnormalities as Adverse Events
Formerly:
A laboratory abnormality should be reported as an adverse event if it is associated with 
an intervention. Intervention includes, but is not limited to, discontinuation of treatment, 
dose reduction/delay, or concomitant therapy. In addition, any medically important 
laboratory abnormality may be reported as an adverse event at the discretion of the 
investigator. This includes laboratory abnormalities for which there is no intervention but 
the abnormal value(s) suggests a disease or organ toxicity. If clinical sequelae are 
associated with a laboratory abnormality, the diagnosis or medical condition should be 
reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated 
creatinine, urine RBC increased).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 12. If a particular lab test is not listed in the Appendix, the lab test should be 
graded as mild, moderate, severe, or life-threatening as specified in Section 7.7.
Modified to:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, 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.
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality 
(eg, elevated creatinine, urine RBC increased).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 12. If a particular lab test is not listed in the Appendix, the lab test should be 
graded as mild, moderate, or severe as specified in Section 7.7.
Section 7.4 Progressive Multifocal Leukoencephalopathy
Formerly:
There have been no reported cases of PML in subjects with SLE or RA treated with 
belimumab. However, patients with SLE may be at increased risk for PML secondary to 


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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 judgment in further 
workup and clinical intervention as appropriate. If PML is suspected this should be 
promptly reported to the HGS.
Modified 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. 
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.
Section 7.6 Reporting a Pregnancy
Formerly:
Pregnancies must be reported to the HGS Drug Safety within 24 hours of the site 
becoming aware of a pregnancy in a study subject. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. All pregnancies are tracked up to term or delivery following the last 
study agent treatment. When pregnancy is reported, HGS Drug Safety sends an 
acknowledgement memorandum to the principal investigator along with a Pregnancy 
Assessment Form. A Pregnancy Assessment Form must be completed every 3 months 
until live birth, elective termination of the pregnancy, or miscarriage. The site is 
responsible for following the subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems 
associated with a pregnancy are considered AEs and may be SAEs. Complications or 
medical problems are reported as AEs/SAEs according to the procedure described in 
Sections7.1and 7.2.
Modified to:
Any pregnancy that occurs during study participation and up to 16 weeks post dose 
must be reported using a clinical trial pregnancy form. To ensure subject safety, 
each pregnancy must be reported to the Sponsor within 2 weeks of learning of its 
occurrence. The pregnancy must be followed to delivery to determine outcome 


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(including premature termination) and status of mother and child. To gain 
additional information on pregnancy outcomes, the subject will be requested to 
complete a 1 year infant questionnaire.
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 the Sponsor.
Section 7.7 Investigator Evaluation of Adverse Events
Formerly:
The investigator will evaluate all adverse events with respect to seriousness (criteria 
listed above), severity (intensity or grade), and causality (relationship to study agent). 
The criteria for seriousness are listed in Section 7.1. The severity of an AE is to be 
evaluated according to the Adverse Event Severity Grading Tables in Appendix 12. If an 
AE does not have Adverse Event Severity Grading in Appendix 12, the following 
severity classifications will be used:
SEVERITY:

Grade 1- Mild
     - causing no limitation of usual activities

Grade 2- Moderate 
     - causing some limitation of usual activities

Grade 3- Severe
    - causing inability to carry out usual activities

Grade 4- Life-threatening*   - potentially life-threatening or disabling
*Note – a severity assessment of Life-threatening is not necessarily the same as Life-
threatening as a  “Serious” criterion. The latter means that the event is an immediate 
threat to life as opposed to a potential threat to life.
CAUSALITY:
Definitely Related
- reasonable temporal relationship to study agent administration
- follows a known response pattern (eg, study agent is known to
  cause this AE)
- there is no alternative etiology
Probably Related
- reasonable temporal relationship
- follows a suspected response pattern (eg, based on similar drugs)
- no evidence for a more likely alternative etiology 
Possibly Related
- reasonable temporal relationship 
- little evidence for a more likely alternative etiology


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Probably Not Related - does not have a reasonable temporal relationship OR
- good evidence for a more likely alternative etiology   
Not Related
- does not have a temporal relationship OR
- definitely due to alternative etiology 
The causality assessment must be made by the investigator based on information 
available at the time that the SAE worksheet is completed. The initial causality 
assessment may be revised as new information becomes available.
Modified to:
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to 
study agent). The investigator will make an assessment of intensity based on the 
Division of Microbiology and Infectious Diseases (DMID) Adverse Event Severity 
Grading Tables (see Appendix 12) 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 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 
or 4 DMID).
Not applicable
Those event(s) where intensity is meaningless or impossible 
to determine (ie, blindness and coma).
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.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that 
there are facts/evidence or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.  The investigator will use clinical judgment to 
determine the relationship.  Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the study treatment will be considered and investigated.  
The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.


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For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK.  However, it is very 
important that the investigator always make an assessment of causality for every 
event prior to the initial transmission of the SAE data to GSK.  The investigator 
may change his/her opinion of causality in light of follow-up information, amending 
the SAE data collection tool accordingly.  The causality assessment is one of the 
criteria used when determining regulatory reporting requirements.
Section 7.8 Follow-up of Adverse Events
Formerly:
Adverse events that occur from the start of study agent administration through 8 weeks 
after the date of last administration of study agent are followed until final outcome is 
known or until the end of the 8-week study follow-up period. Adverse events that have 
not resolved at the end of the 8-week study follow-up visit are recorded on the adverse 
event case report form (AE eCRF) as ONGOING. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to 
obtain a final outcome for a particular SAE (eg, the subject is lost to follow-up), then the 
reason a final outcome could not be obtained must be documented by the investigator. 
Modified to:
Serious and non-serious adverse events that occur from the start of study agent 
administration through 8 weeks after the date of last administration of study agent are 
reported. 
After the initial AE/SAE report, the investigator is required to proactively follow 
each subject at subsequent visits/contacts.  All SAEs and non-serious AEs of special 
interest (see Section 8.6.2) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-
up.  This applies to all subjects, including those withdrawn prematurely. 
Section 7.9 Reporting Serious Adverse Events to Regulatory Authorities and 
Institutional Review Boards/Independent Ethics Committees
Formerly:
7.9 Reporting Serious Adverse Events to Regulatory Authorities and Institutional 
Review Boards/Independent Ethics Committees


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All SAEs that are considered by the sponsor to be unexpected and related to belimumab 
will be reported by the sponsor or designee as expedited (eg, 7/15-Day) reports to the 
appropriate regulatory authorities AND to all participating investigators (exceptions 
discussed below). In addition, the sponsor or designee follows all applicable local and 
national regulatory requirements regarding safety reporting.  Each investigator must also 
comply with the applicable regulatory requirements related to the reporting of SAEs to 
the IRBs/IECs responsible for reviewing the study at their site, as well as the regulatory 
authority(ies) (if applicable). 
All serious adverse events, including serious disease-related events (discussed below),
will be monitored by treatment group by an independent DMC (Section 8.3). 
Investigators and IRBs/IECs, as appropriate, will be notified of the outcome of each 
DMC meeting, and any recommendations made.
The following conditions (preferred terms; MedDRA v. 14.0) are disease related events 
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 7.2. The sponsor will not submit 
these events as expedited reports to regulatory authorities, participating investigators, or 
IRBs/IECs (unless considered by the sponsor to be related to study agent).
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis
Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
Modified to:
7.9 Disease Related Events
Disease related events (DREs) can occur in the study population regardless of 
belimumab exposure and are not reported as AEs or SAEs, unless judged by the 
investigator to be more severe than expected for the subject’s condition.
The following DREs (preferred terms; MedDRA v. 14.0) are common in subjects with 
SLE and can be serious/life-threatening:
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis


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Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
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 7.2. The 
sponsor will not submit these events as expedited reports to regulatory authorities, 
participating investigators, or IRBs/IECs (unless considered by the sponsor to be 
related to study agent).
Section 7.10
The following section has been added:
Section 7.10 Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  The 
Sponsor 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 the Sponsor’s policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Section 8.3 Data Monitoring Committee (DMC)
Formerly:
Data Monitoring Committee (DMC)


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An independent Data Monitoring Committee (DMC) will review unblinded safety data 
for this Phase 3/4 program on an ongoing basis until the data are locked and analyzed. 
The DMC will include at least 3 physicians, and a statistician, none of whom are 
affiliated with the sponsor. The 1st DMC data review meeting will occur after the first 
100 subjects have been treated through Day 56, or within 6 months of the treatment of the 
1st subject, whichever is earlier. After the initial review, the committee will review the 
data approximately every 6 months. The DMC will monitor these trials until the data are 
locked and analyzed through Week 52, after which time monitoring may be assumed by 
an internal HGS committee. Investigators will be notified of the outcome of each DMC 
meeting. 
The DMC will receive information within 72 hours of the sponsor or designee receiving 
notification of all unexpected causally-related SAEs that are life threatening or result in 
death. Other unexpected, causally-related SAEs will be provided to the DMC within 15 
calendar days.
Modified to:
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this Phase 3/4 study on an ongoing basis until the data are locked and analyzed 
through Week 52. The IDMC will include at least 3 physicians, and a statistician, none 
of whom are affiliated with the sponsor. Events to be monitored during the safety 
review include, at a minimum, all serious adverse events (including deaths, serious 
psychiatric events, and serious infections), Grade 3 and Grade 4 laboratory 
abnormalities, opportunistic infections (serious and nonserious), malignancies, and 
hypersensitivity/ anaphylactic reactions.  The 1st IDMC data review meeting will 
occur after the first 100 subjects have been treated through Day 56, or within 6 months of 
the treatment of the 1st subject, whichever is earlier. After the initial review, the 
committee will review the data approximately every 6 months. At all times the sites and 
sponsor will remain blinded to treatment allocation. Investigators and IRBs/IECs, as 
appropriate, will be notified of the outcome of each IDMC meeting.
The IDMC will receive information within 72 hours of the sponsor or designee receiving 
notification of all SAEs that are life threatening or result in death. Other SAEs will be 
provided monthly to the IDMC.
After Week 52, the monitoring may be assumed by an internal GSK/HGS 
committee.
Section 8.4 Sample Size Rationale
Formerly:
Approximately 816 subjects will be randomized and treated in the study, with a target of 
544 subjects in the arm receiving belimumab and 272 subjects in the arm receiving 


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placebo. This sample size provides at least 90% power at a 5% level of significance to 
detect a minimum of a 12% absolute improvement in the response rate for the belimumab 
group (assumed rate = 56%) relative to the placebo group (assumed rate = 44%) at Week 
52. The selection of the 12% absolute improvement is evidence-based on the observed 
response rate from the pooled Phase 3 data (protocols HGS1006-C1056 and C1057). The 
sample size calculation uses the most conservative estimate for the standard deviation in 
the population (ie, population SD = 50%).
Modified to:
Approximately 501 subjects will be randomized and treated in the study, with a target of 
at least 334 subjects in the arm receiving belimumab and 167 subjects in the arm 
receiving placebo. This sample size provides at least 90% power at a 5% level of 
significance to detect a minimum of a 15.55% absolute improvement in the SRI response 
rate with the modified SLEDAI-2K scoring for proteinuria for the 10 mg/kg belimumab 
group relative to the placebo group (assumed rate =43.95%) at Week 52. This sample 
size is also sufficient to provide approximately 80% power at a 5% level of 
significance to detect a minimum of a 13.4% absolute improvement in the SRI 
response rate with the SELENA SLEDAI scoring for proteinuria for the 10 mg/kg 
belimumab group relative to the placebo group (assumed rate = 44.8%).
The selection of the assumed treatment differences is based on the observed SRI 
data from studies BEL112341 (HGS1006-C1115/BLISS SC) and BEL113750 
(Northeast Asia), which are two efficacy studies that concluded in 2015 and 2016, 
respectively, and have nearly identical eligibility criteria to study HGS1006-C1112
including requiring a screening SS score ≥8. SRI results, calculated using the SS 
results and calculated using a modification to the proteinuria scoring based on 
SLEDAI-2K rules, are shown in Table 8-1.
Table 8-1
SRI Results From Studies BEL112341 and BEL113750
SRI
Calculated Using the SS Results 
as Collected
SRI
Calculated Using SS Results with the 
Modified SLEDAI-2K Proteinuria 
Scoring
Dataset
Placebo
Belimumab
Δ
Placebo
Belimumab
Δ
BEL112341*
48.4%
61.4%
12.98%
46.6%
61.7%
15.14%
BEL113750**
40.1%
54.3%
14.17%
40.2%
56.3%
16.16%
Pooled 
BEL112341 and 
BEL113750
44.8%
(222/496)
58.2%
(582/1000)
13.44%
43.95%
(218/496)
59.50%
(595/1000)
15.55%
* Inclusion criterion SS≥8, 200 mg SC dose used.
**Inclusion criterion SS≥8, 10 mg/kg IV dose used. 
All sample size calculations were performed using Power Analysis and Sample Size 
software (PASS 2012).


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Section 8.5.4 Other Efficacy Endpoints, Endpoints Supporting Primary Efficacy 
Endpoint, #2 and Note
Formerly:
Endpoints Supporting Primary Efficacy Endpoint:
2.
Percent of subjects with a ≥ 4 point reduction from baseline in SELENA SLEDAI 
at Week 52 and by visit.
The SRI 5-8 are defined identically to the SRI except for using higher thresholds of 
improvement for SELENA SLEDAI reduction for a patient to be declared a responder 
(eg, SELENA SLEDAI ≥ 5 point reduction for SRI5).
Modified to:
Endpoints Supporting Primary Efficacy Endpoint (SRI where SELENA SLEDAI score 
is modified to use the SLEDAI-2K scoring for proteinuria):
2.
Percent of subjects with a ≥ 4 point reduction from baseline in SELENA SLEDAI 
(modified to use the SLEDAI-2K scoring for proteinuria) at Week 52 and by 
visit.
The SRI 5-8 are defined identically to the SRI except for using higher thresholds of 
improvement for SELENA SLEDAI (modified to use the SLEDAI-2K scoring for 
proteinuria) reduction for a patient to be declared a responder (eg, SELENA SLEDAI ≥ 
5 point reduction for SRI5).
Section 8.5.4 Other Efficacy Endpoints, Disease activity, #2
Formerly:
2.
Mean percent change and mean change in SELENA SLEDAI score by visit.
Modified to:
2.
Mean percent change and mean change in SELENA SLEDAI score with the 
modified SLEDAI-2K scoring for proteinuria by visit.
Section 8.5.4 Other Efficacy Endpoints, Organ Specific, #1 and #2
Formerly:
1.
Percent of subjects with organ improvement by SELENA SLEDAI by visit.
2.
Percent of subjects with organ worsening by SELENA SLEDAI by visit.


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Modified to:
1.
Percent of subjects with organ improvement by SELENA SLEDAI by visit. The 
renal domain will use the SLEDAI-2K proteinuria scoring as the primary 
method with the SELENA SLEDAI proteinuria scoring as a sensitivity 
analysis.
2.
Percent of subjects with organ worsening by SELENA SLEDAI by visit. The 
renal domain will use the SLEDAI-2K proteinuria scoring as the primary 
method with the SELENA SLEDAI proteinuria scoring as a sensitivity 
analysis.
Section 8.5.4 Other Efficacy Endpoints, SFI Flare
Formerly:
SFI Flare:
Modified to:
SFI Flare (SFI where SELENA SLEDAI score is modified to use the SLEDAI-2K 
scoring for proteinuria):
Section 8.5.4 Other Efficacy Endpoints, Biological Markers, footnote
Formerly:
*Anti-dsDNA will be collected monthly throughout the study for SELENA SLEDAI 
scoring. ANA will be collected at screening and baseline only. Other autoantibodies will 
be collected from all patients at baseline, then at regular intervals in patients positive at 
baseline.
Modified to:
*Anti-dsDNA will be collected monthly throughout the study for SELENA SLEDAI 
scoring modified to use the SLEDAI-2K scoring for proteinuria. ANA will be 
collected at screening and baseline only. Other autoantibodies will be collected from all 
patients at baseline, then at regular intervals in patients positive at baseline.
Section 8.5.5 Secondary Efficacy Analyses
Added:
The SRI response rate with the SELENA SLEDAI scoring for proteinuria at Week 52 
will be compared between the belimumab treatment group and the placebo group using 
the same analysis methods as described for the primary endpoint in Section 8.5.2.


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Section 11 References
Added:
Cervera R, Khamashta MA, Font J, et al. Morbidity and Mortality in Systemic Lupus 
Erythematosus During a 10-Year Period: A Comparison of Early and Late Manifestations 
in a Cohort of 1,000 Patients. Medicine 2003;82:299-308.
Cervera R, Khamasta MA, Hughes GRV. The Euro-Lupus project: epidemiology of 
systemic lupus erythematosus in Europe. Lupus. 2009;18:869-874.
Cervera R. Systemic Lupus Erthematosus in Europe at the change of the millennium: 
Lessons from the "Euro-Lupus Project". Autoimmunity Reviews. 2006;5:180-186.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute liver failure. Drug Metab Dispos 2009; 37:1779-1784.
Karassa FB, Magliano M, and Isenberg DA. Suicide attempts in patients with systemic 
lupus erythematosus. Ann Rheum Dis. 2003;62(1):58-60.
Section Appendix 1, Rows 4, 5, and 9
Formerly:
4. Oral ulcers 
Oral or nasopharyngeal ulceration usually painless.
5. Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints characterized 
by tenderness.
9. Hematologic disorder 
a.
Hemolytic anemia (with reticulocytosis)
OR
b.
Leukopenia (< 4000/mL total on 2 or more occasions), OR
c.
Lymphopenia (< 1500/mL on 2 or more occasions), OR
d.
Thrombocytopenia (< 100,000/mL in the absence of offending 
drugs).
Modified to:
4. Oral ulcers 
Oral or nasopharyngeal ulceration usually painless, observed by 
physician.
5. Nonerosive Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints characterized 
by tenderness, swelling, or effusion.


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9. Hematologic disorder 
a.
Hemolytic anemia (with reticulocytosis)
OR
b.
Leukopenia (< 4000/mm3 total on 2 or more occasions), OR
c.
Lymphopenia (< 1500/mm3 on 2 or more occasions), OR
d.
Thrombocytopenia (< 100,000/mm3 in the absence of offending 
drugs).
Appendix 10
Added:
Other Screening Labs
HBsAg and HB Core antibody
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
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
Appendix 11, Pharmacogenetic Research. Study Assessments and Procedures
Formerly:
In addition to any blood samples drawn for the clinical study, a whole blood sample 
(~10 mL) will be collected for the PGx research at baseline.
Modified to:
In addition to any blood samples drawn for the clinical study, a whole blood sample 
(~6 to 8 mL) will be collected for the PGx research at baseline.


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New Appendix 13 
Added:
Appendix 13 Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 

Viral hepatitis serology4

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 antibody5

Blood sample for pharmacokinetic (PK) 
analysis, obtained within approximately 1 
to 2 weeks after the liver event 6

Serum creatine phosphokinase (CPK) and 


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study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 14)

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
lactate dehydrogenase (LDH)

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography)
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.


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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
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].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the study reference manual.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
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 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If 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.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  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):2363–2369.


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New Appendix 14
Added:
Appendix 14 Liver Safety – Study Treatment Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study 
treatment is not granted, then subject must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments,
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (eg, biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator  requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury) or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.


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
Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 7.2.