Clinical trial NCT01639339
Conditions: Lupus Nephritis
Keywords: Antibodies Systemic Lupus Erythematosus Autoimmune Disease Glomerulonephritis Belimumab Lupus Nephritis Kidney Diseases SLE
Sponsor: Human Genome Sciences Inc., a GSK Company
Start date: 2012-07-12; Completion date: 2020-03-12
Enrollment: 448 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of belimumab in adult patients with active lupus nephritis.

Detailed description:
Study participants receive standard therapy (induction and maintenance) for lupus nephritis in addition to receiving either placebo (no active medicine) or belimumab. Induction therapy starts before the first dose of study drug (belimumab or placebo). Maintenance therapy begins after completion of induction therapy and continues for the remainder of the study. Participants receive study drug throughout the entire study, during both induction and maintenance periods. The controlled period of the study is 104 weeks. The random assignment in this study is "1 to 1" which means you have an equal chance of receiving treatment with belimumab or placebo. Participants who successfully complete the 104-week study may enter into a 6-month open-label extension. All participants in the open-label extension receive belimumab.

Arms: arm 1: Placebo IV plus standard therapy; placebo administered on Days 0, 14, 28, and then every 28 days thereafter through Week 100, with a final evaluation at Week 104 in the double-blind period. In the open-label extension period, placebo patients who opt to participate will receive belimumab 10 mg/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 100, with a final evaluation at Week 104 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 10 mg/kg plus standard therapy intervention 3: The standard therapies allowed in this study are:

\- High-dose steroids (for example, methylprednisolone) plus cyclophosphamide for induction therapy followed by azathioprine for maintenance therapy

OR

\- High-dose steroids plus mycophenolate for induction therapy followed by mycophenolate for maintenance therapy

Protocol documents:
SAP_002.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
BEL114054 
1 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for BEL114054: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus 
Standard of Care versus Placebo plus Standard of Care in 
Adult Subjects with Active Lupus Nephritis, Open-Label
Phase
Compound Number 
: GSK1550188 
Effective Date 
: 08-APR-2020 
Description: 

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report (CSR) for Protocol BEL114054 [HGS1006-
C1121], Open-Label Phase.

This RAP prospectively describes the study population, efficacy, safety,
pharmacokinetic and biomarker summaries 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.

This RAP will be provided to the study team members to convey the content of the
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s): 
Author 
Date 
Lead 
 
Principal Statistician (Immuno-Inflammation, Clinical Statistics) 
Co-Author 
 
Principal Statistician (Immuno-Inflammation, Clinical Statistics) 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
The GlaxoSmithKline group of companies 
BEL114054 
2 
RAP Team Review Confirmations 
(Method: E-mail) 
Approver 
Date 
 
07-APR-2020
Director (II Clinical Development) 
 
07-APR-2020
Programming Manager (II Clinical Programming) 
 
Director, Clinical Pharmacology 
07-APR-2020
 
Statistics Leader (II Clinical Statistics) 
07-APR-2020
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature) 
Approver 
 
Director Statistics (II, Clinical Statistics) 
 
Director Programming (II, Clinical Programming) 
RAP Team Reviewers Not Requiring Confirmation 
 
Medical Monitor (II Clinical Development) 
 
Medicines Development Leader 
 
Project Physician Lead 
 
Clinical Investigation Lead 
 
Medical Writer 
 
Director Global Regulatory Affairs 
 
Safety Development Lead (SERM) 
 
Director, RD II DPU Mechanistic Medicine Head 
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CONFIDENTIAL 
BEL114054 
3 
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 Objectives and Endpoints ................................................ 7 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 11 
3.
PLANNED ANALYSES .......................................................................................... 11 
3.1. 
Interim Analyses ......................................................................................... 11 
3.2. 
Final Analyses ............................................................................................ 11 
4.
ANALYSIS POPULATIONS ................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 12 
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS ..................................................................................................... 13 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 13 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Multicentre Studies ..................................................................................... 14 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 14 
5.4.1. 
Covariates and Other Strata ........................................................ 14 
5.4.2. 
Examination of Subgroups ........................................................... 15 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 15 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 15 
6.
STUDY POPULATION ANALYSES ....................................................................... 16 
6.1. 
Overview of Planned Study Population Analyses ........................................ 16 
6.2. 
Subject Disposition ..................................................................................... 16 
6.3. 
Protocol Deviations ..................................................................................... 16 
6.4. 
Demographic and Baseline Characteristics ................................................. 17 
6.5. 
Concomitant Medications ............................................................................ 18 
6.6. 
Extent of Exposure ..................................................................................... 18 
7.
SAFETY ANALYSES ............................................................................................. 19 
7.1. 
Adverse Events........................................................................................... 19 
7.2. 
Adverse Events of Special Interest (AESI) .................................................. 20 
7.3. 
Clinical Laboratory Summaries ................................................................... 20 
7.3.1. 
Laboratory Change from OL Baseline Displays............................ 21 
7.3.2. 
Laboratory Toxicity ≥ 2 Grade Shift Post OL Baseline .................. 21 
7.3.3. 
Liver Monitoring/Stopping Criteria ................................................ 21 
7.4. 
Other Safety Data ....................................................................................... 21 
8.
EFFICACY ANALYSES .......................................................................................... 21 
8.1. 
Primary Efficacy Analyses .......................................................................... 22 
8.2. 
Secondary Efficacy Analyses ...................................................................... 23 
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8.2.1. 
Primary Efficacy Renal Response (PERR) (Observed) ................ 23 
8.2.2. 
Complete Renal Response (CRR) (Observed) ............................ 23 
8.2.3. 
PERR and CRR Supplementary Endpoints .................................. 23 
8.2.4. 
Other Renal Endpoints ................................................................. 23 
8.2.5. 
Corticosteroid Endpoints .............................................................. 24 
8.2.6. 
Maintenance of Response Endpoints ........................................... 24 
8.2.7. 
Exploratory Endpoints .................................................................. 24 
9.
PHARMACOKINETIC ANALYSES ......................................................................... 25 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 25 
10. BIOMARKER ANALYSES ...................................................................................... 25 
10.1. 
Primary Biomarker Analyses ....................................................................... 25 
10.1.1. 
Endpoint / Variables ..................................................................... 25 
10.1.2. 
Population of Interest ................................................................... 26 
10.1.3. 
Strategy for Intercurrent Events ................................................... 26 
10.1.4. 
Statistical Methods ....................................................................... 26 
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 ............................................................. 28 
12.2.1. 
Definitions of Assessment Windows for Analyses ........................ 28 
12.3. 
Appendix 3: OL Phase, OL Concomitant Medications and OL 
Treatment Emergent Adverse Events ......................................................... 30 
12.3.1. 
OL Phase..................................................................................... 30 
12.3.2. 
OL Concomitant Medication ......................................................... 30 
12.3.3. 
Treatment Emergent Flag for OL 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 
12.4.3. 
Reporting Standards for Pharmacokinetics .................................. 32 
12.5. 
Appendix 5: Derived and Transformed Data ............................................... 33 
12.5.1. 
General ........................................................................................ 33 
12.5.2. 
Study Population .......................................................................... 33 
12.5.3. 
Efficacy ........................................................................................ 35 
12.5.3.1. Primary Efficacy Renal Response (PERR) ................. 35 
12.5.3.2. Complete Renal Response (CRR) .............................. 36 
12.5.3.3. Subjects Fulfilling the Programmatic Prohibited 
Medication Responder Criterion – 
Programmatic Checks ................................................ 36 
12.5.3.4. Doubling of Serum Creatinine and End Stage 
Renal Disease (ESRD) ............................................... 40 
12.5.3.5. Proteinuria .................................................................. 41 
12.5.3.6. SLEDAI-S2K............................................................... 41 
12.5.3.6.1. SLEDAI-S2K < 4 ..................................... 41 
12.5.3.6.2. SLEDAI-S2K excluding renal 
items ....................................................... 41 
12.5.3.7. Prednisone ................................................................. 41 
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12.5.3.7.1. Open-Label Baseline Prednisone 
Dose ....................................................... 41 
12.5.3.7.2. Prednisone Average Daily Dose 
Since Previous Visit ................................ 41 
12.5.3.8. SLICC/ACR Damage Index ........................................ 42 
12.5.4. 
Safety .......................................................................................... 42 
12.5.4.1. Adverse Events .......................................................... 42 
12.5.4.2. Laboratory Parameters ............................................... 42 
12.5.5. 
Pharmacokinetic .......................................................................... 42 
12.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 43 
12.6.1. 
Premature Withdrawals ................................................................ 43 
12.6.2. 
Handling of Missing Data ............................................................. 43 
12.6.2.1. Handling of Missing and Partial Dates ........................ 43 
12.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 44 
12.7.1. 
Laboratory Toxicity Grades .......................................................... 44 
12.8. 
Appendix 8: B Cells .................................................................................... 45 
12.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 46 
12.9.1. 
Abbreviations ............................................................................... 46 
12.9.2. 
Trademarks ................................................................................. 47 
12.10. Appendix 10: List of Data Displays.............................................................. 48 
12.10.1. Data Display Numbering .............................................................. 48 
12.10.2. Mock Example Shell Referencing ................................................ 48 
12.10.3. Deliverables ................................................................................. 48 
12.10.4. Study Population Tables .............................................................. 49 
12.10.5. Efficacy Tables ............................................................................ 55 
12.10.6. Efficacy Figures ........................................................................... 66 
12.10.7. Safety Tables ............................................................................... 71 
12.10.8. Biomarker Tables ......................................................................... 81 
12.10.9. Pharmacokinetic Tables ............................................................... 84 
12.10.10. ICH Listings ................................................................................. 85 
12.10.11. Non-ICH Listings ........................................................................ 100 
12.11. Appendix 11: Example Mock Shells for Data Displays .............................. 106 
 
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BEL114054 
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1.
INTRODUCTION
The purpose of this Reporting and Analysis Plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report (CSR) for Protocol: HGS1006-C1121 
(BEL114054). 
This RAP prospectively describes the study population, efficacy, safety, pharmacokinetic 
and biomarker summaries 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.  
This is a phase 3, 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 104-week treatment period (i.e. Double-Blind 
phase) in adult subjects with lupus nephritis Class III, IV, or V using the 2003 
International Society for Nephrology (ISN)/Renal Pathology Society (RPS) criteria.  
Subjects who completed the initial 104-week Double-Blind treatment period could 
choose to enter a 6-month Open-Label extension and receive intravenous (IV) belimumab 
at a dose of 10 mg/kg.  
This Open-Label phase RAP is based upon the following study documents: 
[1]
Study Protocol Amendment 7 (24 January 2019)
[2]
Final Electronic Case Report Form (eCRF) Version 5 (21 August 2017)
[3]
Program Safety Analysis Plan (PSAP) for GSK1550188 Version 7 (15 November
2019). 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 (20 September 2019)
[5]
Double-Blind Phase CSR (30 March 2020)
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 are 
outlined in Table 1. 
Any significant modifications to double-blind AEs and concomitant medication data post 
DB data lock, will be described in the open-label CSR, as necessary. 
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BEL114054 
7 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
The protocol refers to the first 
exposure to study agent as Day 0. 
The analysis plan refers to the 
first exposure to treatment as 
Day 1. 
The terminology was changed 
to be compliant with CDISC 
standards. 
Region subgroup definition is 

US/Canada

Europe/Australia/Israel

Asia

Americas excluding
US/Canada
(Protocol Section 8.5.2.3). 
Region subgroup definition is 

US/Canada

Europe

Asia

Americas excluding
US/Canada
There were no subjects enrolled 
in Australia or Israel, so these 
were removed from the 
subgroup label. 
Corticosteroid use endpoints defined 
as proportion of subjects with 
prednisone ≤ 5 mg and ≤ 7.5 mg by 
visit (Protocol Section 8.5.4). 
Corticosteroid use endpoints 
defined as the proportion of 
subjects with prednisone 
average daily dose ≤ 5 mg and 
≤ 7.5 mg since previous visit 
(RAP Section 12.5.3.7).  An 
additional endpoint ≤ 10 mg has 
been added for the OL RAP. 
Provides clarity around the time 
period used for calculating the 
average daily prednisone dose.  
The additional endpoint is of 
interest as treatment failures 
are not adjudicated in the OL 
study. 
Unless otherwise specified, all 
analyses will be performed on the 
intention to treat (ITT) 
population defined as all subjects 
who are randomized and receive at 
least 1 dose of study agent. 
The modified intention to treat 
population (mITT) will be used 
for analysis of the study 
population, efficacy and 
biomarker endpoints. 
Safety data will be summarised 
based on the Safety population. 
An updated mITT population 
was added to exclude the only 
subject who had an assessment 
at site 
 which was 
investigated for GCP non-
compliance. 
2.2. 
Open-Label Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 

To assess the safety and tolerability of
belimumab plus standard of care
versus placebo plus standard of care in
adult subjects with lupus nephritis
Class III, IV, or V using the 2003
International Society for Nephrology
(ISN)/ Renal Pathology Society (RPS)
criteria.

Adverse Event frequencies for all AEs, Serious AEs and
AEs of Special Interest

Laboratory results by visit for Change from Open-Label
Baseline and Laboratory Toxicity Grade Worsening of at
Least 2 Grades from Open-Label Baseline
Secondary Objectives 
Secondary Endpoints 

To explore the efficacy of belimumab
in combination with standard of care in
adult subjects with lupus nephritis
Class III, IV, or V using the 2003
ISN/RPS criteria.

Primary Efficacy Renal Response (PERR) at OL Week 28
(see Section 12.5.3.1)

Complete Renal Response (CRR) at OL Week 28 (see
Section 12.5.3.2)
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Objectives 
Endpoints 
Renal Specific Measures 
(Supplementary to PERR and CRR) 
PERR and CRR Supplementary Endpoints 

Assess supplementary PERR and
CRR endpoints
Proportion of subjects with the following by OL visit: 

Urinary protein/creatinine ratio (uPCR) ≤ 0.7

uPCR < 0.5

Estimated Glomerular Filtration Rate (eGFR) is ≥ 60
mL/min/1.73 m2 OR no more than 20% below Open-Label
Baseline eGFR value

eGFR is within the normal range (≥ 90 mL/min/1.73 m2)
OR no more than 10% below Open-Label Baseline eGFR
value
Other Renal Specific Measures 
Renal Endpoints 

Assess other renal specific measures

Percent change from OL Baseline in Proteinuria (uPCR)
by OL visit

Change from OL Baseline in Proteinuria (uPCR) by OL
visit

Proportion of subjects with doubling of Serum Creatinine
or progression to End Stage Renal Disease (ESRD) (see
RAP Section 12.5.3.4)
Corticosteroid Use Objectives 
Corticosteroid Endpoints 

Assess corticosteroid use

Proportion of subjects receiving ≤ 5 mg/day Prednisone
by OL visit

Proportion of subjects receiving ≤ 7.5 mg/day Prednisone
by OL visit

Proportion of subjects receiving ≤ 10 mg/day Prednisone
by OL visit
Maintenance of Response Objectives 
uPCR and eGFR Endpoints 

Assess DB and OL data together
including PERR and CRR
components

uPCR absolute values, summary statistics by visit
throughout DB and OL phases combined

uPCR ≤ 0.7 by visit throughout DB and OL phases
combined

uPCR < 0.5 by visit throughout DB and OL phases
combined

eGFR absolute values, summary statistics by visit
throughout DB and OL phases combined

eGFR is ≥ 60 mL/min/1.73 m2 OR no more than 20%
below Baseline value by visit throughout DB and OL
phases combined

eGFR is within the normal range (≥ 90 mL/min/1.73 m2)
OR no more than 10% below Baseline value by visit
throughout DB and OL phases combined

SLICC/ACR absolute values, summary statistics by visit
throughout DB and OL phases combined
Exploratory Objectives 
Other Endpoints of Interest 

Assess exploratory objectives

Change from OL Baseline in SLEDAI-S2K score

Proportion of subjects with SLEDAI-S2K score < 4

Change from OL Baseline in SLICC/ACR Damage Index
score
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Objectives 
Endpoints 

Proportion of subjects with any Worsening in SLICC/ACR
Damage Index score compared with OL Baseline

Change from DB Baseline in SLICC/ACR Damage Index
score

Proportion of subjects with any Worsening in SLICC/ACR
Damage Index score compared with DB Baseline
Biomarker Objectives 
Biomarker Endpoints 

Assess changes in Biomarkers
The change and percent change from OL Baseline by OL visit 
for the following variables: 

Absolute B cell subsets

Total serum immunoglobulin (IgG and other isotypes: IgM
and IgA).

Autoantibodies (anti-dsDNA, ANA, aCL, anti-Sm, and
anti-C1q).

Complement (C3, C4) levels.
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 

Subjects who receive treatment with study agent through Week 100 and complete the
Week 104 assessments in the Double-Blind period may enter the 6-month Open-
Label extension.

The Week 104 visit of the Double-Blind period will serve as the Day 1 visit for subjects
entering the 6-month Open-Label extension.

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 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 if
permissible according to local regulations.
Dosing 

The first dose on the Open-Label extension will be given at the Week 104 visit of the
Double-Blind period after the completion of Week 104 assessments.

In the Open-Label extension, all subjects will receive belimumab 10 mg/kg
approximately every 28 days until Week 24, with a final evaluation at Week 28 (4
weeks after the last OL dose).
Time & 
Events 

Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment 

All subjects will receive background therapy throughout the Double-Blind and Open-
Label phases of the study, consisting of one of the following standard of care
regimens:
o
High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for induction
therapy followed by Azathioprine (AZA) for maintenance therapy
OR 
o
HDCS + Mycophenolate Mofetil (MMF) for induction therapy followed by
MMF for maintenance therapy

During the Open-Label extension phase, all subjects will receive belimumab 10 mg/kg
IV plus standard of care.
Interim 
Analysis 

No interim analysis is planned for this study.
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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 phase) and the end of study (end of Open-Label phase).  
The database was locked for the primary analysis (PERR at Week 104) after data through 
the Week 104 visit (or Exit visit for those subjects who withdraw consent during Double-
Blind treatment or are Lost to Follow Up) for all subjects had been collected, verified and 
validated. This RAP is for the analysis following the final 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 Open-Label phase treatment.  
All subjects and study site personnel (except the unblinded site pharmacist) remain 
blinded to the Double-Blind 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 final planned Open-Label phase analyses will be performed after the completion of 
the following sequential steps: 
1. All subjects entering the 6-month, Open-Label phase have: 
(a) completed the 8-week follow-up period (if not entering the continuation 
protocol),  
(b) completed the Exit visit for those who withdraw consent during the Open-Label 
extension, or  
(c) been lost to follow-up during the Open-Label extension. 
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2. All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management. 
3. Adjudication of protocol deviations, adverse events of special interest and cases of 
progression to end stage renal disease has been completed. 
4. Database freeze (DBF) has been declared by Data Management. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Full Open-Label 
(Full OL) 
 
All subjects who had at least one Open-Label 
assessment or had a dose of Open-Label treatment. 
Note: this includes 2 subjects that the site inadvertently 
enrolled into open-label (OL) while permanently 
discontinued from IP, the subjects did not receive OL 
treatment.  
 
 
All Open-Label 
Listings (apart 
from PK Listing) 
Safety Open-
Label  
(Safety OL) 
 
All subjects who received at least one dose of Open-
Label treatment (i.e. at DB Week 104/OL Day 1 or a 
later OL visit). 
 
 
Open-Label Safety 
Tables 
Modified Intent-
to-Treat Open-
Label  
(mITT OL) 
 
The Modified Intent-To-Treat Open-Label (mITT OL) 
population is defined as the Safety Open-Label 
population excluding the one subject at site 
 due 
to GCP non-compliance issues.  
 
Open-Label Study 
Population Tables 
 
Open-Label 
Efficacy Tables 
 
Open-Label 
Biomarker Tables 
Pharmacokinetic 
(PK OL) 
 
All subjects in the Safety OL population who had at least 
1 non-missing Open-Label PK assessment (Non-
quantifiable [NQ] values will be considered as non-
missing values). 
 
Open-Label PK 
Tables 
 
Open-Label PK 
Listings 
Refer to Appendix 10: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
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: 13 August 
2019 (Version 3).  Additional protocol deviations may be identified during the study and 
will be documented in Protocol Deviation Adjudication Meeting minutes prior to the 
database lock. 
Only important deviations were entered into the database.  Important protocol deviations 
up to and including the first day of OL treatment were reported in the DB phase CSR.  
Important protocol deviations on or after the first day of OL treatment will be reported in 
the Open-Label CSR. 
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
Data will be reviewed prior to freezing the database to ensure all important deviations
are captured and categorized in the protocol deviations dataset.

This dataset will be the basis for the summaries and listings of Open-Label protocol
deviations.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1. 
Study Treatment & Sub-group Display Descriptors
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 treatment that the subject was randomized 
to and the second is the Open-Label treatment.  For all tables, a total column for both 
Open-Label treatment groups combined will also be presented. 
The labels used for Open-Label phase reporting will be: 

Placebo to Belimumab 10 mg/kg (ordered first in Table outputs)

Belimumab 10 mg/kg to Belimumab 10 mg/kg (ordered second in Table outputs)

Total (ordered third in Table outputs)
Most outputs will also be displayed by Induction Regimen (as specified at DB Baseline, 
induction regimen received), with the following labels: 

Overall (ordered first in Table outputs)

CYC (ordered second in Table outputs)

MMF (ordered third in Table outputs)
5.2. 
Baseline Definitions 
There are two baselines used in the Open-Label reports: 
Baseline 
Description 
Used for 
Double-Blind Study 
Baseline (DB 
Baseline) 
This is the same as the Double-Blind phase 
baseline and is defined below: 

The value of the variable measured at DB Day
1 (treatment start date) prior to dosing, unless
otherwise specified.

If timing of assessment is not collected on DB
Day 1, then the assessment will be assumed to
be prior to dosing.

If there are multiple results on DB Day 1 prior to
dosing, the latest result will be used (e.g., if
multiple lab tests are performed).

If a DB Day 1 value is not available, the last
available value prior to DB Day 1 will be used.

Study population (see
Section 6.4)
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Baseline 
Description 
Used for 
Note: The protocol specifies DB Day 0 as 
Baseline/Treatment Start date, but the CDISC 
standard refers to the Baseline/Treatment Start 
date as DB Day 1; therefore Baseline/Treatment 
Start date will appear as DB Day 1 in the displays 
and will be referenced as DB Day 1 in this 
document. 
 
Open-Label Phase 
Baseline (OL 
Baseline) 
The last available value measured prior to dosing 
on or before the date of first dose of Open-Label 
treatment (Open-Label Day 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, 
unless otherwise stated. 
 
Note:  At the DB baseline, subjects were in a flare 
state and under remission induction therapy. While 
at the start of OL, which is 104 weeks after DB 
baseline, subjects have different disease status and 
were under maintenance of remission therapy. The 
pre-belimumab baseline is confounded by these 
differences, and therefore, the OL baseline has 
been used for subjects in the Belimumab to 
Belimumab and Placebo to Belimumab groups.     
 
 Study population 
 Concomitant 
medications 
 Adverse events 
 Laboratory values 
 Vital signs 
 Efficacy 
 Biomarkers 
 
5.3. 
Multicentre Studies 
In this multicentre global study, enrolment was carried out in several regions and 
Countries, as shown in Table 2. 
Table 2 
Regions and Countries 
Region 
Countries 
Asia 
China, Hong Kong, Korea, Philippines, Taiwan, Thailand 
Europe 
Belgium, Czech Republic, France, Germany, Hungary, Netherlands, 
Russian Federation, Spain, United Kingdom 
US/Canada 
United States, Canada 
Americas excluding US/Canada 
Argentina, Brazil, Colombia, Mexico 
 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
No statistical analyses will be carried out in the Open-Label phase. 
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5.4.2. 
Examination of Subgroups 
Subgroups used for the Open-Label phase are shown in Table 3.  The ordering in the 
outputs will be as listed below. 
Table 3 
Subgroups and Categories 
Subgroup 
Categories 
Induction Regimen 

CYC

MMF
As specified at DB Baseline. 
Baseline Renal Biopsy Class 
(local reader assessment) 

Class III or Class IV

Class III+V or IV+V

Class V
As specified at DB Baseline. 
Race 

Black

Non-Black
As specified at DB Baseline. 
Region 

Asia

Europe

US/Canada

Americas excluding US/Canada
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 shown in Table 4. 
Table 4 
List of Appendices 
Section 
Component 
12.2 
Appendix 2: Assessment Windows 
12.3 
Appendix 3: Open-Label Phase, Open-Label Concomitant Medications and Open-Label 
Treatment Emergent Adverse Events 
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 
12.8 
Appendix 8: B Cells 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
Study population summaries will be based on GSK Core Data Standards and Benlysta 
program standards.  Details of the planned displays are presented in Appendix 10: List of 
Data Displays. 
 
Study population tables will be based on the mITT Open-Label population, unless 
otherwise specified.  They will be presented by treatment group and overall, and by 
induction regimen and overall. 
 
Study population listings will be based on the Full Open-Label population and will be 
presented by induction regimen and treatment group. 
 
 
6.2. 
Subject Disposition 
Using the Full Open-Label population, the number of subjects in each population (Full 
Open-Label, Safety Open-Label, Modified Intent-to-Treat Open-Label and 
Pharmacokinetic Open-Label) will be summarized. 
The subject’s completion or withdrawal status at study end will be summarized, along 
with the primary reason for withdrawal. 
A listing of subjects who withdrew from the study, including reason for and date of 
withdrawal will be provided. 
A listing of subjects excluded from any population (Safety OL, mITT OL, PK OL) will 
be provided. An additional listing will be provided of the 2 subjects that the site 
inadvertently enrolled into Open-Label while permanently discontinued from IP, the 
subjects did not receive Open-Label treatment. 
 
6.3. 
Protocol Deviations 
Important Protocol Deviations (PDs) in the Open-Label phase will be summarized and 
listed.  This will include deviations related to study inclusion/exclusion criteria, conduct 
of the trial, patient management and/or patient assessment (see Section 4.1). 
Important PDs up to and including the first day of Open-Label treatment were reported in 
the Double-Blind phase CSR.  Important PDs on or after the first day of Open-Label 
treatment will be reported in the Open-Label CSR.  Note that PDs on the first day of 
Open-Label treatment will be included for both the primary (Double-Blind) and final 
(Open-Label) reporting. 
 
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6.4. 
Demographic and Baseline Characteristics 
Two summary tables of demographic and baseline characteristics will be presented.  The 
first summary will present information from the Double-Blind Baseline for all parameters 
shown in Table 5.  The second summary will present information from the Open-Label 
Baseline for the following parameters shown in Table 5. 
Table 5 
Demographic and Baseline Characteristic Summaries 
Summary 
DB Baseline 
OL Baseline 
Region and Country 
 Yes 
 
Gender 
 Yes 
 
Ethnicity 
 Yes 
 
Age 
 Yes 
 Yes 
Age Group 
 Yes 
 Yes 
Height 
 Yes 
 
Weight 
 Yes 
 Yes 
Body Mass Index (BMI) 
 Yes 
 Yes 
 
The two summary tables of demographic and baseline characteristics will also be 
presented by baseline renal biopsy class, race and region (see Section 5.4.2). 
A listing of demographic and baseline characteristics will be provided.  Note that age, 
weight and BMI will be listed for both the DB baseline and the OL baseline. 
A summary of race and racial combination details will be presented. 
A listing of race and race detail will also be provided. 
Two summary tables of baseline disease activity will be presented.  The first summary 
will present information from the Double-Blind Baseline for all parameters shown in 
Table 6.  The second summary will present information from the Open-Label Baseline 
for the following parameters shown in Table 6. 
Table 6 
Baseline Disease Activity Summaries 
Summary 
DB Baseline 
OL Baseline 
SLE disease duration (see Section 12.5.2) 
 Yes 
 Yes 
LN disease duration (see Section 12.5.2) 
 Yes 
 Yes 
Renal biopsy class and category (local reader) 
 Yes 
 
Renal biopsy class and category (central reader) 
 Yes 
 
End Stage Renal Disease 1 
 No 
 Yes 
urine Protein-Creatinine Ratio (uPCR) 
 Yes 
 Yes 
estimated GFR (eGFR) 
 Yes 
 Yes 
SLEDAI-S2K score 
 Yes 
 Yes 
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Summary 
DB Baseline 
OL Baseline 
Physician’s Global Assessment (PGA) 
Yes
Yes
SLICC/ACR Damage Index (SDI) 
Yes
Yes
1 Subjects who fulfil the ESRD flag during the DB period. 
The two summary tables of baseline disease activity will also be presented by baseline 
renal biopsy class, race and region (see Section 5.4.2). 
6.5. 
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. 
Open-Label concomitant medications are described in more detail in Section 12.3.2. 
A summary of the number and percentage of subjects with concomitant medications by 
ATC level 1 term and ATC level 4 term will be provided.  A further summary of 
concomitant medications by ATC level 4 term and preferred term will also be provided. 
A summary of allowable SLE and LN Medication Usage at Open-Label Baseline will be 
provided. 
The summary table of allowable SLE and LN Medication Usage at Open-Label Baseline 
will also be presented by baseline renal biopsy class, race and region (see Section 5.4.2). 
A listing of all concomitant medication data will be displayed. 
6.6. 
Extent of Exposure 
The extent of exposure to Open-Label study treatment through OL Week 28 will be 
summarised using descriptive statistics for the duration of Open-Label exposure (see 
Section 12.5.2) and the total number of Open-Label infusions.   
The duration of OL exposure will also be summarized using counts and percentages for 
the following categories: < 24 weeks, 24 to 28 weeks, > 28 weeks where weeks are based 
on the Open-Label visit week of the last infusion received.  The total number of infusions 
will be summarized using counts and percentages for the following categories: 1 to 6, 7 
and > 7 infusions.  
A listing of Open-Label investigational product administration and exposure will be 
produced.   
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7.
SAFETY ANALYSES
Safety summaries will be based on GSK Core Data Standards and Benlysta program 
standards.  Details of the planned displays are presented in 12.10Appendix 10: List of 
Data Displays.  
Safety tables will be based on the Safety Open-Label population. They will be presented 
by treatment group and overall, and by induction regimen and overall. Only safety data 
collected during the Open-Label phase will be summarised.  
Summaries that are presented by Open-Label visit will display all relevant visits 
according to the Time and Events schedule (see Section 12.1).  
Safety listings will be based on the Full Open-Label population and will be presented by 
induction regimen and treatment group. 
7.1. 
Adverse Events 
Adverse events analyses including Adverse Events (AEs), Serious Adverse Events 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. The details 
of the planned displays are provided in Appendix 10: List of Data Displays. 
All AEs will be classified using the standard GSK Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary and grouped by System Organ Class (SOC) and 
Preferred Term (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 per the Adverse Event Severity Grade Tables 
Appendix 7 of the Protocol, if a grade is defined for the AE of interest. 
Tabular summaries for each category of AE 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) 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 in the overall column (i.e., summed across all OL treatment 
groups and all induction regimens) for any adverse event within the class, to 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.  The sort order will be repeated for MedDRA PTs within each 
SOC. 
Only treatment-emergent AEs will be summarised.  Treatment-emergent AEs are defined 
as AEs that started on or after the day of the first Open-Label infusion i.e. with no end 
date defined.  Ongoing AEs that started before the first OL infusion that were not 
considered treatment-emergent will be listed. 
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A listing of the hierarchical relationship between MedDRA SOCs, PTs, and verbatim text 
will be displayed for all AEs. 
A listing that displays which subjects reported each AE will be produced by SOC and PT. 
AEs will be grouped and sorted by SOC and PT.   
Listings of all AEs, all SAEs, all Deaths and all AEs leading to study agent 
discontinuation will be presented, including duration and study day of onset/resolution 
relative to the day of first OL infusion.  The study day of onset relative to the first OL 
belimumab infusion will also be presented. 
A listing of reasons for considering AEs to be classified as SAEs will be provided. 
A listing of concomitant immunosuppressants will be produced for subjects with 
treatment-emergent SAEs.  A similar listing for subjects with treatment-emergent non-
serious infections and infestations AEs will be provided. 
7.2. 
Adverse Events of Special Interest (AESI) 
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.  The details of 
the planned Open-Label displays are provided in Appendix 10: List of Data Displays.  
A listing of all AESI will be provided. 
7.3. 
Clinical Laboratory Summaries 
Laboratory evaluations including the summaries of hematology, liver function, 
electrolytes, other chemistries, urinalysis and immunoglobulin data will be based on GSK 
Core Data Standards.  The details of the planned displays are in Appendix 10: List of 
Data Displays. 
For laboratory summaries, only analytes with a numeric normal range will be 
summarized.  Summaries will be performed based on the observed data, no imputation 
will be done for missing data.  Laboratory summaries will use the Open-Label baseline. 
See Protocol Appendix 5 for a list of laboratory parameters and Double-Blind RAP 
Appendix 8 for a definition of the laboratory toxicity grades. 
Listings will be generated for all laboratory results and for Grade 3 or Grade 4 laboratory 
toxicity results.  
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7.3.1. 
Laboratory Change from OL Baseline Displays 
Descriptive statistics for each analyte will be displayed for OL Baseline and change from 
OL baseline for each scheduled visit.  
7.3.2. 
Laboratory Toxicity ≥ 2 Grade Shift Post OL Baseline 
Toxicity grade shifts from OL baseline of ≥ 2 grades will be summarized at any time post 
Open-Label baseline, for each analyte. 
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 and Grade 2 to 4.   
Data for both scheduled and unscheduled visits will be included.    
7.3.3. 
Liver Monitoring/Stopping Criteria 
If any liver monitoring or stopping criteria events occur, a listing will be provided, along 
with a listing of substance use reported with the liver event and a listing of liver stopping 
event information for RUCAM score.   
7.4. 
Other Safety Data 
The summary of vital signs data will be based on GSK Core Data Standards. The details 
of the planned displays are presented in Appendix 10: List of Data Displays.  
Vital signs summaries will use the Open-Label baseline. 
A listing of all concomitant medical/surgical procedures will be presented. 
8. 
EFFICACY ANALYSES 
Efficacy summaries will be based on Benlysta program standards.  Details of the planned 
displays are presented in Appendix 10: List of Data Displays. 
Efficacy summaries will be based on the mITT Open-Label population and use the Open-
Label Baseline, unless otherwise specified.  They will be presented by treatment group 
and overall, and by induction regimen and overall, unless otherwise specified. 
Open-Label efficacy data will be summarised using descriptive statistics only, no formal 
analyses will be carried out.  Summaries will be performed on the observed data up to 
withdrawal, no imputation will be carried out for missing data.  Using the ICH E9 
Addendum Estimand Structure, this can be described as follows: 
Endpoints 
Variables as detailed in Section 8.2 
Summary Measure 
Summary statistics (no formal analysis) of the variables as detailed in Section 8.2 
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Population of Interest 
The analyses will be based on the modified Intent-to-Treat Open-Label population 
Intercurrent Event Strategy 
The intercurrent event strategy is as follows: 
There are five types of intercurrent events (IEs): 
1.
Taking Open-Label concomitant medications that were considered prohibited medications in the
Double-Blind (rescue). See Section 12.5.3.1 and Section 12.5.3.2.
2.
Investigational Product (IP) Discontinuation
3.
Study Withdrawal
4.
Lost to Follow-up
5.
Death
Subjects who discontinued IP should have withdrawn from the study, but a small number of subjects 
remained in the study after IP discontinuation. All efficacy data collected will be included regardless of IP 
discontinuation. The intercurrent event of receiving rescue medication will follow a Composite Strategy in 
the PERR and CRR binary analyses (subjects who take rescue will be considered non-responders); the 
intercurrent event of IP discontinuation will follow a Treatment Policy Strategy; and all other intercurrent 
events will follow an On Treatment Strategy. 
No imputation will be carried out for missing data 
Summaries that are presented by visit will display all relevant visits according to the 
Time and Events schedule (see Section 12.1).  
Efficacy listings will be based on the Full Open-Label population and will be presented 
by induction regimen and treatment group.  Listings for the following data will be 
displayed: 

PERR and CRR results by OL visit (Observed)

Subjects who experience doubling of serum creatinine from Open-Label Baseline
and/or progression to End Stage Renal Disease (ESRD)

Systemic Lupus Erythematosus Disease Activity Index – S2K (SLEDAI-S2K)

Prednisone average daily dose between visits

Systemic Lupus International Collaborating Clinics / American College of
Rheumatology (SLICC/ACR) damage index – Double-Blind and Open-Label
phase data.

uPCR and eGFR – Double-Blind and Open-Label phase data
8.1. 
Primary Efficacy Analyses 
There are no Primary Efficacy analyses being carried out in this study. 
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8.2. 
Secondary Efficacy Analyses 
8.2.1. 
Primary Efficacy Renal Response (PERR) (Observed) 
The PERR is measured as a dichotomous response (Responder vs Non-Responder) and is 
determined by changes in proteinuria and renal function.  Details on the endpoint 
derivation can be found in Section 12.5.3.1. 
The number and percentage of responders will be summarised by Induction Regimen at 
Open Label Weeks 12, 24 and 28. 
The disposition of PERR at OL Week 28 will be summarized, just for the Overall 
Induction Regimen. 
The number and percentage of PERR responders will also be summarised by Baseline 
Renal Biopsy Class, Race and Region (see Section 5.4.2) at OL Week 28. 
8.2.2. 
Complete Renal Response (CRR) (Observed) 
Complete Renal Response (CRR) is measured as a dichotomous response (Responder vs 
Non-Responder).  The endpoint derivation can be found in Section 12.5.3.2.   
The number and percentage of CRR responders will be summarised by Induction 
Regimen at OL Weeks 12, 24 and 28. 
The disposition of CRR at OL Week 28 will be summarized, just for the Overall 
Induction Regimen. 
The number and percentage of CRR responders will also be summarised by Baseline 
Renal Biopsy Class, Race and Region (see Section 5.4.2) at OL Week 28. 
8.2.3. 
PERR and CRR Supplementary Endpoints 
The number and percentage of responders for the PERR component endpoints (uPCR and 
eGFR) will be summarized by Induction Regimen at OL Weeks 12, 24 and 28. 
The number and percentage of responders for the CRR component endpoints (uPCR and 
eGFR) will also be summarized by Induction Regimen at OL Weeks 12, 24 and 28. 
8.2.4. 
Other Renal Endpoints 
Summary statistics will be presented for both the change and the percent change from OL 
Baseline in Urine Protein-Creatinine Ratio (uPCR) at OL Weeks 12, 24 and 28 (see 
Section 12.5.3.5). 
The number and percentage of subjects with a doubling of serum creatinine from OL 
Baseline and/or progression to End Stage Renal Disease will be summarised by Induction 
Regimen at OL Weeks 12, 24 and 28 (see Section 12.5.3.4).  Note Subjects who fulfil the 
ESRD flag during the DB period will be excluded from this summary for both ESRD and 
doubling of serum creatinine.  
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8.2.5. 
Corticosteroid Endpoints 
The number and percentage of subjects meeting the following criteria will be summarised 
by Induction Regimen at OL Baseline, OL Weeks 12, 24 and 28 (see Section 12.5.3.7): 

Prednisone <=5mg/day (average daily dose between visits)

Prednisone <=7.5mg/day (average daily dose between visits)

Prednisone <=10mg/day (average daily dose between visits)
Note: subjects that are still in the study at the specified visit and do not have prednisone 
recorded as concomitant medication, will be assigned a zero dose in the analysis (and will 
be counted as met the pre-specified criteria).  
8.2.6. 
Maintenance of Response Endpoints 
Summary statistics for absolute values of uPCR, eGFR and SLICC/ACR will be 
produced by visit across the entire duration of the study, including both the Double-Blind 
and Open-Label visits, by Induction Regimen. 
The results for uPCR and eGFR will also be displayed graphically over time, by 
Induction Regimen. 
The number of responders for the following uPCR and eGFR components of the PERR 
and CRR endpoints will be summarised by visit across the entire duration of the study, 
including both the Double-Blind and Open-Label visits, by Induction Regimen: 

uPCR ≤ 0.7

uPCR < 0.5

eGFR is ≥ 60 mL/min/1.73m2 OR no more than 20% below Baseline value *

eGFR is within the normal range (≥ 90 mL/min/1.73m2) OR no more than 10% below
Baseline value *
* NOTE that the Double-Blind phase visits will use the DB Baseline, but the Open-Label 
phase visits will use the OL Baseline. 
The number of responders for each of these components will also be displayed 
graphically over time, by Induction Regimen. 
8.2.7. 
Exploratory Endpoints 
Summary statistics will be presented for the change from OL Baseline to OL Week 28 for 
the following: 

SLEDAI-S2K (see Section 12.5.3.6)

SLEDAI-S2K excluding renal items (see Section 12.5.3.6)

SLICC/ACR damage index (Observed, corrected by WOCF) (see Section
12.5.3.8)
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Summary statistics will also be presented for the change from DB Baseline to OL Week 
28 for the following: 

SLICC/ACR damage index (Observed, corrected by WOCF) (see Section
12.5.3.8)
9.
PHARMACOKINETIC ANALYSES
9.1. 
Primary Pharmacokinetic Analyses
Descriptive statistics for serum belimumab concentrations will be displayed for Open-
Label visits where PK was collected (OL Baseline and OL Follow-Up). The table will 
display the mean value, standard deviation, 95% confidence interval, geometric mean, 
geometric standard deviation, geometric 95% confidence interval, coefficient of variation 
(%), median, 25th and 75th percentiles, minimum and maximum (see Section 12.4.3).  No 
statistical tests will be performed. 
A listing of serum belimumab PK concentration-time data will be presented. 
10.
BIOMARKER ANALYSES
10.1. 
Primary Biomarker Analyses
10.1.1. 
Endpoint / Variables
Autoantibodies, complement, immunoglobulin and peripheral B lymphocytes (referred to 
as B cells) will be collected per the study calendar (see Section 12.1). 
The specific biomarkers collected and analyzed are shown in Table 7. 
Table 7 
Biomarkers for Analysis 
Autoantibodies 
aCL 
ANA 
anti-Sm 
anti-C1q 
Anti-dsDNA 
Complement 
C3 
C4 
Immunoglobulin 
IgG, IgM, and IgA 
B cells 
CD19 
CD20 
Naïve CD19+CD20+CD27-  * 
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Autoantibodies 
Memory CD19+CD20+CD27+ * 
Activated CD19+CD20+CD69+ Normalised 
Plasma CD19+CD20-CD138+ Normalised 
Plasmacytoid CD19+CD20+CD138+ Normalised 
Short-lived Plasma CD19+CD20-CD27b+ Normalised 
SLE Subset CD19+CD38b+CD27b+Lymph Normalised 
Transitional CD19+CD24b+CD38b+CD27- Normalised 
*Naïve and Memory B cell subsets will also be expressed as a percentage of CD19.
10.1.2. 
Population of Interest 
The Biomarker summaries will be based on the mITT Open-Label population and use the 
Open-Label Baseline, unless otherwise specified. 
10.1.3. 
Strategy for Intercurrent Events 
The Biomarker summaries will only present observed data, no imputation will be carried 
out for missing data.  The strategy for intercurrent events is as detailed in Section 8. 
10.1.4. 
Statistical Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on Benlysta program standards. 
The endpoints defined in Section 10.1.1 will be summarised using descriptive statistics.  
They will be presented by treatment group and overall, and by induction regimen and 
overall. 
Summaries that are presented by visit will display all relevant visits according to the 
Time and Events schedule (see Section 12.1).  
Additionally, shifts tables will be used to summarise the changes in immunoglobulins, 
autoantibodies, and complement by induction regimen and overall, for each treatment 
group and OL visit.  See DB RAP, Section 11.3.  
Biomarker listings will be based on the Full Open-Label population and will be presented 
by induction regimen and treatment group. 
11.
REFERENCES
Alarcón-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare 
in patients with systemic lupus erythematosus. Arthitis Rheum 2003;48(2):442–54. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–54. 
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12.
APPENDICES
12.1. 
Appendix 1: Schedule of Activities
12.1.1. 
Protocol Defined Schedule of Events
Study Day 
Day 0 A 
Day 28 
± 7 days 
Day 56 
± 7 days 
Day 84 
± 7 days 
Day 112 
± 7 days 
Day 140 
± 7 days 
Day 168 
± 7 days 
Day 196/Exit B  
± 7days  
(4 weeks after last dose) 
Follow-up visit C  
(8 weeks after last dose) 
+7 days
Study Week 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Clinical Assessments 
SELENA SLEDAI, SLE Flare Index and 
PGA 
x 
x 
SLICC Damage 
x 
x 
Record Concurrent Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Symptom-driven Physical Examination 
x 
x 
Weight D 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs L 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record/Assess Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 
Hematology and chemistry (non-fasting) E 
x 
x 
x 
x 
x 
Urinalysis F 
x 
x 
x 
x 
x 
Urinary Microscopy F 
x 
x 
x 
x 
x 
Spot Urine 
x 
x 
x 
x 
x 
Pregnancy Test G 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C3/C4, anti-dsDNA 
x 
x 
x 
Autoantibodies (aCL, ANA, anti-Sm, anti-
C1q) H 
x 
x 
x 
Serum IgG 
x 
x 
x 
x 
Serum IgA & IgM 
x 
x 
x 
Pharmacokinetic sampling I 
x 
x 
Immunogenicity (anti-belimumab antibody) 
x 
x 
x 
Peripheral B lymphocytes 
x 
x 
x 
Protocol Treatments 
Study Agent Administration (belimumab) K 
x 
x 
x 
x 
x 
x 
x 
Maintenance Therapy J 
Throughout the Study 
A Day 0 of the Open-Label extension is the Week 104 study visit of the Double-Blind treatment period and 
represents the first belimumab administration for those subjects continuing on the 6 month Open-Label 
extension.   
B For subjects who discontinue from the study, an Exit visit should be completed 4 weeks after the last dose 
of study agent. 
C For subjects who discontinue from the study, a Follow-up visit should be completed 8 weeks after the last 
dose of study agent. The 8-week follow up visit is not required for subjects entering the separate 
continuation protocol. 
D The weight at the current visit should be used to calculate dose. 
E Refer to Protocol Appendix 5 for a listing of laboratory assessments to be completed.  
F Routine urinalysis and urinary microscopy will be performed locally. 
G For women of child-bearing potential, a urine pregnancy test is required. Results of the urine pregnancy 
test must be available prior to dosing. 
H Samples will only be analyzed for anti-Sm and anti-C1q in subjects with positive results at baseline. 
I For PK sampling times, see Protocol Section 6.7.1. 
J AZA/MMF continued at the discretion of the investigator. 
K 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. 
L Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on 
which study agent is administered, vital signs are to be performed prior to dosing. 
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12.2. 
Appendix 2: Assessment Windows 
12.2.1. 
Definitions of Assessment Windows for Analyses 
All visits after OL Baseline use the CRF visit and will not be slotted based on OL study 
day.  See Section 12.5.1 for the OL study day definition.   
Analysis Visit and Analysis Visit Number 
Visit b 
Analysis Visit 
Analysis 
Visit 
Number 
Study Day a 
Screening 
10 
DB Baseline 
20 
≤ DB Study Day 1 
DB Week 0 + 3 Days 
30 
DB Week 4 
50 
      through to 
DB Week 100 
330 
DB Week 100 + 3 Days 
340 
DB Week 104 
350 
N/A as this is derived 
OL Baseline 
373 
≤ OL Study Day 1c 
Week 104/EXT Week 0 
Unscheduled OL Week 0.01 
373.01 
> OL Study Day 1 c 
N/A as this is derived 
Any time post OL Baseline d 
374 
Week 104/EXT Week 0 + 3 
Days 
OL Week 0 + 3 Days 
376 
N/A as this is derived 
Any Time On OL Treatment e 
377 
N/A as this is derived 
Any Time Post OL Treatment e 
378 
EXT Week 4 
OL Week 4 
380 
EXT Week 8 
OL Week 8 
390 
EXT Week 12 
OL Week 12 
400 
EXT Week 16 
OL Week 16 
410 
EXT Week 20 
OL Week 20 
420 
EXT Week 24 
OL Week 24 
430 
EXT Week 28 
OL Week 28 
440 
EXT Follow-Up 
OL Follow-Up 
450 
LIVER EVENT 1 
LIVER EVENT 1 
8100 
LIVER EVENT 2 
LIVER EVENT 2 
8200 
a.
Study Day for DB visits is relative to DB Baseline; Study Day for OL visits is relative to OL Baseline.
b.
All DB visits from Screening through to DB Week 104 are only kept in the ADSLICC and ADRR dataset.
c.
If the ‘Week 104/Ext Week 0’ visit has an OL Study day of 1, it will be assigned as ‘OL Baseline’.
If the ‘Week 104/Ext Week 0’ visit has an OL Study day of >1, it will be assigned as ‘Unscheduled OL Week 0.01’.
If there are no records with an OL Study day of 1, then the assessment done immediately prior to the first OL dose
will be assigned as ‘OL Baseline’ – this can include unscheduled visits

Renal endpoints: DB Week 96 is earliest data point that will be used.

SELENA SLEDAI: DB Week 88 is earliest data point that will be used.

B cells:  DB data from 30 days prior to first OL infusion will be used.
d.
Any time post OL Baseline will include all data after OL Baseline. This includes scheduled visits and unscheduled
visits.
e.
Please refer to Section 12.5.1 for definition of On OL Treatment and Post OL Treatment.
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Note that unscheduled assessments that occur on or prior to the first OL dose date will be 
included in the derivation of the OL Baseline assessment.  Unscheduled assessments that 
occur after the first OL dose date will be ordered according to visit number and appear in 
the listings as unscheduled assessments.  Post OL baseline unscheduled assessments will 
be included in the derivation of ‘any time post OL Baseline’. 
Two subjects did not receive IP at the first OL visit (DB Week 104 /OL Week 0) but did 
receive it at other visits (Subjects 
 and 
).  In the DB study, data until the first OL 
infusion was included, and therefore, these OL visits are included in the DB displays. 
Please see DB RAP, Section 14.6.1.6 and Section 14.6.1.7. 
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12.3. 
Appendix 3: OL Phase, OL Concomitant Medications and OL 
Treatment Emergent Adverse Events 
12.3.1. 
OL Phase 
Assessments will be included in the Open Label phase if they are >= OL Study Treatment 
Start Date. 
Note: Adverse Events that started on the day of first Open-Label infusion are considered 
treatment-emergent, if the AE start time is present and is after the infusion time, or if the 
AE start time is not present. AEs where start time is not present will be included for both 
the primary (Double-Blind) and final (Open-Label) reporting. 
Note that Concomitant Medications on the Open-Label treatment start date will be 
included for both the primary (Double-Blind) and final (Open-Label) reporting. 
12.3.2. 
OL Concomitant Medication 
OL concomitant medications are defined as:  
(1) medications that start on or before the first dose date of Open-Label treatment 
(i.e. started during or before Double-Blind phase) and end on or after the first 
dose date of Open-Label treatment, or  
(2) medications that start on or after the first dose date of Open-Label treatment.   
Note that medications with missing start and stop dates will be assumed to be OL 
concomitant unless CMCAT = ‘INDUCTION THERAPY’.  For medications with partial 
start and/or stop dates, if the day is missing, then the month and year will be compared to 
the month and year of the first dose date of OL treatment and if the month and year are 
the same or later, then the medication will be considered OL concomitant.   
Please refer to Section 12.6 Reporting Standards for Missing Data for handling of 
missing and partial dates for concomitant medication. 
In the OL Concomitant medication analysis dataset all steroid medication data is required 
in order to calculate the OL baseline 7-day average prednisone equivalent dose. 
12.3.3. 
Treatment Emergent Flag for OL Adverse Events 
Flag 
Definition 
Open-Label 
Treatment- 
Emergent AE 
 
An OL treatment-emergent AE is an adverse event that starts on or after the first 
dose of Open-Label treatment, having been absent pre-OL-treatment.    
 
AEs with missing start dates will be assumed to be OL treatment-emergent 
 
AE Start Date ≥ Open-Label Treatment 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 (V9.4) will be used.
Reporting Area 
HARP Server 
: us1salx00259 
HARP Compound and Reporting Effort 
: \arenv\arprod\gsk1550188\bel114054\final_02 
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG
Version 1.1]. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC
versions are consistent.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be
implemented for conversion from SI to SDTM.
Generation of RTF Files 

RTF files will be generated for all output Tables.
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 
Descriptive Summary Statistics 
Continuous Data 
Mean, median, standard deviation (SD), standard error (SE), 25th and 75th 
percentiles, minimum and maximum. 
Categorical Data 
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. 
Formats 

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.
Unless otherwise stated, the following will apply: 

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
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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 and SE 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.
Planned and Actual Time 

Reporting for Tables and Figures:

Planned time relative to dosing will be used in figures, summaries and calculation of any derived
parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings:

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings.
Unscheduled Visits 

Unscheduled visits will not be included in summary tables or figures.

All unscheduled visits will be included in listings.
12.4.3. 
Reporting Standards for Pharmacokinetics 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics (Logged 
Transformed) and 
Listings 
Concentration values will be imputed as per GUI_51487 for descriptive summary 
statistics/analysis and summarized graphical displays only.  
N, n, mean, standard deviation, 95% confidence interval, geometric mean, 
geometric standard deviation, geometric 95% confidence interval, coefficient of 
variation (CVb (%)*), median, 25th and 75th percentiles, minimum and maximum will 
be reported. 
*CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
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12.5. 
Appendix 5: Derived and Transformed Data 
12.5.1. 
General 
Multiple Measurements at One Analysis Time Point 

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 the Laboratory Toxicity Grade tables.
Open-Label 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.
Change from OL Baseline 

Change from OL Baseline will be calculated as:
       Visit value – OL Baseline value. 

If either value is missing the change from baseline will be missing
Percent Change from OL Baseline 

Percent change from OL Baseline will be calculated as:

Subjects with an OL baseline value of zero will not have a value calculated due to division by zero. If
the OL baseline value is zero or missing, then the percent change will be set to missing.
On OL Treatment and Post OL Treatment Definition for Safety Endpoints 
On OL Treatment 
OL Treatment Start Date ≤ Date ≤ Safety OL On-Treatment End Date 
Where Safety OL On-Treatment End date is defined as:  
•
the OL Week 28 visit date OR
•
the last OL infusion + 28 days, whichever is later.
Post OL Treatment 
Date > Safety On OL Treatment End Date 
On OL Treatment for Efficacy Endpoints 
On OL Treatment 
OL Treatment Start Date ≤ Date 
12.5.2. 
Study Population 
Analysis Age 

See DB RAP Section 14.6.2.1.

Note that age will be calculated twice – once relative to DB Baseline and once relative to OL Baseline.
Race and Race Stratification Factor 

See DB RAP Section 14.6.2.2.
Body Mass Index (BMI) 

See DB RAP Section 14.6.2.3.

Note that BMI will be calculated twice – once relative to DB Baseline and once relative to OL Baseline.
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SLE disease duration 

For DB Baseline summary: (Double-Blind Treatment start date - SLE diagnosis date + 1) / 365.25

For OL Baseline summary: (Open-Label Treatment start date - SLE diagnosis date + 1) / 365.25
LN disease duration 

For DB Baseline summary: (Double-Blind Treatment start date - LN diagnosis date + 1) / 365.25

For OL Baseline summary: (Open-Label Treatment start date - LN diagnosis date + 1) / 365.25
Extent of Exposure to Study Drug during the OL phase 

Number of days of exposure to study drug during the OL phase will be calculated based on the formula:
    Last infusion date in Open-Label – (First infusion in Open-Label) + 28 

If a subject dies < 28 days after the last infusion then OL exposure will be calculated as:
    Death date – (First infusion in Open-Label) + 1 

Participants who did not have an OL infusion date will be assigned 0 days of OL exposure.

Only complete dates will be used when calculating duration of exposure.  First and last OL infusion
dates will be used, regardless of any missed doses.
Extent of Belimumab Exposure Overall 

The number of days of overall belimumab exposure will be calculated as follows:

For subjects randomized to placebo in DB and received their first belimumab dose in the OL
phase, the number of days of overall belimumab exposure =  belimumab exposure during OL (last
belimumab infusion date – first belimumab infusion date in Open-label + 28).

For subjects randomized to placebo in DB but received belimumab in error at certain DB visits: the
number of days of overall belimumab exposure =  belimumab exposure during OL (last belimumab
infusion date – first belimumab infusion date in Open-label + 28) + Exposure to belimumab in the
DB (number of incorrect injections x 28).

For subjects randomized to belimumab in DB and continued to receive belimumab in the OL
phase, the number of days of overall belimumab exposure =  (last belimumab infusion in OL – first
belimumab infusion in DB + 28 days).

If a subject dies < 28 days after the last belimumab infusion in OL then belimumab exposure during OL
will be calculated as (Death date – first belimumab infusion date in Open-label + 1).

Participants who did not have a belimumab infusion date will be assigned 0 days of belimumab
exposure.

Only complete dates will be used when calculating duration of exposure to belimumab.  First and last
belimumab infusion dates within each study phase will be used, regardless of any missed doses.
Lupus Nephritis Medication Categories 

See DB RAP Section 14.6.2.5.
Systemic Medication Flag 

See DB RAP Section 14.6.2.6.
Prednisone Equivalent Conversion 

See DB RAP Section 14.6.2.7.
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12.5.3. 
Efficacy 
12.5.3.1. 
Primary Efficacy Renal Response (PERR) 
PERR 
PERR Responder Criteria 
When a subject meets the following three criteria at a visit, they are a PERR Responder: 

uPCR ≤ 0.7; and

eGFR ≥ 60 mL/min/1.73 m2 or no more than 20% below OL Baseline eGFR [eGFR ≥ OL Baseline
eGFR x (0.80)]; and

no OL Concomitant medications that were considered prohibited (rescue) medications in the
Double-Blind phase
NOTE: The derivation of the PERR responder criteria has been modified from the DB phase.  Firstly, the 
eGFR criteria has been modified to be relative to OL Baseline rather than relative to pre-flare.  Secondly, the 
Treatment Failure criteria were only applicable to the DB phase and are not adjudicated in the OL phase. 
Therefore, this component has been modified in the OL phase to be a programmatic check (Programmatic 
Prohibited Medication Responder Criterion).  Thirdly, the PERR criteria (the above 3 criteria) are not 
required to be reproducible on two consecutive visits in the OL phase.   
uPCR Responder Criterion for PERR 
If uPCR is missing, then responder variable is missing. 
Otherwise if uPCR is not missing, then 
If uPCR ≤ 0.7 then responder variable is 1 (Y) 
If uPCR > 0.7 then responder variable is 0 (N) 
eGFR Responder Criterion for PERR 
If eGFR is missing, then responder variable is missing. 
Otherwise if eGFR is not missing then 
    If eGFR ≥ 60 mL/min/1.73 m2  
    OR 
    If eGFR is no more than 20% below OL Baseline eGFR [eGFR ≥ OL Baseline eGFR x (0.80)] 
       Then the eGFR responder variable is 1 (Y) 
    Else the eGFR responder variable is 0 (N) 
Programmatic Prohibited Medications Responder Criterion for PERR 
See Section 12.5.3.3. 
If the subject meets any of the Programmatic Prohibited Medication Responder Criteria, then the 
Programmatic Prohibited Medication Responder Criterion variable is 0 (N) from the time they met the criteria 
onwards.  
Otherwise the Programmatic Prohibited Medication Responder Criterion variable is 1 (Y).    
Confirmation of PERR Responder Criteria 
During the OL study, the PERR responder criteria are assessed on Observed data at specified visits and 
are not required to be reproducible at consecutive assessments. 
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12.5.3.2. 
Complete Renal Response (CRR) 
CRR 
CRR Responder Criteria 
When a subject meets the following three criteria at a visit, they are a CRR Responder: 

uPCR < 0.5; and

eGFR is within the normal range (≥ 90 mL/min/1.73 m2) or no more than 10% below OL Baseline
eGFR [eGFR ≥ OL Baseline eGFR x (0.90)]; and

no OL Concomitant medications that were considered prohibited (rescue) medications in the
Double-Blind phase
 NOTE: The derivation of the CRR responder criteria has been modified from the DB phase.  Firstly, the 
eGFR criteria has been modified to be relative to OL Baseline rather than relative to pre-flare.  Secondly, the 
Treatment Failure criteria were only applicable to the DB phase and are not adjudicated in the OL phase. 
Therefore, this component has been modified in the OL phase to be a programmatic check (Programmatic 
Prohibited Medication Responder Criterion). Thirdly, the CRR criteria (the above 3 criteria) are not required 
to be reproducible on two consecutive visits in the OL phase.   
uPCR Responder Criterion for CRR 
If uPCR is missing, then responder variable is missing. 
Otherwise if uPCR is not missing, then 
If uPCR < 0.5 then responder variable is 1 (Y) 
If uPCR ≥ 0.5 then responder variable is 0 (N) 
eGFR Responder Criterion for CRR 
If eGFR is missing, then responder variable is missing. 
Otherwise if eGFR is not missing then 
    If eGFR within the normal range (≥ 90 mL/min/1.73 m2) 
    OR 
    If eGFR is no more than 10% below OL Baseline eGFR [eGFR ≥ OL Baseline eGFR x (0.90)] 
         Then the eGFR responder variable is 1 (Y) 
    Else the eGFR responder variable is 0 (N) 
Programmatic Prohibited Medication Responder Criterion for CRR 
See Section 12.5.3.3.  
If the subject meets any of the Programmatic Prohibited Medication Responder Criteria, then the 
Programmatic Prohibited Medication Responder Criterion variable is 0 (N) from the time they met the criteria 
onwards. 
Otherwise, the Programmatic Prohibited Medication Responder Criterion variable is 1 (Y).  
Confirmation of CRR Responder Criteria 
During the OL study, the CRR responder criteria are assessed on Observed data at specified visits and are 
not required to be reproducible at consecutive assessments. 
12.5.3.3. 
Subjects Fulfilling the Programmatic Prohibited Medication Responder 
Criterion – Programmatic Checks 
Subjects Fulfilling the Programmatic Prohibited Medication Responder Criterion 
General Conventions 

Programmatic Prohibited Medication rules only apply to routes of administration that provide
systemic exposure to the medication.

The Programmatic Prohibited Medication date is the earliest date the Programmatic Prohibited
Medication Responder criterion was met during the OL study.
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Subjects Fulfilling the Programmatic Prohibited Medication Responder Criterion 

For a subject who completes the OL phase, Programmatic Prohibited medications/dose started on
the day the subject completes the open-label treatment phase (OL Week 28) do not result in
Programmatic Prohibited Medication Responder designation.

For a subject who withdraws early from the OL phase, Programmatic Prohibited medications/dose
started on the date of the last dose of IP are considered a Programmatic Prohibited Medication.   If
the Programmatic Prohibited medication/dose starts after the date of last dose of IP it will not be
part of the assessment.

Actual visit date, not target visit date, is used to assess DB Prohibited Medication. For example, if
the subject’s OL Week 24 visit occurs on Day 171, the date for Day 171 is used when applying the
DB Prohibited Medication rules.

Assessment of dose is based on analysis dose. Analysis dose is the sum of all doses given on a
single day, accounting for the frequency. For steroids, all systemically administered steroids
(SYSTEMIC=’Y’) given on a single day are converted to a daily prednisone equivalent dose (mg)
adjusting for frequency and then summed for a total daily dose.

Only the first instance of any DB Prohibited Medication rule violation is output programmatically.

The term ‘rescue’ medication refers to the medications that were prohibited during the Double-Blind
phase.
Steroids 

Only steroids with systemic routes of administration are included in prednisone dose calculations
(SYSTEMIC=’Y’).

All systemically administered steroids given on a single day are converted to a daily prednisone
equivalent dose (mg) adjusting for frequency and then summed for a total daily dose. There should
be an analysis dose created for each CMTYPCD and for total steroid use combining steroid doses
across all CMTYPCDs.

QOD dosing regimens (and regimens with frequency < once/day) will be programmatically checked
to ensure the analysis dose is calculated correctly.  Consider an example of a subject taking 5mg
QOD and 7.5 mg QOD. To calculate an analysis average daily dose for a 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 3.75 mg
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 2.5 mg; for subsequent days when the 5 mg
and 7.5 mg dosing intervals overlap, the analysis dose will be 2.5 mg + 3.75 mg = 6.25 mg.

Rules pertaining to rescue doses of steroids are identified by a steroid dose >10 mg/day.
Systemic Steroids for Renal SLE-related Disease Activity  
Identified by  
CMTYPCD =158 [Lupus nephritis induction or maintenance therapy] or 
CMTYPCD=164 [Corticosteroids for non-renal SLE with concurrent worsening of renal disease] 

Prednisone dose >10mg/day for treatment of a renal flare (with or without concurrent non-renal
SLE activity) at any point after OL Baseline will deem the subject has had a Programmatic
Prohibited Medication. [PARAMCD=PRGT1024; PARAM=Prednisone Renal-SLE > 10mg/d]
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Subjects Fulfilling the Programmatic Prohibited Medication Responder Criterion 
Systemic Steroids for Rescue within 90 days of the first rescue for non-Renal Disease Activity 
Identified by 
CMTYPCD=165 [Corticosteroids for non-renal SLE without concurrent worsening of renal disease] or 
CMTYPCD=blank [Other], or a combination of the two. 

2nd Rescue within 3 months (90 days) of the first rescue (a second occurrence of prednisone >
10mg/day) within 90 days of ending the previous one). [PARAMCD=P2RES90;
PARAM=Prednisone 2nd rescue in 90 days]
Systemic Steroids for Non-Renal SLE-related Disease Activity 
Identified by 
CMTYPCD=165 [Corticosteroids for non-renal SLE without concurrent worsening of renal disease] 
The following situations will deem the subject has had a Programmatic Prohibited Medication. 

Prednisone rescue (>10mg/day) at any point after OL baseline. [PARAMCD=PNGT1076;
PARAM=Prednisone Non-Renal SLE > 10 mg/d after OL baseline]

Rescue (prednisone dose >10mg/day) that cannot be tapered to ≤ 10 mg/day by Day 14 of rescue
therapy. [PARAMCD=PNTAP14; PARAM=Prednisone Non-Renal SLE not tapered by Day 14]

3 or more rescues (> 10 mg/day; max of 2 allowed). [PARAMCD=PN3RESC; PARAM=Prednisone
Non-Renal ≥ 3 rescues]

Rescue dose > 20 mg/day (on any given day during the 14-day rescue). [PARAMCD=PNRES20;
PARAM=Prednisone Non-Renal SLE > 20 mg/d]
Systemic Steroids for Non-SLE Disease Activity 
Identified by 
CMTYPCD=blank [Other] 
The following situations will deem the subject has had a Programmatic Prohibited Medication. 

Prednisone rescue (> 10 mg/day) at any point after OL baseline. [PARAMCD=POGT1076;
PARAM=Prednisone Non-SLE > 10 mg/d after OL baseline]

4 or more rescues (> 10 mg/day; max of 3 allowed). [PARAMCD=PO4RESC; PARAM=Prednisone
Non-SLE ≥ 4 rescues]

Rescue (> 10 mg/day) that cannot be tapered to ≤10 mg/day by Day 14 of rescue therapy.
[PARAMCD=POTAP14; PARAM=Prednisone Non-SLE not tapered by Day 14]

Maximum dose (= 60 mg) > 3 days in duration. [PARAMCD=POMAX3; PARAM=PMF Prednisone
Non-SLE = 60 mg for > 3 days consecutively]

Rescue dose > 60mg/day (the max on any given day during the 14-day period).
[PARAMCD=PORESC60; PARAM=Prednisone Non-SLE > 60 mg/d during 14-day period]
Anti-Malarials 

Starting any new anti-malarial treatment after the OL Baseline will deem the subject has had a
Programmatic Prohibited Medication. Select all records with CMCAT=’ANTIMALARIALS’ with a
start date after the OL Baseline.  Exclude any records with non-systemic routes of administration.
[PARAMCD=NEWAMOL; PARAM=New Anti-malarial after OL Baseline]

Programmatic Prohibited Medication date will be the anti-malarial start date occurring post OL
Baseline that resulted in the subject having had a Programmatic Prohibited Medication.
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Subjects Fulfilling the Programmatic Prohibited Medication Responder Criterion 
 
An anti-malarial may be replaced by another anti-malarial at any time during the study.  
 
A dose change is allowed during the OL study if the anti-malarial treatment was initiated on or 
before the OL Baseline regardless of the dose or date of initiation. 
 
Immunosuppressant/Immunomodulatory agents 
IV Cyclophosphamide, mycophenolate, and azathioprine (AZA) are part of subject’s DB induction/ 
maintenance regimen.  Immunosuppressant doses provided in grams (g) should be converted to milligrams 
(mg) by multiplying by 1000. The term MMF will be used to represent all forms of mycophenolate (i.e., 
mycophenolate mofetil, mycophenolate sodium, mycophenolic acid) collectively.  Rules around their use on 
or after the OL Baseline are listed below: 
 
Azathioprine (AZA) taken for maintenance therapy is permitted.  Doses > 200 mg/day will result in 
the subject having had a Programmatic Prohibited Medication. [ty=AZADOSE; PARAM=AZA > 
200 mg/day] 
 
Doses of mycophenolate mofetil or mycophenolic acid > 3 g/day (i.e., 3000 mg/day) or 
mycophenolate sodium > 2160 mg/day will result in the subject having had a Programmatic 
Prohibited Medication. [PARAMCD=MMFDOSE; PARAM=MMF > 3 g or Mycophenolate > 2160 
mg] 
 
MMF administered intravenously (IV) will result in the subject having had a Programmatic 
Prohibited Medication. [PARAMCD=MMFIV; PARAM=Mycophenolate taken IV] 
 
Switching maintenance therapy from AZA to MMF or MMF to AZA due to toxicity is permitted.  
Replacing AZA with MMF or MMF with AZA due to insufficient disease control will constitute the 
subject having had a DB Prohibited Medication. Switches between AZA and MMF (all forms) will be 
assessed during clinical adjudication for evaluating whether this is due to toxicity, lack of efficacy or 
availability.   
 
Restarting cyclophosphamide (CYC) therapy after attempting maintenance therapy (i.e., starting 
AZA or MMF) would constitute the subject having had a Programmatic Prohibited Medication. 
Select first record of CYC that occurs after use of AZA or MMF. [PARAMCD=CYCNEWID; 
PARAM=New CYC induction after attempting maintenance] 
 
The following rule applies to all other immunosuppressants (not CYC, AZA, or MMF) after the OL Baseline: 
 
Starting a new immunosuppressant after OL baseline will deem the subject has had a 
Programmatic Prohibited Medication. Note, immunosuppressants administered as topical, 
conjunctival, or other non-systemic routes are allowed at any time. Select all records with 
CMCAT=’IMMUNOSUPPRESSANT’ with a start date after the first OL dose.  Exclude any records 
with non-systemic routes of administration.  [PARAMCD=NEWIMOL; PARAM=New 
Immunosuppressant post-OL baseline] 
 
Angiotensin Pathway Antihypertensives 
 
Starting a new angiotensin pathway antihypertensive (ACE inhibitor, angiotensin receptor blocker) 
treatment after OL Baseline will deem the subject has had a Programmatic Prohibited 
Medication.   
 
Replacing an angiotensin pathway antihypertensive or titrating an existing agent to dose is allowed. 
 
Select all records with CMCAT=’ACE’ with a start date after the OL Baseline visit date if there was 
no record of an agent in this class (CMCAT) being taken at OL baseline. 
[PARAMCD=NEWACEOL; PARAM=New ACE/ARB after OL Baseline] 
 
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Subjects Fulfilling the Programmatic Prohibited Medication Responder Criterion 
Prohibited medications/non-Drug Therapies 

Date of Programmatic Prohibited Medication is date subject started Programmatic Prohibited
medication/non-Drug Therapy.
In addition to the rules defined for steroids, antimalarials, angiotensin pathway inhibitors, and 
immunosuppressants, the following medications and therapies are forbidden at any time during the OL 
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]

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).

Plasmapheresis

Select all records with CMCAT=’PROHIBITED’ and append all records from Medical Surgical
Procedures form listed as ‘Plasmapheresis’. Note the surgical procedures are in the SURGERY
dataset, variable SPTERM (verbatim text, not coded so will need to check for misspellings also).
[PARAMCD=PROHIB; PARAM=Prohibited Medication]
12.5.3.4. 
Doubling of Serum Creatinine and End Stage Renal Disease (ESRD) 
Doubling of Serum Creatinine and ESRD 
Endpoint 
The proportion of subjects with a doubling of the serum creatinine or progression to end stage renal disease 
(ESRD) as defined below: 

Doubling of serum creatinine compared with OL baseline.

Progression to ESRD defined as the need for chronic dialysis or renal transplantation.
Subjects who fulfil the ESRD flag during the DB period will be excluded. 
Doubling of Serum Creatinine 
Doubling of serum creatinine is defined as a value greater than or equal to double the OL Baseline value.  
During the OL study, the criteria are assessed on Observed data at specified visits and are not required to 
be reproducible at consecutive assessments. 
End Stage Renal Disease (ESRD) 
ESRD is an adjudicated event and is defined as the need for chronic dialysis or renal transplantation during 
the Open-Label phase. Chronicity of dialysis is defined as need for it for at least 90 days. Once ESRD is 
flagged, it should be flagged for all subsequent observed visits.  
If the subject died or is lost to follow up shortly after initiation of dialysis, pre-existing renal function and 
intention of dialysis (chronic vs. acute renal insufficiency management) will be taken into consideration while 
adjudicating ESRD event. 
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12.5.3.5. 
Proteinuria 
Proteinuria 
For analysis, urine protein in g/24-hour will be approximated by the urine protein:creatinine ratio (uPCR) in 
mg/mg, also referred to as the PC Ratio which is stored in the variable for the original unit in the SI dataset, 
not the standard unit which is reported in mg/mmol. In SDTM this variable is mapped to lab test code 
‘PROTCRT’ with units reported as g/g. Note, the value in mg/mg from the SI dataset is the same as the 
value in g/g in the SDTM dataset as the units cancel out so no data conversion is required. The data will be 
reported as g/g in the displays.  
Change from OL baseline and percent change from OL baseline values will be derived as described in 
Section 12.5.1. 
12.5.3.6. 
SLEDAI-S2K 
See DB RAP Section 14.6.3.16. 
12.5.3.6.1. SLEDAI-S2K < 4 
SLEDAI-S2K < 4 
The SLEDAI-S2K < 4 responder endpoint is defined as: 
Endpoint 
Criterion 
Responder 
SLEDAI-S2K < 4 
SLEDAI-S2K < 4 and not missing 
Y 
SLEDAI-S2K ≥ 4 
N 
SLEDAI-S2K post OL baseline = missing 
Missing 
12.5.3.6.2. SLEDAI-S2K excluding renal items 
See DB RAP Section 14.6.3.16.3. 
12.5.3.7. 
Prednisone 
12.5.3.7.1. Open-Label Baseline Prednisone Dose 
Open-Label Baseline Prednisone Dose 
At Open-Label Baseline, the average daily prednisone dose is the sum of all prednisone doses over 7 
consecutive days up to, but not including Open-Label Day 1, divided by 7.   
12.5.3.7.2. Prednisone Average Daily Dose Since Previous Visit 
Average Daily Prednisone Dose Since Previous Visit 
The average daily prednisone dose since previous visit will be calculated at every 4-week visit  post OL 
baseline (OL Weeks 4, 8, 12, 16, 20, 24, 28) 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) and rounding the result to 3 decimal places.  
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. 
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Average Daily Prednisone Dose Since Previous Visit 
For subjects who withdraw from the study prior to one of the 4-week visit intervals, the average daily dose 
for that interval will be calculated as the sum of all prednisone doses since the previous visit up to and 
including the date of withdrawal. 
12.5.3.8. 
SLICC/ACR Damage Index 
See DB RAP Section 14.6.3.18. 
12.5.4. 
Safety 
12.5.4.1. 
Adverse Events 
Adverse Events 
Adverse Events of Special Interest (AESI) 

See DB RAP Section 14.6.4 and DB RAP Attachment 1.
12.5.4.2. 
Laboratory Parameters 
Laboratory Parameters 
Laboratory Parameters 

See DB RAP Section 14.6.4.
12.5.5. 
Pharmacokinetic 
Pharmacokinetic 
Belimumab Concentration Units 

See DB RAP Section 14.6.5.
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12.6. 
Appendix 6: Reporting Standards for Missing Data 
12.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 
Subject study completion of the Open-Label phase was defined as completing the 
Open-Label Week 28 visit.   
 
Withdrawn subjects were not replaced in the study. 
 
All available Open-Label data from participants who were withdrawn from the Open-
Label study will be listed and all available data will be included in summary tables. 
 
12.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the listing.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Observed 
 
Observed data are the data collected or observed for the subject with no imputation for 
missing data. 
 
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 
 
Partial dates cannot be recorded in the CRF. 
Concomitant 
Medications 
 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
 
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
 
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
 
The recorded partial date will be displayed in listings. 
 
Completely missing start or end dates will remain missing. 
 
Both start and end dates missing, then assume medication is OL concomitant 
(excluding induction therapy).  
 
Medication that started prior to Open-Label but with medication end date missing, 
then if CMENRF = ‘AFTER’ then assume medication of OL concomitant.   
 
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12.7. 
Appendix 7: Values of Potential Clinical Importance 
12.7.1. 
Laboratory Toxicity Grades 
See DB RAP Section 14.8 (Appendix 8). 
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12.8. 
Appendix 8: B Cells 
See DB RAP Section 14.10 (Appendix 10). 
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12.9. 
Appendix 9: Abbreviations & Trade Marks 
12.9.1. 
Abbreviations 
Abbreviation 
Description 
aCL 
Anti-cardoiolipin 
ACR 
American College of Rheumatology 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANA 
Anti-nuclear Antibody 
Anti-C1q 
Anti-C1q Antibody 
anti-dsDNA 
Anti-double-stranded DNA 
Anti-Sm 
Anti-Smith Antibody 
ATC 
Anatomical Therapeutic Chemical 
AZA 
Azathioprine 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CRR 
Complete Renal Response 
CSR 
Clinical Study Report 
CYC 
Cyclophosphamide 
DB 
Double-Blind 
DBF 
Database Freeze 
DBR 
Database Release 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
eGFR 
Estimated Glomerular Filtration Rate 
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GSK 
GlaxoSmithKline 
HDCS 
High Dose Corticosteroids 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
ISN 
International Society for Nephrology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
kg 
Kilogram 
LN 
Lupus Nephritis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
MMF 
Mycophenolate Mofetil 
NQ 
Non-quantifiable 
OL 
Open-Label 
OLE 
Open-Label Extension 
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Abbreviation 
Description 
PD 
Protocol Deviation 
PDMP 
Protocol Deviation Management Plan 
PERR 
Primary Efficacy Renal Response 
PGA 
Physician’s Global Assessment 
PK 
Pharmacokinetic 
PSAP 
Program Safety Analysis Plan 
PT 
Preferred Term 
RAP 
Reporting & Analysis Plan 
RPS 
Renal Pathology Society 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SFI 
SLE Flare Index 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SLICC 
Systemic Lupus International Collaborating Clinics 
SDI 
SLICC Damage Index 
SLE 
Systemic Lupus Erythematosus 
SOC 
System Organ Class 
TLF 
Tables, Listings & Figures 
uPCR 
Urine Protein-Creatinine Ratio 
US 
United States 
WD 
Withdraw 
12.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
Benlysta 
SAS 
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12.10. 
Appendix 10: List of Data Displays 
12.10.1. 
Data Display Numbering 
The following numbering will be applied for Open-Label RAP generated displays: 
Section 
Tables (Figures) 
Listings 
Study Population 
11.01 to 11.27 
11.01 to 11.11 
Efficacy 
12.01 to 12.31 (12.01 to 12.06) 
12.01 to 12.06 
Safety 
13.01 to 13.38 
13.01 to 13.25 
Biomarker 
14.01 to 14.15 
14.01 to 14.02 
Pharmacokinetic 
15.01 
15.01 
12.10.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays. 
Section 
Tables (Figures) 
Listings 
Study Population 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Tn  (EFF_Fn) 
EFF_Ln 
Safety 
SAFE_Tn 
SAFE_Ln 
Biomarker 
BIO_Tn 
BIO_Ln 
Pharmacokinetic 
PK_Tn 
PK_Ln 
12.10.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
SAC [1] 
Final Statistical Analysis Complete 
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
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12.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
11.01. 
Full Open-
Label 
POP_T1 
Study Populations 
IDSL 
Add footnotes:
“Note: 2 subjects were inadvertently
enrolled into Open-Label (OL) while
permanently discontinued from
Double-Blind Investigational Product,
the subjects did not receive OL
treatment.”
“Note:  the modified Intent-to-
Treatment (mITT) OL population
excludes one subject at site 
due to GCP non-compliance issues. ”
SAC [1] 
11.02. 
mITT Open-
Label 
DB Table 1.05 
Subject Completion Status by End of Open-Label Phase Week 
28 and Reason for Study Withdrawal 
ICH E3, FDAAA, EudraCT 
SAC [1] 
Protocol Deviations 
11.03. 
mITT Open-
Label 
DB Table 1.10 
Important Protocol Deviations 
ICH E3 
SAC [1] 
Demographic and Baseline Characteristics 
11.04. 
mITT Open-
Label 
DB Table 1.13 
Demographic and Double-Blind Baseline Characteristics 
ICH E3, FDAAA, EudraCT 
SAC [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
11.05. 
mITT Open-
Label 
DB Table 1.13 
Demographic and Open-Label Baseline Characteristics 
ICH E3, FDAAA, EudraCT 
 Only include the following 
parameters: 
o Age (years) 
o Age Group (years) 
o Weight (kg) 
o BMI (kg/m^2) 
SAC [1] 
11.06. 
mITT Open-
Label 
DB Table 1.15 
Race and Racial Combination Details 
ICH E3, FDA, FDAAA, EudraCT 
SAC [1] 
11.07. 
mITT Open-
Label 
DB Table 1.20 
Double-Blind Baseline Disease Activity 
 
SAC [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
11.08.
mITT Open-
Label 
DB Table 1.20 
Open-Label Baseline Disease Activity 
Only include the following
parameters:
o SLE disease duration (years) [1]
o LN disease duration (years) [1]
o End Stage Renal Disease [2]
o Urine Protein-Creatinine Ratio
Category (g/g)
o Urine Protein-Creatinine Ratio
Level (g/g)
o Estimated GFR (mL/min/1.73m2)
Category
o Estimated GFR (mL/min/1.73m2)
o SLEDAI-S2K Category
o SLEDAI-S2K score
o PGA Category
o PGA score
o SLICC Category
o SLICC/ACR Damage Index score
Modify footnote
“[1] Duration defined as (Open-Label
treatment start date - Diagnosis date
+ 1)/365.25.”
Remove footnotes [2], [3] and [4]
Add footnote
“[2] Subjects who fulfil the ESRD flag
during the Double-Blind period.”
SAC [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Concomitant Medications 
11.09.
mITT Open-
Label 
DB Table 1.31 
Concomitant Medications by ATC Level 1 and ATC Level 4 
Term 
ICH E3 
SAC [1] 
11.10.
mITT Open-
Label 
DB Table 1.32 
Concomitant Medications by ATC Level 4 and Preferred Term 
ICH E3 
SAC [1] 
11.11.
mITT Open-
Label 
DB Table 1.30 
Allowable SLE and LN Medication Usage at Open-Label 
Baseline 
SAC [1] 
Extent of Exposure 
11.12.
mITT Open-
Label 
POP_T2 
Exposure to Open-Label Study Treatment through Open-Label 
Week 28 
ICH E3 
Add a footnote 
 “Note: 6 subjects randomised to 
placebo in DB received placebo 
treatment in error at first OL infusion 
(OL Week 0).  A further 2 patients (one 
in each treatment group) received a 
placebo infusion in error during OL.  
Duration of OL exposure includes days 
exposed to placebo in OL.” 
SAC [1] 
Study Population Tables by Baseline Renal Biopsy Class 
11.13.
mITT Open-
Label 
OL Table 11.04 
Demographic and Double-Blind Baseline Characteristics by 
Baseline Renal Biopsy Class 
Repeat OL Table 11.04 by Baseline 
Renal Biopsy Class 
SAC [1] 
11.14.
mITT Open-
Label 
OL Table 11.05 
Demographic and Open-Label Baseline Characteristics by 
Baseline Renal Biopsy Class 
Repeat OL Table 11.05 by Baseline 
Renal Biopsy Class 
SAC [1] 
11.15.
mITT Open-
Label 
OL Table 11.07 
Double-Blind Baseline Disease Activity by Baseline Renal 
Biopsy Class 
Repeat OL Table 11.07 by Baseline 
Renal Biopsy Class 
SAC [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
11.16.
mITT Open-
Label 
OL Table 11.08 
Open-Label Baseline Disease Activity by Baseline Renal Biopsy 
Class 
Repeat OL Table 11.08 by Baseline 
Renal Biopsy Class 
SAC [1] 
11.17.
mITT Open-
Label 
OL Table 11.11 
Allowable SLE and LN Medication Usage at Open-Label 
Baseline by Baseline Renal Biopsy Class 
Repeat OL Table 11.11 by Baseline 
Renal Biopsy Class 
SAC [1] 
Study Population Tables by Race Subgroup 
11.18.
mITT Open-
Label 
OL Table 11.04 
Demographic and Double-Blind Baseline Characteristics by 
Race 
Repeat OL Table 11.04 by Race 
SAC [1] 
11.19.
mITT Open-
Label 
OL Table 11.05 
Demographic and Open-Label Baseline Characteristics by Race 
Repeat OL Table 11.05 by Race 
SAC [1] 
11.20.
mITT Open-
Label 
OL Table 11.07 
Double-Blind Baseline Disease Activity by Race 
Repeat OL Table 11.07 by Race 
SAC [1] 
11.21.
mITT Open-
Label 
OL Table 11.08 
Open-Label Baseline Disease Activity by Race 
Repeat OL Table 11.08 by Race 
SAC [1] 
11.22.
mITT Open-
Label 
OL Table 11.11 
Allowable SLE and LN Medication Usage at Open-Label 
Baseline by Race 
Repeat OL Table 11.11 by Race 
SAC [1] 
Study Population Tables by Region Subgroup 
11.23.
mITT Open-
Label 
OL Table 11.04 
Demographic and Double-Blind Baseline Characteristics by 
Region 
Repeat OL Table 11.04 by Region 
SAC [1] 
11.24.
mITT Open-
Label 
OL Table 11.05 
Demographic and Open-Label Baseline Characteristics by 
Region 
Repeat OL Table 11.05 by Region 
SAC [1] 
11.25.
mITT Open-
Label 
OL Table 11.07 
Double-Blind Baseline Disease Activity by Region 
Repeat OL Table 11.07 by Region 
SAC [1] 
11.26.
mITT Open-
Label 
OL Table 11.08 
Open-Label Baseline Disease Activity by Region 
Repeat OL Table 11.08 by Region 
SAC [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
11.27. 
mITT Open-
Label 
OL Table 11.11 
Allowable SLE and LN Medication Usage at Open-Label 
Baseline by Region 
Repeat OL Table 11.11 by Region 
SAC [1] 
 
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12.10.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Primary Efficacy Renal Response (PERR) 
12.01.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response by Induction Regimen and 
Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.02.
mITT Open-
Label 
EFF_T2 
Disposition of Primary Efficacy Renal Response at Open-Label 
Week 28 (Observed) 
SAC [1] 
12.03.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response at Open-Label Week 28 by 
Baseline Renal Biopsy Class (Observed) 
Modify first column header to be
‘Baseline Renal Biopsy Class’ and
categories to be:
o Class III or Class IV
o Class III+V or IV+V
o Class V
SAC [1] 
12.04.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response at Open-Label Week 28 by 
Race (Observed) 
Modify first column header to be
‘Race’ and categories to be:
o Black
o Non-Black
SAC [1] 
12.05.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response at Open-Label Week 28 by 
Region (Observed) 
Modify first column header to be
‘Region’ and categories to be:
o Asia
o Europe
o US/Canada
o Americas excluding US/Canada
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Complete Renal Response (CRR) 
12.06.
mITT Open-
Label 
EFF_T1 
Complete Renal Response by Induction Regimen and Visit 
(Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.07.
mITT Open-
Label 
EFF_T2 
Disposition of Complete Renal Response at Open-Label Week 
28 (Observed) 
Replace “Primary Efficacy Renal
Responder” with “Complete Renal
Responder”
Update footnote: “[1] uPCR criterion:
< 0.5.”
Update footnote: “[2] eGFR criterion:
≥ 90 mL/min/1.73m^2 or no more
than 10% below OL Baseline value.”
SAC [1] 
12.08.
mITT Open-
Label 
EFF_T1 
Complete Renal Response at Open-Label Week 28 by Baseline 
Renal Biopsy Class (Observed) 
Modify first column header to be
‘Baseline Renal Biopsy Class’ and
categories to be:
o Class III or Class IV
o Class III+V or IV+V
o Class V
SAC [1] 
12.09.
mITT Open-
Label 
EFF_T1 
Complete Renal Response at Open-Label Week 28 by Race 
(Observed) 
Modify first column header to be
‘Race’ and categories to be:
o Black
o Non-Black
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.10.
mITT Open-
Label 
EFF_T1 
Complete Renal Response at Open-Label Week 28 by Region 
(Observed) 
Modify first column header to be
‘Region’ and categories to be:
o Asia
o Europe
o US/Canada
o Americas excluding US/Canada
SAC [1] 
Renal Specific Measures Supplementary to PERR and CRR 
12.11.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response uPCR Component (uPCR ≤ 
0.7) by Induction Regimen and Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.12.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response eGFR Component (eGFR ≥ 
60 mL/min/1.73m^2 or no more than 20% below Open-Label 
Baseline Value) by Induction Regimen and Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.13.
mITT Open-
Label 
EFF_T1 
Complete Renal Response uPCR Component (uPCR < 0.5) by 
Induction Regimen and Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.14.
mITT Open-
Label 
EFF_T1 
Complete Renal Response eGFR Component (eGFR is within 
Normal Range or no more than 10% below Open-Label Baseline 
Value) by Induction Regimen and Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
Add footnote: “Note: Normal Range:
eGFR ≥ 90 mL/min/1.73m^2.”
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Other Renal Endpoints 
12.15. 
mITT Open-
Label 
EFF_T4 
uPCR Percent Change from Open-Label Baseline by Induction 
Regimen and Visit (Observed) 
 Present the following visits: 
o OL Baseline 
o OL Week 12 
o OL Week 24 
o OL Week 28 
SAC [1] 
12.16. 
mITT Open-
Label 
EFF_T4 
uPCR Change from Open-Label Baseline by Induction Regimen 
and Visit (Observed) 
 Present the following visits: 
o OL Baseline  
o OL Week 12 
o OL Week 24 
o OL Week 28 
 Update relevant row in table to be 
“Post OL Baseline Change” 
 Remove footnote [1] 
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.17.
mITT Open-
Label 
EFF_T1 
Doubling of Serum Creatinine from Open-Label Baseline and/or 
Progression to End Stage Renal Disease by Induction Regimen 
and Visit (Observed) 
Subjects who fulfil the ESRD flag in
DB should be excluded from this
table.
Replace ’Response’ with ‘Met an
event’
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
Change ‘Number of subjects in
Induction Regimen’ to ‘Number of
subjects in Induction Regimen/No
ESRD * “
Add a footnote:
“* Only subjects who do not have End
Stage Renal Disease at Open-Label
Baseline are included.  Note:
subjects who fulfil the ESRD flag
during the DB period are excluded
from this table.”
Add a footnote:
“Note: the ESRD event is assigned to
the closest visit on or after the
progression date. For subject 
,
the ESRD event occurred xx days
after the subject’s last visit at OL
Week 12; the ESRD event is
assigned to OL Week 12 in this
summary.”
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Corticosteroid Endpoints 
12.18.
mITT Open-
Label 
EFF_T1 
Prednisone <= 5mg Average Daily Dose Since Previous Visit by 
Induction Regimen and Visit (Observed) 
Present OL Baseline, OL Week 4, 8,
12,16, 20, 24 and 28
SAC [1] 
12.19.
mITT Open-
Label 
EFF_T1 
Prednisone <= 7.5mg Average Daily Dose Since Previous Visit 
by Induction Regimen and Visit (Observed) 
Present OL Baseline, OL Week 4, 8,
12,16, 20, 24 and 28
SAC [1] 
12.20.
mITT Open-
Label 
EFF_T1 
Prednisone <= 10mg Average Daily Dose Since Previous Visit 
by Induction Regimen and Visit (Observed) 
Present OL Baseline, OL Week 4, 8,
12,16, 20, 24 and 28
SAC [1] 
Maintenance of Response Endpoints 
12.21.
mITT Open-
Label 
EFF_T5 
uPCR Absolute Values, Summary Statistics by Visit from 
Double-Blind Baseline through to Open-Label Week 28, by 
Induction Regimen (Observed) 
Present all relevant visits from DB
Baseline to DB Week 104 and OL
Baseline to OL Week 28
Add a footnote: “Note: DB Week 104
visit and the OL Baseline were the
same visit, but the OL Baseline has
been derived where data are missing
at DB Week 104 (i.e. using DB data
from Week 96 onwards).”
SAC [1] 
12.22.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response uPCR Component (uPCR ≤ 
0.7) by Visit from Double-Blind Baseline through to Open-Label 
Week 28, by Induction Regimen (Observed) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Add a footnote:
“Note: DB Week 104 visit and the OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.23.
mITT Open-
Label 
EFF_T1 
Complete Renal Response uPCR Component (uPCR < 0.5) by 
Visit from Double-Blind Baseline through to Open-Label Week 
28, by Induction Regimen (Observed) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Add a footnote:
“Note: DB Week 104 visit and the OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
SAC [1] 
12.24.
mITT Open-
Label 
EFF_T5 
eGFR Absolute Values, Summary Statistics by Visit from 
Double-Blind Baseline through to Open-Label Week 28, by 
Induction Regimen (Observed) 
Present all relevant visits from DB
Baseline to DB Week 104 and OL
Baseline to OL Week 28
Add a footnote: “Note: DB Week 104
visit and the OL Baseline were the
same visit, but the OL Baseline has
been derived where data are missing
at DB Week 104 (i.e. using DB data
from Week 96 onwards).”
SAC [1] 
12.25.
mITT Open-
Label 
EFF_T1 
Primary Efficacy Renal Response eGFR Component (eGFR ≥ 
60 mL/min/1.73m^2 or no more than 20% below Baseline Value 
[1]) by Visit from Double-Blind Baseline through to Open-Label 
Week 28, by Induction Regimen (Observed) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Add a footnote:
“[1] Double-Blind visits are relative to
DB Baseline, whereas Open-Label
visits are relative to OL Baseline.”
Add a footnote:
“Note: DB Week 104 visit and the OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.26.
mITT Open-
Label 
EFF_T1 
Complete Renal Response eGFR Component (eGFR is within 
Normal Range or no more than 10% below Baseline Value [1]) 
by Visit from Double-Blind Baseline through to Open-Label 
Week 28, by Induction Regimen (Observed) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Add a footnote
[1] Double-Blind visits are relative to
DB Baseline, whereas Open-Label
visits are relative to OL Baseline.”
Add a footnote:
“Note: DB Week 104 visit and the OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
Add a footnote:
“Note: Normal Range: eGFR ≥ 90
mL/min/1.73m^2.
SAC [1] 
12.27.
mITT Open-
Label 
EFF_T5 
SLICC/ACR Damage Index Values by Visit from Double-Blind 
Baseline through to Open-Label Week 28, by Induction Regimen 
(Observed, corrected by WOCF) 
Present data at DB Baseline, DB
Week 24, 52, 76, 104, OL Baseline
and OL Week 28.
Add a footnote: “Note: DB Week 104
visit and the OL Baseline were the
same visit, but the OL Baseline has
been derived where data are missing
at DB Week 104 (i.e. using DB data
from Week 52 onwards).”
Add a footnote: “Note: A worst
observation carried forward (WOCF)
approach is used to correct
inconsistent scoring.”
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
SLEDAI-S2K 
12.28.
mITT Open-
Label 
EFF_T4 
SLEDAI-S2K Change from Open-Label Baseline to Open-Label 
Week 28 by Induction Regimen (Observed) 
Present the following visits:
o OL Baseline
o OL Week 28
Insert a row for OL Week 28 and
report
o ‘n’
o ‘Visit Score < 4’, presenting n (%)
Update relevant row in table to be
“Post OL Baseline Change”
Remove footnote [1]
SAC [1] 
12.29.
mITT Open-
Label 
EFF_T4 
SLEDAI-S2K Change from Open-Label Baseline to Open-Label 
Week 28 Excluding Renal Items by Induction Regimen 
(Observed) 
Present the following visits:
o OL Baseline
o OL Week 28
Update relevant row in table to be
“Post OL Baseline Change”
Remove footnote [1]
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
SLICC/ACR Damage Index 
12.30.
mITT Open-
Label 
EFF_T4 
SLICC/ACR Damage Index Change from Open-Label Baseline 
to Open-Label Week 28 and Worsening by Induction Regimen 
(Observed, corrected by WOCF) 
Present the following visits:
o OL Baseline
o OL Week 28
Update relevant row in table to be
“Post OL Baseline Change”
Remove footnote [1]
Add a row at OL Week 28 for
‘Worsening (Change>0)’, presenting
n (%)
Add a footnote: “Note: A worst
observation carried forward (WOCF)
approach is used to correct
inconsistent scoring.”
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.31. 
mITT Open-
Label 
EFF_T4 
SLICC/ACR Damage Index Change from Double-Blind Baseline 
to Open-Label Week 28 and Worsening by Induction Regimen 
(Observed, corrected by WOCF) 
 Present the following visits: 
o DB Baseline 
o OL Baseline (change from DB 
Baseline) 
o OL Week 28 (change from DB 
Baseline) 
 Update relevant row in table to be 
“Post DB Baseline Change” 
 Remove footnote [1] 
 Add a row at OL Baseline and OL 
Week 28 for ‘Worsening 
(Change>0)’, presenting n (%) 
 Add a footnote: “Note: A worst 
observation carried forward (WOCF) 
approach is used to correct 
inconsistent scoring.” 
SAC [1] 
 
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12.10.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Maintenance of Response 
12.01. 
mITT Open-
Label 
EFF_F1 
uPCR Absolute Values by Visit (Observed) (Double-Blind + 
Open-Label) 
 Present all relevant visits from DB 
Baseline to DB Week 104 and OL 
Week 12 to OL Week 28. 
 Y-axis present “Median (units, 
Interquartile Range)” 
 Add a footnote: 
“Note: Subjects randomised to 
placebo in DB started Belimumab 
in the OL phase.” 
 Add a footnote: 
“Note: DB Week 104 and OL 
Baseline were the same visit, but 
only DB Week 104 is displayed.” 
SAC [1] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.02.
mITT Open-
Label 
EFF_F1 
Primary Efficacy Renal Response uPCR Component (uPCR ≤ 
0.7) by Visit (Observed) (Double-Blind + Open-Label) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28.
Y-axis present “Responders (%)
(SE)”
Add a footnote:
“Note: Subjects randomised to
placebo in DB started Belimumab
in the OL phase.”
Add a footnote:
“Note: DB Week 104 and OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
SAC [1] 
12.03.
mITT Open-
Label 
EFF_F1 
Complete Renal Response uPCR Component (uPCR < 0.5) by 
Visit (Observed) (Double-Blind + Open-Label) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Y-axis should present
“Responders (%) ( SE)”
Add a footnote:
“Note: Subjects randomised to
placebo in DB started Belimumab
in the OL phase.”
Add a footnote:
“Note: DB Week 104 and OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
SAC [1] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.04. 
mITT Open-
Label 
EFF_F1 
eGFR Absolute Values by Visit (Observed) (Double-Blind + 
Open-Label) 
 Present all relevant visits from DB 
Baseline to DB Week 104 and OL 
Week 12 to OL Week 28 
 Y-axis present “Median (units, 
Interquartile Range)” 
 Add a footnote: 
“Note: Subjects randomised to 
placebo in DB started Belimumab 
in the OL phase.” 
 Add a footnote: 
“Note: DB Week 104 and OL 
Baseline were the same visit, but 
only DB Week 104 is displayed.” 
SAC [1] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.05. 
mITT Open-
Label 
EFF_F1 
Primary Efficacy Renal Response eGFR Component (eGFR ≥ 
60 mL/min/1.73m^2 or no more than 20% below Baseline Value 
[1]) by Visit (Observed) (Double-Blind + Open-Label) 
 Present all relevant visits from DB 
Week 4 to DB Week 104 and OL 
Week 12 to OL Week 28 
 Y-axis should present 
“Responders (%) ( SE)” 
 Add a footnote: 
“[1] Double-Blind visits are 
relative to DB Baseline, whereas 
Open-Label visits are relative to 
OL Baseline.” 
 Add a footnote: 
“Note: Subjects randomised to 
placebo in DB started Belimumab 
in the OL phase.” 
 Add a footnote: 
“Note: DB Week 104 and OL 
Baseline were the same visit, but 
only DB Week 104 is displayed.” 
 
SAC [1] 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.06.
mITT Open-
Label 
EFF_F1 
Complete Renal Response eGFR Component (eGFR is within 
Normal Range or no more than 10% below Baseline Value [1]) 
by Visit (Observed) (Double-Blind + Open-Label) 
Present all relevant visits from DB
Week 4 to DB Week 104 and OL
Week 12 to OL Week 28
Y-axis present “Responders (%)
( SE)”
Add a footnote:
“[1] Double-Blind visits are
relative to DB Baseline, whereas
Open-Label visits are relative to
OL Baseline.”
Add a footnote:
“Note: Subjects randomised to
placebo in DB started Belimumab
in the OL phase.”
Add a footnote:
“Note: DB Week 104 and OL
Baseline were the same visit, but
only DB Week 104 is displayed.”
Add a footnote:
“Note: Normal Range: eGFR >=
90 mL/min/1.73m^2.
SAC [1] 
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12.10.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
13.01. 
Safety 
Open-Label 
SAFE_T1 
Adverse Events Summary 
 Report one row for Deaths i.e. 
include all deaths during OL 
SAC [1] 
13.02. 
Safety 
Open-Label 
SAFE_T3 
Adverse Events by System Organ Class and Preferred Term 
ICH E3 
SAC [1] 
13.03. 
Safety 
Open-Label 
DB Table 3.17 
Adverse Events by System Organ Class and Preferred Term 
and Region 
 
SAC [1] 
13.04. 
Safety 
Open-Label 
DB Table 3.19 
Adverse Events by System Organ Class and Preferred Term 
and Open-Label Baseline Body Weight Quartiles 
 
SAC [1] 
13.05. 
Safety 
Open-Label 
SAFE_T4 
Adverse Events by System Organ Class, Preferred Term, and 
Maximum Intensity 
ICH E3 
 
SAC [1] 
13.06. 
Safety 
Open-Label 
SAFE_T2 
Adverse Events by Preferred Term 
 
SAC [1] 
13.07. 
Safety 
Open-Label 
SAFE_T2 
Summary of Common (>=5%) Adverse Events by Preferred 
Term 
ICH E3 
 Amend footnote to “Common adverse 
events are defined as >=5% in either 
OL treatment group (Overall).” 
SAC [1] 
13.08. 
 Safety 
Open-Label 
SAFE_T3 
Study Agent Related Adverse Events by System Organ Class 
and Preferred Term 
ICH E3 
SAC [1] 
13.09. 
Safety 
Open-Label 
SAFE_T4 
Study Agent Related Adverse Events by System Organ Class, 
Preferred Term and Maximum Intensity 
ICH E3 
SAC [1] 
13.10. 
Safety 
Open-Label 
SAFE_T3 
Severe Adverse Events by System Organ Class and Preferred 
Term 
 
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.11. 
Safety 
Open-Label 
SAFE_T3 
Non-serious Adverse Events by System Organ Class and 
Preferred Term 
 
SAC [1] 
13.12. 
Safety 
Open-Label 
DB Table 3.28 
Summary of Common (>=5%) Non-serious Adverse Events, by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
FDAAA, EudraCT 
 Display data as shown for each OL 
treatment group. Data for the OL 
treatment groups combined is not 
required for this summary.   
 Update footnote to 
“Common adverse events are 
defined as >=5% in either OL 
treatment group (Total).” 
SAC [1] 
Serious and Other Significant Adverse Events 
13.13. 
Safety 
Open-Label 
SAFE_T3 
Death by Category and Preferred Term 
 Change column 1 header to be 
‘Death [1] Category [2] Preferred 
Term [3]’ 
 Update footnotes as per DB Table 
3.20 
SAC [1] 
13.14. 
Safety 
Open-Label 
SAFE_T3 
Serious Adverse Events by System Organ Class and Preferred 
Term 
 
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.15. 
Safety 
Open-Label 
DB Table 3.29 
Serious Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT 
 Display data as shown for each OL 
treatment group. Data for the OL 
treatment groups combined is not 
required for this summary.  
 Include rows for #SAEs, #DRSAEs, 
#FSAEs and #DRFSAEs for every 
SOC/PT and overall. 
 
SAC [1] 
13.16. 
Safety 
Open-Label 
SAFE_T3 
Study Agent Related Serious Adverse Events by System Organ 
Class and Preferred Term 
 
SAC [1] 
13.17. 
Safety 
Open-Label 
SAFE_T3 
Adverse Events Resulting in Study Agent Discontinuation by 
System Organ Class and Preferred Term 
IDSL 
SAC [1] 
Adverse Events of Special Interest (AESI) 
13.18. 
Safety 
Open-Label 
SAFE_T2 
Adverse Events of Special Interest by Category 
 Change column 1 header to be 
‘Special Interest Category’ 
 Include same categories and 
footnotes as per DB Table 3.30.  For 
deaths, report one row “Deaths” and 
remove footnote [7] and [8] 
SAC [1] 
13.19. 
Safety 
Open-Label 
SAFE_T3 
Malignant Neoplasm Adverse Events of Special Interest by 
Category and Preferred Term 
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.31 
SAC [1] 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.20. 
Safety 
Open-Label 
SAFE_T3 
Post-Infusion Systemic Reactions Adverse Events of Special 
Interest by Category and Preferred Term 
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.32 
SAC [1] 
13.21. 
Safety 
Open-Label 
SAFE_T3 
Serious Post-Infusion Systemic Reactions Adverse Events of 
Special Interest by Category and Preferred Term 
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.33 
SAC [1] 
13.22. 
Safety 
Open-Label 
SAFE_T3 
Infection Adverse Events of Special Interest by Category and PT  
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.39 
SAC [1] 
13.23. 
Safety 
Open-Label 
SAFE_T3 
Infection Adverse Events of Special Interest Leading to Study 
Agent Discontinuation by Category and PT  
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.40 
SAC [1] 
13.24. 
Safety 
Open-Label 
SAFE_T3 
Depression/Suicide/Self-injury Adverse Events of Special 
Interest by Category and PT  
 Change column 1 header to be 
‘Special Interest Category’, with 
‘Preferred Term’ underneath indented 
 Include same categories and 
footnotes as DB Table 3.41 
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hematology 
13.25.
Safety 
Open-Label 
SAFE_T5 
Laboratory Results by Induction Regimen and Visit: Hematology 
Present each lab parameter within
the lab category, each induction
regimen and each visit. Clinical
laboratory parameters and categories
are listed in Appendix 5 of the
Protocol.
Change visit labels to “OL Week xx”
and remove footnote [1]
Exclude the following parameters:
Metamyelocytes (count & %),
myelocytes (count & %), Bands
(count & %), promyelocytes (count &
%).  Note these parameters are not
protocol planned lab tests, their
removal matches the DB outputs.
Add a footnote “Note: Activated
Partial Thromboplastin Time and
Prothrombin Time data were only
collected in the Double-Blind phase
of BEL114054.”
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.26. 
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Hematology 
ICH E3 
 Present each lab parameter within 
the lab category, each induction 
regimen and each visit. Clinical 
laboratory parameters and categories 
are listed in Appendix 5 of the 
Protocol. 
 Change visit labels to “OL Week xx 
(Post OL Baseline Change)” and 
remove footnote [1]  
 Exclude the following parameters: 
Metamyelocytes (count & %), 
myelocytes (count & %), Bands 
(count & %), promyelocytes (count & 
%).  Note these parameters are not 
protocol planned lab tests, their 
removal matches the DB outputs.  
 Add a footnote “Note: Activated 
Partial Thromboplastin Time and 
Prothrombin Time data were only 
collected in the Double-Blind phase 
of BEL114054.” 
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
13.27.
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Hematology 
ICH E3 
Exclude the following parameters:
Metamyelocytes (count & %),
myelocytes (count & %), Bands
(count & %), promyelocytes (count &
%).  Note matches the DB outputs as
these parameters do not have much
data.
Add a footnote:
“Note: scheduled and unscheduled
lab data are included.”
SAC [1] 
Laboratory: Liver Function 
13.28.
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Liver Function 
ICH E3 
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
13.29.
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Liver Function 
ICH E3 
Add a footnote:
“Note: scheduled and unscheduled
lab data are included.”
SAC [1] 
Laboratory: Electrolytes 
13.30.
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Electrolytes 
ICH E3 
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
13.31.
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Electrolytes 
ICH E3 
Add a footnote:
“Note: scheduled and unscheduled
lab data are included.”
SAC [1] 
Laboratory: Other Chemistries 
13.32.
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Other Chemistries 
ICH E3 
Exclude creatinine clearance
adjusted for BSA.  Matches DB
outputs.
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
13.33.
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Other Chemistries 
ICH E3 
Add a footnote:
“Note: scheduled and unscheduled
lab data are included.”
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Urinalysis 
13.34. 
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Urinalysis 
ICH E3 
 Only include protein creatinine. 
 Change visit labels to “OL Week xx 
(Post OL Baseline Change)” and 
remove footnote [1] 
 Add a footnote: 
“Note: ‘Any Time Post OL Baseline’ 
summarises the highest lab result at 
any visit (scheduled or unscheduled) 
during the OL phase.”  
SAC [1] 
13.35. 
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Urinalysis 
ICH E3 
 Add footnote: 
“Note: scheduled and unscheduled 
lab data are included.” 
SAC [1] 
Laboratory: Immunoglobulins 
13.36. 
Safety 
Open-Label 
SAFE_T5 
Laboratory Change from Open-Label Baseline Results by 
Induction Regimen and Visit: Immunoglobulin 
ICH E3 
 Change visit labels to “OL Week xx 
(Post OL Baseline Change)” and 
remove footnote [1]  
SAC [1] 
13.37. 
Safety 
Open-Label 
SAFE_T6 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Open-Label Baseline by Induction Regimen: Immunoglobulin 
ICH E3 
 Add a footnote: 
“Note: scheduled and unscheduled 
lab data are included.” 
SAC [1] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
13.38.
Safety 
Open-Label 
SAFE_T5 
Change from Open-Label Baseline in Vital Signs by Induction 
Regimen and Visit (Observed) 
ICH E3 
Change sub-heading to be ‘Vital
Signs: …’
Include Systolic and Diastolic blood
pressure, pulse rate, temperature
and weight
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1].
SAC [1] 
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12.10.8. 
Biomarker Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Immunoglobulin 
14.01. 
mITT Open-
Label 
SAFE_T5 
Immunoglobulin Levels Percent Change from Open-Label 
Baseline by Visit (Observed) 
 Change sub-heading to be 
‘Immunoglobulin: …’ 
SAC [1] 
14.02. 
mITT Open-
Label 
SAFE_T5 
Immunoglobulin Levels Change from Open-Label Baseline by 
Visit (Observed)  
 Change sub-heading to be 
‘Immunoglobulin: …’ 
 Change visit labels to “OL Week xx 
(Post OL Baseline Change)” and 
remove footnote [1] 
SAC [1] 
14.03. 
mITT Open-
Label 
DB Table 4.03 
Immunoglobulin Levels Shifts from Open-Label Baseline by Visit 
(Observed) 
 Add a ‘Total’ column within each 
Induction Regimen stratum 
 Remove “Note: “ and footnote [2] 
SAC [1] 
Autoantibodies 
14.04. 
mITT Open-
Label 
SAFE_T5 
Autoantibody Levels Percent Change from Open-Label Baseline 
by Visit (Observed)  
 Change sub-heading to be 
‘Autoantibody: …’ 
SAC [1] 
14.05. 
mITT Open-
Label 
SAFE_T5 
Autoantibody Levels Percent Change from Open-Label Baseline 
by Visit among Subjects Positive at Open-Label Baseline 
(Observed)  
 Change sub-heading to be 
‘Autoantibody: …’ 
 Add a footnote: 
“Note: Positive Autoantibody at 
baseline is defined as anti-dsDNA >= 
30 IU/mL, ANA>=80 Titer, 
aC1q>=22.2 U/mL, anti-Smith 
Antibody >=15 IU/mL, aCL-IgG >=14 
U/mL, aCL-IgA >=11 U/mL, and aCL-
IgM >=12 U/mL.” 
SAC [1] 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
14.06.
mITT Open-
Label 
SAFE_T5 
Autoantibody Levels Change from Open-Label Baseline by Visit 
(Observed)  
Change sub-heading to be
‘Autoantibody: …’
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
14.07.
mITT Open-
Label 
SAFE_T5 
Autoantibody Levels Change from Open-Label Baseline by Visit 
among Subjects Positive at Open-Label Baseline (Observed)  
Change sub-heading to be
‘Autoantibody: …’
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
Add a footnote:
“Note: Positive Autoantibody at
baseline is defined as anti-dsDNA >=
30 IU/mL, ANA>=80 Titer,
aC1q=>22.2 U/mL, anti-Smith
Antibody >=15 IU/mL, aCL-IgG >=14
U/mL, aCL-IgA >=11 U/mL, and aCL-
IgM >=12 U/mL.”
SAC [1] 
14.08.
mITT Open-
Label 
DB Table 4.08 
Autoantibody Levels Shifts from Open-Label Baseline by Visit 
(Observed) 
Add a ‘Total’ column within each
Induction Regimen stratum
Remove “Note: “ and footnote [2]
Complement 
14.09.
mITT Open-
Label 
SAFE_T5 
Complement Levels Percent Change from Open-Label Baseline 
by Visit (Observed)  
Change sub-heading to be
‘Complement: …’
SAC [1] 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
14.10.
mITT Open-
Label 
SAFE_T5 
Complement Levels Percent Change from Open-Label Baseline 
by Visit among Subjects with Low Complement at Open-Label 
Baseline (Observed)  
Change sub-heading to be
‘Complement: …’
Add a footnote:
“Note: Low C3 at OL baseline (<90
mg/dL). Low C4 at OL baseline (<10
mg/dL).”
SAC [1] 
14.11.
mITT Open-
Label 
SAFE_T5 
Complement Levels Change from Open-Label Baseline by Visit 
(Observed)  
Change sub-heading to be
‘Complement: …’
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
14.12.
mITT Open-
Label 
SAFE_T5 
Complement Levels Change from Open-Label Baseline by Visit 
among Subjects with Low Complement at Open-Label Baseline 
(Observed)  
Change sub-heading to be
‘Complement: …’
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
Add a footnote:
“Note: Low C3 at OL baseline (<90
mg/dL). Low C4 at OL baseline (<10
mg/dL).
SAC [1] 
14.13.
mITT Open 
Label 
DB Table 4.13 
Complement Levels Shifts from Open-Label Baseline by Visit 
(Observed) 
Add a ‘Total’ column within each
Induction Regimen stratum
Remove “Note: “ and footnote [2]
SAC [1] 
B Cells 
14.14.
mITT Open-
Label 
SAFE_T5 
B cells Percent Change from Open-Label Baseline by Visit 
(Observed)  
Change sub-heading to be ‘B Cell:
…’
SAC [1] 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
14.15.
mITT Open-
Label 
SAFE_T5 
B cells Change from Open-Label Baseline by Visit (Observed) 
Change sub-heading to be ‘B Cell:
…’
Change visit labels to “OL Week xx
(Post OL Baseline Change)” and
remove footnote [1]
SAC [1] 
12.10.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic (PK) 
15.01.
PK Open-
Label 
PK_T1 
Belimumab Concentrations (ug/mL) (Observed) 
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12.10.10. ICH Listings 
Study Population 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
11.01. 
 
Safety 
Open-Label 
DB Listing 1.03 
Reasons for Study Withdrawal 
ICH E3 
 Modify footnote 
“Note: Study day is relative to first dose 
of Open-Label treatment and 
calculated as Withdrawal Date – Open-
Label Treatment Start Date + 1.” 
 Modify 4th column header to be ‘OL 
Study Day’ 
SAC [1] 
11.02. 
Full Open-
Label 
POP_L1 
Subjects who had Data Inadvertently Entered in the Open-Label 
Phase 
 
SAC [1] 
11.03. 
Full Open-
Label 
SP3 
Subjects Excluded from Any Population 
ICH E3 
 Present by Induction Regimen/ 
Treatment Group 
 Include the following columns to 
indicate exclusion: 
o Safety Open-Label 
o mITT Open-Label 
o PK Open-Label 
SAC [1] 
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Study Population 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviations 
11.04.
Full Open-
Label 
DB Listing 1.07 
Important Protocol Deviations 
ICH E3 
Remove column 4 “Will deviation
require exclusion from PP analysis”
Modify 5th column header to be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
SAC [1] 
Demographic and Baseline Characteristics 
11.05.
Full Open-
Label 
DB Listing 1.08 
Demographic and Baseline Characteristics 
ICH E3 
Remove Race as it is covered in
Listing 1.09
Add Age, Weight and BMI for OL
Baseline as well as DB Baseline (make
it clear which baseline each data is for
in column headers or footnotes)
SAC [1] 
11.06.
Full Open-
Label 
DB Listing 1.09 
Race 
ICH E3 
SAC [1] 
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Study Population 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Concomitant Medications 
11.07. 
Full Open-
Label 
DB Listing 1.12 
Concomitant Medications 
IDSL 
 Modify 4th column header to be ‘OL 
Study Day’ 
 Modify 6th column header to be 
“Started Pre-OL?/Ongoing 
Medication?” 
 Update footnote to ‘^ denotes while on 
OL treatment’  
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.”  
SAC [1] 
11.08. 
Full Open-
Label 
DB Listing 
101.01 
Concomitant Immunosuppressants for Subjects with Treatment-
Emergent Serious Adverse Events 
 Modify 4th column header to be ‘OL 
Study Day’ 
 Modify 6th column header to ‘Started 
Pre-OL?/Ongoing Medication?’ 
 Update footnote to ‘^ denotes while on 
OL treatment’ 
SAC [1] 
11.09. 
Full Open-
Label 
DB Listing 
101.02 
Concomitant Immunosuppressants for Subjects with Treatment-
Emergent Non-Serious Infections and Infestations Adverse 
Events 
 Modify 4th column header to be ‘OL 
Study Day’ 
 Modify 6th column header to ‘Started 
Pre-OL?/Ongoing Medication?’ 
 Update footnote to ‘^ denotes while on 
OL treatment.’ 
SAC [1] 
11.10. 
Full Open-
Label 
DB Listing 1.14 
Prohibited Medication (Rescue) 
 
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Study Population 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Extent of Exposure 
11.11. 
Full Open-
Label 
DB Listing 1.15 
Open-Label Investigational Product Administration and 
Exposure 
ICH E3 
 Modify 2nd column to be ‘OL Duration 
[1]’ 
 Add new column for ‘Overall 
Belimumab Duration [2]’ 
 Modify 4th column header to be ‘OL 
Study Day’ 
 Update footnote to say “[1] Duration of 
OL exposure (days) = (Date of last OL 
dose - Date of first OL dose + 28).” 
 Add a footnote to say “[2] Duration of 
Overall Belimumab exposure (days) = 
(Date of last OL dose - Date of first 
Belimumab dose + 28). Note that if 
Belimumab was incorrectly 
administered to Placebo subjects in 
the DB phase, this will be included in 
the Overall Belimumab Exposure.” 
 Add ‘#’ to IP records where placebo 
was administered in error in OL and 
include a footnote “# placebo was 
administered in error”.  
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Safety 
Adverse Events 
13.01. 
Full Open-
Label 
DB Listing 3.01 
All Adverse Events 
ICH E3 
 The 5th column header modify to “Time 
Since First OL / First OL BEL / Last OL 
dose” 
 Update footnote to say “Age and 
Weight at Open-Label Baseline” 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: 
“Note: Treatment-emergent adverse 
events (AEs) are listed (i.e. post-first 
OL infusion) plus any ongoing AEs that 
started before the first OL infusion that 
were not considered treatment-
emergent. AEs that started on the day 
of first OL infusion are considered 
treatment-emergent unless AE start 
time is reported and is before time of 
first OL infusion.” 
SAC [1] 
13.02. 
Full Open-
Label 
DB Listing 3.02 
Subject Numbers for Individual Adverse Events that Started on 
or after First OL Infusion      
ICH E3 
 Only include treatment-emergent AEs 
(see RAP, Section 7.1 and Section 
12.3.112.3.3). 
 Add a footnote: 
“Note: Only treatment-emergent 
adverse events (AEs) are listed i.e. 
post-first OL infusion.”  
 
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91 
 
Safety 
13.03. 
Full Open-
Label 
DB Listing 3.02 
Subject Numbers for Individual Adverse Events that Started 
before First OL Infusion and were Ongoing at OL Baseline Visit 
 Only include ongoing AEs that started 
before the first OL infusion that were 
not considered treatment-emergent 
(see RAP, Section 7.1 and Section 
12.3.1). 
 Add a footnote: 
“Note: Only ongoing adverse events 
that started before the first OL infusion 
that were not considered treatment-
emergent are listed.” 
 
SAC [1] 
13.04. 
Full Open-
Label 
DB Listing 3.07 
Relationship Between Adverse Event System Organ Classes, 
Preferred Terms and Verbatim Text 
IDSL 
 Add a footnote: 
“Note: data are displayed only for 
treatment-emergent adverse events 
i.e. post-first OL infusion.  
 
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92 
Safety 
Serious and Other Significant Adverse Events 
13.05.
Full Open-
Label 
DB Listing 3.04 
Serious Adverse Events 
ICH E3 
The 5th column header modify to “Time
Since First OL / First OL BEL / Last OL
dose”
Update footnote to say “Age and
Weight at Open-Label Baseline”
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote:
“Note: Treatment-emergent adverse
events (AEs) are listed (i.e. post-first
OL infusion) plus any ongoing AEs that
started before the first OL infusion that
were not considered treatment-
emergent. AEs that started on the day
of first OL infusion are considered
treatment-emergent unless AE start
time is reported and is before time of
first OL infusion.”
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Safety 
13.06. 
Full Open-
Label 
DB Listing 3.05 
Deaths 
ICH E3 
 The 5th column header modify to “Time 
Since First OL / First OL BEL / Last OL 
dose”  
 Update footnote to say “Age and 
Weight at Open-Label Baseline”  
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: 
“Note: Treatment-emergent adverse 
events (AEs) are listed (i.e. post-first 
OL infusion) plus any ongoing AEs that 
started before the first OL infusion that 
were not considered treatment-
emergent. AEs that started on the day 
of first OL infusion are considered 
treatment-emergent unless AE start 
time is reported and is before time of 
first OL infusion.” 
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94 
Safety 
13.07.
Full Open-
Label 
DB Listing 3.08 
Reasons for Considering as a Serious Adverse Event 
ICH E3 
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote:
“Note: Treatment-emergent adverse
events (AEs) are listed (i.e. post-first
OL infusion) plus any ongoing AEs that
started before the first OL infusion that
were not considered treatment-
emergent. AEs that started on the day
of first OL infusion are considered
treatment-emergent unless AE start
time is reported and is before time of
first OL infusion.”
Add a footnote:
“Note: Study Day is the day on which
the AE started relative to the day of
first OL infusion.  When Study Day is
negative, the AE started during the DB
period and was ongoing at OL
Baseline.”
SAC [1] 
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95 
 
Safety 
13.08. 
Full Open-
Label 
DB Listing 3.06 
Adverse Events Resulting in Study Agent Discontinuation 
ICH E3 
 The 5th column header modify to “Time 
Since First OL / First OL BEL / Last OL 
dose”  
 Update footnote to say “Age and 
Weight at Open-Label Baseline”  
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: 
“Note: Treatment-emergent adverse 
events (AEs) are listed (i.e. post-first 
OL infusion) plus any ongoing AEs that 
started before the first OL infusion that 
were not considered treatment-
emergent. AEs that started on the day 
of first OL infusion are considered 
treatment-emergent unless AE start 
time is reported and is before time of 
first OL infusion.” 
SAC [1] 
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Safety 
13.09. 
Full Open-
Label 
DB Listing 3.09 
Adverse Events of Special Interest 
ICH E3 
 The 5th column header modify to “Time 
Since First OL / First OL BEL / Last OL 
dose” 
 Update footnote to say “Age and 
Weight at Open-Label Baseline”  
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: 
“Note: Treatment-emergent adverse 
events (AEs) are listed (i.e. post-first 
OL infusion) plus any ongoing AEs that 
started before the first OL infusion that 
were not considered treatment-
emergent. AEs that started on the day 
of first OL infusion are considered 
treatment-emergent unless AE start 
time is reported and is before time of 
first OL infusion.” 
 Add ‘Adjudicated’ to the SI Sub-
Categories for Opportunistic (all 
relevant ones), Serious Suicide/Self-
injury, Suicidal Behaviour. 
 Remove SI Subcategories of “Deaths 
(on-treatment AE with death)” 
SAC [1] 
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Safety 
All Laboratory 
13.10. 
Full Open-
Label 
DB Listing 3.15 
Laboratory Results: Hematology 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
13.11. 
Full Open-
Label 
DB Listing 3.16 
Laboratory Results: Liver Function 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
13.12. 
Full Open-
Label 
DB Listing 3.17 
Laboratory Results: Electrolytes 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
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98 
Safety 
13.13.
Full Open-
Label 
DB Listing 3.18 
Laboratory Results: Other Chemistries 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
For eGFR, OL Baseline values should
be suffixed with ‘*’ where DB Week
104/OL Week 0 is missing or derived.
Include a footnote “* eGFR at DB
Week 104/OL Week 0 is missing, OL
Baseline value was derived using DB
data from Week 96 onwards”
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
13.14.
Full Open-
Label 
DB Listing 3.19 
Laboratory Results: Urinalysis 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
For uPCR, OL Baseline values should
be suffixed with ‘*’ where DB Week
104/OL Week 0 is missing or derived.
Include a footnote “* uPCR at DB
Week 104/OL Week 0 is missing, OL
Baseline value was derived using DB
data from Week 96 onwards.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
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Safety 
13.15.
Full Open-
Label 
DB Listing 3.20 
Laboratory Results: Immunoglobulins 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
13.16.
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: Hematology 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
13.17.
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: Liver Function 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
13.18.
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: Electrolytes 
The 6th column header should be ‘OL
Study Day’
Update footnote to say “^ denotes
while on OL treatment.”
Add a footnote: “Note: Study day will
be missing for subjects who did not
receive OL study drug.”
SAC [1] 
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Safety 
13.19. 
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: Other 
Chemistries 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
13.20. 
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: Urinalysis 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
13.21. 
Full Open-
Label 
DB Listing 3.21 
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Immunoglobulins 
 The 6th column header should be ‘OL 
Study Day’ 
 Update footnote to say “^ denotes 
while on OL treatment.” 
 Add a footnote: “Note: Study day will 
be missing for subjects who did not 
receive OL study drug.” 
SAC [1] 
 
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12.10.11. Non-ICH Listings 
Efficacy 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Efficacy 
12.01.
Full Open-
Label 
 EFF_L2 
PERR and CRR Results by Visit (Observed) 
Present the following visits:
o OL Week 12
o OL Week 24
o OL Week 28
SAC [1] 
12.02.
Full Open-
Label 
DB Listing 2.04 
Doubling of Serum Creatinine from Open-Label Baseline and/or 
Progression to End Stage Renal Disease (ESRD) by Visit 
Present all relevant visits in the
data.
In 3rd and 5th column headers,
change ‘Study Day’ to be ‘OL
Study Day’
Remove 4th column
Remove footnote and
corresponding links
Add a footnote:
“Note: Subjects who fulfil the
ESRD flag during the DB period
are included in this listing with
their DB visit displayed. These
subjects are excluded from the
summary Table 12.17.”
SAC [1] 
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Efficacy 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.03. 
Full Open-
Label 
DB Listing 2.05 
SLEDAI-S2K Results 
 Present DB Baseline and all OL 
visits in the data. 
 Remove 5th column 
 Update 6th column header to be 
“Change from OL Baseline in 
SLEDAI-S2K total score 
(Observed)” 
 Remove footnote and 
corresponding links 
 OL Baseline values should be 
suffixed with ‘*’ where DB Week 
104/OL Week 0 is missing or 
derived. Include a footnote: “* DB 
Week 104/OL Week 0 is missing, 
OL Baseline value was derived 
using DB data from Week 88 
onwards.”   
SAC [1] 
12.04. 
Full Open-
Label 
DB Listing 2.06 
Prednisone Average Daily Dose Since Previous Visit 
 Present all OL visits in the data. 
 Add column for “Average Daily 
Prednisone Dose <= 10 mg” 
 Remove footnote and 
corresponding link 
SAC [1] 
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Efficacy 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12.05.
Full Open-
Label 
DB Listing 2.07 
SLICC/ACR Damage Index Results by Visit Throughout the 
Double-Blind and Open-Label Phases (Observed, corrected by 
WOCF) 
Present all visits from DB
Baseline through to end of study.
Update 4th column header to be
“Change from DB Baseline”
Add new column for “Change
from OL Baseline” and populate
for OL visits
Add a footnote:
“Note: DB Week 104 Visit and the
OL Baseline visit were the same
visit, but the OL Baseline Visit has
been derived where data are
missing at DB Week 104/OL
Week 0 Visit (i.e. using DB data
from Week 52 onwards).”
SAC [1] 
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Efficacy 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.06. 
Full Open-
Label 
EFF_L1 
uPCR and eGFR Results by Visit Throughout the Double-Blind 
and Open-Label Phases (Observed) 
 Present all visits from DB 
Screening through to end of 
study.  
 Derived values for uPCR and/or 
eGFR should be suffixed with ‘*’.  
Include a footnote “* Value 
derived from uPCR/eGFR data 
collected at the scheduled 
assessment for that visit, if one of 
uPCR or eGRF is missing at the 
scheduled visit.”   
 Add a footnote: 
“Note: DB Week 104 Visit and the 
OL Baseline visit are the same 
visit, but the OL Baseline Visit has 
been derived where data are 
missing at DB Week 104/OL 
Week 0 Visit (i.e. using DB data 
from Week 96 onwards).” 
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Safety 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Safety 
13.22 
Full Open-
Label 
DB Listing 3.14 
Medical/Surgical Procedures 
 Modify 4th column to be ‘OL Study 
Day’ 
 Modify footnote to say ‘^ denotes 
while on OL treatment’ 
SAC [1] 
13.23 
Full Open-
Label 
DB Listing 3.34 
Liver Monitoring/Stopping Event Reporting 
 Modify 4th column to be ‘Date first 
detected/OL Study Day’ 
 Modify 5th and 6th columns to be 
‘Time since first (or last) OL dose 
(days)’ 
SAC [1] 
13.24 
Full Open-
Label 
DB Listing 3.35 
Substance Use Reported with Liver Event 
 Modify 3rd column to be ‘OL Study 
Day’ 
SAC [1] 
13.25 
Full Open-
Label 
DB Listing 3.36 
Liver Stopping Event Information for RUCAM Score 
 Modify 3rd column to be ‘Event 
Date/OL Study Day’ 
 Modify 4th column to be ‘Days 
from Last OL Dose to Start of 
Event’ 
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Biomarkers 
Biomarkers 
14.01. 
Full Open-
Label 
DB Listing 4.01 
Biomarker Results 
 Update 5th column header to be 
‘OL Study Day’ 
 Update footnote “^ denotes while 
on OL treatment.” 
SAC [1] 
14.02. 
Full Open-
Label 
DB Listing 4.02 
B Cell Results 
 Update 5th column header to be 
‘OL Study Day’ 
 Update footnote “^ denotes while 
on OL treatment.”   
SAC [1] 
 
Pharmacokinetics 
Pharmacokinetics 
15.01. 
PK Open-
Label 
DB Listing 5.01 
Serum Belimumab PK Concentration-Time Data 
 Update 5th column header to be 
‘OL Study Day’ 
SAC [1] 
 
 
 
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12.11. 
Appendix 11: Example Mock Shells for Data Displays 
These will be defined in a separate document. 
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Signature Page for  114054 TMF-1739039 v1.0
Signature Page for TMF-1739039 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 08-Apr-2020 18:19:31 GMT+0000
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BEL114054
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL114054
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan Addendum
Title
:
Reporting and Analysis Plan Addendum for BEL114054 A 
Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Belimumab plus 
Standard of Care versus Placebo plus Standard of Care in 
Adult Subjects with Active Lupus Nephritis
Compound Number 
:
GSK1550188
Effective Date 
:
20-Feb-2020
Description:

This RAP addendum is supplemental to  the RAP (Dated: 20/SEP/2019), and 
based on protocol amendment 07 (Dated: 24/JAN/2019) of study BEL114054 
(HGS1006-C1121; GSK Document No.: 2013N179093_06), and eCRF Version 
5.0 (Dated: 21/AUG/2017).

The purpose of this RAP addendum is to document additions/clarifications made 
after RAP approval but before unblinding. 
Author(s)
Author 
Date
Approval 
Method
Lead
16-MAR-2020
Email
Director Biostatistics, PAREXEL International
Co-Authors
16-MAR-2020
Email
Statistics Leader , GSK Clinical Statistics
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited
PPD
PPD


CONFIDENTIAL
BEL114054
2
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................4
2.
CHANGES/CLARIFCATIONS TO THE RAP............................................................4
2.1.
BLyS LLOQ (Section 6.7) .............................................................................4
2.2.
Tipping Point Analysis (Section 7.1.6.2)........................................................4
2.3.
Time to Death or Renal-related Event (Section 7.2.3)...................................5
2.4.
Proportion Endpoints (Section 7.3.1) ............................................................5
2.5.
Time to Event Endpoints (Section 7.3.3).......................................................6
2.6.
Biomarker Change and Percent Change from Baseline (Section 
11.2) .............................................................................................................7
2.7.
Imputation of missing visit date (Section 14.3.1) ...........................................7
2.8.
Treatment Emergent Flag for Adverse Events (Section 14.4.2) ....................8
2.9.
IP Discontinuation Date (Section 14.6.1.3)....................................................8
2.10.
Time to First Renal Response Maintained through Week x (Section 
14.6.3.3) .......................................................................................................8
2.11.
SLE Flare Index (SFI) Scoring (Section 14.6.3.14.1) ....................................9
2.12.
Time to First SFI Flare Censoring and Disposition Rules (Section 
14.6.3.14.2) ..................................................................................................9
2.13.
SELENA SLEDAI and SLEDAI-S2K Scoring and Endpoint (Section 
14.6.3.16) ...................................................................................................10
2.14.
SLEDAI-S2K Organ Improvement and Worsening (Section 
14.6.3.16.2) ................................................................................................11
2.15.
Efficacy Tables (Section 14.12.6) ...............................................................11
2.16.
Headline Results (Section 14.14)................................................................11
2.17.
SLE and LN Disease Duration (Section 14.6.2.8) .......................................12
2.18.
Post hoc Analyses ......................................................................................12
2.19.
Endpoint Naming Updates ..........................................................................12


CONFIDENTIAL
BEL114054
3
ABBREVIATIONS
ANCOVA
Analysis of Covariance
BLyS
B-Lymphocyte Stimulator
CRF
Case Report Form
CRR
Complete Renal Response
eGFR
Estimated Glomerular Filtration Rate
IP
Investigational Product
IPD
Investigational Product Discontinuation
IPDISCDT
Investigational Product Discontinuation Date
LLOQ
Lower Limit of Quantification
LOCF
Last Observation Carried Forward
PERR
Primary Efficacy Renal Response
RAP
Reporting and Analysis Plan
SELENA
Safety of Estrogen in Lupus National Assessment
SFI
SLE Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLEDAI-S2K
Systemic Lupus Erythematosus Disease Activity Index
using SLEDAI 2000 scoring for proteinuria
TF
Treatment Failure
TR01SDT
Treatment Start Date
uPCR
Urinary Protein:Creatinine Ratio
WD
Withdrawal


CONFIDENTIAL
BEL114054
4
1.
INTRODUCTION
This RAP addendum is supplemental to the RAP (Dated: 20/SEP/2019), and based on 
protocol amendment 07 (Dated: 24/JAN/2019) of study BEL114054 (HGS1006-C1121; 
GSK Document No.: 2013N179093_06), and eCRF Version 5.0 (Dated: 21/AUG/2017).
The purpose of this RAP addendum is to document additions/clarifications made after 
RAP approval but before unblinding. 
2.
CHANGES/CLARIFCATIONS TO THE RAP
2.1.
BLyS LLOQ (Section 6.7)
Two different assays were used to evaluate BLyS and the assays do not have the same 
lower limit of quantification (LLOQ), therefore the data is reported as <LLOQ without 
the numerical value (ie, <0.061 ng/mL) as it depends on the assay.  
2.2.
Tipping Point Analysis (Section 7.1.6.2)
Replace this paragraph: 
In contrast to the primary analysis, in the event of missing data the tipping point 
analysis evaluates every possible combination of placebo responder/non-
responder with every possible combination of belimumab responder/non-
responder. For the treatment policy intercurrent event strategy, all observed data 
at Week 104 will be used and unobserved (missing) data due to a subject outcome 
of death, study withdrawal, or lost to follow-up will be assessed using all possible 
combinations of responder/non-responder by treatment group. For the hybrid 
treatment policy strategy, a subject experiencing a treatment failure will be 
considered a non-responder at Week 104, otherwise observed and unobserved 
data will be managed the same as the treatment policy strategy.
By these three paragraphs for added clarity: 
In contrast to the primary analysis, in the event of missing data the tipping point 
analysis evaluates every possible combination of placebo responder/non-
responder with every possible combination of belimumab responder/non-
responder. 
For the Treatment Policy (WD=NR) intercurrent event strategy, in the base 
analysis Missing data and Withdrawal (due to outcome of death, study 
withdrawal, or lost to follow-up) are set to NR, while IP Discontinuation and 
Treatment Failure are ignored. In the corresponding Tipping Point analysis, 
Missing data and Withdrawal will have responses sequentially imputed, and IP 
Discontinuation and Treatment Failure will continue to be ignored. 
For the Hybrid Treatment Policy (TF/WD=NR) strategy, in the base analysis 
Missing data, Withdrawal, and Treatment Failure are set to NR, while IP 
Discontinuation is ignored. In the Tipping Point analysis, Missing Data and 


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BEL114054
5
Withdrawal will have responses sequentially imputed, while Treatment Failure 
will continue to be set to NR and IP Discontinuation will continued to be ignored. 
Replace these sentences: 
Reference lines on the hybrid treatment policy heat map will correspond to the 
response rates for the PERR primary analysis using the IPD/TF/WD=NR 
imputation. Reference lines on the treatment policy heat map will correspond to 
the rate using observed Week 104 responders and assuming no subjects with a 
missing response are responders.
With these sentences: 
For both Treatment Policy and Hybrid Treatment Policy Tipping point plots, 
reference line for Placebo and Belimumab will be drawn by assuming that the 
imputed subjects respond at the same rate as the Placebo subjects who are not 
imputed. 
2.3.
Time to Death or Renal-related Event (Section 7.2.3)
Additional analyses of Time to Death or Renal-related Event components.
Repeat displays equivalent to the Time to Death or Renal-related Event endpoint, but in 
each case only for an individual component. When analyzing the individual components, 
ignore other components instead of censoring, because otherwise event count may 
become too small for statistical analyses. In addition, to ensure validity of the inference, 
only report Cox Proportional Hazard model inferences if there are greater than or equal to 
5 events per treatment arm. Repeat this for the Treatment Policy version of Time to Death
and Renal-related event components, except for the Renal-related Treatment Failure 
component which is ignored by definition of Treatment Policy. 
2.4.
Proportion Endpoints (Section 7.3.1)
Add the following under “Statistical Analysis”:
4. No modeling will be performed for the following endpoints since the subgroups are 
based on a post-randomization characteristic:

Proportion of subjects receiving prednisone  5 mg average daily dose since 
previous visit by Week 104 PERR Response.

Proportion of subjects receiving prednisone 7.5 mg average daily dose since 
previous visit by Week 104 PERR Response.


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2.5.
Time to Event Endpoints (Section 7.3.3)

Under “Statistical Analysis,” add “For PERR and CRR, in addition the model will be 
adjusted for baseline uPCR and baseline eGFR.”  

Under “Intercurrent Event Strategy” add portion that is underlined “For time to first 
maintained PERR and CRR, IPD/TF/WD=NR imputation will be used for 
intercurrent events and will thus be censored.“

Under “Variables” add the following bulleted text:

uPCR (at baseline; continuous) [PERR and CRR only]

eGFR (at baseline; continuous) [PERR and CRR only]

Under “Model Results Presentation”, add “Only report Cox Proportional Hazard 
model inferences if there are equal or greater than 5 events per treatment arm.” 

To aid in understanding, add the following tables of the censoring and disposition 
rules 
Table 1
Subject Disposition Rules for Time to the first PERR that is 
maintained through Week 52
Subject Disposition 
Event Met 
Event Date 
Subject has PERR maintained through week 52
Time to the first PERR that 
is maintained through 
Week 52
Yes 
Date of first PERR that is 
maintained through Week 
52
Subject does not have PERR maintained through week 52
Subject completes Week 52 
No 
Censor at the Week 52 
study visit 
Subject discontinues IP 
No 
Censored at IP 
Discontinuation date (see 
Section 14.6.1.3.)
Subject is a treatment 
failure 
No
Censored at Treatment 
failure date
Subject withdraws 
No 
Censored at earliest of 
withdrawal date, Lost to 
Follow-up and death date. 
Lost to Follow-up 
No 
Subject dies 
No 
[1] If a subject belongs in more than one censoring category then the censoring date is 
the earliest of the dates. NB: this implies for subjects with IPD/TF/WD after week 52 
they would be censored at their week 52 visit date.


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Table 2
Subject Disposition Rules for Time to the first PERR that is 
maintained through Week 104
Subject Disposition 
Event Met 
Event Date 
Subject has PERR maintained through week 104
Time to the first PERR that 
is maintained through 
Week 104
Yes 
Date of first PERR that is 
maintained through Week 
104
Subject does not have PERR maintained through week 104
Subject completes Week 
104 
No 
Censored at the Week 104 
study visit 
Subject discontinues IP 
No 
Censored at IP 
Discontinuation date (see 
Section 14.6.1.3.).
Subject is a treatment 
failure
No
Censored at Treatment 
failure date
Subject withdraws 
No 
Censored at earliest of 
withdrawal date, Lost to 
Follow-up and death date. 
Lost to Follow-up 
No 
Subject dies 
No 
[1] If a subject belongs to more than one censoring category then the censoring date is 
the earliest of the dates. 
2.6.
Biomarker Change and Percent Change from Baseline
(Section 11.2)

Analyses for autoantibodies was changed from ANCOVA to rank ANCOVA.

Analyses for complement was changed from rank ANCOVA to ANCOVA.
2.7.
Imputation of missing visit date (Section 14.3.1)
For imputing the visit date of a missing visit, the default method is to compute the 
missing visit date as the target visit date:
Missing visit date = (missing week * 7) + tr01sdt
However, due to visits shifting relative to the planned visits over time, imputing based on 
the target visit date can result in an imputed visit being within days of the next observed 
visit and occasionally even after the next observed visits.  Therefore, an alternative 
method of imputing a missing visit date from a previous non-missing scheduled visit date 
will be used in Prednisone (ADPRED) and Renal Response (ADRR) datasets.  As an 
example, if a subject missed Week 100 after Week 96, then the imputation will be 
calculated as: 
Week 100: (100-96)*7 + Week 96 visit date.


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8
2.8.
Treatment Emergent Flag for Adverse Events (Section 
14.4.2)
The definition states that “A treatment-emergent AE is an adverse event that emerges on 
or after the first treatment dose, having 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.” Worsening of an event is captured in the eCRF by 
modifying the severity of the original event; therefore, it should be clarified for the 
programmers that worsening is accounted for in how the AE is recorded and no 
programming is required to identify worsening events. 
2.9.
IP Discontinuation Date (Section 14.6.1.3)
The definition was updated as follows:
Since the CRF data associated with the IP discontinuation form represents the 
date the form was completed and not the date the investigator made the decision 
to discontinue randomized treatment, subjects with a completed IP 
discontinuation form will have an IP discontinuation date (IPDISCDT) derived 
based on the following rules: 

If the subject does not have a scheduled visit after the last exposure date 
and the EXIT Double Blind visit date is non-missing, then IPDISCDT is 
the earlier of the date of EXIT Double Blind visit or 35 days after the last 
exposure (35 days is used to include the 28 +7 day visit window).

If the subject has a scheduled visit after the last exposure date, then 
IPDISCDT is the date of the first scheduled visit after the last exposure 
date.
2.10.
Time to First Renal Response Maintained through Week x
(Section 14.6.3.3)

Change “The first renal response maintained to Week x refers the earliest 
response in a series of consecutive renal responses that extends to and includes 
Week x.  If a subject does not have a renal response at Week x then the Time to 
First Renal Response that is Maintained to Week x is 0 days.  Intercurrent events 
are incorporated into the renal response endpoints using the IPD/TF/WD=NR 
strategy.”

To “The first renal response maintained to Week x refers the earliest response in 
a series of consecutive renal responses that extends to and includes Week x.  
Subjects without PERR at Week x are censored at the last available visit up 
through Week x.”


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9
2.11.
SLE Flare Index (SFI) Scoring (Section 14.6.3.14.1)
SELENA SLEDAI in this section is replaced with SLEDAI-2K in the scoring algorithm.
2.12.
Time to First SFI Flare Censoring and Disposition Rules
(Section 14.6.3.14.2)
Add underlined text for clarification.
Time to First SFI Flare Censoring and Disposition Rules
The rules described in this section apply to SLE Flares and Severe SLE Flares. 
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.  
Subjects with no post-baseline flare assessments will be excluded from the analysis. If a 
subject is a treatment failure during the period being analyzed, the subject will be considered as 
having a flare at the time of treatment failure.  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.
Time to first flare is calculated as:
Time to first flare (days)
=
Date of first flare – treatment start date + 1.
After Week 24
For the time to first flare from Week 24 to Week 104, flares (not subjects) occurring on or prior to
the Week 24 visit date should be removed from the analysis set prior to determining the first flare. 
Subjects who withdraw from the study, discontinue IP, or have a treatment failure prior to 
Week 24 should be excluded from the analysis.  Similarly subjects with no flare 
assessments after Week 24 will be excluded from the analysis.  If a subject is a treatment 
failure on the Week 24 visit date, the treatment failure will be counted as a flare at Week 24.  Time 
to first flare from Week 24 to Week 104 is calculated as:
Time to first flare (days)
=
Date of first flare – Week 24 visit date + 1.
Table 3
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 an SLE flare [1]
Yes
Date of first SFI flare
Subject is a treatment failure [1] 
Yes
Treatment failure date
Subject does not have a flare and is not a treatment failure
Subject discontinues IP
No
Censored at last flare assessment on or
prior to IP Discontinuation
Subject withdraws
No
Censored at last flare assessment date
Lost to Follow-up
No
Censored at last flare assessment date


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10
Time to First SFI Flare Censoring and Disposition Rules
Subject dies
No
Censored at date of death
Subject completes Week 104
No
Censored at the Week 104 study visit
[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.
2.13.
SELENA SLEDAI and SLEDAI-S2K Scoring and Endpoint
(Section 14.6.3.16)
Add the following paragraph to the end of the section as clarification.  
At baseline, the LOCF and Observed version of the SLEDAI-S2K agree for all 
organ systems with the exception of Renal because of differences in the cross-
referencing with the lab data. For the Observed case, proteinuria lab records 
within the last 10 days of the SLEDAI visit are cross-referenced, if there are none, 
then proteinuria is counted as missing and the Renal 2K Total score is summed 
over the missing. For LOCF, the 10-day limit does not apply and proteinuria lab 
records can be used as far back as baseline provided the value is within the 
baseline analysis visit (AVISITN) window.   For this reason, baseline 
presentations of SLEDAI-S2K use the LOCF version of the score.  

To aid in understanding, add the following table to clarify the derivation of the 
SLEDAI endpoints for different Intercurrent Event strategies. 
Situation
Observed
IPD/TF/WD strategy 
(IPTFOCF)
Missing non-lab parameter
Domain score is the sum of 
non-missing items 
Domain score is the sum of 
non-missing items 
Missing/Unknown lab (including 
proteinuria) parameter
Sum of non-missing items
When cross referencing 
proteinuria from lab data, use 
only results that occurred on or 
in the preceding 10 days.
LOCF will be used
Whole SLE visit missing 
Missing
NR (for SLEDAI-S2K < 4, 
Improvement) 
LO on or prior to IPD/TF/WD 
CF (for Worsening, Change 
from baseline) 
IP/TF event 
Ignore
IPD/TF/WD=NR (for SLEDAI-


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11
Situation
Observed
IPD/TF/WD strategy 
(IPTFOCF)
S2K < 4, Improvement)
LO on or prior to IPD/TF/WD 
CF (for Worsening, Change 
from baseline)
2.14.
SLEDAI-S2K Organ Improvement and Worsening (Section 
14.6.3.16.2)

Remove rows where criterion is “Organ score baseline - missing” under both 
Improvement and Worsening.

Under “Worsening,” move the equals part of the inequality signs such that 
criterion “≤ 0” is N and “> 0” is Y.
2.15.
Efficacy Tables (Section 14.12.6)

Population was updated to ‘Modified Completers on Study Agent’  for Table 2.08 
Primary Efficacy Renal Response at Week 104 (Completer Sensitivity Analysis)
(IPD/TF/WD=NR)

For the following tables, change the parenthetical expression in the title from 
“(WOCF)” to “(Observed with WOCF)” 
o
Table 2.80 SLICC/ACR Damage Index Worsening (Change > 0) 
Compared with Baseline by Visit While on Treatment (Observed with 
WOCF)
o
Table 2.81 SLICC/ACR Damage Index Change from Baseline by Visit 
While on Study (Observed with WOCF)
o
Table 2.82 SLICC/ACR Damage Index Worsening (Change > 0) 
Compared with Baseline by Visit While on Study (Observed with WOCF)

Delete Table 2.109 SLICC/ACR Damage Index Change from Baseline by Visit 
While On Study (Observed with WOCF) duplicate of Table 2.81.

Delete Table 2.110 SLICC/ACR Damage Index Worsening (Change > 0) 
Compared with Baseline by Visit (Observed )  duplicate of Table 2.82.
2.16.
Headline Results (Section 14.14)
Table numbers 2.56 and 2.60 should be 2.57 and 2.61, respectively; the table titles are 
correct as specified analyses for complement was changed from rank ANCOVA to 
ANCOVA.


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2.17.
SLE and LN Disease Duration (Section 14.6.2.8)
Variables for SLE disease duration (SLEDUR) and LN disease duration (LNDUR) were 
not originally defined in the RAP.  There was a footnote on the “Baseline Disease 
Activity” table shell defining the variables as “Screening date – Diagnosis date +1 / 
365.25” which was based on the definition in the IV SLE pivotal studies (BLISS-52 and 
BLISS-76) and BEL112341 (SC). The variables in the ADCOV dataset and presented on 
the table were programmed consistent with recently reported Benlysta studies using 
Treatment start date – Diagnosis date + 1 / 365.25; therefore the table footnote is does not 
match the derivation used. 
SLE disease duration (years) = Treatment start date - SLE diagnosis date + 1 / 365.25
LN disease duration (years) = Treatment start date - LN diagnosis date + 1 / 365.25
2.18.
Post hoc Analyses
To further understand the results, post hoc analyses were performed and are numbered in 
accordance with the report sections as 10n.xx or 20n.xx where ‘n’ is the CSR section (1=
Study Population, 2=Efficacy, 3=Safety, etc.) and ‘xx’ is a sequential display number.
2.19.
Endpoint Naming Updates
Based on FDA feedback, the ‘Hybrid Treatment Policy’ sensitivity analysis is being 
referred to as the “Hybrid Estimand” in the clinical study report; the display titles were 
not updated.  Additionally, the key secondary endpoint of ‘Time to Death or Renal-
related event ‘ is referred to as ‘Time to Renal-related Event or Death’ in the clinical 
study report as renal-related events comprise the large majority of the events; the display 
titles were not updated. 


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1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for BEL114054 A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus 
Standard of Care versus Placebo plus Standard of Care in 
Adult Subjects with Active Lupus Nephritis
Compound Number 
:
GSK1550188
Effective Date 
:
20-SEP-2019
Description:

This RAP is based on protocol amendment 07 (Dated: 24/JAN/2019) of study 
BEL114054 (HGS1006-C1121; GSK Document No.: 2013N179093_06), and eCRF 
Version 5.0 (Dated: 21/AUG/2017).

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol BEL114054 [HGS1006-C1121].

This RAP is intended to describe the planned efficacy, safety, pharmacokinetics and 
biomarker analyses required for the double-blind phase of the study.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author(s)
Author 
Date
Lead
Director Biostatistics, PAREXEL International
Co-Authors
Statistics Leader (II Biostatistics)
RAP Team Review Confirmations 
(Method: E-mail)
Reviewer
Date
Medical Monitor 
18-SEP-2019
Manager, Clinical Pharmacology
18-SEP-2019
PPD
PPD
PPD
PPD


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2
Reviewer
Date
Principal Programmer/Analyst
18-SEP-2019
Statistics Leader (II Biostatistics)
18-SEP-2019
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature)
Approver
Date
20-SEP-2019
Director Statistics 
20-SEP-2019
Director Programming 
RAP Team Reviewers Not Requiring Confirmation 
Reviewer
Medicines Development Leader
Project Physician Lead
Clinical Investigation Lead
Medical Writer 
Director Global Regulatory Affairs
Safety Development Lead (SERM)
Director, RD II DPU Mechanistic Medicine Head
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s).............................................................10
2.3.
Study Design ..............................................................................................13
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................15
3.
PLANNED ANALYSES ..........................................................................................16
3.1.
Interim Analyses .........................................................................................16
3.2.
Final Analyses ............................................................................................16
4.
ANALYSIS POPULATIONS ...................................................................................16
4.1.
Protocol Deviations.....................................................................................17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................18
5.1.
Study Treatment & Sub-group Display Descriptors.....................................18
5.2.
Baseline Definitions ....................................................................................18
5.3.
Multicentre Studies .....................................................................................19
5.4.
Examination of Covariates, Other Strata and Subgroups............................19
5.4.1.
Covariates and Other Strata ........................................................19
5.4.2.
Examination of Subgroups...........................................................20
5.5.
Multiple Comparisons and Multiplicity .........................................................20
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................22
6.1.
Overview of Planned Study Population Analyses........................................22
6.2.
Disposition of Subjects................................................................................22
6.3.
Protocol Deviations.....................................................................................23
6.4.
Demographic and Baseline Characteristics.................................................24
6.5.
Concomitant Medications............................................................................26
6.6.
Extent of Exposure .....................................................................................26
6.7.
Summary of Study Population Analyses .....................................................27
7.
EFFICACY ANALYSES..........................................................................................32
7.1.
Primary Efficacy Analyses ..........................................................................32
7.1.1.
Endpoint ......................................................................................32
7.1.2.
Summary Measure ......................................................................32
7.1.3.
Population of Interest...................................................................32
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................33
7.1.4.1.
Handling of Missing Data............................................33
7.1.4.1.1.
Imputation for Missing Visits ...................33
7.1.4.1.2.
Imputation if Missing a Single Lab 
Component within a Visit ........................33


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7.1.4.1.3.
Example of the Renal Response 
Endpoint Derivation with Missing 
Data........................................................34
7.1.5.
Statistical Analyses / Methods .....................................................35
7.1.6.
Sensitivity Analyses .....................................................................36
7.1.6.1.
Treatment Policy Sensitivity Analyses ........................37
7.1.6.2.
Tipping Point Analysis ................................................38
7.1.7.
Supplementary Analyses .............................................................41
7.2.
Secondary Efficacy Analyses......................................................................42
7.2.1.
Complete Renal Response at Week 104 .....................................42
7.2.2.
Primary Efficacy Renal Response (PERR) at Week 52................44
7.2.3.
Time to Death or Renal-related Event..........................................45
7.2.3.1.
Treatment Policy Analysis ..........................................48
7.2.3.2.
Tipping Point Analysis ................................................48
7.2.4.
Ordinal Renal Response at Week 104.........................................50
7.3.
Other Efficacy Analyses..............................................................................51
7.3.1.
Proportion Endpoints ...................................................................52
7.3.2.
Continuous Endpoints (Change/Percent Change from 
Baseline)......................................................................................55
7.3.3.
Time to Event Endpoints..............................................................57
8.
SAFETY ANALYSES .............................................................................................59
8.1.
Adverse Events Analyses ...........................................................................59
8.2.
Deaths, Serious Adverse Events, and Survival Status ................................61
8.3.
Adverse Events Leading to Discontinuation of Investigational 
Product.......................................................................................................61
8.4.
Adverse Events of Special Interest Analyses..............................................61
8.4.1.
Post-Infusion Systemic Reactions by Infusion..............................64
8.5.
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................64
8.5.1.
C-SSRS Suicidal Ideation or Behavior Post-Baseline ..................65
8.5.2.
Subjects may be counted for ideation and behavior C-
SSRS Suicidal Ideation or Behavior Relative to Pre-
Treatment ....................................................................................65
8.5.3.
C-SSRS Shift Changes in Categories from Pre-Treatment 
to Post-Baseline...........................................................................65
8.6.
Clinical Laboratory Analyses.......................................................................65
8.6.1.
Laboratory Descriptive Statistics by Visit .....................................66
8.6.2.
Worst Laboratory Toxicity Grade Post-Baseline...........................66
8.6.3.
Laboratory Toxicity ≥ 2 Grade Shift Post-Baseline.......................66
8.6.4.
Laboratory Reference Range Shifts from Baseline by Visit ..........66
8.6.5.
Immunoglobulin Reference Range Shifts from Baseline by 
Visit..............................................................................................67
8.6.6.
Immunoglobulin Below LLN by Visit.............................................67
8.6.7.
Immunoglobulin Relative to LLN by Visit......................................67
8.6.8.
Immunogenicity............................................................................67
8.7.
Other Safety Analyses ................................................................................68
8.7.1.
Vital Signs....................................................................................68
8.7.2.
Concomitant Medical/Surgical Procedures...................................68
8.7.3.
Liver Monitoring/Stopping Criteria................................................68
9.
PHARMACOKINETIC ANALYSES.........................................................................68
9.1.
Primary Pharmacokinetic Analyses.............................................................68


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9.1.1.
Endpoint / Variables.....................................................................69
9.1.1.1.
Drug Concentration Measures....................................69
9.1.2.
Population of Interest...................................................................69
9.1.3.
Statistical Analyses / Methods .....................................................69
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................69
10.1.
Strategy......................................................................................................69
10.2.
Statistical Analyses / Methods ....................................................................69
10.3.
Exploratory Analysis ...................................................................................70
10.4.
Population PK Analysis...............................................................................70
10.4.1.
Individual Analysis .......................................................................70
10.4.2.
Population Analysis .....................................................................71
10.5.
Population PK Analysis with Proteinuria as a Time-Dependent 
Model Variable............................................................................................71
10.6.
Dose Adjustment ........................................................................................71
11. BIOMARKER ANALYSES......................................................................................72
11.1.
Biomarker Endpoints ..................................................................................72
11.2.
Biomarker Change and Percent Change from Baseline Analyses...............72
11.2.1.
Adjustment for IgG Loss ..............................................................74
11.3.
Shifts in Immunoglobulins, Autoantibodies, and Complement by 
Visit.............................................................................................................74
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................75
12.1.
Reporting Standards...................................................................................75
13. REFERENCES.......................................................................................................78
14. APPENDICES........................................................................................................80
14.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................80
14.1.1.
Exclusions from Per Protocol Population .....................................80
14.2.
Appendix 2: Schedule of Activities ..............................................................81
14.2.1.
Protocol Defined Schedule of Events...........................................81
14.3.
Appendix 3: Assessment Windows .............................................................88
14.3.1.
Definitions of Assessment Windows for Analyses........................88
14.4.
Appendix 4: Double Blind Data and Treatment Emergent Adverse 
Events ........................................................................................................91
14.4.1.
Double Blind Data Classification..................................................91
14.4.2.
Treatment Emergent Flag for Adverse Events .............................92
14.5.
Appendix 5: Data Display Standards & Handling Conventions....................93
14.5.1.
Reporting Process .......................................................................93
14.5.2.
Reporting Standards for Pharmacokinetics..................................93
14.6.
Appendix 6: Derived and Transformed Data ...............................................95
14.6.1.
General........................................................................................95
14.6.1.1.
Multiple Measurements at One Analysis Time 
Point...........................................................................95
14.6.1.2.
Study Day...................................................................95
14.6.1.3.
IP Discontinuation Date..............................................95
14.6.1.4.
Changes from Baseline ..............................................95
14.6.1.5.
Percent Change from Baseline...................................96
14.6.1.6.
On Treatment for Safety Endpoints ............................96


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14.6.1.7.
On Treatment for Efficacy Endpoints ..........................96
14.6.2.
Study Population..........................................................................97
14.6.2.1.
Analysis Age...............................................................97
14.6.2.2.
Race and Race Stratification Factor ...........................97
14.6.2.3.
Body Mass Index (BMI) ..............................................98
14.6.2.4.
Extent of Exposure .....................................................98
14.6.2.5.
Lupus Nephritis Medication Categories ......................98
14.6.2.6.
Systemic Medication Flag...........................................99
14.6.2.7.
Prednisone Equivalent Conversion.............................99
14.6.3.
Efficacy......................................................................................103
14.6.3.1.
PERR .......................................................................103
14.6.3.2.
PERR uPCR and eGFR components .......................103
14.6.3.3.
Time to First Renal Response Maintained 
through Week x ........................................................103
14.6.3.4.
Treatment Failures ...................................................104
14.6.3.5.
CRR .........................................................................109
14.6.3.6.
CRR uPCR and eGFR components .........................109
14.6.3.7.
Renal Worsening......................................................109
14.6.3.8.
End Stage Renal Disease (ESRD) ...........................110
14.6.3.9.
Doubling of Serum Creatinine...................................110
14.6.3.10. ORR.........................................................................111
14.6.3.11. ORRUS ....................................................................114
14.6.3.12. ORRUS using cGFR at Week 104............................114
14.6.3.13. Calculated GFR (cGFR) ...........................................115
14.6.3.14. SFI Flares.................................................................116
14.6.3.14.1. SLE Flare Index (SFI) Scoring..............116
14.6.3.14.2. Time to First SFI Flare Censoring 
and Disposition Rules...........................118
14.6.3.15. Proteinuria................................................................119
14.6.3.16. SELENA SLEDAI and SLEDAI-S2K Scoring 
and Endpoints ..........................................................119
14.6.3.16.1. SLEDAI-S2K < 4...................................121
14.6.3.16.2. SLEDAI-S2K Organ System 
Improvement and Worsening................121
14.6.3.16.3. SLEDAI-S2K excluding renal 
items.....................................................121
14.6.3.17. Prednisone ...............................................................122
14.6.3.17.1. Baseline Prednisone Dose ...................122
14.6.3.17.2. Prednisone Average Daily Dose 
Since Previous Visit..............................122
14.6.3.18. SLICC/ACR Damage Index Scoring .........................122
14.6.4.
Safety ........................................................................................124
14.6.5.
Pharmacokinetic ........................................................................124
14.7.
Appendix 7: Reporting Standards for Missing Data...................................126
14.7.1.
Premature Withdrawals..............................................................126
14.7.2.
Handling of Missing Data...........................................................126
14.7.2.1.
Handling of Missing and Partial Dates ......................126
14.8.
Appendix 8: Laboratory Toxicity Grades ...................................................128
14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ....................132
14.9.1.
Systems.....................................................................................132
14.9.2.
Data Assembly...........................................................................132
14.9.3.
Model Development...................................................................132


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14.9.4.
Model Qualification ....................................................................133
14.9.5.
Endpoints...................................................................................133
14.9.6.
Simulations................................................................................134
14.10. Appendix 10: B Cells ................................................................................135
14.10.1. B-cell unit conversions and Normalization of Rare B-cell 
Subsets .....................................................................................135
14.10.2. B Cell Mappings.........................................................................136
14.10.3. B cell subsets to be reported......................................................138
14.11. Appendix 11: Abbreviations & Trade Marks ..............................................139
14.11.1. Abbreviations.............................................................................139
14.11.2. Trademarks ...............................................................................142
14.12. Appendix 12: List of Data Displays............................................................143
14.12.1. Data Display Numbering............................................................143
14.12.2. Mock Example Shell Referencing ..............................................143
14.12.3. Deliverables...............................................................................143
14.12.4. Study Population Tables............................................................144
14.12.5. Study Population Figures...........................................................148
14.12.6. Efficacy Tables ..........................................................................149
14.12.7. Efficacy Figures .........................................................................159
14.12.8. Safety Tables.............................................................................162
14.12.9. Safety Figures ...........................................................................171
14.12.10.Biomarker Tables.......................................................................172
14.12.11.Biomarker Figures .....................................................................174
14.12.12.Pharmacokinetic Tables.............................................................176
14.12.13.Pharmacokinetic Figures ...........................................................177
14.12.14.ICH Listings ...............................................................................178
14.12.15.Non-ICH Listings........................................................................180
14.13. Appendix 13: Example Mock Shells for Data Displays ..............................183
14.14. Appendix 14: Headline Results.................................................................184


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the primary analyses 
for the double-blind treatment period be included in the Clinical Study Report for 
Protocol: BEL114054.  The open-label extension reporting will be described in a separate 
RAP.
Protocol Revision Chronology:
Document Number
Approved
Revision
Global
19-Oct-2011
Original
Global
27-Jan-2012
Amendment 01
Global
08-Mar-2012
Amendment 02 
Local
16-Aug-2012
Amendment 02 (Thailand)
2013N179093_00
11-Feb-2014
Amendment 03
2014N205397_00
29-Aug-2014
Amendment 04 (China)
2013N179093_01
16-Mar-2015
Amendment 05
2013N179093_02
17-March-2015
Amendment 05 (France)
2013N179093_03
13-July-2016
Amendment 05 (France-2)
2013N179093_04
25-Apr-2017
Amendment 06
2013N179093_05
26-Apr-2017
Amendment No 06 (France-2)
2013N179093_06
24-Jan-2019
Amendment 07
2013N179093_07
18-Feb-2019
Amendment No 07 (France-2)
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 are 
outlined in Table 1.


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Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
The protocol refers to the first 
exposure to study agent as 
Day 0.
The analysis plan refers to the 
first exposure to treatment as 
Day 1.
The terminology was changed 
to be compliant with CDISC 
standards.
Region subgroup definition is
US/Canada
Europe/Australia/Israel
Asia
Americas excluding 
US/Canada
(Protocol Section 8.5.2.3)
Region subgroup definition is
US/Canada
Europe
Asia
Americas excluding 
US/Canada
(RAP Section 5.3)
There were no subjects 
enrolled in Australia or Israel,
so these were removed from 
the subgroup label.
Corticosteroid use endpoints 
defined as proportion of 
subjects with prednisone ≤5 
mg and ≤7.5 mg by visit
(Protocol Section 8.5.4)
Corticosteroid use endpoints 
are defined as the proportion 
of subjects with prednisone 
average daily dose ≤5 mg 
and ≤7.5 mg since previous 
visit (RAP Section 7.3.1 and 
Section 14.6.3.17.2)
Provides clarity around the 
time period used for calculating 
the average daily prednisone 
dose. 
Calculated GFR (Protocol 
Section 6.7) references the use 
of creatinine clearance 
determined from the
mean creatinine value of 2 
contiguous 24-hour urine 
collections and 2 serum 
creatinine measurements (first 
serum creatinine collected at 
initial visit and the second 
sample taken 3 days later at 
the follow-up visit).
Calculated GFR (RAP Section 
14.6.3.10) defines cGFR as 
the mean of two contiguous 
creatinine clearance values
adjusted for body surface area 
each derived from 24-hour 
urine collections and serum 
creatinine measurements. 
The urine volume data was not 
available to compute the 
calculated GFR per the 
protocol instructions. 
Unless otherwise specified, all 
analyses will be performed on 
the intention to treat (ITT)
population defined as all 
subjects who are randomized 
and receive 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 modified intention to treat 
population will be used for 
analysis of the study 
population, efficacy and 
biomarker endpoints
Safety data will be 
summarised based on the 
safety population
An updated modified ITT 
population was added to 
exclude the only subject who 
had an assessment at site 
 for GCP non-
compliance and the only 
subject with an assessment at
site 
 due to insufficient 
source documentation.
PPD
PPD


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10
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Efficacy Objective
Primary Efficacy Endpoint
To evaluate the efficacy of 
belimumab in combination with 
standard of care in adult subjects 
with lupus nephritis Class III, IV, or V 
using the 2003 International Society 
for Nephrology (ISN)/Renal 
Pathology Society (RPS) criteria.
Primary Efficacy Renal Response (PERR) at Week 104 
defined as a reproducible response:
Responder

Urinary protein:creatinine ratio ≤0.7; and

Estimated GFR (eGFR) is no more than 20% below the 
pre-flare value or ≥60 mL/min/1.73m2; and

Not a Treatment Failure
Non-Responder

Not meeting criteria for PERR renal response
Secondary Efficacy Objectives
Secondary Efficacy Endpoints
Assess Major Secondary Objectives

Complete Renal Response (CRR) at Week 104
defined as a reproducible response:
Responder

Urinary protein:creatinine ratio <0.5; and

Estimated eGFR is no more than 10% below the 
pre-flare value or ≥90 mL/min/1.73m2; and

Not a Treatment Failure
Non-Responder

Not meeting criteria for CRR renal response

PERR at Week 52 (see Section 7.2.2)

Time to Death or Renal-related Event (see Section 
7.2.3)

Ordinal Renal Response (ORR) at Week 104 (see 
Section 7.2.4)
Renal specific measures 
(supplementary to PERR)
PERR Supplementary Endpoints
Supplementary analyses of PERR
PERR Individual components   
Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio ≤0.7

eGFR is no more than 20% below pre-flare value or 
≥60 mL/min/1.73m2

Not a Treatment Failure
PERR

Proportion of subjects with PERR by visit.

Time to the first PERR that is maintained through 
Week 52

Time to the first PERR that is maintained through 
Week 104
Renal Specific Measures 
CRR Supplementary Endpoints


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11
Objectives
Endpoints
(Supplementary to CRR)
Provide supplementary analyses of 
CRR
CRR individual components 
Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio < 0.5

eGFR no more than 10% below the pre-flare value or 
within the normal range (≥90 mL/min/1.73m2)
CRR

Proportion of subjects with CRR by visit.

Time to the first CRR that is maintained through 
Week 52.

Time to the first CRR that is maintained through 
Week 104.
SFI Flares
SFI Flare Endpoints
Assess SFI flares
SFI Flares

Time to first severe SFI flare.

Time to first severe SFI flare after Week 24.
Other Renal Objectives
Renal Endpoints
Assess Renal-specific measures

Percent change in proteinuria by visit.

Change in proteinuria by visit.

Proportion of subjects with a doubling of the serum 
creatinine or progression to end stage renal disease 
(ESRD) as defined below:

Doubling of serum creatinine compared with 
baseline that is confirmed with a second 
measurement at least 3 weeks later.

Progression to ESRD defined as the need for 
chronic dialysis or renal transplantation.
Disease Activity Objectives
SLEDAI-S2K Endpoints
Assess SLEDAI-S2K

Change from baseline in SLEDAI-S2K score by visit.

Change from baseline in SLEDAI-S2K excluding renal 
items by visit.

Proportion of subjects with SLEDAI-S2K < 4 by visit

SLEDAI-S2K Organ Worsening by organ system and 
visit

SLEDAI-S2K Organ Improvement by organ system and 
visit
Corticosteroid Use Objectives
Corticosteroid Endpoints
Assess Corticosteroid Use

Proportion of subjects receiving 5 mg/day prednisone 
by visit.

Proportion of subjects receiving 7.5 mg/day 


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Objectives
Endpoints
prednisone by visit.
Organ Damage Objectives
SLICC Endpoints
Assess changes in SLICC

SLICC/ACR Damage Index (SDI) change from baseline 
by visit. 

Percent of patients with any SLICC/ACR Damage 
Index worsening (change >0) compared with baseline
by visit. 
Primary Safety Objectives
Primary Safety Endpoints
To assess the safety and tolerability 
of belimumab plus standard of care 
versus placebo plus standard of care 
in adult subjects with lupus nephritis 
Class III, IV, or V using the 2003 
ISN/RPS criteria.

Adverse Event frequencies for all AEs, serious 
AEs, and AEs of Special Interest

Laboratory results by visit, worst laboratory toxicity 
grades, laboratory toxicity grade worsening of at
least 2 grades from baseline, and laboratory 
reference range shifts from baseline.

C-SSRS
Biomarker Objectives
Biomarker Endpoints
Assess changes in Biomarkers
The change and percent change from baseline by visit of 
the following variables:

Absolute B cell subsets

Total serum immunoglobulin (IgG and other 
isotypes: IgM and IgA).

Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, 
and anti-C1q).

Complement (C3, C4) levels.
Percent of patients with normalized serological activity at 
Week 104 and over time

IgG, IgM and IgA (high to normal/low).

Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, 
and anti-C1q) 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 treatment period. Other autoantibodies will be 
collected from all patients at baseline, then at regular 
intervals during the study. 
Data collection and analysis of the exploratory renal 
biomarkers will be performed independently of the main 
study and will form the basis of a separate report.


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2.3.
Study Design
Overview of Study Design and Key Features


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BEL114054
14
Design
Features

This is a Phase 3, multi-center, multi-national, randomized, double-blind, 
placebo-controlled study to evaluate the efficacy and safety of IV belimumab 
10 mg/kg plus standard of care compared to placebo plus standard of care in 
adult subjects with active lupus nephritis.

Subjects must have active, biopsy-proven proliferative lupus nephritis Class III 
or IV [excluding Class III(C), IV-S(C), and IV-G(C)] either with or without the 
presence of Class V, or pure Class V membranous using the 2003 ISN/RPS 
criteria.

This is an induction/maintenance study design.  All subjects must start 
induction therapy within 60 days prior to or on Day 1. 

All subjects will receive background therapy consisting of one of the following 
standard of care regimens: 
o
High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for 
induction therapy followed by Azathioprine (AZA) for maintenance 
therapy
OR
o
HDCS + Mycophenolate Mofetil (MMF) for induction therapy followed 
by MMF for maintenance therapy

Randomized treatment with either belimumab 10 mg/kg or placebo will begin 
on Day 1 and continue through the 104-week double-blind treatment period. 

Renal response will be measured as improvement in proteinuria and estimated
GFR without meeting treatment failure criterion.  Week 104 renal response will 
be defined by a response at Week 100 that is confirmed by a repeat 
measurement at Week 104. 

Subjects who receive treatment with study agent through Week 100 and 
complete Week 104 assessments in the double-blind period may enter a 6-
month open-label extension.

The Week 104 visit of the double-blind period will serve as the Day 1 visit for 
subjects entering the 6-month open-label extension. In the open-label 
extension, all subjects will receive 10 mg/kg belimumab every 28 days until 
Week 24, with a final evaluation at Week 28 (4 weeks after the last dose).

All subjects who discontinue treatment with study agent during the double-blind 
period should return for all scheduled visits through Week 104, unless consent 
to participate in the study is withdrawn. 

Subjects who complete the 104-week double-blind period, but do not enter the 
open-label extension will be required to return for an additional follow up visit 8 
weeks after the last dose of study agent.
Dosing

In the double-blind treatment period, subjects will be dosed with study agent on 
Days 1 (baseline), 14, 28 and then every 28 days thereafter through 100 
weeks with a final evaluation at Week 104 (4 weeks after the last double-blind 
dose).

Day 1 of the open-label extension phase is the same date as the Week 104 
visit of the double-blind period. Therefore, the first dose of study agent for 
subjects entering the open-label phase will be at the Week 104/Day 1 visit. In 
the open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the 


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BEL114054
15
last open-label dose).
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

All subjects should start induction therapy within 60 days prior to or on Day 1.

All subjects will receive background therapy consisting of one of the following 
standard of care regimens:
•
High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for 
induction therapy followed by Azathioprine (AZA) for maintenance therapy
OR
•
HDCS + Mycophenolate Mofetil (MMF) for induction therapy followed by 
MMF for maintenance therapy
•
At least 400 and up to approximately 464 lupus nephritis subjects will be 
randomized with a target of at least 200 and up to approximately 232 subjects 
in each treatment group (belimumab or placebo).
•
The randomization will be stratified by induction regimen (HDCS plus CYC vs 
HDCS plus MMF) and race (black vs non-black). Subjects will be allocated to 
belimumab or placebo in a 1:1 ratio.

In the event of recruitment challenges, randomization may be stopped if
the number randomized is ≥ 400 subjects. 

A sample size of N=448 will provide approximately 80% power for the 
dichotomous endpoints of PERR and CRR assuming the underlying 
treatment difference is at least 12.0% (20% vs. 32%) to 13.6% (45% vs. 
58.6%), depending on where the response rates fall, for placebo plus 
standard of care compared with belimumab plus standard of care, 
respectively.

During the open-label extension phase, all subjects will receive belimumab 10 
mg/kg plus standard of care.
Interim 
Analysis

No interim analysis is planned for this study.
2.4.
Statistical Hypotheses / Statistical Analyses

Ho:  There is no difference in renal response rates for belimumab plus standard of 
care vs placebo plus standard of care at Week 104 of the double-blind treatment 
period. 

Ha:  There is a difference in renal response rates for belimumab plus standard of care 
vs placebo plus standard of care at Week 104 of the double-blind treatment period. 


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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 period) and the open-label extension analysis (end of study 
analysis). The open-label extension analysis and reporting will be described in a 
separate RAP.

All subjects and study site personnel (except the unblinded site pharmacist) will 
remain blinded until the open-label extension data is locked.  
Primary Analysis:  The final planned primary analyses will be performed after the 
completion of the following sequential steps:
1.
All subjects have completed the Week 104 visit of the double-blind treatment period 
(or Exit visit for those subjects who withdraw consent during double-blind treatment) 
or are lost to follow-up.  For subjects not entering the open-label extension, data 
collected during the post-treatment follow-up period will be included if it is available 
on or before the last subject completes the Week 104 visit, exit visit, or is lost to 
follow-up.
2.
All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management.
3.
Adjudication of protocol deviations, adverse events of special interest, treatment 
failures, and cases of progression to end stage renal disease has been completed.
4.
All criteria for unblinding the randomization codes have been met. 
5.
Randomization codes have been distributed per GSK procedures.
6.
Database freeze (DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who were screened for the trial, 
irrespective of whether they were randomized.

Study Population
Randomized 

All participants who were randomly assigned to 
treatment in the study.

This population will be based on the treatment to which 
the participant was randomized.

Study Population
Safety

All randomized participants who received at least one 
dose of study treatment.

This population will be based on the randomized 
treatment.

Safety


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Population
Definition / Criteria
Analyses Evaluated

If more than 15% of the subjects received a treatment 
other than their randomized treatment for >50% of 
infusions, the subject will be classified based on the 
actual treatment received for >50% of the infusions.

Note: Participants who were not randomized but 
received at least one dose of study treatment will be 
listed.
Modified Intent-
To-Treat (MITT)

All randomized participants who received at least one 
dose of study treatment.

This population will be based on the treatment to which 
the subject was randomized.

Any subject who receives a treatment randomization 
number in ALMAC will be considered to have been 
randomized.

Excludes the one subject at site 
 due to  GCP 
non-compliance issues and the one subject at site 
 due to insufficient source documentation..

Study Population

Efficacy

Biomarkers
Per-Protocol
(PP)

A subset of the MITT population who comply with the 
protocol.

Protocol deviations that would exclude participants from 
the PP population are defined in Appendix 1.

The PP set will only be analysed if this population 
excludes more than 15% of the MITT population.

Efficacy
Completers on 
Study Agent

Subjects from the MITT population who completed 
through Week 104 and were not permanently 
discontinued from treatment prior to Week 104.

Efficacy
Completers on 
Study

Subjects from the MITT population who completed 
through Week 104 including subjects both on and off 
treatment

Efficacy
Pharmacokinetic 
(PK)

All belimumab-treated subjects in the Safety population 
who had at least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as non-
missing values).

PK
Refer to Appendix 13 which details the population used for each display.
4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 3, 13Aug19].

Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset.

This dataset will be the basis for the summaries and listings of protocol
deviations.
PPD
PPD


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG Randomization System
Data Displays for Reporting 
Code
Description
Description
Order in TFL
0
Placebo
Placebo
1
1
Belimumab 10 mg/kg
Belimumab 10 mg/kg
2
On some safety displays, belimumab is presented without the dose and unit due to space 
restrictions.
Treatment comparisons will be displayed as follows using the descriptors as specified:

Bel 10 mg/kg vs Placebo
Figure Styles
Treatment 
Descriptor
Color
SAS Color
Line Style
Symbol
Belimumab 10mg/kg
Blue
CX0000FF
Dashed
Triangle (filled)
Placebo
Black
CX000000 
Solid
Circle (open)
For Study Population tables presenting baseline demographics and characteristics 
described in Section 6, a total column for both treatment groups combined will also be 
presented for subjects in the double-blind phase.  Other subgroup descriptors will be 
described in more detail in Section 5.4.2.
5.2.
Baseline Definitions
The baseline value of a variable will be defined as the value of the variable measured at
Day 1 (treatment start date) prior to dosing, unless otherwise specified. If timing of 
assessment is not collected on Day 1, then the assessment will be assumed to be prior to 
dosing. For ECGs where timing is collected, the date and time will be compared to the 
infusion date and time to determine baseline; in the event of a missing time, the ECG will 
be assumed to be prior to dosing.
If there are multiple results on Day 1 prior to dosing, the latest result will be used (e.g., if 
multiple lab tests are performed). If a Day 1 value is not available, the last available value 
prior to Day 1 will be used.


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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.
Baseline flares are flares that occur on or prior to the treatment start date.
Baseline values occurring on Day 1 will not be considered on-treatment unless explicitly 
defined as such.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
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 14.3.1.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be carried out in the following Regions 
and Countries:
Region
Countries
Asia
China, Hong Kong, Korea, Philippines, Taiwan, Thailand
US/Canada
United States, Canada
Americas excluding US/Canada
Argentina, Brazil, Colombia, Mexico
Europe
Belgium, Czech Republic, France, Germany, Hungary, Netherlands, 
Russian Federation, Spain, United Kingdom
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Strata
Randomization Stratification Factors 

Induction Regimen

CYC

MMF

Race

Black

Non-Black
Covariates

Baseline uPCR


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Category
Details

Baseline eGFR
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.
If the percentage of subjects is small within a subgroup, then the subgroup categories 
may be refined prior to unblinding the trial or a subgroup may be eliminated.
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the subgroup.
Subgroup
Categories 
Induction Regimen
CYC vs. MMF
Race Stratification Factor
Black vs. Non-Black
Region
Asia, US/Canada, Americas excluding US/Canada, Europe
Baseline anti-dsDNA 
Positive (≥30 IU/mL) vs. Negative (<30 IU/mL)
Baseline Complement 
At least one C3/C4 Low vs. No C3/C4 Low
where Low C3 is <90 mg/dL and Low C4 is <10 mg/dL
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)
Baseline Renal Biopsy Class
(local reader assessment)
Class III or Class IV
Class III+V or IV+V 
Class V 
Gender 
Female vs. Male
Baseline Body Weight Quartile
1st Quartile < q1 kg
2nd Quartile q1 - < q2 kg
3rd Quartile q2 - < q3 kg
4th Quartile ≥q3 kg
Where q1, q2, and q3 are the observed values from the data.
5.5.
Multiple Comparisons and Multiplicity
The primary comparison of interest is the comparison between Belimumab 10mg/kg and 
Placebo for the primary endpoint in the MITT population. This analysis will be adjusted 
for the stratification factors applied at randomization.
An overview of the multiplicity control is provided in Figure 1. 


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Figure 1
Step-down, Sequential Testing Procedure
Primary Efficacy Renal Response (PERR) at Week 104
If p-value 0.05 then inference progresses

Complete Renal Response (CRR) at Week 104
If p-value 0.05 then inference progresses

Primary Efficacy Renal Response (PERR) at Week 52
If p-value 0.05 then inference progresses

Time to Death or Renal-related Event
If p-value 0.05 then inference progresses

Ordinal Renal Response (ORR) at Week 104
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. With this
procedure, the primary and 4 major secondary efficacy endpoints will be evaluated for
statistical significance based on the pre-specified sequence for interpretation shown in 
Figure 1.Specifically, endpoints will be tested in the sequence above (2-sided alpha=0.05) 
provided 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 and 95% 
confidence intervals may be reported and considered descriptive. Analyses of other 
efficacy endpoints will not be subject to any multiplicity adjustment. All statistical tests 
will be two-sided and performed at an overall significance level of 0.05.
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
14.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
14.2
Appendix 2: Schedule of Activities
14.3
Appendix 3: Assessment Windows
14.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events


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Section
Component
14.5
Appendix 5: Data Display Standards & Handling Conventions
14.6
Appendix 6: Derived and Transformed Data
14.7
Appendix 7: Reporting Standards for Missing Data
14.8
Appendix 8: Laboratory Toxicity Grades
14.9
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
14.10
Appendix 10: B cells
14.11
Appendix 11: Abbreviations & Trade Marks
14.12
Appendix 12: List of Data Displays
14.13
Appendix 13: Example Mock Shells for Data Displays
14.14
Appendix 14: Headline Results
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the MITT population, unless otherwise 
specified.
Study population analyses including analyses of subject disposition, protocol deviations, 
demographic and baseline characteristics, prior and concomitant medications, and 
exposure and treatment compliance will be based on GSK Core Data Standards and 
Benlysta program standards, where applicable.  Details of the planned displays are 
presented in Section 6.7: Summary of Study Population Analyses and in Appendix 12: 
List of Data Displays. With few exceptions, displays will be presented  by treatment arm 
for the overall modified Intent-to-Treat population and within induction regimen.
6.2.
Disposition of Subjects
Using the Randomized population, the number and percentage of subjects randomized by 
country and site will be summarized by treatment group and for the combined treatment 
groups.
Using the Screened population, the number of subjects in each population (Screened, 
Randomized, Safety, modified Intent-to-Treat, Per Protocol, Completers on Study Agent, 
Completers on Study, and PK) will be summarized by treatment group and for the 
combined treatment groups.  Using the screened population, a summary of the reasons for 
the screen failures will be provided along with a listing of the subjects who were screen 
failures.
The subject’s status by Week 104 will be assessed to evaluate percentages of subjects 
who completed the study and treatment or withdrew from the study and/or discontinued 
treatment prematurely. The summary will be presented by treatment group for the overall 
modified Intent-to-Treat population and within induction regimen.


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The subject’s completion status will be presented as percentage of withdrawals from the 
study as well as the reasons for withdrawal.  The number and percentage of subjects who 
completed through Week 104 and who withdrew, including the primary reasons for 
withdrawal, will be displayed by treatment group for the overall modified Intent-to-Treat 
population and within induction regimen. The cumulative number and percentage of 
subjects who withdrew from the study by study visit will also be displayed by treatment 
group for the overall modified Intent-to-Treat population and within induction regimen. 
Additionally, a figure for the cumulative proportion of subjects withdrawn from the study 
by visit, derived using assessment windows defined in Appendix 3, will be generated to 
evaluate the pattern of dropouts over time.  
The subject’s investigational product status and reason for investigational product (IP)
discontinuation will be assessed.  The number and percentage of subjects who completed 
treatment through Week 104 and who prematurely discontinued IP, including primary
reason for IP discontinuation, will be displayed by treatment group for the overall 
modified Intent-to-Treat population and within induction regimen. Additionally, the 
cumulative number and percentage of subjects who discontinued IP by study visit, 
derived using assessment windows defined in Appendix 3, will be displayed by treatment 
group for the overall modified Intent-to-Treat population and within induction regimen.
A figure for the cumulative proportion of subjects who discontinued IP will be generated 
to evaluate the pattern of IP discontinuations over time. Subjects that discontinue IP
prematurely will be counted as discontinued at the first visit without a treatment infusion. 
A listing of subject disposition will be provided showing completion status and inclusion
in each population. A listing of subjects who withdrew from the study, including reason 
for and date of withdrawal will also be provided. Both listings will be displayed by 
induction regimen and treatment group.
An additional listing will be provided of subjects who discontinued IP, including reason 
and date of discontinuation. Subjects for whom the treatment blind was broken during the 
study will be listed. These listings will be displayed by induction regimen and treatment 
group.
A listing of planned and actual treatments will be provided for each subject by Country, 
Site ID, and Investigator name.
6.3.
Protocol Deviations

Please refer to the Protocol Deviation Management Plan (PDMP): Dated: 
13Aug2019 (Version 3.0) 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 for the overall modified Intent-
to-Treat population and within induction regimen. Deviations which result in 
exclusion from the PP population will be summarized by treatment group for the 
overall modified Intent-to-Treat population and within induction regimen.


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A listing of subjects experiencing an important protocol deviation, including PP 
population exclusions, will be provided by induction regimen and treatment group (see 
Appendix 1).   A listing of subjects excluded from the PP population will also be 
provided by induction regimen and treatment group.

The number and percentage of subjects who deviated from any inclusion or 
exclusion criteria and each inclusion/exclusion criteria type will be displayed by 
treatment group for the overall modified Intent-to-Treat population and within 
induction regimen. A listing of subjects who had a deviation from the inclusion or 
exclusion criteria will be provided by induction regimen and treatment group. 
Additional protocol deviations may be identified during the study and will be 
documented in Protocol Deviation Adjudication Meeting minutes prior to the first 
database lock and unblinding.  A final list of subjects that have an important protocol 
deviation will be agreed after database release, prior to unblinding.
6.4.
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.
Demographic and baseline characteristics including region and country, sex, ethnicity, 
age, age group, height, weight, and body mass index (BMI) will be summarized by 
induction regimen, treatment group and overall. A summary of age ranges by treatment 
group for the overall modified Intent-to-Treat population and within induction regimen
will also be provided. A listing of demographic and baseline characteristics will be 
displayed by induction regimen and treatment group.
Vital signs at baseline, including diastolic and systolic blood pressure, heart rate, and 
temperature will be summarized by treatment group for the overall modified Intent-to-
Treat population and within induction regimen. 
A listing of ECG findings, including clinically significant abnormalities, will be 
presented by induction regimen and treatment group.
Current and past medical conditions will be summarized separately by any medical 
history, and also by body system or organ class and preferred term, by treatment group 
for the overall modified Intent-to-Treat population and within induction regimen.  A 
listing of subjects with current and past medical conditions will be displayed by induction 
regimen and treatment group.
A summary of race and racial combination details will be presented by treatment group 
for the overall modified Intent-to-Treat population and within induction regimen. 
Subjects who check more than one race category are counted under the Multiple 
category. The following minority rule will be applied to all analyses related to race 
(except for stratification):


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If a subject checks multiple race categories on the eCRF, the subject will be assigned to a 
unique race group according to the following priority order:

Native Hawaiian or Other Pacific Islander

Alaska Native or American Indian from North/Central/South America

Asian

Black

White/Caucasian
Race will be listed for all subjects by induction regimen and treatment group.
Baseline stratification factors, induction regimen (CYC, MMF) and race (Black, Non-
Black), will be presented by treatment group and the combined treatment groups for the 
modified Intent-to-Treat population.  A shift table of differences between stratification 
factors at Screening and as Randomized (data entered into the ALMAC system) will be 
produced for the combined treatment groups.
Stratification factors (randomized and actual strata) will be listed for all subjects by
induction regimen and treatment group.
A summary of baseline disease activity, including SLE and LN (Lupus Nephritis) disease 
duration, renal biopsy class (local and central reader) renal biopsy category (local and 
central reader), urine protein-creatinine ratio (uPCR), estimated GFR (eGFR), SLEDAI-
S2K score, physician’s global assessment (PGA), and SLICC/ACR Damage Index (SDI)
will be presented by treatment group for the overall modified Intent-to-Treat population 
and within induction regimen.
The following indicators of baseline disease activity will be summarized by treatment 
group for the overall modified Intent-to-Treat population and within induction regimen:

Pre-flare serum creatinine and estimated GFR values

Lupus Nephritis therapy history (previous CYC or MMF therapy and response 
[responded/failed] to therapy)

ACR classification criteria at baseline

SLEDAI-S2K organ and item involvement at baseline

Baseline immunoglobulin levels (IgA, IgG, and IgM)

Baseline autoantibody levels (Anti-dsDNA, ANA, Anti-cardiolipin, Anti-
dsDNA and/or ANA positive, Anti-c1q, and Anti-Sm)

Baseline levels of complement and other biomarkers (C3, C4, and BLyS
Protein)

Baseline B cells (CD19, CD20, Naïve CD19+CD20+CD27-, Memory 
CD19+CD20+CD27+, Activated CD19+CD20+CD69+ Normalized, Plasma 
CD19+CD20-CD138+ Normalized, Plasmacytoid CD19+CD20+CD138+ 
Normalized, Short-lived Plasma CD19+CD20-CD27b+ Normalized, SLE subset 
CD19+CD38b+CD27b+ Normalized, Transitional 
CD19+CD24b+CD38b+CD27- Normalized

Pre-treatment Columbia Suicide Severity Rating Scale (C-SSRS) responses by 
behavior and ideation components


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
Allowable SLE and LN medication usage at baseline
Listings for pre-flare serum creatinine and eGFR, Lupus Nephritis therapy history, and
renal biopsy results at Screening will be provided for each subject by induction regimen 
and treatment group.
The demographic and baseline characteristics, baseline disease activity, and allowable 
SLE and LN medication at baseline summaries will be repeated for the subgroups defined 
in Section 5.4.2.
6.5.
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 (1) 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 (2) medications that start after the first dose date of study treatment
and before the open-label period.  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 by induction regimen, 
treatment group and overall.  A further summary of concomitant medications by ATC 
level 4 term and preferred term will be provided by induction regimen, treatment group 
and overall.  A listing of all concomitant medication data for subjects will be displayed 
by induction regimen and treatment group. A listing of the relationship between ATC 
Level 1, ingredient, and verbatim text will also be provided.
Protocol-prohibited medication and allowable medication that results in treatment failure 
designation (see protocol Section 5.5 and Section 5.6) will be summarized by induction 
regimen, treatment group and overall.  A listing of protocol-prohibited medication and 
allowable medications that result in treatment failure designation will be displayed for 
subjects by induction regimen and treatment group.
6.6.
Extent of Exposure
The extent of exposure to study treatment through Week 104 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).
If a subject dies <28 days after the last infusion, then exposure will be calculated as 
(Death date – First Infusion Date + 1). Only complete dates will be used when calculating 
duration of exposure.  First and last infusion dates will be used, regardless of any missed 


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doses. Subjects who were randomized but did not report a treatment start date will be 
categorized as having zero days of exposure. 
The duration of exposure and the total number of infusions will be summarized using 
descriptive statistics.  The duration of exposure will also be summarized using counts and 
percentages for the following categories: <24 weeks, 24 – 52 Weeks, >52 – 76 weeks, 
>76 weeks where weeks are based on the visit week of the last infusion received. The 
total number of infusions will be summarized using counts and percentages for the 
following categories: 1 – 9 doses, 10 – 18 doses, 19 – 27 doses, and ≥28 doses. These 
summaries will be presented by induction regimen, treatment group and overall.
Exposure data will be listed for all subjects by induction regimen and treatment group.
6.7.
Summary of Study Population Analyses
The following Study Population parameters will be summarized:
PARAMETER
SUMMARY TYPE
Randomization by Country and Site
Country, Site, and Investigator Name
Categorical
Populations
Populations
Categorical
Reasons for Failing Screening
Screening Status and Reason for Failed Screening
Categorical
Subject Status by Week 104
Completion / Withdrawal Status
Categorical
Subject Completion Status by End of Double-Blind Phase Week 104
Week 104 Completion and Withdrawn Prior to Week 
104; Includes Reasons for Withdrawal
Categorical
Time to Withdrawal from Study
Completions Through Week 104 and Subjects 
Withdrawn by Week
Categorical
Investigational Product Status and Reasons for Discontinuation 
Investigational Product Status and Primary Reason 
for Premature Discontinuation 
Categorical
Investigational Product Discontinuation by Visit
Investigational Product Completion Through Week 
104 and Discontinuation by Visit
Categorical
Inclusion/Exclusion Criteria Deviations
Any Criteria Deviations and Specific
Inclusion/Exclusion Criteria Not Met
Categorical: Presented if Yes
Important Protocol Deviations
Any Important Protocol Deviations and Deviations 
Presented by Category and Coded Term
Categorical: Presented if Yes
Exclusions from the Per Protocol Population
Exclusion Category and Coded Term
Categorical: Presented if Yes
Shifts in Differences Between Stratification Factors at Screening and as Randomized
Displays induction regimen and race categories at 
screening and as randomized
Induction Regimen (CYC vs. MMF)
Race (Black, Non-Black)
Demographic and Baseline Characteristics (table is also displayed by Subgroups)


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PARAMETER
SUMMARY TYPE
Region and Country
Categorical: Asia, Europe, US/Canada, Americas 
excluding US/Canada
Sex
Categorical: Female, Male
Ethnicity
Categorical: Hispanic or Latino, Not Hispanic or 
Latino
Age (years)
Continuous
Categorical:
≤45 years, 
>45 – <65 years
≥65 years
    ≥65 – <75 years 
    ≥75 years  
Height (cm)
Continuous
Weight (kg)
Continuous
Body Mass Index (BMI) (kg/m2) 
Continuous
Summary of Age Ranges
Age Ranges
Categorical:
Adult (18-64 years)
≥65-84 years
≥85 years
Race and Racial Combination Details
Race
Categorical:
White/Caucasian
     White/Caucasian/European Heritage
      Arabic/North African Heritage
     Mixed Caucasian
Asian
     Central/South Asian Heritage
     Japanese/East Asian/South East Asian Heritage
     Mixed Asian
Black or African American
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander
Multiple
Vital Signs at Baseline
Systolic Blood Pressure
Continuous
Diastolic Blood Pressure
Continuous
Heart Rate
Continuous
Temperature
Continuous
Current and Past Medical Conditions
Current Medical Conditions by Body System or Organ 
Class and Preferred Term
Categorical: present if current medical condition
exists
Past Medical Conditions by Body System or Organ 
Class and Preferred Term
Categorical: present if past medical condition exists
Stratification Factors
Induction Regimen
Categorical: 
- CYC
- MMF


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PARAMETER
SUMMARY TYPE
Race
Categorical:
-Black
-Non-Black
Induction Regimen and Race Strata
Categorical:
CYC and Black
CYC and Non-Black
MMF and Black
MMF and Non-Black
Baseline Disease Activity (table is also displayed by Subgroups)
SLE disease duration (years) 
Continuous
LN disease duration (years)
Continuous
Renal Biopsy Class
(local reader and central reader results will be 
displayed separately)
Categorical:
Class I
Class II
Class III (A)
Class III (A/C)
Class III (C)
Class IV-S (A)
Class IV-G (A)
Class IV-S (A/C)
Class IV-G (A/C)
Class IV-S (C)
Class IV-G (C)
Class V
Class VI
Categorical (Subgroup):
Class III or Class IV
Class V 
Class III+V or Class IV+V
Urine Protein-Creatinine Ratio (uPCR)
Continuous
Categorical:
<0.5, 0.5-<3, ≥3
<=0.7
Estimated GFR (mL/min/1.73m2)
Continuous
Categorical:
<30, 30-<60, 60-<90, ≥90
≥60
SLEDAI-S2K score
Continuous
Categorical: <8, 8 - <12, 12 - <16, ≥ 16
PGA
Continuous
Categorical: 0-1, >1 – 2.5, >2.5, Missing
SLICC/ACR Damage Index score
Continuous
Categorical: 0, 1, >1
Pre-Flare Serum Creatinine and eGFR Values
Pre-Flare Serum Creatinine and Pre-Flare Estimated 
GFR Values (pre-flare estimated GFR values are 
calculated from pre-flare serum creatinine)
Continuous: Serum Creatinine and eGFR
Categorical: eGFR <30, 30-<60, 60-<90, ≥90
≥60
Lupus Nephritis Therapy History


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PARAMETER
SUMMARY TYPE
Previous CYC or MMF Therapy and whether subject 
responded or failed therapy
Categorical
ACR Classification Criteria at Baseline
ACR classification criteria by symptom
Categorical: Presented if Yes
SLEDAI-S2K Organ and Item Involvement at Baseline
SLEDAI-S2K by organ and item at baseline
Categorical: presented if Yes
Immunoglobulin Levels at Baseline
Baseline immunoglobulin levels (g/L): 
IgA, IgG, and IgM
Continuous 
Categorical:
-below the lower limit of normal (LLN)
-above upper limit of normal (ULN)
Autoantibody Levels at Baseline
anti-dsDNA [IU/mL]
Continuous
Categorical:
-positive (30 IU/mL)
-negative (< 30 IU/mL)
ANA [Titer]
Continuous
Categorical:
-positive (80 Titer)
-negative (< 80 Titer)
anti-cardiolipin (aCL)
Categorical:
-positive (if any of the three isotypes IgG, IgA or 
IgM are above the lower limit of quantification)
-negative (if at least one is non-missing and none 
of the isotypes above the limit of quantification)
anti-dsDNA and/or ANA positive 
Categorical: Yes, No
Anti-c1q (U/mL)
Continuous
Categorical:  
-positive (≥22.2 U/mL)
-negative (<22.2 U/mL)
Anti-Sm (KU/L)
Continuous
Categorical:  
-positive (≥15 KU/L)
-negative (<15 KU/L)
Complement Levels and Other Biomarkers 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
At least one C3/C4 Low
No C3/C4 Low


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PARAMETER
SUMMARY TYPE
Complement and anti-dsDNA Level
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 Protein (ng/mL)
Continuous
Categorical: 
-below limit of quantification [LOQ] (<0.061 ng/mL),
-above LOQ
- ≥ 2 ng/mL
B cells at Baseline
CD19
CD20
Naïve CD19+CD20+CD27–
Memory CD19+CD20+CD27+
Activated CD19+CD20+CD69+ Normalized
Plasma CD19+CD20-CD138+ Normalized
Plasmacytoid CD19+CD20+CD138+ Normalized
Short-lived Plasma CD19+CD20-CD27b+ Normalized
SLE subset CD19+CD38b+CD27b+Lymph 
Normalized
Transitional CD19+CD24b+CD38b+CD27-
Normalized
Continuous
Columbia Suicide Severity Rating Scale (C-SSRS) Responses by Behavior and ideation Components 
– Pre-treatment
C-SSRS responses by behavior and ideation 
components for lifetime, current (over the last two 
months) and Baseline (since last visit)
Categorical:
-Ideation: categories 1-5 with corresponding text
-Behavior: categories 6-11 with corresponding text
Allowable SLE and LN Medication Usage at Baseline (table is also displayed by Subgroups)
Average daily prednisone dose (mg/day) at baseline
Continuous
Allowable SLE and LN medications by class and drug 
at baseline
Categorical:
-Steroids
-Anti-malarials
-Immunosuppressants
-ACE/ARBs
Concomitant Medications by ATC Level 1 and ATC Level 4 Term
ATC Level 1 and ATC Level 4
Categorical: Presented if Yes
Concomitant Medications by ATC Level 4 and Preferred Term
ATC Level 4 and Preferred Term
Categorical: Presented if Yes
SLE and LN Medication Usage Resulting in Treatment Failure Designation Through Week 104
Medication Category
Categorical:
-Subjects with Treatment Failure
-Steroids
-Anti-malarials
-Immunosuppressives
-ACE/ARBs
-Prohibited Medications
Exposure to Study Treatment through Week 104
Duration of Exposure 
Continuous (Days)
Categorical: <24 weeks, 24 – 52 weeks, >52 - 76 
weeks, >76 weeks


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PARAMETER
SUMMARY TYPE
Total Number of Infusions
Continuous
Categorical: 1-9,10-18, 19-27, ≥28
7.
EFFICACY ANALYSES
Unless otherwise stated, all analyses will be limited to the double-blind treatment period 
while subjects are on investigational product (IP) defined as on or after the treatment start 
date up through and including the IP discontinuation date . Analyses of data after subjects 
have discontinued IP are described as sensitivity analyses and will be clearly identified.
For the purposes of the analysis plan, the period from Day 1 through Week 24 will be 
referred to as ‘the induction phase’ and the period from Week 24 visit date +1 through the 
Week 104 visit will be referred to as ‘the maintenance phase.’ 
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint
The primary efficacy endpoint is the Primary Efficacy Renal Response (PERR) at 
Week 104 measured as a dichotomous response (Responder vs Non-Responder). 
PERR is determined by reproducible changes in proteinuria and renal function.  The 
PERR at Week 104 is defined by a response at the Week 100 visit that is confirmed by a 
repeat measurement at the Week 104 visit. 
Primary Efficacy Renal Response (PERR)
Responder
-uPCR ≤ 0.7; and
- eGFR is no more than 20% below pre-flare value or ≥60 mL/min/1.73m2; and
-Not a Treatment Failure [1]
Non-Responder
-Not meeting criteria for PERR renal response
[1] Treatment failure is defined in Section 5.5 and Section 5.6 of the protocol with further detail 
in RAP Section 14.6.3.3
Further detail on the endpoint derivation can be found in Section 14.6.3.
7.1.2.
Summary Measure
An odds ratio will measure the treatment effect for the odds of being a responder on 
belimumab vs. placebo.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the modified Intent-to-Treat population.


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7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
There are five types of intercurrent events (IEs):
1.
Treatment Failure (TF)
2.
Investigational Product (IP) Discontinuation
3.
Study Withdrawal
4.
Lost to Follow-up
5.
Death
Intercurrent events of TF and IP discontinuation may have data observed after the event 
unless it coincides with a withdrawal event (Death, lost to follow-up, or study 
withdrawal) while withdrawal events have no data observed after the event. 
The composite strategy is used for intercurrent events where renal response is imputed as 
a non-responder from the date of the earliest intercurrent event and all timepoints 
thereafter through Week 104.  This imputation strategy is referred to as IP 
discontinuation, treatment failure, or withdrawal equals a non-responder and is written as 
IPD/TF/WD=NR.
7.1.4.1.
Handling of Missing Data
7.1.4.1.1.
Imputation for Missing Visits
Per the PERR definition, a Week 104 response is defined as a response at Week 100 
confirmed at Week 104. If a subject misses the Week 100 or Week 104 visit (or is 
missing data for both eGFR and uPCR at the visit), the Week 96 renal response will be 
used to derive the primary endpoint as follows:

If the Week 104 visit is missing, the primary endpoint will be determined using data 
from the Week 96 and the Week 100 visits.

If the Week 100 visit is missing, the primary endpoint will be determined using data 
from the Week 96 and the Week 104 visits.

If subject misses both the Week 100 and the Week 104 visit, the subject’s response 
will be imputed as a non-responder.

If the subject has only one non-missing visit among Week 96, 100, and 104, the 
subject’s response will be imputed as a non-responder.
Imputation for missing visits is limited to the current visit and two previous visits 
therefore limiting reproducibility to three visits.  This three-visit rule is used for 
determining renal response at all visits renal response is derived. 
7.1.4.1.2.
Imputation if Missing a Single Lab Component within a Visit
At a given visit, eGFR and uPCR are required to assess whether a subject is a responder 
for the visit, assuming the subject has not had an intercurrent event on or before the visit. 


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An indicator variable for whether the lab criteria were met (Y or N) will be created for 
each lab component.  
If either lab component (eGFR or uPCR) is missing for the Week 100 or 104 visits, the 
indicator variable for the missing lab component will be imputed based on the value for 
the non-missing visit (Week 100 or Week 104) and the Week 96 visit. Two values are 
required for the imputation to confirm the result. If both lab components are missing at 
the same visit, then the rules for a missing visit (Section 7.1.4.1.1) will be used to impute 
the visit response. 
The following imputation method will be used for the missing response:

If a lab component is missing at the Week 104 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 100 visits.

If a lab component is missing at the Week 100 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 104 visits.

If a lab component is missing at both the Week 100 and the Week 104 visits, then the 
subject’s lab criterion indicator flag will be set to ‘N’ at each visit resulting in the 
subject being a non-responder for the PERR endpoint at Week 104.
Table 2
Imputation for Lab Component Indicator Variables When a Lab 
Component is Missing 
Component Indicator Variable (Imputed Value)
Week 96 Visit
Lab Criterion Met
Week 100 Visit
Lab Criterion Met
Week 104 Visit
Lab Criterion Met
Y
Y
Missing (Y)
Y
N
Missing (N)
N
Y
Missing (N)
N
N
Missing (N)
Y
Missing (Y)
Y
Y
Missing (N)
N
N
Missing (N)
Y
N
Missing (N)
N
Y
Missing (N)
Missing (N)
N
Missing (N)
Missing (N)
Note: This will apply to the eGFR or uPCR criterion separately.
7.1.4.1.3.
Example of the Renal Response Endpoint Derivation with Missing Data
The example in Table 3 illustrates the following:

Imputation of a missing lab component at a single visit (i.e., missing uPCR at Week 
104)


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
Indicator variables for response criterion met within a visit (Y or N; shown in rows 
for each renal response component)

Renal response at the visit (Y or N; shown in the last row for each visit column)

Primary renal response at Week 104 (Y or N; shown in the last row/last column)
Table 3
Example of Renal Response Endpoint Derivation including 
Imputation due to Missing uPCR at Week 104
Responder
Week 96
Week 100
Week 104
Primary 
Renal 
Response
uPCR component 
Y
N
Missing (N)
eGFR component 
Y
Y
Y
Not a Treatment Failure
Y
Y
Y
Renal Response*
Y
N
N
N
*Requires a ‘Y’ indicating criterion met for each component to achieve a response.
7.1.5.
Statistical Analyses / Methods
PERR (Responder vs. Non-Responder) at Week 104 will be compared between 
belimumab and placebo using logistic regression controlling for induction regimen (CYC 
vs. MMF), race (Black vs. Non-Black), baseline uPCR, and baseline eGFR. 
Variables

PERR (Responder vs. Non-Responder)

Treatment (belimumab=1, placebo=0)

Induction (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)

uPCR (at baseline; continuous)

eGFR (at baseline; continuous)
Model Specification
The model will be specified as:  PERR = Treatment Induction Race uPCR eGFR.
Reference cell coding will be used.
Model Checking & Diagnostics
The data will be evaluated by two independent statisticians to determine if the model assumptions 
and fit are reasonably met.  If either is deemed unacceptable, additional sensitivity analysis using 
an alternative method may be performed. 
Model Results Presentation
The primary table will present Week 104 results as the percentage of responders by treatment 
group, SE for the percentage of responders by treatment group, the observed treatment difference 


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(belimumab – placebo), Cochran-Mantel-Haenzel estimates of the treatment difference and 
associated 95% confidence interval adjusted for induction regimen and race, odds ratio (OR) for 
the treatment effect (belimumab/placebo), 95% confidence interval (CI) for the odds ratio, and p-
value.  Additionally, a table for the model parameters (intercept and main effects: treatment, 
induction, race, uPCR, and eGFR) will display the parameter estimate, standard error, odds ratio 
(95% CI), and p-value for each parameter.  
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 2 binary covariates will be consolidated to give 4 strata levels and the 
Cochran-Mantel-Haenszel strata-adjusted proportion difference and stratified Wald 95% 
confidence intervals will be produced (Kim, 2013).
Subgroup Analyses
Subgroup analysis of the PERR endpoint at Week 104 will be performed in the following 
subgroups:

Induction Regimen (CYC, MMF)

Race (Black, Non-Black)

Region (Asia, US/Canada, Americas excluding US/Canada, Europe)

Baseline anti-dsDNA (Anti-dsDNA≥30 IU/mL, Not [anti-dsDNA≥30IU/mL])

Baseline Complement (At least one C3/C4 Low, No C3/C4 Low)

Baseline C3/C4 levels & anti-dsDNA (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])

Baseline Renal Biopsy Class (Class III or Class IV, Class V, Class III+V or Class IV+V)
To assess the treatment effect within a subgroup, the data will be modelled using BY-group 
processing where the subgroup is the BY-group.  The independent variables in the model will be 
treatment group, induction regimen, race, baseline uPCR, baseline GFR.  If the subgroup variable 
is one of the covariates, then the corresponding covariate will be removed (i.e., for the induction 
regimen subgroup, induction regimen will not be a covariate in the model. 
The treatment-by-subgroup interaction will be assessed in a separate model, without BY-group 
processing, and with covariates as described above plus the subgroup variable and the treatment-
by-subgroup interaction term.  If the subgroup of interest is one of the independent variables 
defined for the model, then only the interaction term will be added.
Statistical significance will be declared for main effects with p ≤ 0.05 and interaction term with p ≤ 
0.10.
7.1.6.
Sensitivity Analyses
Sensitivity analyses will be performed to evaluate the robustness of the primary efficacy 
results if the primary endpoint is statistically significant.  The sensitivity analyses will use 
the same estimand parameters described in Section 7.1.1 through Section 7.1.5 unless 


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otherwise stated.  Sensitivity analyses will include comparing PERR at Week 104 
between treatment groups for:
Sensitivity analysis
Summary Measure 
Population
Intercurrent Event 
Strategy (Imputation 
[1])
Completer
Adjusted Odds Ratio
Completer
Composite 
(IPD/TF/WD=NR)
Per Protocol [2]
Adjusted Odds Ratio
Per Protocol
Composite 
(IPD/TF/WD=NR)
Hybrid Treatment Policy [3]
Adjusted Odds Ratio
MITT
Hybrid Treatment 
Policy
(TF/WD=NR)
Treatment Policy [3]
Adjusted Odds Ratio
MITT
Treatment Policy
(WD=NR)
Unadjusted
Unadjusted Odds Ratio 
MITT
Composite 
(IPD/TF/WD=NR)
[1] IPD=Investigational Product Discontinuation, TF=Treatment Failure, WD=Withdrawal, 
NR=Non-responder.  The terminology indicates the intercurrent events in the list result in a non-
responder imputation from the date of the earliest intercurrent event through the Week 104 visit.
[2] Performed only if ≥15% of subjects are excluded from the Per Protocol population.
[3] See Section 7.1.6.1.
7.1.6.1.
Treatment Policy Sensitivity Analyses
Two treatment policy analyses will be performed.  One analysis, referred to as the 
Treatment Policy analysis, ignores intercurrent events of IP discontinuation and treatment 
failure such that all data observed after these events will be used in the analysis.  
Additionally, a hybrid treatment policy analysis implements the composite strategy for 
treatment failure since it is a component of the primary endpoint, and a treatment policy 
strategy for intercurrent events of IP discontinuation.  In this hybrid treatment policy 
analysis, treatment failures are treated as non-responders from the date of treatment 
failure onward and IP discontinuations are ignored such that all observed data after IP 
discontinuation is used in the analysis.
Missing data due to study withdrawal, loss to follow-up, or death will be treated as non-
responders from the date of the intercurrent event onward (see Section 7.1.4.1.). Table 4
provides a comparison of the management of TF and IP discontinuation between the 
primary endpoint and treatment policy analyses.


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Table 4
Management of Intercurrent events in Primary Analysis vs. 
Treatment Policy Sensitivity Analyses
Analysis
TF retained as part 
of Endpoint?
Observed Data 
post-TF used?
Observed Data 
Post IP 
Discontinuation 
Used?
Primary [1]
Y
N
N
Hybrid Treatment Policy [2]
Y
N
Y
Treatment Policy [3]
N
Y
Y
[1] IPD/TF/WD=NR imputation.
[2] TF/WD=NR imputation.
[3] WD=NR imputation.
7.1.6.2.
Tipping Point Analysis
Tipping point analyses will be performed for the primary endpoint (PERR) and the 
complete renal response (CRR) endpoint if either endpoint is statistically significant per 
the pre-specified testing hierarchy and it is plausible that the imputation strategy for 
missing data could alter the conclusions of the analysis. Plausible occurs when the
endpoint p-value is ≤ 0.05 and > 0.001. The tipping point analysis will be based on the 
modified Intent-to-treat population using both the hybrid treatment policy and treatment 
policy intercurrent event strategies described in Section 7.1.6.1.  
In the primary analysis, subjects for whom the Week 104 PERR response status cannot 
be determined due to missing data, either due to intercurrent events that preclude 
observation of data (study withdrawal, lost to follow-up, or death; Section 7.1.4) or due to 
missing visit data (see Section 7.1.4.1), are imputed as non-responders. This imputation 
will be referred to as IPD/TF/WD=NR imputation.
In contrast to the primary analysis, in the event of missing data the tipping point analysis
evaluates every possible combination of placebo responder/non-responder with every 
possible combination of belimumab responder/non-responder.  For the treatment policy 
intercurrent event strategy, all observed data at Week 104 will be used and unobserved 
(missing) data due to a subject outcome of death, study withdrawal, or lost to follow-up 
will be assessed using all possible combinations of responder/non-responder by treatment 
group.  For the hybrid treatment policy strategy, a subject experiencing a treatment 
failure will be considered a non-responder at Week 104, otherwise observed and 
unobserved data will be managed the same as the treatment policy strategy. 
Each possible combination of responder/non-responder outcome by treatment will be 
tested using a Mantel-Haenszel chi-square test. Table 5 provides an example for 
illustrative purposes.


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Table 5
Example of Responders, Non-Responders, and Missing Data
PERR
Placebo
(N=10)
Belimumab
(N=10)
Responders, n (%)
3 (30%)
5 (50%)
Non-Responders, n (%)
3 (30%)
2 (20%)
Missing Data, n (%)
4 (40%)
3 (30%)
Table 6 provides all possible combinations of imputation of responders among the 
4 placebo subjects and 3 belimumab subjects with missing data due to missed visits or an 
intercurrent event.
Table 6
All Possible Combinations of Responders Among Subjects with 
Missing Data
Combination
Number
Placebo Responders
Belimumab Responders
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
0/4 (0%)
0/4 (0%)
0/4 (0%)
0/4 (0%)
1/4 (25%)
1/4 (25%)
1/4 (25%)
1/4 (25%)
2/4 (50%)
2/4 50%)
2/4 (50%)
2/4 (50%)
3/4 (75%)
3/4 (75%)
3/4 (75%)
3/4 (75%)
4/4 (100%)
4/4 (100%)
4/4 (100%)
4/4 (100%)
0/3 (0%)
1/3 (33%)
2/3 (67%)
3/3 (100%)
0/3 (0%)
1/3 (33%)
2/3 (67%)
3/3 (100%)
0/3 (0%)
1/3 (33%)
2/3 (67%)
3/3 (100%)
0/3 (0%)
1/3 (33%)
2/3 (67%)
3/3 (100%)
0/3 0%)
1/3 (33%)
2/3 (66%)
3/3 (100%)
Belimumab and placebo percentages will be graphed on the x-axis and y-axis, respectively.
Table 7 provides an example of the results for the placebo/belimumab responder 
combination in row 2 of Table 5. In this example, if there is one additional responder in
each treatment arm among subjects with missing data, then the overall response rate 
becomes 40% Placebo and 60% Belimumab.  


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Table 7
Example of Imputation of Responders Among Subjects with Missing 
Data
PERR
Placebo
(N=10)
Belimumab
(N=10)
Responders, n 
3 
5 
Non-Responders, n 
3 
2 
Missing Data
Responders
1 
1
Non-Responders
3
2
Overall Responders
(3+1)/10 or 40%
(5+1)/10 or 60%
No covariates will be used in the tipping point analysis; this simplifies the analysis and 
interpretation by removing the impact of response within stratum on the overall analysis.  
Additionally, removing the covariates allows for the outcomes of all possible 
combinations of responders/non-responders by treatment to be presented on a single heat 
map graph which aids the interpretation. The heat map (Figure 2) will display the 
percentage of placebo responders on the Y-axis and belimumab responders on the X-axis
for each of the possible combinations of responders/non-responders for missing data. 
Each incremental step will represent a difference in the overall percentage of responders 
for each additional subject assumed to respond, up to the maximum percentage which 
assumes all missing data were classified as responders. Reference lines on the hybrid 
treatment policy heat map will correspond to the response rates for the PERR primary 
analysis using the IPD/TF/WD=NR imputation.  Reference lines on the treatment policy 
heat map will correspond to the rate using observed Week 104 responders and assuming 
no subjects with a missing response are responders. The statistical significance of the 
treatment difference under each response scenario will be assessed by a Mantel-Haenszel 
chi-square test.  A table presenting all response scenarios and associated Mantel-Haenszel 
test will be produced for each treatment policy approach.
Figure 2
Tipping Point for PERR at Week 104 


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7.1.7.
Supplementary Analyses
The following endpoints are described in greater detail in Section 7.3 and are considered 
as supplementary analyses of the PERR: 
PERR Individual components   
Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio ≤0.7 (IPD/TF/WD=NR)

eGFR is no more than 20% below pre-flare value or ≥60 mL/min/1.73m2
(IPD/TF/WD=NR)

Not a Treatment Failure

PERR and the individual components at Week 104 using the Treatment Policy 
Strategy (WD=NR)
Other Supplementary PERR Analyses

Proportion of subjects with PERR by visit.

Time to the first PERR that is maintained through Week 52

Time to the first PERR that is maintained through Week 104
Analyses of these endpoints are described in Section 7.3.
Additionally, a table providing the disposition of subjects for the PERR endpoint will be 
provided to understand the reasons for not being a PERR responder. The categories will 
be arranged hierarchically such that a subject is only presented in one category in the 
following order: 
Intercurrent event without treatment failure
Study withdrawal without prior study drug discontinuation
Study drug discontinuation
Insufficient Renal Response due to:
Urine protein:creatinine ratio (uPCR) only
            Estimated Glomerular Filtration Rate (eGFR) Only
Treatment Failure (TF) Only
uPCR and eGFR
uPCR and TF
eGFR and TF
uPCR and eGFR and TF
A table of the first criterion met to deem a subject a treatment failure will also be 
provided for all treatment failures while on treatment and renal event-related treatment 
failures while on treatment. If more than one criterion is met on the earliest treatment 
failure date, all criteria met on the earliest treatment failure date will be presented. To 
support the treatment policy analysis, an additional table will be provided that includes 
the number and percentage of subjects experiencing each unique treatment failure 
criterion, including criterion met after IP discontinuation.


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7.2.
Secondary Efficacy Analyses
7.2.1.
Complete Renal Response at Week 104
Endpoint
Complete Renal Response (CRR)
Defined as reproducible changes
Responder

uPCR < 0.5; and

eGFR no more than 10% below pre-flare GFR or within normal range; and

Not a Treatment Failure [1]
Non-Responder

Not meeting criteria for a responder
[1] Treatment failure is defined in Section 5.5 and Section 5.6 of the protocol and further described 
in Section 14.6.3.3 of this RAP.
Statistical Analysis
CRR (Responder vs. Non-Responder) at Week 104 will be compared between belimumab and 
placebo using logistic regression with covariates for induction regimen (CYC vs. MMF), race (Black 
vs. Non-Black), baseline uPCR, and baseline eGFR.
Summary Measure
An odds ratio will measure the treatment effect for the odds of being a responder on belimumab vs. 
placebo.
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
The intercurrent events strategy is the IPD/TF/WD=NR strategy as defined in Section 7.1.4.
Variables

CRR (Responder vs. Non-Responder)

Treatment (belimumab=1, placebo=0)

Induction regimen (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)

uPCR (at baseline; continuous)

eGFR (at baseline; continuous)
Model Specification
model CRR = Treatment Induction Race uPCR eGFR
Model Checking & Diagnostics
See Section 7.1.5.
Model Results Presentation
See Section 7.1.5.
Subgroup Analyses


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See Section 7.1.5.
Sensitivity Analyses
Sensitivity analyses analogous to the sensitivity analyses described for the PERR endpoint in 
Section 7.1.6 will be performed for CRR if the endpoint is statistically significant per the testing 
hierarchy and includes:

Hybrid Treatment Policy and Treatment Policy analyses (see Section 7.1.6.1)

Completer Population 

Per Protocol Population (will be performed only if ≥15% of subjects are excluded from the Per Protocol 
population) 

Modified Intent-to-Treat population unadjusted for covariates to complement the tipping point analysis 
which is also unadjusted for covariates

Tipping point analysis (see Section 7.1.6.2).
Supplementary Analyses
The following endpoints are supplementary analyses of the CRR endpoint.  These will be analysed 
and presented as described in Section 7.3.  Derivations of these endpoints are found in Section 
14.6.3. The Not a Treatment Failure component is identical to the PERR component and is 
presented with the PERR supplementary analyses. 
CRR individual components 
Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio < 0.5.(IPD/TF/WD=NR)

eGFR no more than 10% below the pre-flare value or within the normal range
.(IPD/TF/WD=NR)

CRR and the individual components at Week 104 using the Treatment Policy 
Strategy (WD=NR)
CRR

Proportion of subjects with CRR by visit.

Time to the first CRR that is maintained through Week 52.

Time to the first CRR that is maintained through Week 104.
Additionally, a table providing the disposition of subjects for the CRR endpoint will be provided to 
understand the reasons for not being a CRR responder. The categories will be arranged 
hierarchically such that a subject is only presented in one category in the following order: 
Intercurrent event without treatment failure
Study withdrawal without prior study drug discontinuation
Study drug discontinuation
Insufficient Renal Response due to:
Urine protein:creatinine ratio (uPCR) only
            Estimated Glomerular Filtration Rate (eGFR) Only
Treatment Failure (TF) Only
uPCR and eGFR
uPCR and TF
eGFR and TF


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uPCR and eGFR and TF
7.2.2.
Primary Efficacy Renal Response (PERR) at Week 52
Endpoint
Primary Efficacy Renal Response at Week 52 is defined in the same manner as PERR at Week 
104 defined in Section 7.1.1. only using a response at the Week 48 visit that is confirmed by a 
repeat measurement at the Week 52 visit to derive the endpoint.
Statistical Analysis
PERR (Responder vs. Non-Responder) at Week 52 will be compared between the belimumab plus 
standard of care treatment group and placebo plus standard of care group using logistic regression 
with covariates for induction regimen (CYC vs. MMF), race (Black vs. Non-Black), baseline uPCR, 
and baseline eGFR. 
Summary Measure
An odds ratio will measure the treatment effect for the odds of being a responder on belimumab vs. 
placebo.
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
The intercurrent events strategy will be analogous to that described in Section 7.1.4.
Variables

PERR at Week 52 (Responder vs. Non-Responder)

Treatment (belimumab=1, placebo=0)

Induction (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)

uPCR (at baseline; continuous)

eGFR (at baseline; continuous)
Model Specification
model PERR at Week 52 = Treatment Induction Race uPCR eGFR
Model Checking & Diagnostics
See Section 7.1.5.
Model Results Presentation
See Section 7.1.5.
Subgroup Analyses
Subgroup analysis of the PERR endpoint at Week 52 will be done for 

Induction Regimen (CYC, MMF), and 

Baseline C3/C4 levels & anti-dsDNA (At least one C3/C4 low and anti-dsDNA ≥30 IU/mL, 


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Not [At least one C3/C4 low and anti-dsDNA ≥30 IU/mL]). 
See Section 7.1.5. for more details.
Sensitivity Analyses
Sensitivity analysis using the treatment policy strategy described in Section 7.1.6.1 may be 
performed if PERR at Week 52 is statistically significant per the testing hierarchy.  If required, this 
sensitivity analysis will be carried out after SAC.
Supplementary Analyses
A table providing the disposition of subjects for the PERR endpoint at Week 52 will be provided to 
understand the reasons for not being a Week 52 PERR responder. The categories will be arranged 
hierarchically such that a subject is only presented in one category in the following order: 
Intercurrent event without treatment failure
Study withdrawal without prior study drug discontinuation
Study drug discontinuation
Insufficient Renal Response due to:
Urine protein:creatinine ratio (uPCR) only
            Estimated Glomerular Filtration Rate (eGFR) Only
Treatment Failure (TF) Only
uPCR and eGFR
uPCR and TF
eGFR and TF
uPCR and eGFR and TF
7.2.3.
Time to Death or Renal-related Event
Endpoint
Time to Death or Renal-related event is defined as the first event occurring among the following: 
i)
Death
ii)
End stage renal disease (ESRD), 
iii) Doubling of serum creatinine,
iv) Renal worsening as evidenced by increased proteinuria and/or impaired renal function, or
v)
Renal event-related treatment failure.
Events are only counted if they occur on or before IP discontinuation and treatment failure not 
related to renal disease. A subject will be classified as having an event or being censored based on 
the earliest occurrence of endpoint and censoring events in Table 8. 


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Table 8
Disposition of Events and Censoring (IPD/TF not related to renal 
disease/WD=Censor)
Endpoint Event
Disposition
Death 
Event at date of death
End stage renal disease
Event at date of progression to end stage renal disease
Doubling of serum creatinine
Event at date of first doubling of serum creatinine relative to 
baseline
Renal worsening
Event at date of renal worsening
Renal event- related treatment failure
Event at renal event-related treatment failure date
The following events will result in censoring if an endpoint event has not occurred:  
Censoring Event
Disposition
Discontinue investigational product (IP)
Censor at IP discontinuation date.
Treatment Failure not related to Renal 
Event
Censor at treatment failure date not related to renal event
Withdraw (WD) from Study 
Censor at double blind withdrawal date
Lost to Follow-up
Censor at lost to follow-up date (i.e., last visit in double blind 
period)
Completes Week 104
Censor at Week 104 visit date
Continues to open-label extension but 
missing Week 104 visit
Censor at the last visit in the double-blind period
Statistical Analysis
A Cox proportional hazards model controlling for induction regimen (CYC, MMF), race (Black, Non-
Black), baseline uPCR, and baseline eGFR will be used to evaluate time to death or renal-related 
event.
Summary Measure
A hazard ratio will measure the treatment effect for belimumab vs. placebo.
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
Intercurrent events are defined in Section 7.1.4. Intercurrent events of IP discontinuation, treatment 
failure not related to renal event, lost to follow-up, and study withdrawal will result in censoring 
unless they occur after a renal-related event.  The intercurrent events of death and treatment 
failure related to renal event are counted as an event if they occur on or before the intercurrent
events that result in censoring.  This strategy is referred to as IPD/TF not related to renal 
disease/WD=Censor.


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Variables

Time (time to first event in days)

Censor (Yes=1, No=0)

Treatment (belimumab=1, placebo=0)

Induction (CYC=1, MMF=0)

Race (Black=1, Non-Black=0)

uPCR (at baseline; continuous)

eGFR (at baseline; continuous)
The endpoint derivations are described in Section 14.6.3.
Model Specification
model Time*Censor = Treatment Induction Race uPCR eGFR
Ties will be managed using Efron’s approximation.
Model Checking & Diagnostics
The data will be evaluated by two independent statisticians to determine if the model assumptions 
and fit are reasonably met.  If either is deemed unacceptable, additional sensitivity analysis using 
an alternative method may be performed
Model Results Presentation
The following results will be displayed by treatment group: number and percentage of subjects with 
an event and the median, 25th percentile, and 75th percentile of days to first event, hazard ratio, 
95% CI, and p-value be presented for the effect of belimumab vs. placebo for proportional hazards 
models.  For subjects with an event, the median, 25th percentile, 75th percentile, minimum, and 
maximum values of the study day of the first event will be presented.
Subgroup Analyses
Subgroup analysis of Time to Death or Renal-related Event will be done for

Induction regimen (CYC, MMF), and 

Baseline C3/C4 levels & anti-dsDNA (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]).
See Section 7.1.5. for more details.
Supplementary Analyses
A Kaplan-Meier (KM) plot of time to event will be produced to evaluate the pattern of events over 
time as well as a supporting table of Kaplan-Meier estimates.  
Each component of the composite endpoint will be assessed individually for time to ‘component’ 
using the ‘IPD/TF not related to renal disease/WD=Censor’ strategy for intercurrent events. To 
assess the impact of the component independent of the other events, a subject’s follow-up time will 
not be censored if another component event occurs. Censoring will be applied as described in 
Table 8.
Additionally, a table displaying the number and percentage of subjects with a first event by event 
type, induction regimen, and induction regimens combined will be provided.  


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7.2.3.1.
Treatment Policy Analysis
For the treatment policy analysis of Time to Death or Renal-related Event, the renal event-related 
treatment failure will not be one of the components of the composite endpoint as this is also an 
intercurrent event. A subject will be classified as having an event based on the earliest occurrence 
of one of the four endpoint events in Table 9.
Table 9
Disposition of Events and Censoring (Treatment Policy)
Endpoint Event
Disposition
Death 
Event at date of death
End stage renal disease
Event at date of progression to end stage renal disease
Doubling of serum creatinine
Event at date of first doubling of serum creatinine relative to 
baseline
Renal worsening
Event at date of renal worsening
The following will result in censoring if an endpoint event has not occurred:  
Censoring Event
Disposition
Withdraw (WD) from Study 
Censor at double blind withdrawal date
Lost to Follow-up
Censor at lost to follow-up date (i.e., last visit in double blind 
period)
Completes Week 104
Censor at Week 104 visit date
Continues to open-label extension but 
missing Week 104 visit 
Censor at the last visit in the double-blind period
Analyses of the components will be managed as described in Section 7.2.3. under 
Supplementary Analyses using censoring rules in Table 9.
7.2.3.2.
Tipping Point Analysis
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 an endpoint event at the time of censoring (worst 
case scenario corresponding to an infinite event rate for subjects who dropped out/lost to 
follow-up) to assuming that all prematurely censored subjects on a particular treatment 
arm had completed the study without experiencing an event (best case scenario 


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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 
114054. 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 
with separate multiplying factors for experimental and control.
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 729
days), the subject will be considered to have experienced an endpoint at the 
imputed event time. Otherwise the subject was administratively censored at 729
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 time to Death or Renal-related event 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 


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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.
7.2.4.
Ordinal Renal Response at Week 104
Endpoint
Complete Renal Response (CRR)

uPCR < 0.5; and

eGFR no more than 10% below pre-flare GFR or within normal range; and

Not a Treatment Failure [1]
Partial Renal Response (PRR)

≥ 50% decrease from baseline in uPCR and one of the following: value <1 if baseline ≤3, or 
value <3 if the baseline was >3; and

eGFR no more than 10% below baseline GFR or within normal range; and

Not a Treatment Failure [1]
No Response

Not meeting criteria for either complete or partial renal response
[1] Treatment failure is defined in Section 5.5 and Section 5.6 of the protocol and further described 
in Section 14.6.3.3 of this RAP.
See Section 14.6.3.10 for more details on the endpoint derivation.
Statistical Analysis
A rank analysis of covariance model controlling for induction regimen (CYC, MMF), race (Black, 
Non-Black), baseline uPCR, and baseline eGFR will be used to evaluate the treatment effect for 
ORR. 
Summary Measure
A treatment difference for the proportion of subjects in each response category (CRR, PRR, and 
NR) will measure the treatment effect for belimumab vs. placebo.   
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
The intercurrent events strategy is the IPD/TF/WD=NR strategy as defined in Section 7.1.4.  
Handling of missing data is defined in Section 7.1.4.1.
Variables

Ordinal Renal Response (Complete=2, Partial=1, Non-Responder=0)

Treatment (belimumab=1, placebo=0)

Induction (CYC=1 vs. MMF=0)


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
Race (Black=1 vs. Non-Black=0)

uPCR (at baseline; continuous)

eGFR (at baseline; continuous)

Model Specification
model ORR = Treatment Induction Race uPCR eGFR
Model Checking & Diagnostics
Not applicable.
Model Results Presentation
At Week 104, each response category (complete, partial, no response) will have the number, 
percentage, standard error of the percentage and treatment difference displayed along with the p-
value from the rank ANCOVA analysis. 
Subgroup Analyses
Subgroup analysis of the ORR endpoint at Week 104 will be done for

Induction Regimen (CYC, MMF), and 

Baseline C3/C4 levels & anti-dsDNA (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]). 
The subgroup analysis for induction regimen will be provided on the by-visit table for the Week 104 
visit only.  To assess the treatment effect within a subgroup, the data will be modelled using BY-
group processing where the subgroup is the BY-group.  The independent variables in the model 
will be treatment group, induction, race, baseline uPCR, baseline GFR.  If the subgroup variable is 
one of the covariates, then the corresponding covariate will be removed (i.e., for the induction 
regimen subgroup, induction regimen will not be a covariate in the model). 
Sensitivity Analyses
Sensitivity analysis using the treatment policy strategy described in Section 7.1.6.1 may be 
performed if the endpoint is statistically significant per the testing hierarchy.  If required, this 
sensitivity analysis will be carried out after SAC.
Supplementary Analyses
The following endpoints are supplementary analyses of the ORR endpoint.  Derivations of these 
endpoints are found in Section 14.6.3.

Proportion of subjects with ORR by visit.

ORR including Urinary Sediment at Week 104 which will be analysed with a rank ANCOVA.

ORR including Urinary Sediment and using calculated GFR at Week 104 which will be 
analysed using a Van Elteren test.
7.3.
Other Efficacy Analyses
Other Efficacy endpoints and supplementary efficacy endpoints identified in Section 2.2
have been grouped by endpoint type (proportion; change/percent change from baseline;


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and time to flare) to provide a blanket explanation of the estimands and analysis methods 
for each endpoint type. 
7.3.1.
Proportion Endpoints
Endpoints
Individual Components of PERR

Urinary protein:creatinine ratio ≤0.7

eGFR is no more than 20% below pre-flare value or ≥60 mL/min/1.73m2

Not a Treatment Failure
PERR

Proportion of subjects with PERR by visit.
CRR individual components
Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio < 0.5.

eGFR no more than 10% below the pre-flare value or within the normal range
(≥90 mL/min/1.73m2).
CRR

Proportion of subjects with CRR by visit.
Renal-Specific Measures 

Proportion of subjects with a doubling of the serum creatinine or progression to end stage renal 
disease (ESRD) as defined below:
o
Doubling of serum creatinine compared with baseline that is confirmed with a second 
measurement at least 3 weeks later.
o Progression to ESRD defined as the need for chronic dialysis or renal transplantation.
SLEDAI-S2K

Proportion of subjects with SLEDAI-S2K <4 by visit

Proportion of subjects with improvement in SLEDAI-S2K organ systems by visit among 
subjects with organ system involvement at baseline.

Proportion of subjects with worsening in SLEDAI-S2K organ systems by visit among subjects 
with no organ system involvement at baseline.
Corticosteroids

Proportion of subjects receiving prednisone  5 mg average daily dose since previous visit

Proportion of subjects receiving prednisone 7.5 mg average daily dose since previous visit
Supplementary Analyses

Proportion of subjects receiving prednisone  5 mg average daily dose since previous visit by 
Week 104 PERR Response.

Proportion of subjects receiving prednisone 7.5 mg average daily dose since previous visit
by Week 104 PERR Response.
SLICC Damage Index


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
Percent of patients with any SLICC Damage Index worsening (change >0) compared with 
baseline by visit.
The endpoint derivations are described in Section 14.6.3.
Statistical Analysis
Each proportion endpoint will be compared between belimumab and placebo using logistic 
regression controlling for baseline value, induction regimen (CYC vs. MMF) and race (Black vs. 
Non-Black).  
Exceptions: 
1.
Endpoints without a baseline value (treatment failures, PERR by visit, and CRR by visit) 
will be evaluated using logistic regression controlling for induction regimen (CYC vs. MMF) 
and race (Black vs. Non-Black).
2.
Renal Specific Measures is a composite endpoint but only serum creatinine has a baseline 
value, therefore this endpoint will be evaluated using logistic regression controlling for 
baseline serum creatinine, induction regimen (CYC vs. MMF) and race (Black vs. Non-
Black).  
3.
SLEDAI-S2K organ worsening and organ improvement endpoints will not have statistical 
analysis performed. 
Summary Measure
An odds ratio will measure the treatment effect for the odds of being a responder on belimumab vs. 
placebo at Week 104 only.
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
Intercurrent events are defined in Section 7.1.4. 

PERR- and CRR-based endpoints, prednisone endpoints, and SLEDAI-S2K < 4 will impute 
a Non-Responder for all planned time points after the first intercurrent event occurs
(IPD/TF/WD=NR strategy).  

Endpoints for Renal-Specific measures, SLEDAI-S2K organ worsening, serum creatinine 
doubling/ESRD will use a LO on or prior to IPD/TF CF strategy for timepoints post an 
intercurrent event in which the last observed value on or before the intercurrent event will 
be carried forward for all subsequent time points through Week 104.

SLEDAI-S2K organ improvement will use an IPD/TF/WD=No improvement imputation 
strategy in which the last observed post-baseline value on or prior to the intercurrent event 
will be carried forward for all subsequent time points through Week 104.

SLICC Damage Index will use a Worst Observation Carried Forward (WOCF) imputation 
and will be presented for data for both on-treatment and on-study analyses.
Variables

Endpoint (Responder vs. Non-Responder or Yes vs. No)

Baseline_Value (Continuous)*


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
Treatment (belimumab=1, placebo=0)

Induction regimen (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)
*Note: For Renal Specific Measures Baseline_Value is the baseline serum creatinine.
Model Specification
For endpoints with a baseline value:
model Endpoint = Treatment Baseline_Value Induction Race 
For endpoints without a baseline value:
model Endpoint = Treatment Induction Race
Model Checking & Diagnostics
See Section 7.1.5.
Model Results Presentation
See Section 7.1.5.
For SLEDAI-S2K organ worsening and organ improvement endpoints, the number and percentage 
of subjects who experience worsening or improvement will be presented within induction regimen 
and overall for combined induction regimens by organ domain and visit.
Subgroup Analyses
Analyses will be performed within induction regimen (CYC, MMF). The independent variables in 
the model will be treatment group and race. Model results will be presented as defined in Section 
7.1.5 with the exception of the p-value. 
Sensitivity Analyses
Sensitivity analyses of the endpoints based on observed data ignoring intercurrent events will be 
performed for the following:
Renal Response
•
PERR and its components at Week 104
•
CRR and its components at Week 104
Renal-Specific Measures 

Proportion of subjects with a doubling of the serum creatinine or progression to end stage renal 
disease (ESRD) 
SLEDAI-S2K

Proportion of subjects with SLEDAI-S2K <4 by visit

Proportion of subjects with improvement in SLEDAI-S2K organ systems by visit among 
subjects with organ system involvement at baseline.

Proportion of subjects with worsening in SLEDAI-S2K organ systems by visit among subjects 
with no organ system involvement at baseline.
Corticosteroids

Proportion of subjects receiving prednisone  5 mg average daily dose since previous visit


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
Proportion of subjects receiving prednisone 7.5 mg average daily dose since previous visit
SLICC Damage Index

Percent of patients with any SLICC Damage Index worsening (change >0) compared with 
baseline by visit.
(Note: The WOCF is used for SLICC in the observed case to ensure the highest score for an 
individual item is carried forward to subsequent observed visits, it does not impute missing visits.)
7.3.2.
Continuous Endpoints (Change/Percent Change from Baseline)
Endpoints
Renal Endpoints

Percent change in proteinuria by visit.

Change in proteinuria by visit.
SLEDAI-S2K

Change from baseline in SLEDAI-S2K score by visit.

Change from baseline in SLEDAI-S2K excluding renal items by visit.
SLICC Damage Index
SLICC Damage Index (SDI) change from baseline by visit.
Statistical Analysis
An ANCOVA will be used to evaluate SLEDAI-S2K change from baseline endpoints for the 
treatment effect controlling for baseline value, induction regimen (CYC, MMF) and race (Black, 
Non-Black).
A rank ANCOVA will be used to evaluate proteinuria and SLICC Damage Index change from 
baseline endpoints for the treatment effect controlling for baseline value, induction regimen (CYC, 
MMF) and race (Black, Non-Black).
Summary Measure
The difference in the Least Square (LS) means (belimumab – placebo) will be used to assess the 
treatment effect for the ANCOVA analyses.
Population of Interest
The modified Intent-to-Treat population will be used for the analysis.
Strategy for Intercurrent Events
Intercurrent events are defined in Section 7.1.4.  

Data will be presented as ‘While on Treatment (Observed)’ meaning only data collected 
while the subject is on IP is presented, intercurrent events of treatment failure are ignored, 
and there is no imputation for unobserved data (e.g., after withdrawal events). 

For SLICC change from baseline, data will be presented as ‘While on Treatment  
(Observed with WOCF) meaning only data collected while the subject is on IP is 
presented, intercurrent events of treatment failure are ignored, for observed visits only a 
Worst Carried Forward (WOCF) imputation (see Section 14.6.3.18 for more detail). will be 
applied at the item level but will not carry forward to missed visits, and there is no 


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imputation for unobserved data (e.g., after withdrawal events.  
Variables

Endpoint (defined in Section 14.6.3)

Treatment (belimumab=1, placebo=0)

Baseline Value (continuous)

Induction (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)
Model Specification
model Endpoint = Treatment Baseline_Value Induction Race
Model Checking & Diagnostics
The data will be evaluated by two independent statisticians to determine if the model assumptions 
and fit are reasonably met.  If either is deemed unacceptable, additional sensitivity analysis using 
an alternative method may be performed
Model Results Presentation
The following results will be displayed by treatment group: mean, standard deviation, standard 
error, median, 25th percentile, 75th percentile, minimum, and maximum.  The following will also be 
presented at Week 104: LS mean and its standard error, the difference (belimumab – placebo) in 
LS Means, 95% CI, and p-value from ANCOVA for difference in LS Means will be presented.
For rank ANCOVA, the following results will be displayed by induction regimen and treatment 
group: mean, standard deviation, standard error, median, 25th percentile, 75th percentile, minimum, 
maximum.  The p-value for the rank ANCOVA will be presented for the treatment comparison for 
the combined induction regimens at Week 104 only.
Subgroup Analyses
Subgroup analysis will be performed within each induction regimen (CYC, MMF) using the model 
Endpoint = Treatment Baseline_Value Race.  Model results as defined above will be presented 
with the exception of the p-value.
Sensitivity Analyses
Sensitivity analyses of the endpoints based  ‘While on Study (Observed)’ uses all observed data 
whether on or off IP, ignores intercurrent events of treatment failure, and does not impute values 
for unobserved data (e.g., after withdrawal events) for the following:
Renal Endpoints

Percent change in proteinuria by visit.

Change in proteinuria by visit.
SLEDAI-S2K

Change from baseline in SLEDAI-S2K score by visit.

Change from baseline in SLEDAI-S2K excluding renal items by visit.
For SLICC, sensitivity analyses will be based on ‘While on Study (Observed with WOCF) which 
follows the same intercurrent event strategy as the ‘While on Study (Observed)’ and applies WOCF 
on the observed visits only.
SLICC Damage Index
SLICC Damage Index (SDI) change from baseline by visit.


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Further exploration of the impact of missing data on these endpoints may be undertaken post-SAC. These 
analyses will use multiple imputation methodology.
7.3.3.
Time to Event Endpoints
Endpoint
PERR Supplementary Endpoints

Time to the first PERR that is maintained through Week 52 (see Section 14.6.3.3)

Time to the first PERR that is maintained through Week 104 (see Section 14.6.3.3)
CRR Supplementary Endpoints

Time to the first CRR that is maintained through Week 52 (see Section 14.6.3.3)

Time to the first CRR that is maintained through Week 104 (see Section 14.6.3.3)
SFI Flares

Time to first severe SFI flare. (see Section 14.6.3.14)

Time to first severe SFI flare from Week 24. (see Section 14.6.3.14)
Statistical Analysis
A cox proportional hazards model controlling for induction regimen (CYC, MMF) and race (Black, 
Non-Black) will be used to evaluate time to event endpoints.
Summary Measure
A hazard ratio will measure the treatment effect for belimumab vs. placebo.   
Population of Interest
The analyses will be based on the modified Intent-To-Treat population.
Intercurrent Event Strategy
Intercurrent events are defined in Section 7.1.4.
For time to first maintained PERR and CRR, IPD/TF/WD=NR imputation will be used for 
intercurrent events.
For severe SFI flares, a treatment failure is imputed as an event while IP discontinuation and study 
withdrawal are censoring events (TF=Flare, IPD/WD=Censor). 
Variables

Time (time to first event in days)

Censor (Yes=1, No=0)

Treatment (belimumab=1, placebo=0)

Induction (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)
The endpoint derivations are described in Section 14.6.3.


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Model Specification
model Time*Censor = Treatment Induction Race
Ties will be managed using Efron’s approximation.
Model Checking & Diagnostics
The data will be evaluated by two independent statisticians to determine if the model assumptions 
and fit are reasonably met. 
Model Results Presentation
The following results will be displayed by treatment group: number and percentage of subjects with 
an event and the median, 25th percentile, and 75th percentile of days to first response, hazard ratio, 
95% CI, and p-value be presented for the effect of belimumab vs. placebo for proportional hazards 
models.
Subgroup Analyses
Time to event analyses will be performed within each Induction Regimen (CYC, MMF). The 
independent variables in the model will be treatment group and race. Model results will be 
presented as defined above with the exception of the p-value. 
Supplementary Analyses
A Kaplan-Meier (KM) plot of time to event will be produced to evaluate the pattern of events over 
time as well as a supporting table of Kaplan-Meier estimates.


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8.
SAFETY ANALYSES
Unless otherwise stated, all analyses will be limited to the double-blind treatment period 
while subjects are on investigational product (IP). For safety analyses this is defined as 
the period of exposure defined in Section 14.6.2.4. Safety will be evaluated by adverse 
events (AEs), changes in laboratory parameters, vital signs and immunogenicity. The 
safety analyses will be based on the safety population, unless otherwise specified.  The 
safety population is defined in Section 4 as all randomized subjects who received at least 
one dose of investigational product and includes the subject enrolled at site 
 and 
the subject at site 
 who are excluded from the efficacy analyses.  Analyses of the 
safety population is based on the randomized treatment; however, if there are more than 
15% of subjects who receive a study treatment that is different from the randomized 
treatment for > 50% of infusions, safety analysis will be performed based on the actual 
treatment received. Unless otherwise specified, the safety tables and listings will be 
presented by induction regimen and treatment group; an overall summary by treatment 
group will also be presented on the tables.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious Adverse 
Events (SAEs) and other significant AEs will be based on GSK Core Data Standards. The 
details of the planned displays are provided in Appendix 12: List of Data Displays.
1. All subjects will be followed for safety through the end of the double-blind treatment 
period including data through the post-treatment follow-up period per Section 3.2
(unless continuing treatment in the open-label phase of the study). 
2. A table summarizing AEs that occurred prior to treatment start date will be presented, 
for each system organ class (SOC) and preferred term (PT). 
3. 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 per the Adverse Event 
Severity Grade Tables Appendix 7 of the Protocol, if a grade is defined for the AE of 
interest.  
4. All treatment-emergent AEs will be summarized for both the double-blind phase.
5. 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, AE 
resulting in study agent discontinuation, AE resulting in study withdrawal, and 
deaths.
6. 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)

Serious AEs (by SOC; by SOC and PT; by PT)

Severe AEs (by SOC; by SOC and PT; by PT)

Related AEs (by SOC; by SOC and PT; by PT)
PPD
PPD


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
AEs leading to discontinuation of study agent (by SOC; by SOC and PT; by PT)

Deaths (by Category and PT)

Common Non-Serious AEs (by SOC and PT)

Related Serious AEs (by SOC and PT)

Related Fatal Serious AEs (by SOC and PT)

Non-Fatal Serious AEs (by SOC and PT)

Related Non-Fatal Serious AEs (by SOC and PT)

Pre-Treatment AEs (by SOC and PT)

Post-Treatment AEs for Serious AEs (by SOC and PT)
AEs Through Week 24 for AEs (by SOC and PT) and SAEs (by SOC and PT)
AEs Post Week 24 for AEs (by SOC and PT) and SAEs (by SOC and PT)
7. 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) 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 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.
8. Common AEs will be defined as ≥ 5% incidence in any treatment group.
9. The table for all AEs by SOC and PT will be repeated for the age, gender, race, 
region, baseline C3/C4 levels & anti-dsDNA categories, and body weight quartile 
subgroups.  See Section 5.4.2 for details on the subgroup categories.
10. A summary of study agent related AEs by SOC, PT, and maximum intensity will be 
provided by induction regimen.  For this display, the number and percentage of 
subjects will be summarized as mild, moderate, or severe for each treatment group 
based on the maximum severity observed within each PT, and within each SOC.
11. A summary of AEs by SOC, PT and maximum intensity will also be provided by 
induction regimen.  The number and percentage of subjects will be summarized as 
mild, moderate, or severe for each treatment group based on the maximum severity 
observed within each PT, and within each SOC.
12. A summary of serious AEs by SOC and PT will be presented.  The number of SAEs 
will be summarized for each of the following categories:

Subjects with SAEs

SAEs

Drug-related SAEs

Fatal SAEs

Drug-related Fatal SAEs
13. The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text will be 
displayed in a listing for all AEs.


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14. Drug-related AEs will be summarized by seriousness (serious and Non-serious) by 
overall frequency
15. A listing that displays which subjects reported each AE will be produced by SOC and 
PT. AEs will be grouped and sorted by SOC and PT.  Listings of all AEs, and Post-
Treatment Serious and Non-Serious AEs will be presented, including duration and 
study day of onset/resolution.  
16. A listing of all AEs for subjects who participated in the study from Mexico, and a
listing of SAEs for subjects in countries other than Mexico will be presented.
8.2.
Deaths, Serious Adverse Events, and Survival Status
In addition to the tabular summaries of AEs described in Section 8.1, listings for all 
SAEs, all deaths, all non-fatal SAEs, and reasons for considering an AE a serious AE will 
be produced.  The categorization of the cause of death will be adjudicated by GSK.
Survival status will also be summarized at Week 104. The number and percentage of
subjects will be summarized for each of the following categories:
1.
Alive
2.
Consent Withdrawn
3.
Lost to Follow-up
4.
All Deaths

Deaths on Treatment

Deaths Post-Treatment
A listing of survival status will also be presented.
8.3.
Adverse Events Leading to Discontinuation of 
Investigational Product
In addition to the tabular summaries described in Section 8.1, a listing of all AEs leading 
to discontinuation of study treatment will be produced.   
8.4.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
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 (PSAP, 


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2018) and reporting of AESIs for these analyses is defined in Section 8.4.  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 AESIs will be provided. The 
following AESIs will be identified using the list of preferred terms in the PSAP (PSAP,
2018) and adjudicated by GSK to further categorize the events as follows:
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

Active Tuberculosis
–
Non-Opportunistic 
–
Opportunistic

Herpes Zoster
–
Non-Opportunistic 
–
Opportunistic

Recurrent 

Disseminated

Sepsis
Depression (including mood disorders and anxiety)/suicide/self-injury (All and Serious, separately) 

Depression (including mood disorders and anxiety) (excluding suicide and self-injury) 

Suicide/self-injury

Serous suicide/self-injury per GSK adjudication 
–
Suicidal Behaviour 


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Adverse Events
Adverse Events of Special Interest (AESI)

Completed Suicide 
–
Suicidal Ideation 
–
Self-injurious Behaviour without Suicidal Intent  

Deaths
Malignant neoplasm events identified as “tumours of unspecified malignancy” will be 
reviewed for classification as malignant per GSK adjudication and will be presented by 
category and PT.
Post-infusion systemic reactions and serious post-infusion systemic reactions will be 
presented using nine different definitions as indicated above. These will 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 the 
PSAP (PSAP, 2018).  
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 the PSAP (PSAP, 2018).  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.
The post-infusion systemic reactions per Anaphylactic Reaction CMQ algorithmic search 
are defined in the PSAP (PSAP, 2018).  The SAEs that are identified by the algorithmic 
search will be reviewed further for potential classification as serious post-infusion 
systemic reactions per GSK adjudication.  For all post-infusion, systemic reaction AESIs 
defined via narrow, broad, or algorithmic search, the AEs need to have occurred on the 
day of an infusion or within 3 days after an infusion. GSK will adjudicate serious events 
identified via the broad search occurring within 21 days after an infusion, and these will 
be divided into a category based on time to onset: acute (onset ≤ 1 day), delayed acute 
(onset 2-3 days), or delayed non-acute (onset 4-21 days).  Adverse events with partial or 
missing start dates will be included unless there is evidence through comparison of partial 
dates to suggest otherwise.
Possible cases of serious anaphylaxis per Sampson criteria will be identified as defined in
the PSAP (PSAP, 2018).
Infection AESIs will be presented by Category and PT for all infections and for infections
leading to study agent discontinuation. 
A summary table of AESIs by Category will be presented for AESIs during the induction 
phase (through Week 24) and maintenance phase (post Week 24).


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Post-Treatment AESIs will be summarized and presented by Category. A listing of Post-
Treatment AESIs will also be presented.
Depression, suicide and self-injury are defined using terms from the ‘Depression 
(excluding suicide and self-injury)’ CMQ plus additional terms added by Marketing 
Authorization Holder (MAH) and ‘Suicide/self-injury’ CMQ. Depression, suicide, and 
self-injury AESIs will be presented by Category and PT.
A listing of all adverse events of special interest will be presented.
8.4.1.
Post-Infusion Systemic Reactions by Infusion
Summaries of post-infusion systemic reactions will be presented by treatment group, by 
the first six infusions and over all 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 (onset within 24 hours of infusion)

Serious Delayed Acute Hypersensitivity Reactions per GSK adjudication (onset 
2-3 days post-infusion)

Serious Delayed Non-Acute Hypersensitivity Reactions per GSK adjudication
(onset 4-21 days post-infusion)

Post-Infusion Systemic Reactions Adverse Events of Special Interest by 
Category and PT (on the day of the infusion or within 3 days after the infusion)

Serious Post-Infusion Systemic Reactions Adverse Events of Special Interest by 
Category and PT (on the day of the infusion or within 3 days after the infusion)
The first six infusions represent the first 6 dosings for each subject and is not based on a 
defined set of scheduled visits.
8.5.
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality assessments are completed at every visit during the double-blind phase.  
Assessments are done using the investigator-administered C-SSRS.  If a “yes” response is 
given to any suicidal behavior or a “yes” response is given 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) 


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
Behavior details for subjects who have any suicidal behavior recorded at any 
point on the study (including screening) 

The most severe suicidal ideation details for subjects who have any suicidal 
ideation recorded at any point on the study (including screening).
8.5.1.
C-SSRS Suicidal Ideation or Behavior Post-Baseline

The number and percentage of subjects with each category of suicidal ideation or 
behavior post-baseline (starting after Day 1 assessment onwards including data 
collected post-IP discontinuation) 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.   Subjects may have 
more than one type of behavior.

For the rows pertaining to suicidal ideation, the number of subjects whose 
maximum ideation on-treatment is the specified ideation is presented.  Subjects 
will be counted once for the maximum ideation.
8.5.2.
Subjects may be counted for ideation and behavior C-SSRS 
Suicidal Ideation or Behavior Relative to Pre-Treatment 
The number and percentage of subjects with treatment-emergent suicidal ideation or 
behavior post-baseline (starting after Day 1 assessment onwards) will be presented.  A 
subject must have at least one pre-treatment assessment and at least one post-baseline
assessment in order to be included in this display. A subject may have more than one 
treatment-emergent suicidal ideation and/or behavior. 
8.5.3.
C-SSRS Shift Changes in Categories from Pre-Treatment to Post-
Baseline
A summary of the shift from maximum pre-treatment C-SSRS category to maximum 
post-baseline (up to and including Week 104 including any data collected after IP 
discontinuation) category will be produced by treatment group.  The pre-treatment period 
is based on the lifetime evaluation at screening.  A subject must have at least one pre-
treatment assessment and at least one post-baseline assessment 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.  
8.6.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of hematology, liver function, electrolytes, 
other chemistries, urinalysis and immunoglobulin data will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.  
Laboratory analyses will be presented for data while subjects are on randomized 
treatment.  Analyses of laboratories for worst toxicity grade and toxicity with a ≥2 grade 
shift will also be presented for all data collected after IP discontinuation.


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For laboratory analyses, the following will be analyzed: (1) analytes with a numeric 
normal range, and (2) urinalysis analytes with categorical results (i.e., positive/negative 
and present/absent).  Summaries and analyses will be performed based on the observed 
data for planned assessment visits per the study calendar (Section 14.2.1) for the given 
analytes; time points corresponding to unscheduled visits or exit visits which fall at an 
unplanned time for an analyte will not be presented in the tables or figures but will be 
reported in the listings.  No imputation will be done for missing data.  Baseline is defined 
as described in Section 5.6.  See Protocol Appendix 5 for a list of laboratory parameters 
and RAP Appendix 8 for a definition of the laboratory toxicity grades.
Listings will be generated for all laboratory results and for Grade 3 or Grade 4 laboratory 
toxicity results.
8.6.1.
Laboratory Descriptive Statistics by Visit
Descriptive statistics for each analyte will be displayed for each visit. The tables will 
display the mean value, 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 by visit 
and treatment group by induction regimen and overall.
8.6.2.
Worst Laboratory Toxicity Grade Post-Baseline
Laboratory toxicity will be graded using Adverse Event Severity Grading Tables when 
possible. The worst laboratory toxicity grade during treatment 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 (including 
follow-up). Additionally, these toxicity tables will be repeated using all data collected 
after IP discontinuation.
8.6.3.
Laboratory Toxicity ≥ 2 Grade Shift Post-Baseline
Toxicity grade shifts from baseline of ≥ 2 grades will be summarized during treatment 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 and Grade 2 to 4.  Data for both scheduled and unscheduled visits will be included 
throughout the double-blind phase.  Additionally, these shift tables will be repeated using 
all collected after IP discontinuation.
8.6.4.
Laboratory Reference Range Shifts from Baseline by Visit
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 normal/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:  remained low and normal/high to 


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low. For the ‘to normal/high’ category the percentage of subjects with at least one high 
post-baseline value relative to baseline will be displayed using the categories:  remained
normal/high and low to normal/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.
8.6.5.
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.  
8.6.6.
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 test will be performed.
8.6.7.
Immunoglobulin Relative to LLN by Visit
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) 
greater than or equal to the LLN at each visit will also be presented for all subjects and 
then repeated for subjects < LLN at baseline. No statistical test will be performed.
8.6.8.
Immunogenicity
Immunogenicity will be assessed in 3 basic steps utilizing a binding assay (screening and 
confirming), titration assay, and neutralizing assay. Step 1 is a screening assessment 
(positive/negative) of the binding assay.  If the screening result is negative the sample is 
deemed negative and no further steps are performed.  If the screening result is positive, 
then Step 2 is to run a confirming assay (positive/negative) on the sample.  If the 
confirming assay is negative the sample is deemed negative and no further steps are 
performed.  If the confirming assay is positive, the sample is deemed positive and Step 3 
is performed to obtain a titer value to quantify the degree of binding and to run a 
neutralizing assay.
Binding assay results are categorized and presented as negative, persistent positive 
(defined as a positive immunogenic response that occurs 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 
result is unknown if the confirmatory result is missing when the screening result is 
positive.


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A table displaying the proportion of subjects within each immunogenic category will be 
presented by visit and anytime post-baseline where anytime post-baseline summarizes the 
highest category obtained for each subject (lowest to highest result is Negative, Transient 
Positive, Persistent Positive).  A listing will also be presented. 
8.7.
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 12: List of Data Displays.
8.7.1.
Vital Signs
A summary of vital signs and change from baseline of vital signs will be presented by 
visit.
8.7.2.
Concomitant Medical/Surgical Procedures
A listing of all concomitant medical/surgical procedures will be presented.
8.7.3.
Liver Monitoring/Stopping Criteria
If any liver monitoring or stopping criteria events occur, a listing will be provided along 
with a listing of substance use reported with liver event.  Any medical conditions 
reported associated with the liver event will be included in the Current and Past Medical 
Conditions listing.
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
Pharmacokinetic analyses will be based on the PK population. PK samples erroneously 
collected more than 8-weeks post IP discontinuation will be excluded from all analyses 
and displays and can be identified due to no corresponding visit and date recorded in the 
eCRF. Descriptive statistics for serum belimumab concentrations will be displayed for 
each visit for the double-blind phase. The tables will display the mean value, standard 
deviation, 95% confidence interval, geometric mean, geometric standard deviation, 
geometric 95% confidence interval, coefficient of variation (%), median, 25th and 75th
percentiles, minimum, and maximum. No statistical tests will be performed.
A line graph will be produced which displays the median belimumab concentration 
values along with 25th and 75th percentiles by visit for the double-blind phase. 
To assess the effect of body size, proteinuria, and immunogenicity on belimumab 
exposure, the table and line graph described above will also be repeated for the subgroups 
of baseline body weight quartiles, baseline BMI categories (Underweight <18.5, Normal 
18.5 - <25, Overweight 25 - <30, Obese ≥ 30), and baseline proteinuria categories (<0.5, 
0.5-<3, ≥3) and may be repeated for immunogenicity status (persistent positive vs. 


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transient persistent vs. negative) if the number of subjects with a positive status warrants
it.  
A listing of serum belimumab PK concentration-time data will be presented.
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.2
Reporting Standards for Pharmacokinetic).
9.1.2.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic PK
population, unless otherwise specified.
9.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
10.1.
Strategy
The objective of this analysis is to explore the relationship between proteinuria, PK and 
PD response. The analysis will be split into two parts:

An exploratory analysis to assess overall trends and variability in the observed data.

A population PK analysis to link proteinuria levels to exposure and to compare 
individual predicted exposure parameters with the observed PD response.
A relationship between proteinuria levels and the PK or PD response would support the 
recommendation of a dose adjustment to correct for the effects of proteinuria, and any 
proposed change in dosing regimen will be investigated. A more complex population PK 
analysis, treating proteinuria as a time dependent model predicted variable, may also be 
carried out time permitting.
10.2.
Statistical Analyses / Methods
Belimumab serum concentration-time data will be analyzed by population 
pharmacokinetic (popPK) methods using a non-linear mixed-effects modelling approach.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 


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summarized descriptively. A summary of study PK and PD parameters will be reported 
with respect to the mean, standard deviation, median and range (median and maximum). 
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D. Details for the PopPK methodology are provided in Appendix 9.
10.3.
Exploratory Analysis
The exploratory analysis is intended to be a straight forward comparison between the 
observed proteinuria levels, PK and PD response, and will not include more in-depth 
modelling or data manipulation. The PK will be specified by the pre-dose (Cmin) and 
post-infusion (Cmax) concentrations at weeks 2, 4, 8, 24, 52 and 104. The proteinuria and 
PD biomarkers will be specified by their observed values, change from baseline and 
percent change from baseline, at the weeks the samples were taken (which is different for 
each biomarker). The analysis may include:

Response over time
Plot and summary table of the proteinuria levels, PK (Cmin, Cmax) and PD response 
over time.

Effect of proteinuria on PK
Plot of observed Cmin and Cmax values versus proteinuria levels measured at the 
same week.

Effect of PK on PD biomarker response
Plot of the biomarker response at week N against the PK (Cmin and Cmax) at the 
same or earlier time points.

Effect of proteinuria on PD biomarker response
Plot of biomarker response at each week versus baseline proteinuria levels.
10.4.
Population PK Analysis
The proteinuria/PK and the PK/PD exposure response relationships will be explored in 
more detail through a population PK analysis. A population PK model will be constructed 
from the observed data. The effect of body size (for example, body weight, body-mass 
index, fat-free mass) and proteinuria will be evaluated and included in the model if 
shown to be a pharmacokinetically relevant covariate or the fit to the data is substantially 
improved. Additional covariates of potential clinical importance, such as age, gender, 
race and co-medication, may also be tested. 
10.4.1.
Individual Analysis 
The population PK model will be used to derive the post-hoc belimumab concentration-
time profiles for each subject, based on the observed changes in proteinuria during the 
study. The analysis may include:

Response over time
Plot of the individual predicted time course profiles for belimumab.


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Plot and summary table of the post-hoc exposure parameters (Cmin, Cavg, Cmax) at 
selected time points throughout the study.

Effect of proteinuria on PK
Plot of the individual predicted post-hoc exposure parameters (Cmin, Cavg, Cmax) 
versus the observed proteinuria level measured at the same week.

Effect of PK on PD biomarker response
Plot of the observed biomarker response at week N versus the average exposure from 
week 0 to week N, calculated as the area under the concentration-time curve to week 
N divided by this time period.
10.4.2.
Population Analysis
The population PK model will be used to simulate the PK over an adult lupus-nephritis 
population. All covariate information required by the model (for example, proteinuria and 
body weight) will be sampled from an appropriate distribution, consistent with the 
variability in the study population, or sampled with replacement from the study dataset 
itself. The results from the simulation will be used to explore the time course of the PK, 
and the effects of body weight and proteinuria on the PK. The PK will be expressed by its 
median, inter-quartile range and 95% prediction, as a function of time or any other 
covariate. The analysis may include:

Effect of proteinuria on PK
Plot of average concentration at steady state versus proteinuria level.

Effect of body weight on PK
Plot of average concentration at steady state versus body weight.
For all simulation-based plots the individual predicted post-hoc values will also be 
superimposed to verify consistency with the simulated population results.
10.5.
Population PK Analysis with Proteinuria as a Time-
Dependent Model Variable
Time permitting, proteinuria levels will be treated as a time-dependent model variable, as 
opposed to a covariate parameter of the model, and a population PK model fitted to the 
observed PK and proteinuria data simultaneously. The population PK analysis described 
above may be updated using this alternative model, which has the advantage that 
proteinuria levels in response to drug can be predicted over time. This more detailed level 
of analysis will be strictly optional, dependent on time available, the requirement to 
predict the proteinuria response over time, and the likelihood of a successful outcome 
following assessment of the data.
10.6.
Dose Adjustment
Based on the exposure-proteinuria relationship derived from the population PK analysis, 
a decision may be made to increase the dose if proteinuria is above a chosen threshold


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with the aim of maintaining exposures at or close to the target value (Cavg of 
approximately 100 µg/mL). The exposure-proteinuria relationship incorporating any 
proposed change in dosing frequency will be calculated and characterised accordingly.
11.
BIOMARKER ANALYSES
Unless otherwise stated, all analyses will be limited to the double-blind treatment period 
while subjects are on investigational product (IP).
11.1.
Biomarker Endpoints
Autoantibodies, complement, and peripheral B lymphocytes (referred to as B cells) will 
be collected per the study calendar (Appendix 2, Section 14.2). In geographies where 
feasible, the peripheral B lymphocytes will be measured (using FACS analysis). The 
specific biomarkers collected and analyzed are listed in Table 10:
Table 10
Biomarkers for Analysis
Autoantibodies 
B cells
aCL 
CD19
ANA
CD20
anti-Sm
Naïve CD19+CD20+CD27-  *
anti-C1q
Memory CD19+CD20+CD27+ *
Anti-dsDNA
Activated CD19+CD20+CD69+ Normalised
BLyS (only collected at baseline)
Plasma CD19+CD20-CD138+ Normalised
Complement
Plasmacytoid CD19+CD20+CD138+ Normalised
C3
Short-lived Plasma CD19+CD20-CD27b+ Normalised
C4
SLE Subset CD19+CD38b+CD27b+Lymph Normalised
Immunoglobulin
Transitional CD19+CD24b+CD38b+CD27- Normalised
IgG, IgM, and IgA
*Naïve and Memory B cell subsets will also be expressed as 
a percentage of CD19.
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.
11.2.
Biomarker Change and Percent Change from Baseline 
Analyses
Endpoints
The change from baseline and percent change from baseline will be evaluated for each of the 
biomarkers listed in Table 10.
Statistical Analysis
For immunoglobulins an ANCOVA will be used to evaluate the treatment effect controlling for 
baseline value, induction regimen (CYC, MMF) and race (Black, Non-Black).


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For autoantibodies and complement a rank ANCOVA will be used to evaluate the treatment effect 
controlling for baseline value, induction regimen (CYC, MMF) and race (Black, Non-Black).
Summary Measure
The difference in the Least Square (LS) means (belimumab – placebo) will be used to assess the 
treatment effect.
Population of Interest
The modified Intent-to-Treat population will be used for the analysis.
Intercurrent Event Strategy
These analyses will be performed on the observed data up to IP discontinuation.  No imputation 
will be done for missing data.
Variables

Biomarker (B cells defined in Appendix 10)

Treatment (belimumab=1, placebo=0)

Baseline_Value (continuous)*

Induction (CYC=1 vs. MMF=0)

Race (Black=1 vs. Non-Black=0)
Model Specification
model Endpoint = Treatment Baseline_Value Induction Race
Model Checking & Diagnostics
The data will be evaluated by two independent statisticians to determine if the model assumptions 
and fit are reasonably met.  If either is deemed unacceptable, additional sensitivity analysis using 
an alternative method may be performed. Model checking diagnostics are not applicable for rank 
ANCOVA.
Model Results Presentation
For the baseline visit, the table will display the number, mean, standard deviation of the mean, 
median, 25th and 75th percentiles, minimum and maximum. At each post-baseline visit, the tables 
will display the number, mean percent change from baseline, standard deviation of the mean, 
median, 25th and 75th percentiles, minimum and maximum.  Additionally, at Week 104 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 will be presented.
For rank ANCOVA, the following results will be displayed by induction regimen and treatment 
group: mean, standard deviation, standard error, median, 25th percentile, 75th percentile, minimum, 
maximum.  The p-value for the rank ANCOVA will be presented for the treatment comparison for 
the combined induction regimens at Week 104 only.
A line graph for the observed median change from baseline in each of these biomarkers will be 
presented by treatment group (overall and by induction regimen) for both the double-blind phase.
Subgroup Analyses

For autoantibodies (anti-dsDNA, ANA, aCL, Anti-C1q, and Anti-Sm), analyses will be 


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performed on subjects who were positive at baseline.  

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).
11.2.1.
Adjustment for IgG Loss
For IgG and autoantibodies (anti-dsDNA, aCL, Anti-C1q, and Anti-Sm) analyses which adjust the 
results for IgG loss due to proteinuria will be performed to reduce confounding of the treatment 
effect.  
Specifically, for each autoantibody listed above, 
•
Log(IgG) and Log(Autoantibody) will be fitted jointly in a multivariate ANCOVA model with 
terms for "Autoantibody x Treatment x Time", "Autoantibody x Baseline x Time", "Autoantibody
x Induction Regimen", “Autoantibody x Race Stratification Factor”, Autoantibody x Baseline 
uPCR”, and "Autoantibody x Baseline eGFR”.
•
Models will be fitted using restricted maximum likelihood (REML) methods and have an un-
structured variance-covariance matrix for both treatments.
•
Model adjusted mean estimates with associated 95% CIs will be produced for both the 
autoantibody and IgG by treatment at each timepoint (by exponentiation of Least Square 
Means estimates) with a corresponding plot by treatment over time.
•
Model adjusted ratio of mean estimates (Autoantibody/IgG) with associated 95% CIs will be 
produced by treatment at each timepoint with a corresponding plot by treatment over time.
11.3.
Shifts in Immunoglobulins, Autoantibodies, and 
Complement by Visit
Endpoints
Shift tables will be used to summarize the changes in immunoglobulins, autoantibodies, and 
complement by induction regimen and overall for each treatment group and visit.  
Autoantibody
Positive
Negative
Anti-dsDNA
≥30 IU/mL
<30 IU/mL
ANA
≥80 Titer
<80 Titer
aCL
If any of the three aCL 
parameters, IgG (≥14 U/mL), 
IgA (≥11 U/mL) or IgM (≥12 
U/mL), is positive.
If at least 1 is non-missing 
then aCL is negative; 
otherwise aCL is missing.
Anti-C1q
≥22.2 U/mL
<22.2 U/mL
Anti-Sm
≥15 KU/L
<15 KU/L
Ig 
High
Normal/Low
IgG
> 16.18 g/L
≤16.18 g/L
IgA
> 4.63 g/L
≤ 4.63 g/L
IgM
> 2.71 g/L
≤ 2.71 g/L
Complement
Low
Normal/High


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C3
<90 mg/dL
≥90 mg/dL
C4
<10 mg/dL
≥10 mg/dL
Statistical Analysis
Fisher’s exact test will be performed within each baseline category to evaluate the treatment effect.
Population of Interest
The modified Intent-to-Treat population will be used for the analysis.
Intercurrent Event Strategy
These analyses will be performed on the observed data up to IP discontinuation.  No imputation 
will be done for missing data.
Variables

Immunoglobulins, autoantibodies, and complement endpoints evaluated one at a time.

Treatment (belimumab=1, placebo=0)
Results Presentation
For IgG, IgA, IgM, C3 and C4 baseline data will be summarized as the number and percent of 
subjects who are high or normal/low at baseline.  For post-baseline visits the data will be 
summarized by baseline status defined as high or normal/low.  Among subjects high at baseline 
the shifts presented will be high or normal/low and high to high. Among subjects normal/low at 
baseline, the shifts presented will be normal/low to high and normal/low to normal/low.  
For anti-dsDNA, ANA, aCL, Anti-C1q, and Anti-Sm, 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 or negative.  Among subjects 
positive at baseline the shifts presented will be positive to negative and positive to positive (no 
change).  Among subjects negative at baseline, the shifts presented will be negative to negative 
(no change) and negative to positive.  Anti-C1q and anti-SM are only analyzed post-baseline for 
subjects positive at baseline, therefore shifts for subjects negative at baseline will not be 
presented. 
Subgroup Analyses
Subgroup analysis will be performed by Induction Regimen (CYC, MMF).
12.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
Pharmacokinetic/Pharmacodynamic (PD) analyses are not prospectively planned for this 
study.  Based on the results obtained, exploratory analyses may be performed on an ad 
hoc basis.
12.1.
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/SupportingDocumentation.aspx):

4.03 to 4.24: General Principles


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
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 

Subject level listings will not be included 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.

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 as outlined in Section 14.13 which follow the Benlysta 
program standards and, as far as possible, follow the GSK Integrated Data Standards 
Library (IDSL).
Formats

All data will be reported per the actual treatment the subject received unless otherwise 
stated.

GSK IDSL Statistical Principles (4.24) 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.
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.


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
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 at which the data was to be 
collected will be presented. Unscheduled visits will be included in patient listings 

Listings will be sorted by induction regimen, 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.

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.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures displaying data By 
Visit.

Data collected at unscheduled visits will be used in summaries that present the most 
extreme values on treatment such as laboratory shift tables or maximum toxicity grades.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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13.
REFERENCES
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.
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables, May 
2001.http://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Document
s/dmidadulttox.doc 
Eibl MM, Rosen FS. Intravenous gamma globulin and plasmapheresis. In Frank MM et al 
(eds): Samter's Immunologic Diseases (5th ed.). Boston: Little, Brown, 1995;1529- 36.
From the Systemic Lupus International Collaborating Clinics (SLICC) and the American 
College of Rheumatology Diagnostic and Therapeutic Criteria Committee, 1996
Gastonguay M. Full covariate models as an alternative to methods relying on statistical 
significance for inferences about covariate effects: a review of methodology and 42 case 
studies. PAGE Conference, June 2011, Athens, Greece. Available at http://www.page-
meeting.org/?abstract=2229 (last accessed 12 Apr 2018).
Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The 
development and initial validation of the Systemic Lupus International Collaborating 
Clinics/American College of Rheumatology Damage Index for systemic lupus 
erythematosus. Arthritis Rheum 1996;39(3):363-9.
Gladman D, Ibañez D, Urowitz, M.  Systemic Lupus Erythematosus Disease Activity 
Index 2000. J Rheumatol 2002, 29 (2) 288-291.
Goldfarb NS, Avery RK, Goormastic M, et al. Hypogammaglobulinemia in lung
transplant recipients. Transplantation 2001;71(2):242-6.
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.
Kim Y, Won S “Adjusted proportion difference and confidence interval in stratified 
randomized trials” PharamSUG 2013 Paper SP04
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using
standardized serum creatinine values in the modification of diet in renal disease study
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–54.
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.
PSAP, Program Safety Analysis Plan for Belimumab, GSK1550188, Effective Date: 02-
OCT-2018.


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Rubin DB. Multiple Imputations for Nonresponse in Surveys. John Wiley & Sons. 1987.
Struemper, H., Cai, W., Chen, C. Population pharmacokinetics of belimumab following 
intravenous administration in patients with systemic lupus erythematosus. J Clin 
Pharmacol 2013; 53(7):711-20.
Yamani MH, Avery RK, Mawhorter SD, et al. Hypogammaglobulinemia following
cardiac transplantation: a link between rejection and infection. J Heart Lung Transplant
2001;20(4):425-30.
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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14.
APPENDICES
14.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
14.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Did not have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology (ACR) criteria (Inclusion 2)
02
Did not have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding 
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or pure 
Class V membranous using the 2003 ISN/RPS criteria (Inclusion 3)
03
Did not have unequivocally positive anti-nuclear antibody (ANA titer ≥ 1:80) test results 
and/or a positive anti-dsDNA (≥ 30 IU/mL based on ELISA assay) serum antibody test at 
the screening visit based on the study’s central laboratory results. (Inclusion 4)
04
Did not have documentation of active renal disease at screening requiring induction.
(Inclusion 5)
05
Did not have active renal disease defined as above which requires induction therapy with 
high dose corticosteroids (HDCS) with either intravenous (IV) cyclophosphamide (CYC) or 
mycophenolate mofetil (MMF) or other oral forms of mycophenolate. (Inclusion 6)
06
Previously failed both CYC and MMF (or other forms of mycophenolate) induction therapies 
based on the investigator’s opinion. (Exclusion 1)
07
Received an induction therapy with CYC within 3 months prior to the planned initiation of the 
current induction for the study. (Exclusion 2)
08
Received treatment with belimumab within 364 days of baseline (Day 1). (Exclusion 6)
09
Received treatment with one of the excluded therapies within 364 days of baseline (Day 1).
(Exclusion 7)
10
Received treatment with one of the excluded therapies within 90 days of baseline (Day 1).
(Exclusion 8)
11
Received a non-biological investigational agent within 60 days of baseline (Day 1).
(Exclusion 9)
12
Subjects who had been on dialysis within 364 days of baseline (Day 1). (Exclusion 13)
13
Had an estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit (using 
the simplified Modification of Diet in Renal Disease [MDRD] equation). (Exclusion 14)
14
Received an incorrect treatment most of the time (>50% of the time).
15
Missed 3 or more consecutive study agent infusions.
16
Study blind/unblind procedures:   Investigator/site staff/GSK Clinical team did not remain 
blinded to treatment assignment through Week 104/Exit visit efficacy evaluation, includes 
emergency unblinding for medical reasons.
17
Other, a deviation that does not satisfy the above criteria, however, in the judgment of the 
clinical team, including the medical monitor, constitutes an exclusion from the Per Protocol 
population.


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14.2.
Appendix 2: Schedule of Activities
14.2.1.
Protocol Defined Schedule of Events
Table 11
Study Calendar - Double-Blind Treatment Period (Screening to Week 52)
Screeni
ng
Baselin
e
Double-Blind Treatment Period
Study Day
-35 days
Day 0
Day 3
14 ± 3 days
28 ± 3 days
56 ± 7 days
84 ± 7 days
112 ±7 days
140 ± 7 days
168 ± 7 days
196 ± 7 days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
Wk 
-5
Wk 2
Wk 4
Wk 8
Wk 
12
Wk 
16
WK 
20
Wk 
24
W
k 
24 
+ 
3d
Wk 
28
Wk 
32
Wk 
36
WK4
0
Wk 
44
Wk 
48
W
k 
48 
+ 
3d
Wk 
52
W
k 
52 
+ 
3d
Written Informed 
Consent
x
Demographics 
(including race)
x
Medical History
x
SLE History
x
Therapy History
x
Eligibility Criteria
x
Biopsy ReportA
x
Pre-flare GFRB
x
Biopsy sample 
shipment for central 
evaluation 
After 
Day 0
Clinical 
Assessments
SELENA SLEDAI, 
SLE Flare Index and 
PGA
x
x
x
x
x
SLICC Damage
x
x
x
C-SSRS 
Screening/Baseline
x
C-SSRS Since Last 
VisitC
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Screeni
ng
Baselin
e
Double-Blind Treatment Period
Study Day
-35 days
Day 0
Day 3
14 ± 3 days
28 ± 3 days
56 ± 7 days
84 ± 7 days
112 ±7 days
140 ± 7 days
168 ± 7 days
196 ± 7 days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
Wk 
-5
Wk 2
Wk 4
Wk 8
Wk 
12
Wk 
16
WK 
20
Wk 
24
W
k 
24 
+ 
3d
Wk 
28
Wk 
32
Wk 
36
WK4
0
Wk 
44
Wk 
48
W
k 
48 
+ 
3d
Wk 
52
W
k 
52 
+ 
3d
Record Concurrent 
Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete Physical 
Exam
x
Symptom-driven 
Physical Exam
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
WeightD
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signsP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG
x
Record/Assess 
Adverse EventsE
xR
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory 
Assessments 
Hematology and 
chemistry (non-
fasting)F
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum CreatinineG
x
x
x
x
UrinalysisH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinary MicroscopyH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Spot urine 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
24-hour UrineG
X
x
x
x
Urine Biomarkers
x
x
x
x
BLyS protein 
(baseline only)
x
Pregnancy TestI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ANA
x
x
x
x
Complement 
(C3/C4), anti-dsDNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
aCL (IgA, IgG, IgM 
isotypes) 
x
x
x
Anti-Sm, anti-C1qJ
x
x
x


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Screeni
ng
Baselin
e
Double-Blind Treatment Period
Study Day
-35 days
Day 0
Day 3
14 ± 3 days
28 ± 3 days
56 ± 7 days
84 ± 7 days
112 ±7 days
140 ± 7 days
168 ± 7 days
196 ± 7 days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
Wk 
-5
Wk 2
Wk 4
Wk 8
Wk 
12
Wk 
16
WK 
20
Wk 
24
W
k 
24 
+ 
3d
Wk 
28
Wk 
32
Wk 
36
WK4
0
Wk 
44
Wk 
48
W
k 
48 
+ 
3d
Wk 
52
W
k 
52 
+ 
3d
Serum IgG
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum IgA & IgM
x
x
x
x
x
PT/PTT
x
x
x
x
x
HIV, Hep B and Hep 
C serology, and 
HBV DNAQ
x
Pharmacokinetic 
SamplingK
x
x
x
x
x
x
x
x
Immunogenicity 
(anti-belimumab 
antibody)
x
x
x
x
Peripheral B 
lymphocytes
x
x
x
x
Pharmacogenetics 
Sampling 
(consenting subjects 
only)L
x
Protocol 
Treatments
Study Agent 
Administration
(Belimumab/Placebo
)M,N
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Induction/Maintenan
ce TherapyO
Throughout the Study


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ABiopsy report indicating proliferative lupus nephritis. Should be from a renal biopsy obtained in the 6 months prior to the screening visit or during the 
screening period. A tissue sample from the renal biopsy used to qualify the subject for randomization needs to be sent to a central reading center 
after Day 0 (baseline).
BMost recent GFR prior to the current renal flare.
C The Columbia-Suicidality Severity Rating Scale (C-SSRS) Since Last Visit form (see Protocol Appendix 9) will be used at Day 0 and all subsequent 
visits. The C-SSRS Baseline/Screening form (see Protocol Appendix 8) is only used at Screening. 
DThe weight at the current visit should be used to calculate dose.
EFor subjects who discontinue treatment with study agent during the double-blind period (for reasons other than withdrawal of consent), all adverse 
events will be collected through 8 weeks following the administration of the last dose of study agent. After this time, SAEs, regardless of relationship to 
study drug, will be collected through Week 104.
F Refer to Protocol Appendix 5 for a listing of laboratory assessments to be completed. 
GTwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  baseline, Weeks 24, 48 and 52.  Serum 
creatinine for these visits will be collected at the initial visit which will take place within 3 days prior to or on the day of the scheduled visit, and then 3 
days after the initial visit. For urinary sediment assessments, both menstrual cycles and genitourinary tract infections may be confounders.  Urine 
collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract infection is present at time of 
urinalysis or anytime during the 24 hour urine collection.
HRoutine urinalysis and urinary microscopy will be performed locally.
IFor women of child-bearing potential, serum pregnancy test is required at screening. At subsequent visits, a urine pregnancy test is required. Results 
of the pregnancy test must be available prior to dosing.
JSamples will only be analyzed in subjects with positive results at baseline.
KFor PK sampling times, see Protocol Section 6.7.1.
LPharmacogenetic sampling informed consent must be obtained prior to any blood being taken for PGx research. Sample should be drawn prior to 
dosing.
MSubjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawal of consent) should continue to 
follow the study calendar and have all assessments completed through Week 104 (with the exception of study agent administration).
N 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.
OInduction therapy may begin before Screening but should be initiated within 60 days prior to or on Day 0 (baseline).
P Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administered, vital 
signs are to be performed prior to dosing.
QNote: if anti-HBc result is reactive, the sample drawn for HBV DNA will be tested for viral DNA; otherwise, the sample will be destroyed. Subjects in 
China with positive hepatitis C screening results will be excluded without confirmatory hepatitis C RNA-PCR testing.
RNote: For subjects in China, SAEs will be collected from the time a subject consents to participate in the study (see Protocol Section 7.2).


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Table 12
Study Calendar - Double-Blind Treatment Period (Week 56 to 104)
Double-Blind Treatment Period
Study Day
392 ± 7days
420 ± 7days
448 ± 7days
476 ± 7days
504 ± 7days
532 ± 7days
560 ± 7days
588 ± 7days
616 ± 7days
644 ± 7days
672 ± 7days
700 ± 7days
Day 728/ Exit A
± 7days
(4  weeks after 
last dose)
Follow-up visitB
(8 week after 
last dose)
+7 days
Unscheduled 
VisitC
Study Week
Wk 
56
Wk60
Wk64
Wk 
68
Wk 
72
Wk
76
Wk 
76 
+ 3 
d
Wk
80
Wk 
84
Wk88
Wk92
Wk 
96
Wk 
100
Wk 
100
+ 3 d
Wk 
104
Wk 
104 
+ 3 d
Clinical Assessments
SELENA SLEDAI, SLE Flare 
Index and  PGA
x
x
x
x
x
SLICC Damage
x
x
C-SSRS Since Last Visit
x
x
x
x
x
x
x
x
x
x
x
x
x
Record Concurrent Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom-driven Physical 
Examination
x
x
x
x
x
x
x
x
x
x
x
x
x
WeightD
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signsN
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Record/Assess Adverse EventsE
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Survival AssessmentF
x
Laboratory Assessments
Hematology and chemistry (non-
fasting)G
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum CreatinineH
x
x
x
UrinalysisI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinary MicroscopyI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Spot urine 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
24-hour UrineH
x
x
x
Urine Biomarkers
x
Pregnancy TestJ
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complement (C3/C4), anti-dsDNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ANA, aCL (IgA, IgG, IgM isotypes)
x
x
Anti-Sm, anti-C1qK
x
x
Serum IgG
x
x
x
x
x
Serum IgA & IgM
x
x
PT/PTT
x
x


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Double-Blind Treatment Period
Study Day
392 ± 7days
420 ± 7days
448 ± 7days
476 ± 7days
504 ± 7days
532 ± 7days
560 ± 7days
588 ± 7days
616 ± 7days
644 ± 7days
672 ± 7days
700 ± 7days
Day 728/ Exit A
± 7days
(4  weeks after 
last dose)
Follow-up visitB
(8 week after 
last dose)
+7 days
Unscheduled 
VisitC
Study Week
Wk 
56
Wk60
Wk64
Wk 
68
Wk 
72
Wk
76
Wk 
76 
+ 3 
d
Wk
80
Wk 
84
Wk88
Wk92
Wk 
96
Wk 
100
Wk 
100
+ 3 d
Wk 
104
Wk 
104 
+ 3 d
Pharmacokinetic SamplingL
x
x
Immunogenicity (anti-belimumab 
antibody)
x
x
x
Peripheral B lymphocytes
x
x
Protocol Treatments
Study Agent Administration
(Belimumab/Placebo)M
x
x
x
x
x
x
x
x
x
x
x
x
If entering 
extension
Induction/Maintenance Therapy
Throughout the Study
AFor subjects completing 100 weeks of treatment with study agent and continuing into the 6-month open-label extension, the Week 104 visit will also 
serve as the Day 0 visit of the 6-month open-label extension. Only subjects who continue in the open-label extension study will have study agent 
(belimumab) administered at the Week 104 visit after the completion of Week 104 assessments. Subjects who are withdrawn from treatment with 
study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to follow the study calendar and have all assessments 
perfomed through Week 104 (with the exception of study agent administration).  For subjects who withdrew consent and agreed to have follow-up 
safety data collected or subjects who are not continuing into the open label extension, the Week 104/Exit visit will occur approximately 4 weeks after 
the last dose of study agent.  
BThe 8-week follow-up visit is not required for subjects entering the open-label extension.
CAdverse events and concurrent medications should be assessed at each unscheduled visit.  When a subject has worsening nephritis or SLE, a 
complete disease activity assessment (SELENA SLEDAI, SLE Flare Index, and PGA), and laboratory assessments (hematology, chemistry, 
urinalysis, anti-dsDNA, and complement) should be performed to document disease activity worsening (eg, renal flare/relapse) prior to instituting 
treatment that results in treatment failure designation as defined in Protocol Section 5.5 and Protocol Section 5.6. Other assessments should be 
performed as clinically indicated.
DThe weight at the current visit should be used to calculate dose.
EFor subjects who discontinue treatment with study agent during the double-blind period (for reasons other than withdrawal of consent), all adverse 
events will be collected through 8 weeks following the administration of the last dose of study agent. After this time, SAEs, regardless of relationship to 
study drug, will be collected through Week 104.
FIn the event that a subject withdraws consent from the study, an attempt should be made at the time of consent withdrawal to obtain consent to 
collect survival status at Week 104.


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GRefer to Protocol Appendix 5 for a listing of laboratory assessments to be completed. 
HTwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  Weeks 76, 100 and 104. The serum creatinine 
for these visits will be collected on the day of the initial visit and then 3 days after the initial visit. For urinary sediment assessments, both menstrual 
cycles and genitourinary tract infections may be confounders.  Urine collection may be postponed up to 14 days at the investigators discretion if 
menstrual bleeding or a genitourinary tract infection is present at anytime during the 24 hour urine collection.
I Routine urinalysis and urinary microscopy will be performed locally.
JFor women of child-bearing potential, a urine pregnancy test is required. Results of the urine pregnancy test must be available prior to dosing.
KSamples will only be analyzed in subjects with positive results at baseline.
LFor PK sampling times, see Protocol Section 6.7.1.
MSubjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to 
follow the study calendar and have all assessments completed through Week 104 (with the exception of study agent administration).
N Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs 
are to be performed prior to dosing.


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14.3.
Appendix 3: Assessment Windows
14.3.1.
Definitions of Assessment Windows for Analyses
Analysis Visit and Analysis Visit Number
The Analysis Visit and Analysis Number are assigned based on the VISIT and VISITNUM for the 
planned visits. Exit, withdrawal, and unscheduled visits which are not associated with a specific 
planned time are slotted into one of the planned times based on the interval in which the Study Day  
falls per the intervals (inclusive) provided below.  For completeness, the table also includes visit 
intervals representing planned study times for which no visits are not slotted; these visits will have 
‘na’ for ‘not applicable’ listed for the Interval Start and End Day.  Since baseline values are defined 
as the most recent value prior to the first infusion, the baseline value could correspond to a 
screening visit, Week 0 visit, or an unscheduled visit prior to first infusion; therefore, the analysis 
visit is labeled ‘Baseline’ while the analysis visit number (AVISITN) equals the original visit number 
(VISITNUM). Similarly, a subject’s final visit in the double-blind period will be ‘Week 104’ if the 
subjected completed all 104 weeks of the study but did not enter the open-label extension phase.  
Subjects who completed the study and entered the open-label extension phase will have their final 
visit labeled ‘Week 104/EXT Week 0’.  Subjects who withdrew from the study prior to Week 104 will 
have their final visit labeled ‘EXIT DOUBLE BLIND’.  Each of these categories is mutually 
exclusive.  The Week 104 and ‘Week 104/EXT Week 0’ will both have an analysis visit of ‘Week 
104’ and an analysis visit number of 350. EXIT DOUBLE BLIND visits will be slotted based on the 
visit widows. 
Visit
Visit Number 
Target Study 
Day
Interval Start 
Day
Interval End 
Day
Screening
10
-35
na
na
Week 0
20
1
-35
1
Week 0 +3 days
30
4
na
na
Week 2
40
15
2
21
Week 4
50
29
22
42
Week 8
60
57
43
70
Week 12
70
85
71
98
Week 16
80
113
99
126
Week 20
90
141
127
154
Week 24
100
169
155
182
Week 24 + 3 days
110
172
na
na
Week 28
120
197
183
210
Week 32
130
225
211
238
Week 36
140
253
239
266
Week 40
150
281
267
294
Week 44
160
309
295
322
Week 48
170
337
323
350
Week 48 + 3 days
180
340
na
na
Week 52
190
365
351
378
Week 52 + 3 days
200
368
na
na
Week 56
210
393
379
406
Week 60
220
421
407
434


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Analysis Visit and Analysis Visit Number
Week 64
230
449
435
462
Week 68
240
477
463
490
Week 72
250
505
491
518
Week 76
260
533
519
546
Week 76 + 3 days
270
536
na
na
Week 80
280
561
547
574
Week 84
290
589
575
602
Week 88
300
617
603
630
Week 92
310
645
631
658
Week 96
320
673
659
686
Week 100
330
701
687
714
Week 100 + 3 days
340
704
na
na
Week 104
350
729
715
742
Week 104 + 3 days
360
732
na
na
IP DISC
365
na
na
na
EXIT DOUBLE BLIND
366
SLOT
EOS DOUBLE BLIND
368
na
na
na
FOLLOW-UP
370
757
na
na
Survival
372
729
na
na
Week 104/EXT Week 0
375
729
715
742
UNSCHEDULED
901
SLOT
UNSCHEDULED
902
SLOT
UNSCHEDULED
903
SLOT
LIVER EVENT 1
8100
na
LIVER EVENT 2
8200
na
14.3.1.1.
Exit/Withdrawal and Unscheduled Visits
Exit/Withdrawal and Unscheduled Visits
The data is analyzed per the planned visit assignment. 
Exit/withdrawal visit (listed below) must be slotted to the appropriate planned visit for subjects who 
withdraw prior to the end of the double-blind treatment  phase.  If the Exit visit is slotted into the 
same visit as the visit prior to withdrawal, slot the Exit visit to the next scheduled visit. For example, 
if the subject’s last visit prior to the Exit visit was Week 20 and the Exit visit mapped as another 
Week 20, map the Exit visit to Week 24.
For safety reporting, 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 hierarchical rules apply:

If the scheduled visit exists, use the scheduled visit as is.

If no scheduled visit exits, use the unscheduled visit closest to the target study day.

If there are two visits equidistant from the target date, the earliest date will be used as the 
scheduled visit
For efficacy reporting, data will be used based on the visit it was collected, scheduled or 


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Exit/Withdrawal and Unscheduled Visits
unscheduled, and any visits with missing data will follow the imputation rules (e.g., last observation 
carried forward) as indicated in the endpoint derivation section.
Exit/withdrawal Visits
Phase
Visit
Visit Number
Double-Blind
Exit Double Blind
366


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14.4.
Appendix 4: Double Blind Data and Treatment Emergent 
Adverse Events
14.4.1.
Double Blind Data Classification
Assessments and events will be classified according to the time of occurrence relative to 
the randomized treatment start date.  For subjects not entering the open-label extension, 
all data will be reported in the double-blind reporting; otherwise data will be reported up 
to the first infusion in the open-label extension. The classifications below also define the 
data to be included in the ADaM datasets for the double-blind reporting.
Classification
Definition
Screening 
Date < Treatment Start Date
Double Blind
Treatment Start Date ≤Date ≤ Double blind end date 
where double blind end date is as follows:
For subjects continuing in the open-label phase:

The date of the first infusion in the open-label period.
For subjects not continuing in the open-label phase, all data in the double-
blind/follow-up phase will be included in the ADaM datasets; therefore, 
depending on the subject’s course in the study, the following hierarchy illustrates 
the last date for a subject in descending order:

8-Week Follow-up visit date

Week 104 visit date

Exit visit date

Earliest of death date or early termination date 

Last date of contact.
NB: For labs, serum creatinine is collected at Week 104 + 3 days and used to 
derive cGFR; therefore, the date of the Week 104 + 3 days visit is used in the 
above hierarchy in place of the Week 104 visit.  Exit visits for subjects that 
withdrew early in the double-blind phase will be slotted to a visit based on the 
calculated Study Day. Non-withdrawal visits will be assigned a visit based on the 
case report form Visit tab the data was entered under.  The primary (Double-
blind) reporting will include all records where the assessment date is less than or 
equal to the Open label period start date. For Pharmacokinetic Concentration 
and Laboratory datasets, all records where assessment date/time is less than or 
equal to Open label period start date/time are included. For Adverse Events 
include all records where AE start date is less than or equal to date of first 
infusion in the open-label period.   For Concomitant Medications include all 
records where imputed start date is less than or equal to the date of first infusion 
in the open-label period.  Note that Adverse Events and Concomitant 
Medications beginning on the first Open label treatment start date will be 


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Classification
Definition
included for both the primary (Double-blind) and final (Open-label) reporting.
14.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

A treatment-emergent AE is an adverse event that emerges on or after the 
first treatment dose, having 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.

Study Treatment Start Date ≤ AE Start Date


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14.5.
Appendix 5: Data Display Standards & Handling 
Conventions
14.5.1.
Reporting Process
Software
The currently supported versions of SAS software will be used.
Reporting Area for end of Double Blind
HARP Server
: us1salx00259
HARP Compound
: \arenv\arprod\gsk1550188\bel114054
HARP Area
: \arenv\arprod\gsk1550188\bel114054\primary_02
QC Spreadsheet
: \arenv\arprod\gsk1550188\bel114054\primary_02\documents
Analysis Datasets 

Analysis datasets will be created per CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.0). If the Study Data Standardization Plan (SDSP) exists for a study, ensure the 
CDISC versions are consistent.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be
implemented for conversion from SI to SDTM.
Generation of RTF Files
RTF files will be generated for all reporting efforts.
14.5.2.
Reporting Standards for Pharmacokinetics
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics (Logged 
Transformed),
Graphical Displays 
and Listings
Concentration values will be imputed as per GUI_51487 for descriptive summary 
statistics/analysis and summarized graphical displays only. 
N, n, mean, standard deviation, 95% confidence interval, geometric mean, 
geometric standard deviation, geometric 95% confidence interval, coefficient of 
variation (CVb (%)*), median, 25th and 75th percentiles, minimum, and maximum
will be reported.
*CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
NONMEM/Pop PK 
File
An input data set (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created. Data set specifications guiding 
the generation of the input data set will be reported together with the PK results.
NONMEM/PK/PD 
File
Not applicable.


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Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the POP-PK analysis:
•
Steady-state trough concentration: Cmin (g/mL)
•
Steady-state maximal concentration: Cmax (g/mL)
•
Steady-state area under the serum drug time-concentration curve and/or 
average concentration for the dosing interval:  AUC0-(day*g/mL) and/or 
Cavg (g/mL)
•
Distribution half-life: t1/2(day)
•
Terminal half-life: t1/2(day)
•
Steady-state volume of distribution: Vss (mL)
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
In the POP-PK NQ values will be excluded, unless more than 10% of the total 
number of PK values are NQ in which case available methods to model NQ values 
will be considered. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Geometric mean, geometric standard deviation, coefficient of variation (CVb (%)*), 
geometric 95% confidence interval, minimum, and maximum will be reported.


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14.6.
Appendix 6: Derived and Transformed Data
14.6.1.
General
14.6.1.1.
Multiple Measurements at One Analysis Time Point
Multiple Measurements at One Analysis Time Point

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target, then use the value prior to the 
target visit date.

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 the Laboratory Toxicity 
Grade tables.
14.6.1.2.
Study Day
Study Day
Calculated as the number of days from treatment start date:

Ref Date = Missing                      → Study Day = Missing 

Ref Date < Treatment Start Date → Study Day = Ref Date –  Treatment Start Date

Ref Date ≥ Treatment Start Date → Study Day = Ref Date – (Treatment Start Date) + 1    
14.6.1.3.
IP Discontinuation Date
IP Discontinuation Date
Since the CRF data associated with the IP discontinuation form represents the date the form was 
completed and not the date the investigator made the decision to discontinue randomized 
treatment, IP discontinuation will be assigned the date of the first visit IP is not administered after 
the final infusion.  For example, if a subject’s last infusion is at Week 60, then the Week 64 visit will 
be the first Week the subject missed an infusion; therefore, the Week 64 visit date will be 
considered the IP discontinuation date.  If the subject misses a visit after the last IP infusion without 
withdrawing from the study, the target date for the next planned visit will be used for the IP 
discontinuation date. For subjects who withdraw from IP without a follow-up, the date of last 
infusion + 28 days or the date of last contact, whichever is earlier, will be considered the IP 
discontinuation date.
14.6.1.4.
Changes from Baseline
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


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14.6.1.5.
Percent Change from Baseline
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.  
14.6.1.6.
On Treatment for Safety Endpoints
Safety 
Definition
Pre-Treatment 
Date < Treatment Start Date
On-Treatment
Treatment Start Date ≤ Date ≤ Safety On-Treatment End Date
Where Safety On-Treatment End date is defined as: 
For subjects who Complete DB phase through Week 104 without IP 
Discontinuation, End date for Safety On-Treatment End Date is 
•
the Week 104 visit date, OR 
•
the first infusion in open-label extension, whichever is later.
For subjects who prematurely discontinue IP prior to Week 104, Safety On-
Treatment End Date is
•
IP Discontinuation date (see Section 14.6.1.3), OR 
•
last infusion + 28 days, whichever is later.
Post-Treatment
Date > Safety On-Treatment End Date
14.6.1.7.
On Treatment for Efficacy Endpoints
Efficacy and 
Biomarker 
Treatment 
Phase
Definition
Pre-Treatment 
Date < Treatment Start Date
On-Treatment
Treatment Start Date ≤ Date ≤ Efficacy On-treatment End Date
Where Efficacy On-Treatment End date is defined as: 
For subjects who prematurely discontinue IP prior to Week 104, Efficacy On-
Treatment End Date is
•
IP Discontinuation date (see Section 14.6.1.3).
For subjects who Complete DB phase through Week 104 without IP 
Discontinuation, Efficacy  On-Treatment End Date is 


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Efficacy and 
Biomarker 
Treatment 
Phase
Definition
•
the Week 104 visit date,
•
else if Week 104 is missing, then use the first infusion in open-label 
extension.
Otherwise, use the last date of IP infusion.
Post-Treatment
Date > Efficacy On-Treatment End Date
14.6.2.
Study Population
14.6.2.1.
Analysis Age
Analysis Age

Analysis age will be calculated from birth date to Day 1.

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Age will be rounded down to the nearest year and stored as an integer.
14.6.2.2.
Race and Race Stratification Factor
Race and Race Stratification Factor

Subjects who check more than one race category are counted under an individual race 
category per the minority rule as well as the multiracial category.  

The following minority rule will be applied to all analyses related to race (except for 
stratification):
If a subject checks multiple race categories on the CRF, the subject will be assigned to a unique 
race group per the following priority order:
•
Native Hawaiian or Other Pacific Islander
•
Alaska Native or American Indian from North/Central/South America
•
Asian
•
Black
•
White/Caucasian

Race stratification is sometimes entered into the randomization system incorrectly.  If the 
subject is randomized with an incorrect race stratum (black vs other); this cannot be corrected 
as it could impact the treatment assignment of the subject in question as well as that of subjects 
randomized subsequently. Therefore, another race variable will be derived as Black vs. Non-
Black which is determined based on Black being ticked on the CRF or not.  Note the minority 
rule does not apply.  This race variable will be used as the race stratification variable for the 


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subgroup analyses and as a covariate in the efficacy analyses.
14.6.2.3.
Body Mass Index (BMI)
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.
14.6.2.4.
Extent of Exposure
Extent of Exposure

Extent of Exposure to study treatment through end of Double-Blind Week will be assessed by 
examining the total number of infusions a subject receives and the duration of exposure to 
study treatment in days.  

The Treatment Stop Date for the Double-Blind period will be the date of the last infusion prior 
to Week 104 (Note: Week 104 infusions represent Day 1 of the Open Label period.)

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 28

Participants who were randomized but did not report a treatment start date will be categorised 
as having zero days 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. 
14.6.2.5.
Lupus Nephritis Medication Categories
Lupus Nephritis Medication Categories
Medication Category
Rule
Anti-malarials
Set to "ANTIMALARIALS" if the preferred term begins with 
"QUINACRINE", "QUININE", "HYDROXYCHLOROQUINE", 
"MEPACRINE", or CHLOROQUINE" 
Steroids
Set to ‘STEROIDS’ if at least one associated ATC code (ATCCD1 –
ATCCD6) begins with ‘H02’ 
Immunosuppressants
Set to ‘IMMUNOSUPPRESSANTS’ if at least one associated ATC code 
(ATCCD1 – ATCCD6) begins with ‘L04A’ and is NOT one of the anti-
malarial preferred terms or the preferred term begins with 
“CYCLOPHOSPHAMIDE” or “MERCAPTOPURINE”.
Angiotensin Pathway 
Set to ‘ACE’ if at least one associated ATC code (ATCCD1 – ATCCD6) 


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Lupus Nephritis Medication Categories
Antihypertensive
begins with ‘C09A’ or ‘C09C’.
Prohibited
Set to "PROHIBITED" if any of the following conditions are met, 
if preferred term contains "INVESTIGATIONAL DRUG", 
"IMMUNOGLOBULIN",
"ADALIMUMAB", “BELIMUMAB”, "ETANERCEPT", "INFLIXIMAB", 
"RITUXIMAB", "ABATACEPT", "ANAKINRA", "GOLIMUMAB" or 
"CERTOLIZUMAB" 
and/or 
A review of the surgeries/procedures form indicates the subject had 
"PLASMAPHERESIS", “PLEX PLASMA EXCHANGE”.
14.6.2.6.
Systemic Medication Flag
Systemic Medication Flag
Systemic Flag
Rule
Blank 
If medication category =blank
Y
‘Y’ if medication category ne blank and the route of administration is 
"INTRADERMAL", "INTRAMUSCULAR", "INTRAVENOUS", "ORAL", 
or "SUBCUTANEOUS" 
N
‘N’ otherwise and medication category ne blank
14.6.2.7.
Prednisone Equivalent Conversion
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 for 
mineralocorticords is set to 0.

Only systemic routes of administration are used in the prednisone equivalent conversions; 
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.  

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. ).  Doses 
recorded in micrograms will be converted to milligrams by dividing the dose in micrograms by 
1000 prior to applying the conversion factor.

Reported dose for systemic steroid is converted to prednisone equivalent dose using 
conversion factor for each medication (refer to online calculator 


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Prednisone Equivalent Conversion
http://www.globalrph.com/corticocalc.htm).
Prednisone Conversion Factors (mg)
Single Ingredient Products: 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
DECADRON (NOS) 
6.6667
DEFLAZACORT
0.8333
DEXAMETHASONE
6.6667
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


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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
Frequency Factors
Frequency
Factor
BID
2
BIW
2/7
CONTINUOUS
1
HS
1
OAM
1/30
Once
1
PRN
null
Q2H
12
Q2W
1/14
Q3H
8
Q3M
1/84
Q3MO
1/84
Q3w
1/21
Q4H
6
Q4W
1/28
Q6H
4
Q8H
3
QAM
1
QD
1
QH
24
QHS
1
QID
4
QM
1/30
QOD
1/2
QPM
1
QW
1/7
QWK
1/7
TID
3
TIW
3/7
UNK
null


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Frequency Factors
Frequency
Factor
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
Prednisone Equivalent Daily Dose (mg)
Prednisone Equivalent Daily Dose (mg) = Collected Dose (mg) x Conversion Factor x Frequency 
Factor.  The prednisone conversion factors and frequency conversion factors should be rounded to 
4 decimal places and the resulting prednisone equivalent dose rounded to 3 decimal places.


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14.6.3.
Efficacy
14.6.3.1.
PERR
Primary Efficacy Renal Response (PERR)
When all 3 criteria are met at two consecutive assessments, a subject is a PERR responder at the 
confirmatory assessment.  PERR criteria are: 

eGFR ≥ 60 mL/min/1.73m2 or no decrease in eGFR from pre-flare of >20% [eGFR pre-
flare eGFR x (0.80)] ; and

uPCR 0.7; and 

Not a Treatment Failure (see Section 14.6.3.3)
14.6.3.2.
PERR uPCR and eGFR components
uPCR Responder Criterion for PERR
If uPCR is missing, then responder variable is missing
If uPCR is not missing, then
If uPCR ≤ 0.7 then responder variable is 1 (Y)
If uPCR > 0.7 then responder variable is 0 (N)
eGFR Responder Criterion for PERR
If eGFR is missing then responder variable is missing
Else if eGFR is not missing then
     If eGFR ≥ 60 mL/min/1.73m2
    OR 
    eGFR no more than 20% below pre-flare eGFR [eGFR pre-flare eGFR x (0.80)]
    then the eGFR responder variable is 1 (Y)
    Else the eGFR responder variable is 0 (N)
14.6.3.3.
Time to First Renal Response Maintained through Week x
Time to First Renal Response Maintained to Week x 
The following endpoints are covered by this section:

Time to the first PERR that is maintained through Week 52 

Time to the first PERR that is maintained through Week 104 

Time to the first CRR that is maintained through Week 52.

Time to the first CRR that is maintained through Week 104
The definition is written generically to cover all four endpoints where ‘renal response’ can represent 
PERR or CRR, and Week x represents Week 104 or Week 52.
The first renal response maintained to Week x refers the earliest response in a series of 
consecutive renal responses that extends to and includes Week x.  If a subject does not have a 


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Time to First Renal Response Maintained to Week x 
renal response at Week x then the Time to First Renal Response that is Maintained to Week x is 0 
days.  Intercurrent events are incorporated into the renal response endpoints using the 
IPD/TF/WD=NR strategy.
Time to first renal response maintained through Week x is calculated as:
Time to first Renal Response
maintained to Week x (days)
=
Date of first of a consecutive series of RR 
‘responder’ outcomes through Week x – treatment 
start date + 1.
14.6.3.4.
Treatment Failures
Treatment Failures
General Conventions

Treatment failure (TF) rules are only applicable during the double-blind treatment phase 
from the treatment start date to the discontinuation of investigational product (see definition 
for IP Discontinuation Date in Section 14.6.1.3).

To accommodate a regulatory request, treatment failure rules post-IP discontinuation will 
be assessed and reported but will not be included in the intercurrent event strategy.

Treatment failure rules only apply to routes of administration that provide systemic 
exposure to the medication.

The treatment failure date is the earliest date a treatment failure criterion was met.

Prohibited medications/dosages started on the day the subject completes the double-blind 
treatment phase (Week 104) do not result in TF designation. 

Prohibited medications/dosages started on the date of early IP discontinuation are 
considered a TF.   If the prohibited medication/dose starts after the date of withdrawal it will 
not be part of the TF assessment.

Actual visit date, not target visit date, is used to assess treatment failures. For example, 
the Week 24 visit (target Day 169) can occur on study day 169 7 days.  If the subject’s 
Week 24 visit occurs on Day 171, the date for Day 171 is used when applying the 
treatment failure rules. 

If a critical visit (Week 24, 76 or 104) is missing then the date is imputed as the target date 
for the visit (target visit date = treatment start date + visit study day – 1). 

Assessment of dose is based on analysis dose. Analysis dose is the sum of all doses 
given on a single day, accounting for the frequency. For steroids, all systemically 
administered steroids (SYSTEMIC=’Y’) given on a single day are converted to a daily 
prednisone equivalent dose (mg) adjusting for frequency and then summed for a total daily 
dose.


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Treatment Failures

Generally, only the first instance of each unique TF rule violation type is output 
programmatically. If this instance is adjudicated as 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., 
prednisone dose > 10mg/kg after Week 24). 
Steroids

Only steroids with systemic routes of administration are included in prednisone dose 
calculations (SYSTEMIC=’Y’).

All systemically administered steroids given on a single day are converted to a daily 
prednisone equivalent dose (mg) adjusting for frequency and then summed for a total daily 
dose. There should be an analysis dose created for each CMTYPCD and for total steroid 
use combining steroid doses across all CMTYPCDs. 

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 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.

Rules pertaining to rescue doses of steroids are specific to the maintenance phase of the 
study and are identified by a steroid dose >10mg/day.  
Systemic Steroids for Renal SLE-related Disease Activity 
Identified by 
CMTYPCD =158 [Lupus nephritis induction or maintenance therapy] or
CMTYPCD=164 [Corticosteroids for non-renal SLE with concurrent worsening of renal disease]

Prednisone dose >10mg/day for treatment of a renal flare (with or without concurrent non-
renal SLE activity) after the Week 24 visit date will deem the subject a treatment failure. 
[PARAMCD=PRGT1024; PARAM=Prednisone Renal-SLE > 10mg/d after Week 24]
Systemic Steroids for Rescue within 90 days for non-Renal Disease Activity 
Identified by
CMTYPCD=165 [Corticosteroids for non-renal SLE without concurrent worsening of renal disease]
or
CMTYPCD=blank [Other],


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Treatment Failures
or a combination of the two

2nd Rescue within 3 months (90 days) of the first rescue (a second occurrence of 
prednisone > 10mg/day) within 90 days of ending the previous one). 
[PARAMCD=P2RES90; PARAM=Prednisone 2nd rescue in 90 days]
Systemic Steroids for Non-Renal SLE-related Disease Activity
Identified by
CMTYPCD=165 [Corticosteroids for non-renal SLE without concurrent worsening of renal disease]
The following situations will deem the subject a treatment failure.

Prednisone rescue (>10mg/day) from Week 76 to Week 104. [PARAMCD=PNGT1076; 
PARAM=Prednisone Non-Renal SLE > 10mg/d from Week 76]

Rescue (prednisone dose >10mg/day) that cannot be tapered to ≤10mg/day by Day 14 of 
rescue therapy. [PARAMCD=PNTAP14; PARAM=Prednisone Non-Renal SLE not tapered 
by Day 14]

3 or more rescues (>10mg/day; max of 2 allowed). [PARAMCD=PN3RESC; 
PARAM=Prednisone Non-Renal >= 3 rescues]

Rescue dose >20mg/day (on any given day during the 14-day rescue). 
[PARAMCD=PNRES20; PARAM=Prednisone Non-Renal SLE > 20mg/d]
Systemic Steroids for Non-SLE Disease Activity
Identified by
CMTYPCD=blank [Other]
The following situations will deem the subject a treatment failure.

Prednisone rescue (>10mg/day) from Week 76 to Week 104. [PARAMCD=POGT1076; 
PARAM=Prednisone Non-SLE > 10mg/d from Week 76]

4 or more rescues (>10mg/day; max of 3 allowed). [PARAMCD=PO4RESC; 
PARAM=Prednisone Non-SLE >= 4 rescues]

Rescue (>10mg/day) that cannot be tapered to ≤10mg/day by Day 14 of rescue therapy. 
[PARAMCD=POTAP14; PARAM=Prednisone Non-SLE not tapered by Day 14]

Maximum dose (=60mg) >3 days in duration. [PARAMCD=POMAX3; PARAM=TF 
Prednisone Non-SLE =60mg for > 3 days consecutively]

Rescue dose >60mg/day (the max on any given day during the 14-day period). 
[PARAMCD=PORESC60; PARAM=Prednisone Non-SLE >60mg/d during 14-day period]
Anti-Malarials

Starting any new anti-malarial treatment after the Week 24 visit date will deem the subject 
a treatment failure. Select all records with CMCAT=’ANTIMALARIALS’ with a start date 
after the Week 24 visit date if there was no record of an agent in the same class (CMCAT) 
being taken from baseline through Week 24.  Exclude any records with non-systemic 
routes of administration. [PARAMCD=NEWAM24; PARAM=New Anti-malarial after Week 


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Treatment Failures
24]

An anti-malarial treatment will be considered new if the subject did not receive the anti-
malarial at any time in the interval from baseline through the Week 24 visit date. 

Treatment failure date will be the anti-malarial start date occurring post the Week 24 visit 
date that resulted in treatment failure. 

An anti-malarial may be replaced by another anti-malarial at any time during the study. 

A dose change is allowed during the study if the anti-malarial treatment was initiated by 
Week 24 visit
Immunosuppressant/Immunomodulatory agents
IV Cyclophosphamide, mycophenolate, and azathioprine (AZA) are part of subject’s 
induction/maintenance regimen.  Immunosuppressant doses provided in grams (g) should be 
converted to milligrams (mg) by multiplying by 1000. The term MMF will be used to represent all 
forms of mycophenolate (i.e., mycophenolate mofetil, mycophenolate sodium, mycophenolic acid)
collectively.  Rules around their use are listed below:

Azathioprine (AZA) taken for maintenance therapy is permitted.  Doses > 200mg/day will 
result in treatment failure. [PARAMCD=AZADOSE; PARAM=AZA >200mg/day]

Doses of mycophenolate mofetil or mycophenolic acid > 3g/day (i.e., 3000mg/day) or 
mycophenolate sodium > 2160 mg/day will result in treatment failure. 
[PARAMCD=MMFDOSE; PARAM=MMF >3g or Mycophenolate >2160mg]

MMF administered intravenously (IV) will result in treatment failure. [PARAMCD=MMFIV; 
PARAM=Mycophenolate taken IV]

Switching maintenance therapy from AZA to MMF or MMF to AZA due to toxicity is 
permitted.  Replacing AZA with MMF or MMF with AZA due to insufficient disease control 
will constitute treatment failure. Instances of AZA to MMF/MMF to AZA switches should be 
output for clinical adjudication to identify cases of lack of efficacy.
[PARAMCD=MNTSWTCH; PARAM=AZA to MMF/MMF to AZA switch for lack of efficacy].
Instances of using MMF for maintenance post CYC induction without first attempting AZA 
should be output for clinical adjudication to assess potential of using MMF as new 
induction. [PARAMCD=MMFNEWID; PARAM=MMF as new Induction post IV CYC]

Restarting cyclophosphamide (CYC) therapy after attempting maintenance therapy (i.e., 
starting AZA or MMF) would constitute a treatment failure. Select first record of CYC that 
occurs after use of AZA or MMF. [PARAMCD=CYCNEWID; PARAM=New CYC induction 
after attempting maintenance]

Replacement due to toxicity/lack of availability will be assessed during clinical adjudication 
for switches between AZA and mycophenolate (all forms).
The following rule applies to all other immunosuppressants (not CYC, AZA, or mycophenolate):

Starting a new immunosuppressant after baseline will deem the subject a treatment 
failure. Note, immunosuppressants administered as topical, conjunctival, or other non-
systemic routes are allowed at any time. Select all records with 
CMCAT=’IMMUNOSUPPRESSANT’ with a start date on or after the IP start date 
(TRTSDT).  Exclude any records with non-systemic routes of administration.  
[PARAMCD=NEWIM; PARAM=New Immunosuppressant post-baseline]


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Treatment Failures
Angiotensin Pathway Antihypertensives

Starting a new angiotensin pathway antihypertensive (ACE inhibitor, angiotensin receptor 
blocker) treatment after Week 24 absent any use from baseline through the Week 24 visit 
will deem the subject a treatment failure.  

Replacing an angiotensin pathway antihypertensive or titrating a new agent to dose is 
allowed.

Select all records with CMCAT=’ACE’ with a start date after the Week 24 visit date if there 
was no record of an agent in this class (CMCAT) being taken from baseline through Week 
24. [PARAMCD=NEWACE24; PARAM=New ACE/ARB after Week 24]
Prohibited medications/non-Drug Therapies

Date of treatment failure is date subject started Prohibited medication/non-Drug Therapy.
In addition to the rules defined for steroids, antimalarials, angiotensin pathway inhibitors, and 
immunosuppressants, 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.]

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).

Plasmapheresis 

Select all records with CMCAT=’PROHIBITED’ and append all records from Medical 
Surgical Procedures form listed as ‘Plasmapheresis’. Note the surgical procedures are in 
the SURGERY dataset, variable SPTERM (verbatim text, not coded so will need to check 
for misspellings also). [PARAMCD=PROHIB; PARAM=Prohibited Medication]


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14.6.3.5.
CRR
Complete Renal Response (CRR)
When all 3 criteria are met at two consecutive assessments, a subject is a CRR responder at the 
confirmatory assessment.  CRR criteria are: 

eGFR no more than 10% below pre-flare GFR [eGFR pre-flare eGFR x (0.90)] or within 
normal range (eGFR ≥ 90 mL/min/1.73m2); and

uPCR < 0.5; and 

Not a Treatment Failure (see Section 14.6.3.3)
14.6.3.6.
CRR uPCR and eGFR components
uPCR Responder Criterion for CRR
If uPCR is missing, then responder variable is missing
If uPCR is not missing, then
If uPCR < 0.5 then responder variable is 1 (Y)
If uPCR 0.5 then responder variable is 0 (N)
eGFR Responder Criterion for CRR
If eGFR is missing, then responder variable is missing
Else if eGFR is not missing then
     If eGFR is within the normal range (eGFR ≥ 90 mL/min/1.73m)
    OR 
    eGFR pre-flare eGFR x (0.90) 
    then the eGFR responder variable is 1 (Y)
    Else the eGFR responder variable is 0 (N)
14.6.3.7.
Renal Worsening
Renal Worsening
Renal worsening is the development of increased proteinuria and/or impaired renal function 
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


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Renal Worsening
Impaired Renal Function
A reproducible decrease in GFR of >20% accompanied by at least one of the following: proteinuria 
(>1), RBC casts, WBC casts.
The definition above expresses proteinuria in g/24-hour which is a 1:1 equivalent to proteinuria 
assessed using the urine protein:creatinine ratio (uPCR) in mg/mg (i.e., 1 g/24-hours = 1 mg/mg). 
GFR is estimated from serum creatinine by the simplified MDRD formula [Levey , 2006] and will 
be used for the renal function assessments at all study visits,
eGFR = 175 x serum creatinine-1.154x Age-0.203 x [1.212 if Black] x [0.742 if Female]
where serum creatinine concentration is expressed in mg/dL.
“Reproducible” requires the criterion to be met at two consecutive visits, including unscheduled 
visits and the 8-week Follow-up.
The following table identifies the lab parameters to be used to evaluate the criteria in the renal flare 
definition above.  
Criterion
Parameter
SI Dataset 
LBTESTCD
Proteinuria 
Urine Protein:Creatinine Ratio (mg/mg)
PRTCRT_URQ
GFR
estimated GFR by the MDRD equation 
(mL/min)
GFRMDR_PLR
RBC cellular casts
RBC cellular casts
RBCSTM_URQ
WBC cellular casts
WBC cellular casts
WBCSTM_URQ
14.6.3.8.
End Stage Renal Disease (ESRD)
End Stage Renal Disease (ESRD)
ESRD is an adjudicated event and is defined as the need for chronic dialysis or renal 
transplantation. Chronicity of dialysis is defined as need for it for at least 90 days. Once ESRD is 
flagged, it should be flagged for all subsequent observed visits.
If the subject died or is lost to follow up shortly after initiation of dialysis, pre-existing renal function 
and intention of dialysis (chronic vs. acute renal insufficiency management) will be taken into 
consideration while adjudicating ESRD event.
14.6.3.9.
Doubling of Serum Creatinine
Doubling of Serum Creatinine
Doubling of serum creatinine is defined as a value greater than or equal to double the baseline 
value that is confirmed with a second consecutive measurement at least 3 weeks later; there can 


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Doubling of Serum Creatinine
be no values between the first and confirmatory assessment that do not meet the doubling criteria.
Since the final serum creatinine value in the double-blind period will not have a second 
measurement in the period to confirm the result, a rule will be applied such that if the Week 
100/visit prior to the final value is greater than or equal to double the baseline value, then the Week 
104/final double blind visit result will be considered a confirmed doubling. 
14.6.3.10. ORR
Ordinal Renal Response (ORR)
Complete Renal Response (CRR)

uPCR < 0.5; and

eGFR no more than 10% below pre-flare GFR [eGFR pre-flare eGFR x (0.90)] or within 
normal range (eGFR ≥ 90 mL/min/1.73m2); and

Not a Treatment Failure [1]


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Ordinal Renal Response (ORR)
Partial Renal Response (PRR)

≥ 50% decrease from baseline in uPCR and one of the following: value <1 if baseline ≤3, or 
value <3 if the baseline was >3; and

eGFR no more than 10% below baseline GFR [eGFR baseline eGFR x (0.90)] or within 
normal range (eGFR ≥ 90 mL/min/1.73m2); and

Not a Treatment Failure [1]
No Response

Not meeting criteria for either complete or partial renal response
[1] Treatment failure is defined in Section 5.5 and Section 5.6 of the protocol and further described 
in Section 14.6.3.3 of this RAP.
The ORR at Week 104 is defined by a response at the Week 100 visit that is confirmed by a repeat 
measurement at the Week 104 visit. Table 13 provides the derived primary Week 104 renal 
response based on the combination of possible responses at Week 100 and 104.
Table 13
Ordinal Renal Response Derived from Week 100 and Week 104
Week 100
Week 104
ORR Endpoint at Week 104*
Complete
Complete
Complete
Complete
Partial
Partial
Partial
Complete
Partial
Partial
Partial
Partial
Complete
No Response
No Response
Partial
No Response
No Response
No Response
Complete
No Response
No Response
Partial
No Response
No Response
No Response
No Response
*Requires a response at Week 100 that is reproduced at Week 104.  
Ordinal Renal Response (ORR)
Example of the Ordinal Renal Response Endpoint Derivation
The example in Table 14 illustrates the following:

Imputation of a missing lab component at a visit (i.e., missing eGFR at Week 100 and uPCR at 
Week 104)

Indicator variables for response criterion met within a visit (Y or N; shown in black)

Imputed indicator variable for missing lab component (Y or N; shown in parentheses)

Indicator variables for renal response category (complete, partial, or no response) met within a 
visit (Y or N; shown in bold italic).  Complete and partial response categories are assessed 
independently.

Ordinal Renal Response at the visit (complete, partial, or no response; shown in bold italic in 


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Ordinal Renal Response (ORR)
last row within visit column); each visit is assessed independently.

Confirmed Ordinal Renal Response at Week 104 (complete, partial, or no response; shown in 
bold last row/last column) based on Week 100 and Week 104 as detailed in Table 13.
Table 14
Example of Renal Response Endpoint Derivation including 
Imputation due to Missing uPCR at Week 104
Week
96
Week 100
(Imputed)
Week 104
(Imputed)
ORR at 
Week 
104
CRR
eGFR no more than 10% below pre-flare
or w/in NR
Y
Missing
(Y)
Y
uPCR < 0.5
Y
N
Missing
(N)
Not a Treatment Failure
Y
Y
Y
Complete Response**
N
N
PRR
eGFR no more than 10% below baseline
or w/in NR
Y
Missing
(Y)
Y
≥ 50% decrease from baseline in uPCR 
which is <1 if baseline ≤3, or <3 if the 
baseline was >3*
Y
Y
Missing
(Y)
Not a Treatment Failure
Y
Y
Y
Partial Response**
Y
Y
NRR
Not meeting criteria for either complete 
or partial renal response
N
N
--
No Response
N
N
Ordinal Renal Response
Partial
Partial
Partial
*If baseline uPCR is missing such that the %decrease from baseline cannot be calculated, then 
the ordinal endpoint will be treated as missing and the subject will not contribute to the analysis.
**Requires a ‘Y’ indicating criterion met for each component within the response category 
(complete or partial) at the visit to be a responder for that category.


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14.6.3.11. ORRUS
Ordinal Renal Response including Urinary Sediment (ORRUS)
Ordinal renal response including urinary sediment component (ORRUS): measured by complete, 
partial or no response at Week 104 defined as follows:
Complete Renal Response including urinary sediment (CRRUS):
- Complete renal response (as defined in Section 14.6.3.10
AND
-Inactive urinary sediment [< 5 RBCs/hpf and < 5 WBCs/hpf (or within the reference range 
of the laboratory)]; and no cellular casts (no RBC or WBC casts)  
Partial Renal Response including urinary Sediment (PRRUS):
-Partial response (as defined in Section 14.6.3.10)
AND
-[RBCs/hpf ≥ 50% reduction from baseline or < 5 RBCs/hpf (or within the normal reference 
range for the central laboratory)]; and no RBC casts 
No Renal Response:
-Not meeting criteria for either complete or partial renal response above.
14.6.3.12. ORRUS using cGFR at Week 104
Ordinal Renal Response including Urinary Sediment using calculated GFR (ORRUS using 
cGFR)
Ordinal renal response including urinary sediment component (ORRUS) and using calculated (vs. 
estimated) GFR: measured by complete, partial or no response at Week 104 defined as 
follows:
Complete Renal Response including urinary sediment (CRRUSC):
-Complete renal response (as defined in Section 14.6.3.9) using calculated GFR with the 
exception of the pre-flare assessment which uses the estimated GFR since cGFR was not 
measured pre-flare: 

cGFR no more than 10% below pre-flare eGFR [cGFR pre-flare eGFR x 
(0.90)] or within normal range (cGFR ≥ 90 mL/min/1.73m2); and
AND
-Inactive urinary sediment [< 5 RBCs/hpf and < 5 WBCs/hpf (or within the reference range 
of the laboratory)]; and no cellular casts (no RBC or WBC casts)  
Partial Renal Response including urinary Sediment (PRRUSC):
-Partial response (as defined in Section 14.6.3.9) using calculated GFR


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Ordinal Renal Response including Urinary Sediment using calculated GFR (ORRUS using 
cGFR)
AND
-[RBCs/hpf ≥ 50% reduction from baseline or < 5 RBCs/hpf (or within the normal reference 
range for the central laboratory)]; and no RBC casts 
No Renal Response:
-Not meeting criteria for either complete or partial renal response above.
For a complete renal response to be declared at Week 104, a calculated GFR (as defined in RAP 
Section 14.6.3.12) should be available for both of the Week 100 and 104 assessments. However, if 
a calculated GFR is only available for one of the timepoints, a complete renal response can be 
based on estimated GFR for the missing calculated GFR assessment. If calculated GFR is missing 
for both assessments, then the best response possible will be partial renal response using 
estimated GFR.
14.6.3.13. Calculated GFR (cGFR)
Calculated GFR (cGFR)
At baseline (Week 0), Week 24, 48, 52, 76, 100 and 104 the calculated GFR will be based on the 
mean of two creatinine clearance values derived from 24-hour urine collection and serum 
creatinine, one set of measurements taken at the visit and another taken 3 days later. Since the 
protocol allows the urine collection to be postponed for up to 14 days at the investigator’s discretion 
if menstrual bleeding or a genitourinary tract infection is present at anytime during the 24-hour 
urine collection period, a 14-day window will be applied to the creatinine clearance values.
cGFR = (Week x Value + Week x+3 days Value) / 2, 
where ‘Value’ is Creatinine Clearance adjusted for BSA (original units in mL/min/1.73m2).


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14.6.3.14. SFI Flares
14.6.3.14.1.
SLE Flare Index (SFI) Scoring
SLE Flare Index
CRF Information


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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.  
o
In this case, if any of the mild/moderate reasons are checked or if the modified SELENA 
SLEDAI score has a change from previous visit of at least 3, then the flare will be 
considered Mild/Moderate.

Flares that are marked mild/moderate where the only reason checked is SELENA SLEDAI 
increase of at least 3 points but not more than 12 points will be re-derived using the modified 
SELENA SLEDAI score.  
o
If it’s found that the change is not actually ≥ 3, and no other reasons are checked, then the 
flare will not be counted.


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14.6.3.14.2.
Time to First SFI Flare Censoring and Disposition Rules
Time to First SFI Flare Censoring and Disposition Rules
The rules described in this section apply to SLE Flares and Severe SLE Flares. 
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. 
If a subject is a treatment failure during the period being analyzed, the subject will be considered 
as having a flare at the time of treatment failure.  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.
Time to first flare is calculated as:
Time to first flare (days)
=
Date of first flare – treatment start date + 1.
After Week 24
For the time to first flare from Week 24 to Week 104, flares (not subjects) occurring on the Week 
24 visit date should be removed from the analysis set prior to determining the first flare. If a subject 
is a treatment failure on the Week 24 visit date, the treatment failure will be counted as a flare at 
Week 24.  Time to first flare from Week 24 to Week 104 is calculated as:
Time to first flare (days)
=
Date of first flare – Week 24 visit date + 1.
Table 15
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 an SLE flare [1]
Yes
Date of first SFI flare
Subject is a treatment failure [1] 
Yes
Treatment failure date
Subject does not have a flare and is not a treatment failure
Subject discontinues IP
No
Censored at last flare assessment prior 
to IP Discontinuation
Subject withdraws
No
Censored at last flare assessment date
Lost to Follow-up
No
Censored at last flare assessment date
Subject dies
No
Censored at date of death
Subject completes Week 104
No
Censored at the Week 104 study visit
[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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14.6.3.15. Proteinuria
Proteinuria
For analysis, urine protein in g/24-hour will be approximated by the urine protein:creatinine ratio 
(uPCR) in mg/mg, also referred to as the PC Ratio which is stored in the variable for the original 
unit in the SI dataset, not the standard unit which is reported in mg/mmol.  In SDTM this variable is 
mapped to lab test code ‘PROTCRT’ with units reported as g/g.  Note, the value in mg/mg from the 
SI dataset is the same as the value in g/g in the SDTM dataset as the units cancel out so no data 
conversion is required.  The data will be reported as g/g in the displays. 
Change from baseline and percent change from baseline values will be derived as described in 
Section 14.6.1.4 and Section 14.6.1.5.
14.6.3.16. SELENA SLEDAI and SLEDAI-S2K Scoring and Endpoints
SELENA SLEDAI 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 in Table 16.  If any items are missing, the domain score is the sum of non-missing items.
Table 16
SELENA SLEDAI Scoring
Organ System
Descriptor
Weight
Definition
CNS
Seizure
8
Recent onset (last 10 days). Exclude metabolic, infectious drug 
cause, or seizure due to past irreversible CNS damage.
Psychosis
8
Altered ability to function in normal activity due to severe 
disturbance in the perception of reality. Include hallucinations, 
incoherence, marked loose associations, impoverished thought 
content, marked illogical thinking, bizarre, disorganized, or 
catatonic behavior. Exclude uremia and drug causes.
Organic Brain 
Syndrome
8
Altered mental function with impaired orientation, memory or 
other intellectual function with rapid onset and fluctuating 
clinical features. Include clouding of consciousness with 
reduced capacity to focus and inability to sustain attention to 
environment, plus at least 2 of the following: perceptual 
disturbance, incoherent speech, insomnia or daytime 
drowsiness, or increased or decreased psychomotor activity. 
Exclude metabolic, infectious, or drug causes.
Visual Disturbance
8
Retinal and eye changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudate of hemorrhage in the choroid, 
optic neuritis, scleritis or episcleritis. Exclude hypertension, 
infection, or drug causes.
Cranial Nerve 
8
New onset sensory or motor neuropathy involving cranial 


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Organ System
Descriptor
Weight
Definition
Disorder
nerves. Include vertigo due to lupus.
Lupus Headache
8
Severe persistent headache: may be migrainous, but must be 
non-responsive to narcotic analgesia.
CVA
8
New onset of CVA(s). Exclude arteriosclerosis or hypertensive 
causes.
Vascular
Vasculitis
8
Ulceration, gangrene, tender finger nodules, periungual 
infarction, splinter hemorrhages, or biopsy or angiogram proof 
of vasculitis.
Musculoskeletal
Arthritis
4
More than 2 joints with pain & signs of inflammation (i.e., 
tenderness, swelling or effusion).
Myositis
4
Proximal muscle aching/weakness associated with elevated 
creatine phosphokinase/aldolase or electromyogram changes 
or a biopsy showing myositis.
Renal
Urinary Casts
4
Heme-granular or red blood cell casts.
Hematuria
4
>5 red blood cells/high power field. Exclude stone, infection, or 
other causes.
Proteinuria
4
New onset or recent increase of more than 0.5 g/24 hours.
Pyuria
4
>5 white blood cells/high power field. Exclude infection.
Mucocutaneous
Rash
2
New or ongoing inflammatory lupus rash.
Alopecia
2
New or ongoing abnormal, patchy or diffuse loss of hair due to 
active lupus.
Mucosal Ulcers
2
New or ongoing oral or nasal ulcerations due to active lupus.
Cardiovascular & 
Respiratory
Pleurisy
2
Classic and severe pleuritic chest pain or pleural rub or 
effusion or new pleural thickening due to lupus.
Pericarditis
2
Classic and severe pericardial pain or rub or effusion, or 
electrocardiogram confirmation.
Immunologic
Low Complement
2
Decrease in CH50, C3, or C4 below the lower limit of normal 
for testing laboratory.
Increased DNA 
Binding
2
>25% binding by Farr assay or above normal range for testing 
laboratory.
Constitutional
Fever 
1
>38C. Exclude infectious cause.
Hematologic
Thrombocytopenia
1
<100,000 platelets/mm3.
Leukopenia
1
<3,000 white blood cells/mm3. Exclude drug causes.
SS-S2K- differs from SS [Gladman, 2002] in that it also reflects persistent disease activity in certain 
descriptors whereas the SS only reflects new or recurrent disease activity (see Table 17).
Table 17
SELENA SLEDAI compared with S2K
Descriptors
Original SELENA SLEDAI
SELENA SLEDAI-2K
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.  
Proteinuria is evaluated using spot-urine protein [represented as urine protein-creatinine ratio 
(uPCR) or PC Ratio in the laboratory dataset] in lieu of the 24-hour urine collection (see 


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Section 14.6.3.15). Only proteinuria is programmatically re-scored per the S2K rules as the other 
clinical descriptors would require subjective assessment by the investigator.
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.
14.6.3.16.1.
SLEDAI-S2K < 4
SLEDAI-S2K < 4
The SLEDAI-S2K < 4 responder endpoints is defined as :
Endpoint
Criterion
Responder
SLEDAI-S2K < 4
SLEDAI-S2K < 4 and not missing
Y
SLEDAI-S2K 4
N
SLEDAI-S2K post-baseline = missing
TF/IP Disc = NR
S2K baseline = missing 
Missing
14.6.3.16.2.
SLEDAI-S2K Organ System Improvement and Worsening
SLEDAI-S2K Organ System Improvement and Worsening
For the SS, each organ system (as defined in Section 14.6.3.16.2) will be evaluated for 
improvement and worsening as follows:
Endpoint
Criterion 
Responder
Improvement
Organ score post-baseline – baseline organ score<0
Y
Organ score post-baseline – baseline organ score 0
N
Organ score post-baseline = missing  
TF/IP Disc = NR
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  
LOCF of worsening 
status
Organ score baseline = missing
Missing
14.6.3.16.3.
SLEDAI-S2K excluding renal items 
SLEDAI-S2K excluding renal items 
SLEDAI-S2K score excluding renal items will be computed by adding up the score of all items 
marked as present in the SLEDAI-S2K except for the Renal items (urinary casts, hematuria, pyuria, 
proteinuria). See Section 14.6.3.16.3 for further details. 


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14.6.3.17. Prednisone
14.6.3.17.1.
Baseline Prednisone Dose
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.  
14.6.3.17.2.
Prednisone Average Daily Dose Since Previous Visit
Prednisone Average Daily Dose Since Previous Visit
The prednisone average daily dose since previous visit will be calculated at every 4-week visit
post-baseline (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 
88, 92, 96, 100, and 104)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) and rounding the result to 3 decimal 
places.  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 one of the 4-
week visit intervals, the average daily dose for that interval will be calculated as the sum of all 
prednisone doses since the previous visit up to and including the date of withdrawal, IP 
discontinuation date or date of treatment failure, whichever is earlier.
See RAP Section 7.3.1 for imputation rules for this endpoint.
14.6.3.18. SLICC/ACR Damage Index Scoring
SLICC/ACR Damage Index Scoring

The SLICC/ACR Damage Index (SDI) score is the sum of all points for items marked as 
present on the instrument.

The SDI increases over time. Once a subject meets the criteria for positive scoring of an 
item, that item should always be marked as present, even if the subject subsequently 
recovered. 

In the event the SLICC/ACR Damage Index is scored inconsistently (a decrease relative to 
previous items has occurred) and the data are unable to be queried and/or corrected, a 
worst observation carried forward (WOCF) approach will be used at the item level for the 
SLICC/ACR damage Index questions.  The WOCF approach will carry baseline forward if 
there is a decrease from baseline.  Note: renal items are an exception such that if a 
subject had scored points for glomerular filtration rate (GFR) or proteinuria which are each 
1-point items and progresses to end stage renal disease (ESRD), a 3-point item, then GFR 
and proteinuria should no longer be scored, and the renal total would be assigned a value 
of 3 for ESRD. The WOCF values will be used to calculate the total score.  

Worsening is defined as an increase from baseline in SLICC/ACR Damage Index score 


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SLICC/ACR Damage Index Scoring
[(post-baseline visit score – baseline score)] >0.

SLICC/ACR Damage Index for Systemic Lupus Erythematosus
Item
Score
Ocular (either eye, by clinical assessment)
Any cataract ever
1
Retinal change or optic atrophy
1
Neuropsychiatric
Cognitive impairment (eg memory deficit, difficulty with
1
calculation, poor concentration, difficulty in spoken or written
language, impaired performance levels) or major psychosis
Seizures requiring therapy for 6 months
1
Cerebrovascular accident ever (score 2 >1)
1(2)
Cranial or peripheral neuropathy (excluding optic)
1
Transverse myelitis
1
Renal
Estimated or measured glomerular filtration rate <50%
1
Proteinuria >3.5 gm/24hours
1
Or
End-stage renal disease (regardless of dialysis or transplantation)
3
Pulmonary
Pulmonary hypertension (right ventricular prominence, or loud P2)
1
Pulmonary fibrosis (physical and radiograph)
1
Shrinking lung (radiograph)
1
Pleural fibrosis (radiograph)
1
Pulmonary infarction (radiograph)
1
Cardiovascular
Angina or coronary artery bypass
1
Myocardial infarction ever (score 2 if >1)
1(2)
Cardiomyopathy (ventricular dysfunction)
1
Valvular disease (diastolic, murmur, or systolic murmur >3/6)
1
Pericarditis for 6 months, or pericardiectomy
1
Peripheral vascular
Claudication for 6 months
1
Minor tissue loss (pulp space)
1
Significant tissue loss ever (eg loss of digit or limb) (score 2 if >1 site)
1(2)
Venous thrombosis with swelling, ulceration, or venous stasis
1
Gastrointestinal
Infarction or resection of bowel below duodenum, spleen, liver, or
1(2)
gall bladder ever, for cause any (score 2 if >1 site)
Mesenteric insufficiency
1
Chronic peritonitis
1
Stricture or upper gastrointestinal tract surgery ever
1


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SLICC/ACR Damage Index Scoring
Musculoskeletal
Muscle atrophy or weakness
1
Deforming or erosive arthritis (including reducible deformities, excluding avascular
necrosis)
1
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis)
1
Avascular necrosis (score 2 if >1)
1(2)
Osteomyelitis
1
Skin
1
Extensive scarring or panniculum other than scalp and pulp space
1
Skin ulceration (excluding thrombosis) for >6 months
1
Premature gonadal failure
1
Diabetes (regardless of treatment)
1
Malignancy (exclude dysplasia) (score 2 if >1 site)
1(2)
([SLICC, 1996; and Gladman, 1996]
14.6.4.
Safety
Adverse Events
AEs of Special Interest

Adverse Events of Special Interest (AESIs) will be reported based on the current version of the 
Program Safety Analysis Plan (PSAP) at the time of reporting. See the PSAP (PSAP, 2018) for 
a list of preferred term definitions for each category of AESI. AESIs currently include malignant 
neoplasms, post-infusion systemic reactions, infections, depression/suicide/self-injury, and 
fatalities.
Laboratory Parameters

If a laboratory value is expected to have a numeric value for summary purposes, but the 
numeric value is missing, and the character value starts with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field), the numeric version of the value must be 
derived.  The derived value will be set to one unit less (if <x) or more (if >x) based on the 
number of significant digits in the observed values. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
14.6.5.
Pharmacokinetic
Belimumab Concentration Units
Belimumab concentration data should be reported as ug/mL in the data displays.  If the data is 
transferred in ng/mL it should be converted to ug/mL using the following formula:


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Belimumab Concentration Units
ug/mL = ng/mL x 1000


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14.7.
Appendix 7: Reporting Standards for Missing Data
14.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Completion of the Double-Blind treatment period is defined as completing 
through the Week 104 visit without permanent discontinuation of study 
treatment.  Similarly, completion through the end of Open Label is defined as 
completing through the Open Label Week 28 visit. 

Withdrawn subjects were not replaced in the study.

Data from participants who were withdrawn from the study will be listed and 
planned data will be included in summary tables and figures, unless otherwise 
specified.

Withdrawal visits will be slotted as per Section 14.3.1 or will be summarised as 
withdrawal visits.
14.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated using a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
LOCF

For the LOCF imputation, missing values will be carried forward from the 
previous, non-missing assessment per the intercurrent event strategy being 
employed for the endpoint.
14.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events
o
Partial stop dates will not be imputed.

Partial and completely missing start or end dates will remain partial/missing, with 
no imputation applied. Consequently, time to onset and duration of such events 
will be missing.
Concomitan
t 
Medications
/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 


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Element
Reporting Detail
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.

Completely missing start or end dates will remain missing.


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14.8.
Appendix 8: Laboratory Toxicity Grades
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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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, 2001; Yamani, 2001; and Eibl, 1995).
Modified from (DMID) Adult Toxicity Tables, 2001


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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
> 3 - < 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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14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
Belimumab serum concentration-time data will be analyzed by population 
pharmacokinetic (PopPK) methods using a non-linear mixed-effects modelling approach.
The key objectives of this analysis are:

Develop a PopPK model that characterizes the PK disposition of belimumab 
following intravenous administration in adult subjects with active lupus 
nephritis

Evaluate the potential effect of selected covariates including proteinuria on
belimumab PK parameters

Estimate and summarize individual subject PK parameters and document these 
for the purposes of any subsequent exposure-response (PK/PD) analysis
14.9.1.
Systems
The quantitative analysis will be performed using NONMEM (ICON Solutions) and PsN 
(Perl Speaks NONMEM) or another software platform deemed appropriate. Graphical 
displays and, if needed, modifications of the dataset will be produced using R (The R 
Foundation for Statistical Computing). The analysis will be performed by, or under the 
direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), 
GlaxoSmithKline using the currently supported versions of all software packages.
14.9.2.
Data Assembly
Subject data will be collected in the electronic CRF and will be transmitted into a 
validated database by GSK data management. Derived/processed variables will be 
provided by or under the guidance of Clinical Programming. Serum samples will be 
analyzed under supervision of Department of Bioanalysis, Immunogenicity and 
Biomarker, IVIVT, GSK, using approved analytical methodology. Data will be 
transferred electronically to data managers to be processed and stored in the GSK 
database. GSK or a designated third party will generate the NONMEM input dataset.
A previously generated NONMEM data set of PK data from adult systemic lupus 
erythematosus (SLE) patients (without active lupus nephritis) may be merged with the 
PK data from this study to allow for a pooled PopPK analysis, if deemed appropriate. 
Data set specifications guiding the generation of the NONMEM input data set will be 
reported together with the PK results.  
14.9.3.
Model Development
A population pharmacokinetic model for IV belimumab in adult SLE patients without 
active nephritis (SLE PopPK model) was developed [Struemper, 2013; model version 
with continuous proteinuria covariate] and will be the starting point for this population 
PK analysis. 


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Initially, the appropriateness of the structure and parameters of the original SLE PopPK 
model for representing also the PK data form this study will be explored by applying (i) 
either the complete set of parameters (MAXEVAL=0 option) to the PK data from this 
study or (ii) by re-estimating only specific parameters (e.g. only for proteinuria effect) 
and leaving the other parameters fixed to the values of the SLE PopPK model.   
If the parameter set of the SLE PopPK model applied to the PK data from this study 
results in substantial bias or if a further exploration of the covariate effect in the lupus 
nephritis population is deemed necessary, the parameters of the SLE PopPK model will 
be re-estimated for the PK data from this study alone and/or for a pooled SLE/lupus 
nephritis data set.  Covariate not available for this study but present in the SLE PopPK 
model may be removed from the PopPK model.  The set of remaining covariate-
parameter relationships of the SLE PopPK model may then be reduced using the full 
model approach [Gastonguay, 2011]. Lastly, a model refinement step may be applied 
including a qualification and possible modification of the PopPK model’s random effect 
structure. 
14.9.4.
Model Qualification
Any model development will be supported and the final model will be qualified using the 
following criteria where appropriate: 

Scientific plausibility of parameter estimates

Goodness of fit plots

Relative standard errors (RSE) of the parameter estimates

Objective function value

Distribution and shrinkage of random effects;

Successful minimization and execution of covariance step

Condition number (ratio of the largest and smallest eigenvalue of the covariance 
matrix

Visual predictive check

Bootstrap (if deemed necessary/feasible)
14.9.5.
Endpoints
Along with model PK parameters (e.g. central clearance etc.) the following parameters, if 
appropriate relative to the final model structure, will be derived, listed for each subject 
and summarized:

Steady-state trough concentration: Cmin (g/mL)

Steady-state maximal concentration: Cmax (g/mL)

Steady-state area under the serum drug time-concentration curve and/or average 
concentration for the dosing interval:  AUC0-(day*g/mL) and/or Cavg 
(g/mL)


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
Distribution half-life: t1/2(day)

Terminal half-life: t1/2(day)

Steady-state volume of distribution: Vss (mL)
14.9.6.
Simulations
If one or more covariate effect of clinical interest for lupus nephritis subjects is identified, 
simulations to characterize the impact of any such covariate effect on belimumab 
exposure may be performed. 


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14.10.
Appendix 10: B Cells
14.10.1.
B-cell unit conversions and Normalization of Rare B-cell Subsets
The Benlysta program standard is to report common B-cells (CD19, CD20, naïve, and memory) in counts per microliter (uL). Common B-
cells are not normalized but they must be converted to uL for reporting. To convert values reported from GI/L (= 109/L) to count per uL (= 
cells/mm3), multiply the value by 103 or 1000.
Example: (0.25 GI/L) x (1000) = 250/uL  
Rare B-cell subsets are reported in counts per milliliter (mL). Rare B-cell subsets reported in GI/L will be converted to cells/ml using the 
following formula:
Normalized count/mL = (rare cell events) / (CD19+ events) * (CD19+ count/uL) * 1000
Note, the total B-cell (CD19+) concentration from the TBNK panel should be converted to count/uL prior to the normalization and 
conversion of the Rare B-cell subset. 
Example: Normalization and conversion of Plasma CD20-CD138+ to count/mL
Given:

Plasma CD20-CD138+ number of events = 16

CD19+ number of events on Plasma panel = 10250

CD19+ concentration on TBNK panel = 0.35 GI/L
Then:


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Plasma CD20-CD138+ Normalized (count/mL) = 16 / 10250 * (0.35*1000) * 1000 = 546.34 count/mL
14.10.2.
B Cell Mappings
B Cell Panel
(BIMETHCD/
LBMETHCD)
Biomarker 
Category Code
[BICATCD]
Biomarker Category
[BICAT]
Lab Test Code
(LBTESTCD)
Lab Test Code
(LBTESTCD)
Units of Measurement
(BIORRESU/
LBORRESU)
FLWTBNK
CD19
CD19
CD19LY
CD19_Percentage
%
FLWTBNK
CD19
CD19
CD19
CD19_Concentration
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_Percentage
%
FLWPLSM
CD20
CD20
CD20
CD20_Number of events 
EVENTS
FLWPLSM
CD20
CD20
CD20E
CD20_Concentration
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
CDX155
CD19+CD20+CD69+
CDX155E
CD19+CD20+CD69+ Number 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


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B Cell Panel
(BIMETHCD/
LBMETHCD)
Biomarker 
Category Code
[BICATCD]
Biomarker Category
[BICAT]
Lab Test Code
(LBTESTCD)
Lab Test Code
(LBTESTCD)
Units of Measurement
(BIORRESU/
LBORRESU)
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 CD20-
CDX154
CD27+b CD20-
GI/L
FLWPLSM
CDX156
CD27+CD38+CD19+
CDX15619
CD27+CD38+CD19+/CD19+
%
FLWPLSM
CDX156
CD27+CD38+CD19+
CDX156E
CD27+CD38+CD19+ Number of Events
EVENTS
FLWPLSM
CDX156
CD27+CD38+CD19+
CDX156
CD27+CD38+CD19+
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/CUMM
FLWTRANS
CDX199
CD19+ CD24b+ CD38b+ CD27
CDX199E
CD19+ CD24b+ CD38b+ CD27 Number of Events
EVENTS


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14.10.3.
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_Concentration
GI/L
CD19 (/uL)
CD20
CD20_Concentration
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+ Normalized (COUNT/mL)
CDX143N
CD20- CD138+
GI/L
Plasma CD19+CD20-CD138+ Normalized (COUNT/mL)
CDX145N
CD20+ CD138+
GI/L
Plasmacytoid CD19+CD20+CD138+ Normalized (COUNT/mL)
CDX154N
CD27+b CD20-
GI/L
Short-lived Plasma CD19+CD20-CD27b+ Normalized (COUNT/mL)
CDX156N
CD27+CD38+CD19+
GI/L
SLE Subset CD19+CD38b+CD27b+Lymph Normalized (COUNT/mL)
CDX199N
CD19+ CD24b+ CD38b+ CD27-
GI/L
Transitional CD19+CD24b+CD38b+CD27- Normalized (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.


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14.11.
Appendix 11: Abbreviations & Trade Marks
14.11.1.
Abbreviations
Abbreviation
Description
aCL
Anti-cardiolipin
ACR
American College of Rheumatology
ACE
Angiotensin Converting Enzyme
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike's Information Criteria
ANA
Anti-nuclear Antibody
ANCOVA
Analysis of Covariance
anti-C1q
Anti-C1q Antibody
anti-dsDNA
Anti-double-stranded DNA
anti-Sm
Anti-Smith Antibody
A&R
Analysis and Reporting 
ARB
Angiotensin Receptor Antagonists/Blockers
ATC
Anatomical Therapeutic Chemical
AZA
Azathioprine
BLyS
B Lymphocyte Stimulator
BMI
Body Mass Index
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
cm
Centimeter
CMQ
Customized MedDRA Query 
CPMS
Clinical Pharmacology Modelling & Simulation
CRR
Complete Renal Response
CS
Clinical Statistics
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
CYC
Cyclophosphamide
DBF
Database Freeze
DBR
Database Release
DC
Discontinue
dL
Deciliter
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
ESRD
End Stage Renal Disease


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Abbreviation
Description
FACS
Florescence Activated Cell Sorting
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
HDCS
High Dose Corticosteroids 
HZ
Herpes Zoster 
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMMS
International Modules Management System
IP
Investigational Product
IPD
Investigational Product Discontinuation
ISN
International Society for Nephrology
IU
International Unit
IV
Intravenous
GUI
Guidance
kg
Kilogram
KU
International Unit for enzymatic activity
L
Litre
LLN
Lower Limit of Normal
LN
Lupus Nephritis
LOC
Last Observation Carries Forward
LOQ
Limit of Quantification
LS
Least Squares
MAH
Marketing Authorization Holder 
m
Meter
MedDRA
Medical Dictionary for Regulatory Activities 
mg
Milligram
min
Minute
mL
Milliliter
MMF
Mycophenolate Mofetil
MMRM
Mixed Model Repeated Measures
M=NR
Missing = Non-Responder
MITT
Modified Intent-To-Treat
ng
nanogram
NMSC
Mon-melanoma Skin Cancer
NQ
Non-quantifiable
NR
Non-Responder
OI
Opportunistic Infections
OR
Odds Ratio 


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Abbreviation
Description
ORR
Ordinal Renal Response.
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PERR
Primary Efficacy Renal Response
PGA
Physician’s Global Assessment
PISR
Post-Infusion Systemic Reactions
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
PSAP
Program Safety Analysis Plan 
PT
Preferred Term
PSRQ
Possible Suicidality Related Questionnaire
QC
Quality Control
QL
Likelihood Ratio chi-square
QP
Pearson chi-square
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RPS
Renal Pathology Society
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SBC
Schwarz Bayesian criterion
SAE
Serious Adverse Event
SFI
SLE Flare Index
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SDI
SLICC Damage Index
SLE
Systemic Lupus Erythematosus
SOC
System Organ Class 
SOP
Standard Operation Procedure
SRT
Safety Review Team 
TA
Therapeutic Area
TB
Tuberculosis 
TF
Treatment Failure
TFL
Tables, Figures & Listings 
ULN
Upper Limit of Normal
uPCR
Urine Protein-Creatinine Ratio
WD
Withdraw


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14.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
Benlysta
NONMEM
SAS
WinNonlin


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14.12.
Appendix 12: List of Data Displays
14.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.52
1.01 to 1.02
Efficacy
2.01 to 2.70
2.01 to 2.39
Safety
3.01 to 3.83
3.01 to 3.06
Biomarker
4.01 to 4.15
4.01 to 4.12
Pharmacokinetic
5.01 to 5.05
5.01 to 5.05
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
14.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced based on the display number and  example 
mock-up displays provided in Appendix 13: Example Mock Shells for Data Displays.
14.12.3.
Deliverables
Delivery [Priority] [1]
Description
DB [1]
Double Blind Statistical Analysis Complete – Primary SAC
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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14.12.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.01.
Randomized
NS1
Randomization by Country and Site ID
EudraCT, IDSL
DB [1]
1.02.
Screened
SP1
Populations
IDSL
DB [1]
1.03.
Screened
Reasons for Failing Screening
DB [1]
Population Analysed
1.04.
MITT
Subject Status by Week 104
DB [1]
1.05.
MITT
ES1
Subject Status and Reason for Study Withdrawal 
IDSL
DB [1]
1.06.
MITT
Study Withdrawal by Visit
DB [1]
1.07.
MITT
SD1
Investigational Product Status and Reasons for Discontinuation
ICH E310.1, IDSL
DB [1]
1.08.
MITT
Investigational Product Discontinuation by Visit
DB [1]
Protocol Deviation
1.09.
MITT
IE3
Inclusion/Exclusion Criteria Deviations
1.10.
MITT
DV1
Important Protocol Deviations 
ICH E310.2, IDSL
DB [1]
1.11.
MITT
SP2
Exclusions from the Per Protocol Population
IDSL
DB [1]
Demographic and Baseline Characteristics
1.12.
MITT
Shift Table of Differences between Stratification Factors at 
Screening and as Randomized
1.13.
MITT
DM1
Demographic and Baseline Characteristics
ICH E3 12.5, FDAAA, EudraCT, 
IDSL
DB [1]
1.14.
Randomized
DM11
Summary of Age Ranges
EudraCT, IDSL
DB [1]


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.15.
MITT
DM6
Race and Racial Combination Details
IDSL
DB [1]
1.16.
MITT
Vital Signs at Baseline
DB [1]
1.17.
MITT
MH4
Current Medical Conditions
ICH E3 12.5
DB [1]
1.18.
MITT
MH4
Past Medical Conditions
ICH E3 12.5
DB [1]
1.19.
MITT
Stratification Factors at Baseline
DB [1]
1.20.
MITT
Baseline Disease Activity
DB [1]
1.21.
MITT
Pre-Flare Serum Creatinine and eGFR Values
DB [1]
1.22.
MITT
Lupus Nephritis Therapy History
DB [1]
1.23.
MITT
ACR Classification Criteria at Baseline
DB [1]
1.24.
MITT
SLEDAI-S2K Organ and Item Involvement at Baseline
DB [1]
1.25.
MITT
Immunoglobulin Levels at Baseline
DB [1]
1.26.
MITT
Autoantibody Levels at Baseline
DB [1]
1.27.
MITT
Complement Levels and Other Biomarkers at Baseline
DB [1]
1.28.
MITT
B Cells at Baseline
DB [1]
1.29.
MITT
C-SSRS Responses by Behaviour and Ideation Components -
Pre-treatment
DB [1]
Prior and Concomitant Medications
1.30.
MITT
Allowable SLE and LN Medication Usage at Baseline
1.31.
MITT
Concomitant Medications by ATC Level 1 and ATC Level 4 
Term 
DB [1]
1.32.
MITT
Concomitant Medications by ATC Level 4 and Preferred Term 
DB [1]


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
1.33.
MITT
First Medication Usage Resulting in Treatment Failure 
Designation through Week 104
DB [1]
1.34.
MITT
EX3
Exposure to Study Treatment through Week 104
ICH E3 16.2.5Dose and/or time on 
treatment, as applicable. IDSL
DB [1]
Subgroup Displays
1.35.
MITT
Demographic and Baseline Characteristics by Gender
DB [1]
1.36.
MITT
Baseline Disease Activity by Gender
DB [1]
1.37.
MITT
Allowable SLE Medication Usage at Baseline by Gender
DB [1]
1.38.
MITT
Demographic and Baseline Characteristics by Race Stratification 
Factor
DB [1]
1.39.
MITT
Baseline Disease Activity by Race Stratification Factor
DB [1]
1.40.
MITT
Allowable SLE and LN Medication Usage at Baseline by Race 
Stratification Factor
DB [1]
1.41.
MITT
Demographic and Baseline Characteristics by Region
DB [1]
1.42.
MITT
Baseline Disease Activity by Region
DB [1]
1.43.
MITT
Allowable SLE and LN Medication Usage at Baseline by Region
DB [1]
1.44.
MITT
Demographic and Baseline Characteristics by Baseline Anti-
dsDNA
DB [1]
1.45.
MITT
Baseline Disease Activity by Baseline Anti-dsDNA
DB [1]
1.46.
MITT
Allowable SLE and LN Medication Usage at Baseline by 
Baseline Anti-dsDNA
DB [1]
1.47.
MITT
Demographic and Baseline Characteristics by Baseline C3/C4 
Levels
DB [1]


CONFIDENTIAL
BEL114054
147
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.48.
MITT
Baseline Disease Activity by Baseline C3/C4 Levels
DB [1]
1.49.
MITT
Allowable SLE Medication Usage at Baseline by Baseline C3/C4 
Levels
DB [1]
1.50.
MITT
Demographic and Baseline Characteristics by Baseline C3/C4 
Levels and Anti-dsDNA
EMA Labeled population
DB [1]
1.51.
MITT
Baseline Disease Activity by Baseline C3/C4 Levels and Anti-
dsDNA
EMA Labeled population
DB [1]
1.52.
MITT
Allowable SLE Medication Usage at Baseline by Baseline C3/C4 
Levels and Anti-dsDNA
EMA Labeled population
DB [1]
1.53.
MITT
Demographic and Baseline Characteristics by Baseline Body 
Weight Quartiles
DB [1]
1.54.
MITT
Baseline Disease Activity by Body Weight Quartiles
DB [1]
1.55.
MITT
Allowable SLE Medication Usage at Baseline by Baseline Body 
Weight Quartiles
DB [1]
1.56.
MITT
Demographic and Baseline Characteristics by Renal Biopsy 
Subgroup
DB [1]
1.57.
MITT
Baseline Disease Activity by Renal Biopsy Subgroup
DB [1]
1.58.
MITT
Allowable SLE Medication Usage at Baseline by Renal Biopsy 
Subgroup
DB [1]


CONFIDENTIAL
BEL114054
148
14.12.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.01.
MITT
Study Withdrawal by Visit
DB [1]
1.02.
MITT
Investigational Product Discontinuation by Visit
DB [1]


CONFIDENTIAL
BEL114054
149
14.12.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Efficacy Renal Response
2.01.
MITT
Primary Efficacy Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.02.
MITT
Logistic Regression Analysis of Primary Efficacy Renal 
Response at Week 104 (IPD/TF/WD=NR)
DB [1]
2.03.
MITT
Primary Efficacy Renal Response and the 3 Components at 
Week 104 (IPD/TF/WD=NR)
DB [1]
2.04.
MITT
Disposition of Primary Efficacy Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.05.
MITT
Primary Efficacy Renal Response and the 3 Components at 
Week 104 (Hybrid Treatment Policy for Non-TF Intercurrent 
Events Sensitivity Analysis) (TF/WD=NR)
DB [1]
2.06.
MITT
Primary Efficacy Renal Response and the 3 Components at 
Week 104 (Treatment Policy for All Intercurrent Events 
Sensitivity Analysis) (WD=NR)
DB [1]
2.07.
MITT
Primary Efficacy Renal Response at Week 104 (Unadjusted 
Sensitivity Analysis) (IPD/TF/WD=NR)
DB [1]
2.08.
Completer
Primary Efficacy Renal Response at Week 104 (Completer 
Sensitivity Analysis) (IPD/TF/WD=NR)
DB [1]
2.09.
PP
Primary Efficacy Renal Response at Week 104 (Per Protocol 
Sensitivity Analysis) (IPD/TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
150
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
MITT
PERR Responder Rate Grid Values with 95% CI for the 
Difference in Proportions (Tipping Point Analysis of Hybrid 
Treatment Policy for Non-TF Intercurrent Events)
DB [1]
2.11.
MITT
PERR Responder Rate Grid Values with 95% CI for the 
Difference in Proportions (Tipping Point Analysis of Treatment 
Policy for All Intercurrent Events)
DB [1]
2.12.
MITT
Primary Efficacy Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
2.13.
MITT
PERR uPCR Component (uPCR <=0.7) by Visit
(IPD/TF/WD=NR)
DB [1]
2.14.
MITT
PERR eGFR Component (eGFR no more than 20% below Pre-
flare Value or >= 60 mL/min/1.73m2) by Visit (IPD/TF/WD=NR)
DB [1]
2.15.
MITT
Not a Treatment Failure by Visit (IPD/TF/WD=NR)
DB [1]
2.16.
MITT
Treatment Failure Reason by First Criterion Met While on 
Treatment 
DB [1]
2.17.
MITT
Time to First PERR that is maintained through Week 52
(IPD/TF/WD=NR)
DB [1]
2.18.
MITT
Kaplan Meier Estimates of Time to First PERR that is 
maintained through Week 52 (IPD/TF/WD=NR)
DB [1]
2.19.
MITT
Time to First PERR that is maintained through Week 104
(IPD/TF/WD=NR)
DB [1]
2.20.
MITT
Kaplan Meier Estimates of Time to First PERR that is 
maintained through Week 104 (IPD/TF/WD=NR)
DB [1]
2.21.
MITT
Primary Efficacy Renal Response at Week 104 by Induction 
Regimen (IPD/TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
151
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.22.
MITT
Primary Efficacy Renal Response at Week 104 by Race
Stratification Factor (IPD/TF/WD=NR)
DB [1]
2.23.
MITT
Primary Efficacy Renal Response at Week 104 by Region
(IPD/TF/WD=NR)
DB [1]
2.24.
MITT
Primary Efficacy Renal Response at Week 104 by Baseline Anti-
dsDNA (IPD/TF/WD=NR)
DB [1]
2.25.
MITT
Primary Efficacy Renal Response at Week 104 by Baseline 
C3/C4 Levels (IPD/TF/WD=NR)
DB [1]
2.26.
MITT
Primary Efficacy Renal Response at Week 104 by Baseline 
C3/C4 Levels and Anti-dsDNA (IPD/TF/WD=NR)
DB [1]
2.27.
MITT
Primary Efficacy Renal Response at Week 104 by Baseline 
Renal Biopsy Subgroup (IPD/TF/WD=NR)
DB [1]
Complete Renal Response
2.28.
MITT
Complete Renal Response at Week 104 (IPD/TF/WD=NR)
DB [1]
2.29.
MITT
Logistic Regression Analysis of Complete Renal Response at 
Week 104 (IPD/TF/WD=NR)
DB [1]
2.30.
MITT
Complete Renal Response and the 3 Components at Week 104
(IPD/TF/WD=NR)
DB [1]
2.31.
MITT
Disposition of Complete Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.32.
MITT
Complete Renal Response and the 3 Components at Week 104 
(Hybrid Treatment Policy for Non-TF Intercurrent Events 
Sensitivity Analysis) (TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
152
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.33.
MITT
Complete Renal Response and the 3 Components at Week 104 
(Treatment Policy for All Intercurrent Events Sensitivity Analysis)
(WD=NR)
DB [1]
2.34.
MITT
Complete Renal Response at Week 104 (Unadjusted Sensitivity 
Analysis) (IPD/TF/WD=NR)
DB [1]
2.35.
Completer
Complete Renal Response at Week 104 (Completer Sensitivity 
Analysis) (IPD/TF/WD=NR)
DB [1]
2.36.
PP
Complete Renal Response at Week 104 (Per Protocol 
Sensitivity Analysis) (IPD/TF/WD=NR)
DB [1]
2.37.
MITT
CRR Responder Rate Grid Values with 95% CI for the 
Difference in Proportions (Tipping Point Analysis of Hybrid 
Treatment Policy for non-TF Intercurrent Events)
DB [1]
2.38.
MITT
CRR Responder Rate Grid Values with 95% CI for the 
Difference in Proportions (Tipping Point Analysis of Treatment 
Policy for All Intercurrent Events)
DB [1]
2.39.
MITT
Complete Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
2.40.
MITT
CRR uPCR Component (uPCR <0.5) by Visit (IPD/TF/WD=NR)
DB [1]
2.41.
MITT
CRR eGFR Component (eGFR no more than 10% below Pre-
flare Value or within Normal Range) by Visit (IPD/TF/WD=NR)
DB [1]
2.42.
MITT
Time to First CRR that is maintained through Week 52
(IPD/TF/WD=NR)
DB [1]
2.43.
MITT
Kaplan Meier Estimates of Time to First CRR that is maintained 
through Week 52 (IPD/TF/WD=NR)
DB [1]
2.44.
MITT
Time to First CRR that is maintained through Week 104
(IPD/TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
153
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.45.
MITT
Kaplan Meier Estimates of Time to First CRR that is maintained 
through Week 104 (IPD/TF/WD=NR)
DB [1]
2.46.
MITT
Complete Renal Response at Week 104 by Induction Regimen
(IPD/TF/WD=NR)
DB [1]
2.47.
MITT
Complete Renal Response at Week 104 by Race
(IPD/TF/WD=NR)
DB [1]
2.48.
MITT
Complete Renal Response at Week 104 by Region
(IPD/TF/WD=NR)
DB [1]
2.49.
MITT
Complete Renal Response at Week 104 by Baseline Anti-
dsDNA (IPD/TF/WD=NR)
DB [1]
2.50.
MITT
Complete Renal Response at Week 104 by Baseline C3/C4 
Levels (IPD/TF/WD=NR)
DB [1]
2.51.
MITT
Complete Renal Response at Week 104 by Baseline C3/C4 
Levels and Anti-dsDNA (IPD/TF/WD=NR)
DB [1]
2.52.
MITT
Complete Renal Response at Week 104 by Baseline Renal 
Biopsy Subgroup (IPD/TF/WD=NR)
DB [1]
PERR at Week 52
2.53.
MITT
Primary Efficacy Renal Response and the 3 Components at 
Week 52 (IPD/TF/WD=NR)
DB [1]
2.54.
MITT
Disposition of Primary Efficacy Renal Response at Week 52 
(IPD/TF/WD=NR) 
DB [1]
2.55.
MITT
Primary Efficacy Renal Response at Week 52 by Induction 
Regimen (IPD/TF/WD=NR)
DB [1]
2.56.
MITT
Primary Efficacy Renal Response at Week 52 by Baseline 
C3/C4 levels and Anti-dsDNA (IPD/TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
154
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Death or Renal-related Event
2.57.
MITT
Time to Death or Renal-related Event Overall and by Induction 
Regimen (IPD/TF not related to renal disease/WD=Censor)
DB [1]
2.58.
MITT
Event Summary for Time to Death or Renal-related Event
(IPD/TF not related to renal disease/WD=Censor)
DB [1]
2.59.
MITT
Kaplan-Meier Estimates of Time to Death or Renal-related Event
(IPD/TF not related to renal disease/WD=Censor)
DB [1]
2.60.
MITT
Time to Death or Renal-related Event by Baseline C3/C4 Levels 
and Anti-dsDNA (IPD/TF not related to renal 
disease/WD=Censor)
DB [1]
Ordinal Renal Response
2.61.
MITT
Ordinal Renal Response at Week 104 (IPD/TF/WD=NR)
DB [1]
2.62.
MITT
Ordinal Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
2.63.
MITT
Ordinal Renal Response including Urinary Sediment at Week 
104 (IPD/TF/WD=NR)
DB [1]
2.64.
MITT
Ordinal Renal Response at Week 104 by Baseline C3/C4 Levels 
and Anti-dsDNA (IPD/TF/WD=NR)
DB [1]
SFI Flare
2.65.
MITT
Time to First Severe SFI Flare (TF=Flare, IPD/WD=Censor)
DB [1]
2.66.
MITT
Kaplan Meier Estimates of Time to First Severe SFI Flare
(TF=Flare, IPD/WD=Censor)
DB [1]
2.67.
MITT
Time to First Severe SFI Flare from Week 24 (TF=Flare, 
IPD/WD=Censor)
DB [1]


CONFIDENTIAL
BEL114054
155
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.68.
MITT
Kaplan Meier Estimates of Time to First Severe SFI Flare from 
Week 24 (TF=Flare, IPD/WD=Censor)
DB [1]
uPCR
2.69.
MITT
uPCR Percent Change from Baseline by Visit While On 
Treatment (Observed) 
DB [1]
2.70.
MITT
uPCR Change from Baseline by Visit While On Treatment
(Observed)
DB [1]
Serum Creatinine from Baseline and/or End Stage Renal Disease  
2.71.
MITT
Doubling of Serum Creatinine from Baseline and/or Progression 
to End Stage Renal Disease (ESRD) by Visit (LO on or prior to 
IPD/TF CF)
DB [1]
SLEDAI-S2K
2.72.
MITT
SLEDAI-S2K Change from Baseline by Visit While On 
Treatment (Observed)
DB [1]
2.73.
MITT
SLEDAI-S2K Change from Baseline Excluding Renal Items by 
Visit While On Treatment (Observed)
DB [1]
2.74.
MITT
SLEDAI-S2K Score < 4 by Visit (IPD/TF/WD=NR)
DB [1]
2.75.
MITT
SLEDAI-S2K Organ System Improvement by Organ System and 
Visit among Subjects with Organ System Involvement at 
Baseline (IPD/TF/WD=No Improvement)
DB [1]
2.76.
MITT
SLEDAI-S2K Organ System Worsening by Organ System and 
Visit among Subjects with No Organ System Involvement at 
Baseline (LO on or prior to IPD/TF CF)
DB [1]


CONFIDENTIAL
BEL114054
156
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prednisone
2.77.
MITT
Prednisone ≤5 mg Average Daily Dose Since Previous Visit 
(IPD/TF/WD=NR)
DB [1]
2.78.
MITT
Prednisone ≤7.5 mg Average Daily Dose Since Previous Visit
(IPD/TF/WD=NR)
DB [1]
SLICC
2.79.
MITT
SLICC/ACR Damage Index Change from Baseline by Visit While 
on Treatment (Observed with WOCF)
DB [1]
2.80.
MITT
SLICC/ACR Damage Index Worsening (Change > 0) Compared 
with Baseline by Visit While on Treatment (WOCF)
DB [1]
2.81.
MITT
SLICC/ACR Damage Index Change from Baseline by Visit While 
on Study (WOCF)
DB [1]
2.82.
MITT
SLICC/ACR Damage Index Worsening (Change > 0) Compared 
with Baseline by Visit While on Study (WOCF)
DB [1]
Supplementary Analyses
2.83.
MITT
Renal-related Treatment Failure Reason by First Criterion Met 
While on Treatment
DB [1]
2.84.
MITT
Treatment Failure Reason  for Each Unique Criterion Met While 
on Study
DB [1]
2.85.
MITT
Ordinal Renal Response including Urinary Sediment and using 
Calculated GFR at Week 104 (IPD/TF/WD=NR)
DB [1]
2.86.
MITT
Primary Efficacy Renal Response and the 3 Components at 
Week 104 (Treatment Policy, WD=NR)
DB [1]
2.87.
MITT
Time to Death Overall and by Induction Regimen (IPD/TF not 
related to renal disease/WD=Censor)
DB [1]


CONFIDENTIAL
BEL114054
157
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.88.
MITT
Time to End Stage Renal Disease (ESRD) Overall and by 
Induction Regimen (IPD/TF not related to renal 
disease/WD=Censor)
DB [1]
2.89.
MITT
Time to Doubling of Serum Creatinine Overall and by Induction 
Regimen (IPD/TF not related to renal disease/WD=Censor)
DB [1]
2.90.
MITT
Time to Renal Worsening Overall and by Induction Regimen 
(IPD/TF not related to renal disease/WD=Censor)
DB [1]
2.91.
MITT
Time to Renal Event-related Treatment Failure Overall and by 
Induction Regimen (IPD/TF not related to renal 
disease/WD=Censor)
DB [1]
2.92.
MITT
Time to Death or Renal-related Event Overall and by Induction 
Regimen (Treatment Policy)
DB [1]
2.93.
MITT
Time to Death Overall and by Induction Regimen (Treatment 
Policy)
DB [1]
2.94.
MITT
Time to End Stage Renal Disease (ESRD) Overall and by 
Induction Regimen (Treatment Policy)
DB [1]
2.95.
MITT
Time to Doubling of Serum Creatinine Overall and by Induction 
Regimen (Treatment Policy)
DB [1]
2.96.
MITT
Time to Renal Worsening Overall and by Induction Regimen 
(Treatment Policy)
DB [1]
2.97.
MITT
uPCR Percent Change from Baseline by Visit While On Study 
(Observed)
DB [1]
2.98.
MITT
uPCR Change from Baseline by Visit While On Study 
(Observed)
DB [1]
2.99.
MITT
Doubling of Serum Creatinine from Baseline and/or Progression 
to End Stage Renal Disease by Visit (Observed)
DB [1]


CONFIDENTIAL
BEL114054
158
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.100.
MITT
SLEDAI-S2K Change from Baseline by Visit While On Study 
(Observed)
DB [1]
2.101.
MITT
SLEDAI-S2K Change from Baseline Excluding Renal Items by 
Visit While On Study (Observed)
DB [1]
2.102.
MITT
SLEDAI-S2K Score < 4 by Visit  (Observed)
DB [1]
2.103.
MITT
SLEDAI-S2K Organ System Improvement by Organ System and 
Visit among Subjects with Organ System Involvement at 
Baseline [1] (Observed)
DB [1]
2.104.
MITT
SLEDAI-S2K Organ System Worsening by Organ System and 
Visit among Subjects with No Organ System Involvement at 
Baseline [1] (Observed)
DB [1]
2.105.
MITT
Prednisone ≤5 mg Average Daily Dose Since Previous Visit by 
Week 104 PERR Response (IPD/TF/WD=NR)
DB [1]
2.106.
MITT
Prednisone ≤7.5 mg Average Daily Dose Since Previous Visit 
by Week 104 PERR Response (IPD/TF/WD=NR)
DB [1]
2.107.
MITT
Prednisone ≤5 mg/day Average Daily Dose Since Previous Visit 
(Observed)
DB [1]
2.108.
MITT
Prednisone ≤7.5 mg/day Average Daily Dose Since Previous 
Visit (Observed)
DB [1]
2.109.
MITT
SLICC/ACR Damage Index Change from Baseline by Visit While 
On Study (Observed with WOCF)
DB [1]
2.110.
MITT
SLICC/ACR Damage Index Worsening (Change > 0) Compared 
with Baseline by Visit (Observed)
DB [1]


CONFIDENTIAL
BEL114054
159
14.12.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Efficacy Renal Response
2.01.
MITT
Primary Efficacy Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.02.
MITT
Disposition of Primary Efficacy Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.03.
MITT
Primary Efficacy Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
2.04.
MITT
PERR uPCR Component (uPCR <=0.7) by Visit
(IPD/TF/WD=NR)
DB [1]
2.05.
MITT
PERR eGFR Component (eGFR no more than 20% below Pre-
flare Value or >= 60 mL/min/1.73m2) by Visit (IPD/TF/WD=NR)
DB [1]
2.06.
MITT
Not a Treatment Failure by Visit (IPD/TF/WD=NR)
DB [1]
2.07.
MITT
Time to First PERR that is maintained through Week 52
(IPD/TF/WD=NR)
DB [1]
2.08.
MITT
Time to First PERR that is maintained through Week 104
(IPD/TF/WD=NR)
DB [1]
2.09.
MITT
Odds Ratio of Primary Efficacy Renal Response at Week 104 by 
Subgroup (IPD/TF/WD=NR)
DB [1]
2.10.
MITT
Odds Ratio of Primary Efficacy Renal Response at Week 104 
Sensitivity Analyses (IPD/TF/WD=NR)
DB [1]
Complete Renal Response
2.11.
MITT
Complete Renal Response at Week 104 (IPD/TF/WD=NR)
DB [1]


CONFIDENTIAL
BEL114054
160
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
MITT
Disposition of Complete Renal Response at Week 104
(IPD/TF/WD=NR)
DB [1]
2.13.
MITT
Complete Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
2.14.
MITT
CRR uPCR Component (uPCR <0.5) by Visit (IPD/TF/WD=NR)
DB [1]
2.15.
MITT
CRR eGFR Component (eGFR no more than 10% below Pre-
flare Value or within Normal Range) by Visit (IPD/TF/WD=NR)
DB [1]
2.16.
MITT
Time to First CRR that is maintained through Week 52
(IPD/TF/WD=NR)
DB [1]
2.17.
MITT
Time to First CRR that is maintained through Week 104
(IPD/TF/WD=NR)
DB [1]
2.18.
MITT
Odds Ratio of Complete Renal Response at Week 104 by 
Subgroup (IPD/TF/WD=NR)
DB [1]
2.19.
MITT
Odds Ratio of Complete Renal Response at Week 104 by 
Sensitivity Analyses (IPD/TF/WD=NR)
DB [1]
PERR at Week 52
2.20.
MITT
Disposition of PERR at Week 52 (IPD/TF/WD=NR)
DB [1]
Death or Renal-related Event
2.21.
MITT
Time to Death or Renal-related Event (IPD/TF not related to 
renal disease/WD=Censor)
DB [1]
Ordinal Renal Response
2.22.
MITT
Ordinal Renal Response by Visit (IPD/TF/WD=NR)
DB [1]
SFI Flare
2.23.
MITT
Time to First Severe SFI Flare (TF=Flare, IPD/WD=Censor)
DB [1]


CONFIDENTIAL
BEL114054
161
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.24.
MITT
Time to First Severe SFI Flare from Week 24 (TF=Flare, 
IPD/WD=Censor)
DB [1]
Proteinuria
2.25.
MITT
uPCR Percent Change from Baseline by Visit While on 
Treatment (Observed) 
DB [1]
2.26.
MITT
uPCR Change from Baseline by Visit While on Treatment 
(Observed) 
DB [1]
Serum Creatinine from Baseline and/or End Stage Renal Disease 
2.27.
MITT
Doubling of Serum Creatinine from Baseline and/or Progression 
to End Stage Renal Disease (ESRD) by Visit (LO on or prior to 
IPD/TF CF)
DB [1]
SLEDAI-S2K
2.28.
MITT
SLEDAI-S2K Change from Baseline by Visit While on Treatment 
(Observed) 
DB [1]
2.29.
MITT
SLEDAI-S2K < 4 by Visit (IPD/TF/WD=NR)
DB [1]
Prednisone
2.30.
MITT
Prednisone ≤5 mg Average Daily Dose Since Previous Visit by 
Week 104 PERR Response (IPD/TF/WD=NR)
DB [1]
2.31.
MITT
Prednisone ≤7.5 mg Average Daily Dose Since Previous Visit 
by Week 104 PERR Response (IPD/TF/WD=NR)
DB [1]
Tipping Point (if applicable)
2.32.
MITT
Tipping Point for PERR at Week 104 – Hybrid Treatment Policy 
for Non-TF Intercurrent Events
DB [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.33.
MITT
Tipping Point for PERR at Week 104 – Treatment Policy for All 
Intercurrent Events
DB [1]
2.34.
MITT
Tipping Point for CRR at Week 104 – Hybrid Treatment Policy 
for Non-TF Intercurrent Events
DB [1]
2.35.
MITT
Tipping Point for CRR at Week 104 – Treatment Policy for All 
Intercurrent Events
DB [1]
2.36.
MITT
Tipping Point for Time to Death or Renal-related Event –
Treatment Policy using Censored-at-Random Assumption for 
Placebo
DB [1]
SLEDAI-S2K Excluding Renal Items
2.37.
MITT
SLEDAI-S2K Change from Baseline Excluding Renal Items by 
Visit While on Treatment (Observed)
DB [1]
14.12.8.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.01.
Safety
Pre-treatment Adverse Events by SOC and PT
DB [1]
3.02.
Safety
Adverse Events Summary 
DB [1]
3.03.
Safety
Adverse Events by SOC
DB [1]
3.04.
Safety
IDSL1.1.1 AE1
Adverse Events by SOC and PT 
IDSL
DB [1]


CONFIDENTIAL
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163
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.05.
Safety
IDSL 1.1.4 AE3
Adverse Events by PT 
IDSL
DB [1]
3.06.
Safety
Study Agent Related Adverse Events by SOC 
DB [1]
3.07.
Safety
IDSL 1.1.2 AE1
Study Agent Related Adverse Events by SOC and PT 
IDSL
DB [1]
3.08.
Safety
Study Agent Related Adverse Events by PT 
DB [1]
3.09.
Safety
IDSL 1.1.7 
AE5A
Adverse Events by SOC, PT, and Maximum Intensity 
FDAAA, IDSL
DB [1]
3.10.
Safety
IDSL 1.1.8
Study Agent Related Adverse Events by SOC, PT, and 
Maximum Intensity 
IDSL
DB [1]
3.11.
Safety
Severe Adverse Events by SOC 
DB [1]
3.12.
Safety
Severe Adverse Events by SOC and PT 
DB [1]
3.13.
Safety
Severe Adverse Events by PT 
DB [1]


CONFIDENTIAL
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164
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events by Subgroup
3.15.
Safety
Adverse Events by SOC and PT and Gender 
DB [1]
3.16.
Safety
Adverse Events by SOC and PT and Race Stratification Factor
DB [1]
3.17.
Safety
Adverse Events by SOC and PT and Region 
DB [1]
3.18.
Safety
Adverse Events by SOC and PT and Baseline C3/C4 Levels and 
Anti-dsDNA 
DB [1]
3.19.
Safety
Adverse Events by SOC and PT and Baseline Body Weight 
Quartiles 
DB [1]
Serious and Other Significant Adverse Events
3.20.
Safety
Death by Category and PT 
DB [1]
3.21.
Safety
Serious Adverse Events by SOC 
DB [1]
3.22.
Safety
IDSL 1.1.6 
AE16
Serious Adverse Events by SOC and PT
IDSL
DB [1]
3.23.
Safety
Serious Adverse Events by PT 
DB [1]
3.24.
Safety
Study Agent Related Serious Adverse Events by SOC and PT 
DB [1]
3.25.
Safety
Adverse Events Resulting in Study Agent Discontinuation by 
SOC 
DB [1]
3.26.
Safety
Adverse Events Resulting in Study Agent Discontinuation by 
SOC and PT 
DB [1]
3.27.
Safety
Adverse Events Resulting in Study Agent Discontinuation by PT 
DB [1]
3.28.
Safety
IDSL 1.1.5 
AE15
Common (>=5%) Non-Serious Adverse Events by SOC and PT 
FDAAA, EUDraCT, IDSL
DB [1]
3.29.
Safety
IDSL AE16
Serious Adverse Events by SOC and PT (Number of Subjects 
and Occurrences)
FDAAA, EUDraCT, IDSL
DB [1]


CONFIDENTIAL
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165
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events of Special Interest
3.30.
Safety
Adverse Events of Special Interest by Category 
DB [1]
3.31.
Safety
Malignant Neoplasm Adverse Events of Special Interest by 
Category and PT 
DB [1]
3.32.
Safety
Post-Infusion Systemic Reactions Adverse Events of Special 
Interest by Category and PT 
DB [1]
3.33.
Safety
Serious Post-Infusion Systemic Reactions Adverse Events of 
Special Interest by Category and PT 
DB [1]
3.34.
Safety
Post-Infusion Systemic Reactions per Anaphylactic Reactions 
CMQ Broad Search by PT in First Six Infusions 
DB [1]
3.35.
Safety
Serious Post-Infusion Systemic Reactions per Anaphylactic 
Reactions CMQ Broad Search by PT in First Six Infusions 
DB [1]
3.36.
Safety
Serious Acute Post-Infusion Systemic 
Reactions/Hypersensitivity per GSK Adjudication by PT in First 
Six Infusions 
DB [1]
3.37.
Safety
Serious Delayed Acute Hypersensitivity Reactions per GSK 
Adjudication by PT in First Six Infusions 
DB [1]
3.38.
Safety
Serious Delayed Non-Acute Hypersensitivity Reactions per GSK 
Adjudication by PT in First Six Infusions 
DB [1]
3.39.
Safety
Infection Adverse Events of Special Interest by Category and PT 
DB [1]
3.40.
Safety
Infection Adverse Events of Special Interest Leading to Study 
Agent Discontinuation by Category and PT 
DB [1]
3.41.
Safety
Depression/Suicide/Self-injury Adverse Events of Special 
Interest by Category and PT 
DB [1]


CONFIDENTIAL
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166
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
C-SSRS
3.42.
Safety
IDSL CSSRS1
C-SSRS Suicidal Ideation or Behaviour Post-Baseline
IDSL
DB [1]
3.43.
Safety
IDSL CSSRS2
Treatment-Emergent C-SSRS Suicidal Ideation or Behaviour 
Relative to Pre-treatment 
IDSL
DB [1]
3.44.
Safety
IDSL CSSRS3
Shift Table of Changes in C-SSRS Categories from Pre-
treatment to Post-Baseline
IDSL
DB [1]
Laboratory: Hematology
3.45.
Safety
Laboratory Results by Visit: Hematology 
DB [1]
3.46.
Safety
Worst Laboratory Toxicity Grade: Hematology 
DB [1]
3.47.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Hematology 
DB [1]
3.48.
Safety
Laboratory Reference Range Shifts from Baseline by Visit: 
Hematology 
DB [1]
Laboratory: Liver Function
3.49.
Safety
Laboratory Results by Visit: Liver Function 
ICH E3 12.4.2.1
DB [1]
3.50.
Safety
Worst Laboratory Toxicity Grade: Liver Function 
DB [1]
3.51.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Liver Function 
ICH E3 12.4.2.2
DB [1]
3.52.
Safety
Laboratory Reference Range Shifts from Baseline by Visit: Liver 
Function 
ICH E3 12.4.2.2.
DB [1]
Laboratory: Electrolytes
3.53.
Safety
Laboratory Results by Visit: Electrolytes 
ICH E3 12.4.2.1
DB [1]
3.54.
Safety
Worst Laboratory Toxicity Grade: Electrolytes 
DB [1]


CONFIDENTIAL
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167
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.55.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Electrolytes 
ICH E3 12.4.2.2
DB [1]
3.56.
Safety
Laboratory Reference Range Shifts from Baseline by Visit: 
Electrolytes 
ICH E3 12.4.2.2
DB [1]
Laboratory: Other Chemistries
3.57.
Safety
Laboratory Results by Visit: Other Chemistries 
ICH E3 12.4.2.1
DB [1]
3.58.
Safety
Worst Laboratory Toxicity Grade: Other Chemistries 
DB [1]
3.59.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Other Chemistries 
ICH E3 12.4.2.2
DB [1]
3.60.
Safety
Laboratory Reference Range Shifts from Baseline by Visit: Other 
Chemistries 
ICH E3 12.4.2.2
DB [1]
Laboratory: Urinalysis
3.61.
Safety
Laboratory Results by Visit: Urinalysis 
DB [1]
3.62.
Safety
Worst Laboratory Toxicity Grade: Urinalysis 
DB [1]
3.63.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Urinalysis 
ICH E3 12.4.2.2
DB [1]
Laboratory: Immunoglobulins
3.64.
Safety
Laboratory Results by Visit: Immunoglobulins 
ICH E3 12.4.2.1
DB [1]
3.65.
Safety
Worst Laboratory Toxicity Grade: Immunoglobulins 
DB [1]
3.66.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Immunoglobulins 
ICH E3 12.4.2.2
DB [1]


CONFIDENTIAL
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168
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.67.
Safety
Laboratory Reference Range Shifts from Baseline by Visit: 
Immunoglobulins 
ICH E3 12.4.2.2
DB [1]


CONFIDENTIAL
BEL114054
169
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunoglobulin 
3.68.
Safety
Immunoglobulin Levels below the Lower Limit of Normal (LLN) 
by Visit 
DB [1]
3.69.
Safety
Immunoglobulin Levels below the Lower Limit of Normal (LLN) 
at each Visit among Subjects with Immunoglobulins >= LLN at 
Baseline 
DB [1]
3.70.
Safety
Immunoglobulin Levels >= the Lower Limit of Normal (LLN) by 
Visit 
DB [1]
3.71.
Safety
Immunoglobulin Levels >= the Lower Limit of Normal (LLN) at 
each Visit among Subjects with Immunoglobulins < LLN at 
Baseline 
DB [1]
3.72.
Safety
Immunogenic Response by Visit 
DB [1]
Vital Signs
3.73.
Safety
Vital Signs by Visit (Observed) 
DB [1]
3.74.
Safety
IDSL VS1
Vital Signs Change from Baseline by Visit (Observed)
ICH E3 12.5
DB [1]
Survival Status
3.75.
Safety
Survival Status at Week 104
DB [1]
Adverse Events (Through/Post Week 24)
3.76.
Safety
Adverse Events by SOC and PT from Baseline through Week 24 
DB [1]
3.77.
Safety
Adverse Events by SOC and PT Post Week 24 
DB [1]
3.78.
Safety
Serious Adverse Events by SOC and PT from Baseline through 
Week 24 
DB [1]
3.79.
Safety
Serious Adverse Events by SOC and PT Post Week 24 
DB [1]


CONFIDENTIAL
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170
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.80.
Safety
Adverse Events of Special Interest by Category from Baseline 
through Week 24 
DB [1]
3.81.
Safety
Adverse Events of Special Interest by Category Post Week 24 
DB [1]
Adverse Events (Post-Treatment)
3.82.
Safety
Post-Treatment Serious Adverse Events by SOC and PT 
DB [1]
3.83.
Safety
Post-Treatment Adverse Events of Special Interest by Category
DB [1]
Serious and Non-Serious Drug-Related Events by Overall Frequency 
3.84.
Safety
Non-Serious Drug-Related Adverse Events by Overall 
Frequency
DB [1]
3.85.
Safety
Serious Drug-Related Adverse Events by Overall Frequency
DB [1]
Worst Laboratory Toxicity Grade While on Study
3.86.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: Hematology 
DB [1]
3.87.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: Liver Function 
DB [1]
3.88.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: Electrolytes 
DB [1]
3.89.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: Other 
Chemistries 
DB [1]
3.90.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: Urinalysis 
DB [1]
3.91.
Safety
Worst Laboratory Toxicity Grade Post-Treatment: 
Immunoglobulins
DB [1]
Laboratory Toxicity Grade Worsening  Post-Treatment
3.92.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Hematology 
DB [1]


CONFIDENTIAL
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171
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.93.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Liver Function 
DB [1]
3.94.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Electrolytes 
DB [1]
3.95.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Other Chemistries 
DB [1]
3.96.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Urinalysis 
DB [1]
3.97.
Safety
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline Post-Treatment: Immunoglobulins 
DB [1]
14.12.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.01.
Safety
Laboratory Results by Visit: Hematology
DB [1]
3.02.
Safety
Laboratory Results by Visit: Liver Function
DB [1]
3.03.
Safety
Laboratory Results by Visit: Electrolytes
DB [1]
3.04.
Safety
Laboratory Results by Visit: Other Chemistries
DB [1]
3.05.
Safety
Laboratory Results by Visit: Urinalysis
DB [1]
3.06.
Safety
Laboratory Results by Visit: Immunoglobulins
DB [1]


CONFIDENTIAL
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14.12.10. Biomarker Tables
Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunoglobulin
4.01.
MITT
Immunoglobulin Levels Percent Change from Baseline by Visit 
(Observed) 
DB [1]
4.02.
MITT
Immunoglobulin Levels Change from Baseline by Visit 
(Observed) 
DB [1]
4.03.
MITT
Immunoglobulin Levels Shifts from Baseline by Visit (Observed)
DB [1]
Autoantibodies
4.04.
MITT
Autoantibody Levels Percent Change from Baseline by Visit 
(Observed) 
DB [1]
4.05.
MITT
Autoantibody Levels Percent Change from Baseline by Visit 
among Subjects Positive at Baseline (Observed) 
DB [1]
4.06.
MITT
Autoantibody Levels Change from Baseline by Visit (Observed) 
DB [1]
4.07.
MITT
Autoantibody Levels Change from Baseline by Visit among 
Subjects Positive at Baseline (Observed) 
DB [1]
4.08.
MITT
Autoantibody Levels Shifts from Baseline by Visit (Observed)
DB [1]
Complement (C3/C4)
4.09.
MITT
Complement Levels Percent Change from Baseline by Visit 
(Observed) 
DB [1]
4.10.
MITT
Complement Levels Percent Change from Baseline by Visit 
among Subjects with Low Complement at Baseline (Observed) 
DB [1]
4.11.
MITT
Complement Levels Change from Baseline by Visit (Observed) 
DB [1]


CONFIDENTIAL
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Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.12.
MITT
Complement Levels Change from Baseline by Visit among 
Subjects with Low Complement at Baseline (Observed) 
DB [1]
4.13.
MITT
Complement Levels Shifts from Baseline by Visit (Observed)
DB [1]
B Cells
4.14.
MITT
B cells Percent Change from Baseline by Visit (Observed) 
DB [1]
4.15.
MITT
B cells Change from Baseline by Visit (Observed) 
DB [1]
Autoantibodies Adjusted for IgG
4.16.
MITT
Autoantibody Levels Change from Baseline by Visit Adjusted for 
IgG using Joint Modeling (Observed)
DB [1]


CONFIDENTIAL
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14.12.11. Biomarker Figures
Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunoglobulin
4.01.
MITT
Immunoglobulin Levels Percent Change from Baseline by Visit 
(Observed)
DB [1]
4.02.
MITT
Immunoglobulin Levels Change from Baseline by Visit 
(Observed)
DB [1]
Autoantibodies
4.03.
MITT
Autoantibody Levels Percent Change from Baseline by Visit
(Observed)
DB [1]
4.04.
MITT
Autoantibody Levels Percent Change from Baseline by Visit 
among Subjects Positive at Baseline (Observed)
DB [1]
4.05.
MITT
Autoantibody Levels Change from Baseline by Visit (Observed)
DB [1]
4.06.
MITT
Autoantibody Levels Change from Baseline by Visit among 
Subjects Positive at Baseline (Observed)
DB [1]
Complement (C3/C4)
4.07.
MITT
Complement Levels Percent Change from Baseline by Visit
(Observed)
DB [1]
4.08.
MITT
Complement Levels Percent Change from Baseline by Visit 
among Subjects with Low Complement at Baseline (Observed)
DB [1]
4.09.
MITT
Complement Levels Change from Baseline by Visit (Observed)
DB [1]
4.10.
MITT
Complement Levels Change from Baseline by Visit among 
Subjects with Low Complement at Baseline (Observed)
DB [1]


CONFIDENTIAL
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Biomarker: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
B Cells
4.11.
MITT
B cells Percent Change from Baseline by Visit (Observed)
DB [1]
4.12.
MITT
B cells Change from Baseline by Visit (Observed)
DB [1]
Autoantibodies Adjusted for IgG
4.13.
MITT
Autoantibody Levels Mean Difference in Change from Baseline 
by Visit Adjusted for IgG using Joint Modeling (Observed)
DB [1]
4.14.
MITT
Autoantibody Levels Ratio of Means for Change from Baseline 
by Visit Adjusted for IgG using Joint Modeling (Observed)
DB [1]


CONFIDENTIAL
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14.12.12. Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Belimumab Concentrations 
5.01.
PK
Belimumab Concentrations (ug/mL) (Observed) 
DB [1]
5.02.
PK
Belimumab Concentrations (ug/mL) (Observed) by Baseline 
Body Weight Quartiles 
DB [1]
5.03.
PK
Belimumab Concentrations (ug/mL) (Observed) by Baseline BMI 
Categories 
DB [1]
5.04.
PK
Belimumab Concentrations (ug/mL) (Observed) by Baseline 
Proteinuria Categories 
DB [1]
5.05.
PK
Belimumab Concentrations (ug/mL) (Observed) by 
Immunogenicity Status 
DB [1]


CONFIDENTIAL
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14.12.13. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Belimumab Concentrations
5.01.
PK
Median Belimumab Concentrations (Observed)
DB [1]
5.02.
PK
Median Belimumab Concentrations (Observed) by Baseline 
Body Weight Quartile
DB [1]
5.03.
PK
Median Belimumab Concentrations (Observed) by Baseline BMI 
Category
DB [1]
5.04.
PK
Median Belimumab Concentrations (Observed) by Baseline 
Proteinuria Category
DB [1]
5.05.
PK
Median Belimumab Concentrations (Observed) by 
Immunogenicity Status
DB [1]


CONFIDENTIAL
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14.12.14. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.01.
Screened
ES7
Reasons for Screen Failure
Journal Guidelines
DB [1]
1.02.
MITT
ES1
Subject Disposition and Populations
DB [1]
1.03.
MITT
ES2 / ES3
Reasons for Study Withdrawal 
ICH E3
DB [1]
1.04.
MITT
SD2/SD3
Reasons for Treatment Discontinuation 
ICH E3
DB [1]
1.06
MITT
IE3 / IE4
Subjects with Inclusion/Exclusion Criteria Deviations 
ICH E3
DB [1]
1.07
MITT
DV2
Important Protocol Deviations 
ICH E3
DB [1]
1.08
MITT
DM2 / DM4
Demographic and Baseline Characteristics
ICH E3
DB [1]
1.09
MITT
DM9 / DM10
Listing of Race
ICH E3
DB [1]
1.10
MITT
Randomized and Actual Strata
IDSL Treatment Assignment standard
DB [1]
1.11
MITT
Current and Past Medical Conditions
IDSL Medical Conditions Displays
DB [1]
1.12
MITT
CP_CM3 / 
CP_CM4
Concomitant Medications 
IDSL
DB [1]
1.15
MITT
Investigational Product Administration 
ICH E3 11.3
DB [1]
1.16
MITT
TA1 / 
CP_RD1x
Randomized and Actual Treatments 
IDSL
DB [1]
1.17
MITT
BL1 / BL2
Subjects for Whom the Treatment Blind was Broken During the 
Study 
ICH E3
DB [1]
1.18
MITT
EG3 / EG4
ECG Findings at Baseline
IDSL
DB [1]


CONFIDENTIAL
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179
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.01
Safety
AE8 / AE8CP / 
AE9 / AE9CP
All Adverse Events
ICH E3 12.2.4 (16.2.7)
DB [1]
3.02
Safety
AE7
Subject Numbers for Individual Adverse Events 
ICH E3, IDSL 1.3.1 required AE7
DB [1]
Serious and Other Significant Adverse Events
3.05
Safety
AE8 / AE8CPa/ 
AE9 / AE9CPa
Deaths
ICH E3
DB [1]
3.06
Safety
AE8 / AECP8 / 
AE9 / AE9CP
Adverse Events Resulting in Study Agent Discontinuation
ICH E3 12.3.1.2 / IDSL 1.3.5 required
DB [1]
All Laboratory
3.15
Safety
LB5 / LB6
Laboratory Results: Hematology
ICH E3
DB [1]
3.16
Safety
LB5 / LB6
Laboratory Results: Liver Function
ICH E3
DB [1]
3.17
Safety
LB5 / LB6
Laboratory Results: Electrolytes
ICH E3
DB [1]
3.18
Safety
LB5 / LB6
Laboratory Results: Other Chemistries
ICH E3
DB [1]
3.19
Safety
LB5 / LB6
Laboratory Results: Urinalysis
ICH E3
DB [1]
3.20
Safety
LB5 / LB6
Laboratory Results: Immunoglobulins
ICH E3
DB [1]
3.21
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: Hematology
ICH E3
DB [1]
3.22
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: Liver Function
ICH E3
DB [1]
3.23
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: Electrolytes
ICH E3
DB [1]
3.24
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: Other 
Chemistries
ICH E3
DB [1]
3.25
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: Urinalysis
ICH E3
DB [1]


CONFIDENTIAL
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.26
Safety
LB5 / LB6
Grade 3 or Grade 4 Laboratory Toxicity Results: 
Immunoglobulins
ICH E3
DB [1]
14.12.15. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.05.
MITT
SP3A
Subjects Excluded from Per Protocol Population
IDSL
DB [1]
1.13.
MITT
Relationship Between ATC Level 1, Ingredient and Verbatim 
Text
DB [1]
1.14.
MITT
Treatment Failures
DB [1]
1.19.
MITT
Pre-Flare Serum Creatinine and eGFR Values
DB [1]
1.20.
MITT
Lupus Nephritis Therapy History
DB [1]
1.21.
MITT
Renal Biopsy at Screening
DB [1]
Efficacy
2.01
MITT
PERR, CRR, and ORR Results by Visit (IPD/TF/WD=NR)
DB [1]
2.02
MITT
Death or Renal-related Event
DB [1]
2.03
MITT
Severe SFI Flares
DB [1]
2.04
MITT
Doubling of Serum Creatinine from Baseline and/or Progression 
to End Stage Renal Disease (ESRD) by Visit
DB [1]
2.05
MITT
SLEDAI-S2K Results
DB [1]


CONFIDENTIAL
BEL114054
181
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.06
MITT
Prednisone Average Daily Dose Since Previous Visit While on 
Treatment
DB [1]
2.07
MITT
SLICC/ACR Damage Index Results
DB [1]
Safety
3.03
Safety
Survival Status 
DB [1]
3.04
Safety
Serious Adverse Events While on Treatment
DB [1]
3.07
Safety
AE2
Relationship Between System Organ Class and Verbatim Text
IDSL 1.3.7 required  AE2
DB [1]
3.08
Safety
AE14
Reasons for Considering as a Serious Adverse Event
IDSL 1.3.8 required AE14
DB [1]
3.09
Safety
Adverse Events of Special Interest While on Treatment
DB [1]
3.10
Safety
C-SSRS Suicidal Ideation and Behaviour Data
DB [1]
3.11
Safety
C-SSRS Suicidal Behavior Details
DB [1]
3.12
Safety
Details of Most Severe C-SSRS Suicidal Ideation at Each C-
SSRS Assessment
DB [1]
3.13
Safety
Possible Suicidality-Related Questionnaire
DB [1]
3.14
Safety
Medical/Surgical Procedures
DB [1]
3.27
Safety
IgG Protocol Specified Events
DB [1]
3.28
Safety
Immunogenicity Results
DB [1]
3.29
Safety
AE8 / AE8CP / 
AE9 / AE9CP
All Adverse Events for Subjects in Mexico
DB [1]
3.30
Safety
Serious Adverse Events for Subjects in Countries Other than 
Mexico
DB [1]
3.31
Safety
Post-Treatment Serious Adverse Events
DB [1]
3.32
Safety
Post-Treatment Non-Serious Adverse Events
DB [1]


CONFIDENTIAL
BEL114054
182
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.33
Safety
Post-Treatment Adverse Events of Special Interest
DB [1]
Liver Events
3.34
Safety
LIVER5
Liver Monitoring/Stopping Event Reporting
DB [1]
3.35
Safety
SU2
Substance Use Reported with Liver Event
DB [1]
3.36
Safety
LIVER6
Liver Stopping Event Information for RUCAM Score
DB [1]
Biomarker Results
4.01
MITT
Biomarker Results
DB [1]
4.02
MITT
B Cell Results
DB [1]
PK Concentration
5.01
PK
Serum Belimumab PK Concentration-Time Data
DB [1]


CONFIDENTIAL
BEL114054
183
14.13.
Appendix 13: Example Mock Shells for Data Displays
Data display specifications are available on request.


CONFIDENTIAL
BEL114054
184
14.14.
Appendix 14: Headline Results
The following tables will be produced as headline results:
Display
Display Title
Table 1.02
Populations
Table 1.04
Subject Status by Week 104
Table 1.07
Investigational Product Status and Reasons for Discontinuation
Table 1.13
Demographic and Baseline Characteristics
Table 1.20
Baseline Disease Activity
Table 2.01
Primary Efficacy Renal Response at Week 104 (IPD/TF/WD=NR)
Table 2.03
Primary Efficacy Renal Response and the 3 Components at Week 104 (IPD/TF/WD=NR)
Table 2.12
Primary Efficacy Renal Response by Visit (IPD/TF/WD=NR)
Table 2.21
Primary Efficacy Renal Response at Week 104 by Induction Regimen (IPD/TF/WD=NR)
Table 2.28
Complete Renal Response at Week 104 (IPD/TF/WD=NR)
Table 2.30
Complete Renal Response and the 3 Components at Week 104 (IPD/TF/WD=NR)
Table 2.39
Complete Renal Response by Visit
Table 2.46
Complete Renal Response at Week 104 by Induction Regimen (IPD/TF/WD=NR)
Table 2.53
Primary Efficacy Renal Response and the 3 Components at Week 52 (IPD/TF/WD=NR)
Table 2.56
Time to Death or Renal-related Event Overall and by Induction Regimen (IPD/TF not related 
to renal disease/WD=Censor)
Table 2.60
Ordinal Renal Response at Week 104 (IPD/TF/WD=NR)
Table 2.77
Prednisone ≤5 mg/day Average Daily Dose Since Previous Visit (IPD/TF/WD=NR)
Table 2.78
Prednisone ≤7.5 mg/day Average Daily Dose Since Previous Visit (IPD/TF/WD=NR) 
Table 2.105
Prednisone <= 5 mg Average Daily Dose Since Previous Visit by Week 104 PERR 
Response (IPD/TF/WD=NR)
Table 2.106
Prednisone <= 7.5 mg Average Daily Dose Since Previous Visit by Week 104 PERR 
Response (IPD/TF/WD=NR)
Table 3.02
Adverse Events Summary
Table 3.04
Adverse Events by SOC and PT (Double-Blind Phase)
Table 3.20
Death by Category and PT (Double-Blind Phase)
Listing 3.05
Deaths 
Table 3.22
Serious Adverse Events by SOC and PT
Table 3.30
Adverse Events of Special Interest by Category 

Prot_000.pdf: 
CLINICAL PROTOCOL HGS1006-C1121
Protocol Amendment: 07
EudraCT Number: 2011-004570-28
Date: 24 January 2019
TITLE OF STUDY: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus 
Standard of Care in Adult Subjects with Active Lupus Nephritis
STUDY SPONSOR:
Human Genome Sciences, Inc.
9910 Belward Campus Drive
Rockville, Maryland 20850
U.S.A.
Confidential and Proprietary
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 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-C1121 (BEL114054)
Date
Document*
Global
19 October 2011
Original
Global
27 January 2012
Amendment No 01
Global
08 March 2012
Amendment No 02
Local
16 August 2012
Amendment 02 for Thailand
Global
2013N179093_00
11 February 2014
Amendment No 03
Local
2014N205397_00
29 August 2014
Amendment 04 for China
Global
2013N179093_01
16 March 2015
Amendment No 05
Local
2013N179093_02
17 March 2015
Amendment No 05 for France
Local
2013N179093_03
13 July 2016
Amendment No 05/France-2
Global
2013N179093_04
25 April 2017
Amendment No 06
Local
2013N179093_05
26 April 2017
Amendment No 06/France-2
Global
2013N179093_06
24 January 2019
Amendment No 07
*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-C1121
Title of the Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo 
plus Standard of Care in Adult Subjects with Active Lupus Nephritis
Clinical Development Phase: 3
Objectives:
•
To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV, or V using the 2003 International Society 
for Nephrology (ISN)/Renal Pathology Society (RPS) criteria.
•
To assess the safety and tolerability of belimumab plus standard of care versus 
placebo plus standard of care in adult subjects with lupus nephritis Class III, IV, or V 
using the 2003 ISN/RPS criteria.
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria:
1. Males or females at least 18 years of age.
2. Have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology (ACR) criteria (Appendix 1).
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding 
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or
pure Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy 
must be performed in the 6 months prior to the screening visit or during the screening 
period. The local biopsy report will be used to confirm subject eligibility. A tissue 
sample from the renal biopsy used to qualify the subject for randomization needs to
be sent to a central reading center after Day 0 (baseline). 
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an 
ANA titer ≥ 1:80 (based on Hep-2 immunofluorescence assay or equivalence by 
enzyme immunoassay assay), and/or a positive anti-dsDNA (≥30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results.
5. Have documentation of active renal disease at screening requiring induction therapy 
with high dose corticosteroids (HDCS) with either intravenous (IV)
cyclophosphamide (CYC) or mycophenolate mofetil (MMF) or other oral forms of 
mycophenolate. The following factors will be used to define active renal disease at 
screening:

Urinary protein:creatinine ratio of ≥ 1.0 AND 

Active urinary sediment as defined by at least 1 of the following (in absence 
of menses and genitourinary tract infection).  


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
> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory 
reference range.

> 5 white blood cell (WBC)/hpf or above the laboratory reference range.

Presence of cellular casts (RBC or WBC).

Subjects without active urinary sediment are eligible if they meet at least 1 of 
the following criteria: 

Have a confirmatory biopsy performed within 3 months prior to the 
screening visit or during the screening period meeting the criteria outlined 
in Inclusion Criterion 3.

Have proteinuria ≥3.5 grams/day (or urinary protein:creatinine ratio≥ 3.5).
6. Have active renal disease defined as above which requires induction therapy with 
high dose corticosteroids (HDCS) with either intravenous (IV) cyclophosphamide 
(CYC) or mycophenolate mofetil (MMF) or other oral forms of mycophenolate:
Induction therapy may begin before Screening but should be initiated within 60 days 
prior to or on Day 0 (baseline). Initiation of induction is when both HDCS and either 
MMF or CYC have been started.
The study recommended doses for induction therapy are as follows, adjustments may 
be made for tolerability issues (refer to Section 5.5.1 Standard of Care Medication for 
details): 
-
MMF 1-3g/day orally or Mycophenolate sodium 720 - 2160 mg/day orally 
-
corticosteroids: 0-3 IV pulses of methylprednisolone 500 -1000 mg/pulse 
followed by oral prednisone 0.5-1.0 mg/kg/day with total daily dose up to 60 
mg/day (or equivalence)
-
CYC 500 mg by IV infusion every 2 weeks (3 days) for 6 infusions 
Subjects who have been on MMF for SLE including lupus renal disease may be
eligible if they have received, or will receive, the following induction therapy within 
60 days prior to or on Day 0: 
-
initiation of HDCS with MMF dose increase to reach the target dose for induction 
in the subject (if the subject did not previously fail MMF induction based on the 
investigator’s opinion), OR
-
initiation of HDCS with discontinuation of MMF and initiation of CYC. 
Note: It is recommended that subject eligibility should be discussed with the Medical 
Monitor if a subject initiated but did not complete an induction therapy within 6 
months prior to the initiation of current induction therapy for the study.
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 


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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 study, and for 
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 sterilisation with documentation of azoospermia prior to the 
female subject’s entry into the study, and this male is the sole partner for 
that subject. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination 
and/or semen analysis, or medical history interview provided by her or her 
partner.
Note: If stricter female or male contraception requirements are specified in the 
country-specific label for induction and/or maintenance standard of care 
medications, they must be followed.
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). 


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Exclusion Criteria: Subjects will be excluded from participating in the study if they 
meet any of the following exclusion criteria:
1. Subjects who have previously failed both CYC and MMF (or other forms of 
mycophenolate) induction therapies based on the investigator’s opinion. If a subject 
has failed only 1 of the 2 therapies for induction, they may be eligible for study 
inclusion if the other induction therapy is initiated within 60 days prior to or on Day 0 
(ie, a subject who failed MMF is eligible if newly initiating induction therapy with 
CYC or a subject who failed CYC is eligible if newly initiating induction therapy 
with MMF).
2.
Subjects who received an induction therapy with CYC within 3 months prior to the
planned initiation of the current induction for the study.
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4
based on the Adverse Event Severity Grading Tables (Appendix 7).
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, azathioprine (AZA), 
corticosteroids).
5. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins or monoclonal antibodies.
6. Have received treatment with belimumab within 364 days of baseline (Day 0).
7. Received any of the following within 364 days of baseline (Day 0):  

Nitrogen mustard

Chlorambucil

Vincristine

Procarbazine

Etoposide

Abatacept

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, or LY2127399 [anti-BAFF])

A biologic investigational agent (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.

Treatment with interleukin-6 targeted therapy (e.g., tocilizumab, sirukumab).
8. Received any of the following within 90 days of baseline (Day 0):  

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab, certolizumab, 
golimumab pegol)

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

Plasmapheresis.
9. Received a non-biological investigational agent within 60 days of baseline (Day 0).


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10. Received a live vaccine within 30 days of baseline (Day 0).
11. 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 baseline (Day 0).
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant or are due to receive transplantation.
13. Subjects who have been on dialysis within 364 days of baseline (Day 0).
14. An estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit
(using the simplified Modification of Diet in Renal Disease [MDRD] equation).
15. 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.
16. 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.
17. 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.  
18. Have acute or chronic infection requiring management, as follows:

Currently on any suppressive therapy for a chronic infection (such as 
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes 
zoster, or atypical mycobacteria).

Hospitalization for treatment of infection within 60 days of baseline (Day 0).

Have had infection requiring treatment with parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days 
of baseline (Day 0).
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to baseline (Day 0). 
20. Have a historically positive test or test positive at screening for HIV antibody.  
21. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:

Patients positive for HBsAg are excluded.

Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-
HBs antibody status, will require clarification of their status by testing for 
HBV DNA

o
if HBV DNA positive, patients will be excluded from participation

o
if HBV DNA negative, patients will be eligible to enrol.

NOTE: For those subjects randomised, additional ongoing assessment during
the study is required (see Section 6.7.5).


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22. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate. Subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing.
23. Have an IgA deficiency (IgA level < 10 mg/dL).
24. Have a Grade 3 or greater laboratory abnormality (including serum IgG level) based 
on the Adverse Event Severity Grading Tables (Appendix 7) except for the following 
that are allowed:

Urinalysis (eg, proteinuria)

Hematuria

Pyuria

Casts

Hypoalbuminemia due to lupus nephritis

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 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 the ALT and/or AST must be ≤ 
Grade 2.

Stable Grade 3 reduction in hemoglobin levels due to SLE

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count [with the 
exception of subjects receiving CYC who will be excluded if WBC is Grade 3 
or 4 per Exclusion Criterion 3]. Note that WBC count should be obtained 
immediately prior to starting induction therapy. If immediate pre-induction 
WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used. 

Hyperuricemia or blood urea nitrogen (BUN) elevation due to lupus nephritis 
or SLE.
25. 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) (Appendix 8) in the last 2 months 
or who, in the investigator's opinion, pose a significant suicide risk.
Study Design and Schedule:
This is a Phase 3, multi-centre, multi-national, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of IV belimumab 10 mg/kg plus 


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standard of care compared to placebo plus standard of care in adult subjects with active 
lupus nephritis. 
Subjects who meet the eligibility criteria during screening will be randomized to 1 of 2
treatment groups in a 1:1 ratio: 10 mg/kg belimumab plus standard of care or placebo 
plus standard of care. The randomization of all eligible subjects will be stratified by their 
induction regimen (high dose cortiocsteroids [HDCS] plus CYC vs HDCS plus MMF) 
and race (black race vs other). Subjects will be dosed with study agent on Days 0
(baseline), 14, 28 and then every 28 days thereafter through 100 weeks with a final 
evaluation for the double-blind treatment period at 104 weeks. At least 400 and up to 
approximately 464 lupus nephritis subjects will be randomized with a target of at least 
200 and up to approximately 232 subjects in each treatment group (belimumab or
placebo). All subjects will receive background therapy consisting of one of the following 
standard of care regimens:
•
High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for induction 
therapy followed by Azathioprine (AZA) for maintenance therapy
OR
•
HDCS + Mycophenolate Mofetil (MMF) for induction therapy followed by MMF for 
maintenance therapy
The standard of care medications are described in Section 5.5.1. 
All subjects should start the above induction therapy within 60 days prior to or on Day 0 
(baseline visit). This will allow subjects to be screened and potentially enrolled and will 
not be excluded on the basis of necessary acute management. The primary efficacy 
endpoint of a renal response will be determined by changes in proteinuria and renal 
function at Week 104. For the renal function assessments at all study visits, the 
glomerular filtration rate (GFR) will be estimated using the simplified MDRD formula; 
proteinuria will be evaluated using the urinary protein: urinary creatinine ratio. In 
addition, at baseline, Week 24, 48, 52, 76, 100 and 104, GFR will be calculated based on 
creatinine clearance determined from the mean creatinine value of 2 contiguous 24 hour 
urine collections and 2 serum creatinine measurements. The first serum creatinine will be 
collected at an initial visit which will take place within 3 days prior to or on the day of 
the scheduled visit. At the initial visit, subjects will be provided with the materials for 
collecting the two 24 hour urine collections beginning the next morning following their 
initial clinic visit. On the third day following the initial visit, subjects will return to the 
clinic for the second serum creatinine sample. 
Urine collection may be postponed up to 14 days at the investigators discretion if 
menstrual bleeding or a genitourinary tract infection is present at any time during the 24 
hour urine collection. 
The primary endpoint will be measured using the Primary Efficacy Renal Response 
(PERR) based on study defined criteria (see Section 8.5). Week 104 PERR will be 


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defined by a response at Week 100 that is confirmed by a repeat measurement at Week 
104.  
All subjects who discontinue treatment with study agent during the double-blind period
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104. 
In the event that a subject withdraws consent from the study, an attempt should be made 
to obtain consent to collect follow-up safety data (at an exit visit approximately 4 weeks 
after the last dose of study agent as well as a follow-up visit approximately 8 weeks after 
the last dose of study agent) and to obtain survival status at Week 104. Any subject that 
withdraws consent for use and disclosure of research-related health information will be 
considered withdrawn from the study and will not be followed for mortality. 
Subjects who receive treatment with study agent through Week 100 and complete Week 
104 assessments in the double-blind period may enter into a 6-month open-label 
extension. The Week 104 visit of the double-blind period will serve as the Day 0 visit for 
subjects entering the open-label extension. In the open-label extension, all subjects will 
receive 10 mg/kg belimumab every 28 days until Week 24, with a final evaluation at 
Week 28 (4 weeks after the last dose). The first dose on the open-label extension will be 
given at the Week 104 visit of the double-blind period following the completion of all 
Week 104 assessments. Subjects participating in the open-label extension will continue to 
be monitored for efficacy and safety as per the study calendar (see Table 6-3). Subjects 
who complete the 104-week double-blind period, but do not enter the open-label 
extension will be required to return for an additional follow up visit 8 weeks after the last 
dose of study agent. All subjects who enter the open-label extension period and withdraw 
early 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. 
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 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 if 
permissible according to local regulations. 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.
Efficacy Endpoints and Analysis:
The primary efficacy endpoint is Primary Efficacy Renal Response (PERR) at Week 104, 
as follows:
•
Responder: Defined by a response at Week 100 confirmed by a repeat measurement 
at Week 104, as follows:
Estimated glomerular filtration rate (GFR) is no more than 20% below the pre-
flare value or ≥60 mL/min/1.73m2


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AND
Urinary protein:creatinine ratio ≤0.7
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
Non-responder: Not meeting criteria for the PERR.
Major Secondary Endpoints: 
•
Complete Renal Response (CRR) at Week 104 (see definition under Ordinal Renal 
Response).
•
PERR at Week 52.
•
Time to Death or Renal-related Event defined as any of the following: i) end stage 
renal disease (ESRD), ii) doubling of serum creatinine, iii) renal worsening as 
evidenced by increased proteinuria and/or impaired renal function, or iv) renal 
disease-related treatment failure.
•
Ordinal Renal Response (ORR; complete, partial or no response) at Week 104
defined as follows:
•
Complete Renal Response (CRR):
Estimated glomerular filtration rate (GFR) is no more than 10% below the 
pre-flare value or within normal range 
AND
Urinary protein:creatinine ratio < 0.5 
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
Partial Renal Response (PRR):
Estimated GFR no more than 10% below the baseline value or within normal 
range 
AND
≥ 50% decrease in the urine protein:creatinine ratio with one of the 
following:  

a urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0 
OR

a urine protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0


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AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
No Renal Response (NRR):
Not meeting criteria for either CRR or PRR.
Sample Size Calculation:
The sample size was calculated using the ORR as the primary endpoint and assuming the 
primary endpoint proportions of complete, partial, and no renal response will be 25%, 
25%, and 50% respectively, for subjects on placebo plus standard of care (Appel et al, 
2009; Sinclair, 2007; Dooley et al, 2011) and 32.5%, 32.5% and 35%, respectively, for
subjects on belimumab plus standard of care. Using these assumptions, simulations were 
performed using Van Elteren methods at the 5% significance level and a 1:1 
randomization allocation ratio, a target sample size of N=464 subjects (232 per arm) is 
required to achieve at least 85% power to detect a treatment difference for the primary 
endpoint. 
For the new primary endpoint, PERR (Responder vs. Non-Responder), and the final 
sample size of N=448, there is 80% power to detect a 13.6% treatment difference and a 
minimum detectable difference of 9.7% for response rates spanning the 50% mark of the 
binomial distribution (40% vs. 53.6%), the area of maximum variance.
Analysis of Primary Efficacy Endpoint:
PERR (Responder vs. Non-Responder) at Week 104 will be compared between 
belimumab and placebo using logistic regression controlling for induction regimen (CYC 
vs. MMF), race (Black vs. Non-Black), baseline proteinuria, and baseline eGFR.
Analysis of Major Secondary Efficacy Endpoints:
Time to death or renal-related event will be compared between belimumab vs. placebo
using a Cox proportional hazards model controlling for induction regimen (CYC vs. 
MMF), race (Black vs. Non-Black), baseline proteinuria, and baseline eGFR.
CRR at Week 104 and PERR at Week 52 will be compared between belimumab and 
placebo using logistic regression controlling for induction regimen (CYC vs. MMF), race 
(Black vs. Non-Black), baseline proteinuria, and baseline eGFR.
Analysis of ORR (complete, partial or no response) at Week 104 will be compared 
between belimumab vs. placebo using rank analysis of covariance (ANCOVA) 
controlling for induction regimen (CYC vs. MMF), race (Black vs. Non-Black), baseline 
proteinuria, and baseline eGFR. 
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 (Section 8.1). 


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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 incidence of laboratory 
abnormalities will be tabulated by treatment group. The frequency and incidence of AEs 
will be tabulated by MedDRA system organ class (SOC) and preferred term and 
compared between placebo and the belimumab treatment group.
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
on an ongoing basis until data through Week 104 of the double-blind treatment period are 
locked and analyzed (after which time monitoring may be assumed by an internal 
GSK/HGS committee). The IDMC will include physicians with expertise in infectious 
disease, rheumatology or nephrology and a statistician, none of whom are affiliated with 
the sponsor. The first review will occur 6 months after the first subject is randomized or 
after the first 20 subjects are randomized and have completed a Week 8 visit, whichever 
is sooner.  Thereafter, the IDMC will review the data approximately every 6 months. At 
all times the sites and sponsor will remain blinded to treatment allocation. 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 
104 and open-label extension portions of the study. Investigators (and IRBs/IECs, as 
appropriate,) will be notified of the outcome of each IDMC meeting.
Pharmacokinetics 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 at the baseline visit (Day 0), 
Week 8, Week 24, Week 52, Week 76 and Week 104. During the 6 month open-label 
extension, samples will be obtained at Week 24. Additionally, a sample will be collected 
at the 8-week follow-up visit. 
Biological Markers and Autoantibodies: 
The following biomarkers will be measured at baseline (Day 0) and at selected timepoints 
thereafter:
•
Autoantibodies: ANA, anti-dsDNA, aCL (IgG, IgM, IgA isotypes), anti-Sm, and anti-
C1q
•
Serum immunoglobulin isotypes: IgA, IgG, IgM
•
Serum complement (C3,C4)
•
BLyS protein (baseline only)


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In geographies where feasible, the following biological markers will be measured (using 
FACS analysis) at baseline (Day 0) and at multiple time points thereafter:
•
Peripheral 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 cells, and CD20-/138+ plasma cells.
An exploratory analysis of urinary biomarkers related to lupus nephritis may be 
performed at baseline (pre-dose) and at selected timepoints thereafter. Data collection and 
analysis will be performed independently of the main study and will form the basis of a 
separate report. The biomarkers include, but are not limited to, MCP-1, hepcidin, NGAL, 
LFABP, Angiogenin, Angiopoietin 2, Angiostatin, IL-6r, Osteopontin, PAI-1, PF4, 
RAGE, RANK, Sgp130, Siglec 5, Siglec 9, Tgf-beta1, TIM1, TIMP-2, TLSP, TNFR-II, 
Trem1, VCAM-1, Vegf-C, and VEGF-R3.
Study Calendar:
See Table 6-1, Table 6-2, and Table 6-3 for a calendar of study visits and assessments.
Study Schematic:  See Figure 1-1.


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Figure 1-1
Study schematic


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TABLE OF CONTENTS
Investigator Agreement...............................................................................................................3
Study Synopsis............................................................................................................................4
Table of Contents......................................................................................................................17
List of Tables ............................................................................................................................20
List of Figures...........................................................................................................................21
List of Abbreviations ................................................................................................................22
1.
Background...................................................................................................................25
1.1.
Disease Background Relevant to Clinical Study....................................................25
1.2.
Belimumab..............................................................................................................26
1.2.1.
Mechanism of Action....................................................................................26
1.2.2.
Clinical Experience with Belimumab...........................................................26
1.3.
Rationale for the Study ...........................................................................................27
1.4.
Benefit-Risk Assessment ........................................................................................29
1.4.1.
Risk Assessment ...........................................................................................29
1.4.2.
Benefit Assessment.......................................................................................36
1.4.3.
Overall Benefit:Risk Conclusion..................................................................36
2.
Study Objectives ...........................................................................................................36
3.
Study Design.................................................................................................................37
3.1.
Basic Design Characteristics...................................................................................37
4.
Inclusion and Exclusion Criteria...................................................................................39
4.1.
Inclusion Criteria ....................................................................................................39
4.2.
Exclusion Criteria ...................................................................................................41
5.
Study Treatment Regimen ............................................................................................44
5.1.
Study Agent Name and Formulation ......................................................................44
5.2.
Packaging, Labeling, Preparation, and Storage ......................................................45
5.3.
Dose, Route of Administration, and Schedule........................................................46
5.4.
Alteration of Dose/Schedule Due to Toxicity.........................................................46
5.5.
Concurrent Medications During the Double-blind Treatment Period ....................47
5.5.1.
Standard of Care Medication ........................................................................48
5.5.2.
Immunosuppressives.....................................................................................50
5.5.3.
Angiotension Pathway Antihypertensives....................................................50
5.5.4.
Anti-malarials ...............................................................................................51
5.5.5.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin...................51
5.5.6.
Corticosteroids..............................................................................................51
5.6.
Prohibited Medications and Non-Drug Therapies During the Double-Blind 
Treatment Period.....................................................................................................52
5.6.1.
Live Vaccines................................................................................................53


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5.7.
Prohibited Medications During Open-Label Extension..........................................53
6.
Study Procedures ..........................................................................................................53
6.1.
Screening Procedures (Day -35 to Day 0) ..............................................................54
6.2.
Study Enrollment Procedures .................................................................................55
6.3.
Double-Blind Treatment Period..............................................................................55
6.4.
Open-Label Extension ............................................................................................62
6.5.
Unscheduled Visits .................................................................................................65
6.6.
Renal Biopsies ........................................................................................................65
6.7.
Laboratory Tests .....................................................................................................65
6.7.1.
Pharmacokinetics..........................................................................................66
6.7.2.
Liver Chemistry Stopping and Follow-up Criteria.......................................67
6.7.3.
Increased Monitoring Criteria with Continued Therapy...............................70
6.7.4.
Study Treatment Restart ...............................................................................70
6.7.5.
Additional Hepatitis B Monitoring...............................................................71
6.7.6.
Immunogenicity............................................................................................71
6.8.
Withdrawal of Subjects from Treatment.................................................................72
6.9.
Subject Unblinding .................................................................................................72
7.
Adverse Event Reporting..............................................................................................73
7.1.
Definitions...............................................................................................................73
7.2.
Reporting Adverse Events to the Sponsor ..............................................................75
7.3.
Other Events Requiring Rapid Reporting (Protocol Specified Events)..................76
7.4.
Laboratory Abnormalities as Adverse Events ........................................................76
7.5.
Progressive Multifocal Leukoencephalopathy........................................................76
7.6.
Suicidality Assessment ...........................................................................................77
7.6.1.
Possible Suicidality Related Questionnaire (PSRQ).....................................78
7.7.
Reporting a Pregnancy............................................................................................78
7.8.
Investigator Evaluation of Adverse Events.............................................................78
7.9.
Follow-up of Adverse Events .................................................................................79
7.10.
Disease Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAEs...................................................................................................................80
7.11.
Regulatory Reporting Requirements for SAEs.......................................................81
8.
Endpoints and Statistical Analysis................................................................................81
8.1.
General Statistical Considerations..........................................................................81
8.2.
Randomization Procedure and Assignment to Treatment Groups..........................82
8.3.
Independent Data Monitoring Committee (IDMC)................................................82
8.4.
Sample Size Rationale ............................................................................................83
8.4.1.
Power for PERR Endpoint............................................................................83
8.5.
Efficacy...................................................................................................................84
8.5.1.
Primary Efficacy Endpoint ...........................................................................84


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8.5.2.
Primary Efficacy Analyses ...........................................................................85
8.5.3.
Secondary Efficacy Endpoints......................................................................86
8.5.4.
Other Efficacy Endpoints..............................................................................87
8.5.5.
Secondary Efficacy Analyses .......................................................................89
8.5.6.
Other Efficacy Analyses ...............................................................................89
8.6.
Safety ......................................................................................................................89
8.6.1.
Definition of Safety Variables ......................................................................89
8.6.2.
Analysis of Safety Variables.........................................................................89
8.7.
Pharmacokinetics....................................................................................................90
8.7.1.
Definition of Pharmacokinetic Evaluation....................................................90
8.7.2.
Analysis of Pharmacokinetics.......................................................................90
9.
Pharmacogenetics (PGx)...............................................................................................91
10.
Study Administration....................................................................................................91
10.1.
Informed Consent....................................................................................................91
10.2.
Institutional Review Board Review/Independent Ethics Committee 
Review and Approval .............................................................................................91
10.3.
Protocol Compliance...............................................................................................92
10.4.
Protocol Revisions ..................................................................................................92
10.5.
Data Collection and Management...........................................................................92
10.6.
Study Monitoring....................................................................................................93
10.7.
Drug Accountability................................................................................................93
10.8.
Retention of Records...............................................................................................93
10.9.
Financial Disclosure................................................................................................94
10.10. Publication Policy...................................................................................................94
10.11. Study or Study Site Termination.............................................................................94
11.
References.....................................................................................................................96
List of Appendices..................................................................................................................100


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LIST OF TABLES
Table 1-1
Renal endpoints at Week 52-Phase 3 SLE trials...............................................28
Table 1-2
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk .............30
Table 5-1
Recommended oral prednisone taper regimen..................................................50
Table 6-1
Study Calendar - Double-Blind Treatment Period (Screening to Week 
52) .....................................................................................................................57
Table 6-2
Study Calendar - Double-Blind Treatment Period (Week 56 to 104) ..............60
Table 6-3
Study Calendar- 6-Month Open-Label Extension ............................................63
Table 6-4
PK Visit Days and Sample Times.....................................................................67


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LIST OF FIGURES
Figure 1-1
Study schematic ................................................................................................16


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LIST OF ABBREVIATIONS
aCL
anticardiolipin
ACE
angiotensin converting enzyme
ACR
American College of Rheumatology
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody 
ANCOVA
analysis of covariance
ARB
angiotensin receptor antagonists/blockers
anti-dsDNA
anti-double-stranded DNA
anti-HBc
hepatitis B core antibody 
anti-HBs
hepatitis B surface antigen antibody
anti-Sm
anti-Smith antibody 
anti-TNF
anti-tumor necrosis factor
AST
aspartate aminotransferase
AUC
area under the serum drug concentration-time curve
AUCi
area under the curve for an individual subject
AZA
azathioprine
bid
twice a day
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
compact disc
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CRR
complete renal response
C-SSRS
Columbia-Suicide Severity Rating Scale
CYC
cyclophosphamide
CVA
cerebrovascular accident
dL
deciliter
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
dsDNA
double-stranded DNA
eCRF
electronic case report form
ECL
electrochemiluminescence
EDC
electronic data capture
eGFR 
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorobent assay
ESRD
end stage renal disease
EU
European Union
FACS
florescence activated cell sorting
FDA
United States Food and Drug Administration


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g
gram
GCP
Good Clinical Practice
GCSP 
Global Clinical Safety and Pharmacovigilance
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSK
GlaxoSmithKline Pharmaceuticals
HB
Hepatitis B
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBc
Hepatitis B core antigen
HCV
Hepatitis C virus
HDCS
high dose corticosteroids
Hep-2
human epithelial cell line 2
HGS
Human Genome Sciences, Inc.
HIV
human immunodeficiency virus
hpf
high power field
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IM
intramuscular
IRB
Institutional Review Board
ISN
International Society for Nephrology
ITT
intention to treat
IU
international unit
IUD
intrauterine device
IV
intravenous
IVIG
intravenous immunoglobulin
IWRS
Interactive Web Response System 
KDOQI
Kidney Disease Outcomes Quality Initiative
kg
kilogram
LDH
lactic dehydrogenase
LOCF
last observation carried forward
MDD 
major depressive disorder
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMF
mycophenolate mofetil
MTX
methotrexate
μg
microgram
mg
milligram
mL
milliliter
mmHG
millimeters of mercury
NMSC 
non-melanoma skin cancer
NR
no response
NSAIDs
non-steroidal anti-inflammatory drugs
NWHIC
National Women’s Health Information Center


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OMHRC 
Office of Minority Health Resource Center
ORR
ordinal renal response
PERR
primary efficacy renal response
PGA
Physician’s Global Disease Assessment
PGx
pharmacogenetics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PRR
partial renal response
PSE
protocol-specified event
PSRHQ
possible suicidality-related history questionnaire
PSRQ
possible suicidality related questionnaire
PT
prothrombin time
PTT
partial thromboplastin time
PY
patient-years
RA
rheumatoid arthritis
RBC
red blood cell
RPS
Renal Pathology Society
RRGFR60
renal response using 60 mL/min/1.73m2 eGFR cut off
RRUS
renal response including urinary sediment component
SAE
serious adverse event
SAS
statistical analysis system
SC
subcutaneous
SELENA
Safety of Estrogen in Lupus National Assessment trial
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
TACI-Fc
transmembrane activator attached to Fc portion of an immunoglobulin 
tid
three times daily
TNF
tumor necrosis factor
ULN
upper limits of normal
uPCR
urine protein-creatinine ratio
US
United States of America
USAN/INN
United States adopted name/international nonproprietary name
WBC
white blood cell
WHO
World Health Organization


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1.
BACKGROUND
1.1.
Disease Background Relevant to Clinical Study
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). In community-based studies 
among Asians, the prevalence (per 100,000) of SLE ranged from 3.2 to 70.4 (Thumboo
and Wee, 2006). The disease onset is generally between the ages of 20 and 40. 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).
Approximately 35% of all adult patients with SLE develop clinically significant lupus 
nephritis and despite improvements in both diagnosis and treatment over the last few 
decades it remains an indicator of poor prognosis (Gordon et al, 2009; Waldman and 
Appel, 2006). Manifestations of lupus nephritis include proteinuria, elevations in serum 
creatinine, and the presence of urinary sediment. Alongside these clinical manifestations, 
morphological changes can be observed in renal biopsy specimens. In 1975 the World 
Health Organization (WHO) proposed a classification system for renal biopsies in SLE 
which was continually revised by them up until 1995. In 2004 updated criteria jointly 
developed by the International Society of Nephrology (ISN) and the Renal Pathology 
Society (RPS) were published (Weening et al, 2004). Within the 5 overall classes, 
Classes I and II reflect disease restricted to mesangial abnormalities. Classes III and IV 
represent either focal (< 50% glomeruli involved - Class III) or diffuse (≥50% glomeruli 
involved - Class IV) segmental or global glomerulonephritis. Class V represents 
membranous disease with Class VI representing advanced sclerosis. Classes I and II are 
rarely accompanied by clinical manifestations and there is no activity in Class VI only 
damage, so therapy has traditionally focused on Classes III-V.
Belimumab (BENLYSTA™) administered intravenously (IV) is approved in the US, 
Canada, and EU for the treatment of adult patients with active autoantibody-positive SLE 


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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 IV 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™; BENLYSTA™) 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 pharmacology, pharmacokinetic (PK), and toxicology data generated with
belimumab are provided in the Investigator’s Brochure (IB).
1.2.2.
Clinical Experience with Belimumab
Belimumab administered as an IV infusion has been studied in SLE patients in 1 Phase 1 
trial (LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial (LBSL02),
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).
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the 
basis of the approval of IV belimumab in the US, Canada, and 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 was also observed. Treatment with belimumab plus standard of care 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 of care 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 


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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 subjects
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.
1.3.
Rationale for the Study
Current standard of care treatment for lupus nephritis consists of corticosteroids and 
immunosuppressants. Several studies have now been conducted in lupus nephritis; 
however at this time no therapies have been approved for lupus nephritis. In the Euro-
lupus trial, a low dose IV cyclophosphamide (CYC) regimen achieved similar clinical 
results with respect to treatment failures, renal remission and renal flares when compared 
to a high dose IV CYC regimen (Houssiau et al, 2002). A recent systematic review of 
recent trials in lupus nephritis concluded that mycophenolate mofetil (MMF) is as 
effective as CYC in inducing disease remission (Touma et al, 2011).
Belimumab treatment at a dose of 10 mg/kg in combination with standard SLE therapy 
demonstrated a statistically significant and clinically meaningful reduction in SLE 
disease activity vs placebo plus standard SLE therapy at week 52 in 2 Phase 3 clinical 
studies (HGS1006-C1056/BLISS 76 and HGS1006-C1057/BLISS 52) in subjects with 
active, autoantibody-positive SLE. While the 2 Phase 3 studies did explore the effect of 
belimumab on individual organ systems, these findings were limited for the renal organ
domain as subjects were excluded if they had severe active lupus nephritis. However, 267 
subjects (16%) included in the Phase 3 trials had renal involvement by SELENA 
SLEDAI (comprising hematuria, proteinuria, pyruia and/or urinary casts). In a post-hoc 
analysis of the pooled data (Table 1-1), there were trends towards SELENA SLEDAI 
renal organ domain improvement, especially in the subgroup of subjects who were anti-
dsDNA positive and had low C3 and/or low C4 at baseline. There were favorable trends 
of greater reduction in proteinuria, hematuria, pyuria, and lower renal flare rate in the 
belimumab treatment groups versus placebo. Understanding whether belimumab plus 
standard of care can reduce the disease activity in subjects with active lupus nephritis 
subjects is of interest to prescribing physicians and health authorities. 


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Table 1-1
Renal endpoints at Week 52-Phase 3 SLE trials
Phase 3 Studies Pooled
Placebo 
N = 562
1 mg/kg 
N = 559
10 mg/kg 
N = 563
SELENA SLEDAI Renal Improvement1
In patients with the following at baseline:
Renal involvement2
39/92 (42.4%)
43/90 (47.8%)
42/85 (49.4%)
Renal involvement + high activity3
37/87 (42.5%)
39/86 (45.3%)
42/82 (51.2%)
Renal involvement + anti-dsDNA+low 
C4
21/62 (33.9%)
24/60 (40.0%)
28/60 (46.7%)
Proteinuria
(n = 116)
(n = 110)
(n = 112)
Median % reduction5
27.5
48.3
39.1
Renal Flare 
Subjects with renal flare6
16 (2.8%)
14 (2.5%)
8 (1.4%)
Relevant Biomarkers
Anti-dsDNA7
Positive to Negative
19/280 (6.8%)
47/314 (15.0%)
50/313 (16.0%)
C38
Low to Normal/High
30/176 (17.0%)
51/193 (26.4%)
77/202 (38.1%)
C49
Low to Normal/High
40/218 (18.3%)
86/246 (35.0%)
115/259 (44.4%)
1
SELENA SLEDAI renal domain includes hematuria, proteinuria, pyuria, and urinary casts.
2
In subjects with renal involvement at baseline (dropout=failure).
3
In subjects with renal involvement and SELENA SLEDAI score ≥7 at baseline (dropout=failure).
4
In subjects with renal involvement and anti-dsDNA+/low complement at baseline (dropout=failure).
5
In subjects with > 0.5 g at baseline (LOCF).
6
Censored at last assessment or start of rescue medications.
7
Anti-dsDNA: Positive (≥ 30 IU/mL); Negative (< 30 IU/mL).
8
C3: Normal/High (≥ 900 mg/L); Low (< 900 mg/L).
9
C4: Normal/High (≥ 16 mg/dL); Low (< 16 mg/dL).
TE24.1, TE26.1, TE26.2 (C1056); TE24.1, TE26.1, TE26.2 (C1057); 
TA46.7, TAC790, TAC340, TAC397, TA1 (ISE)
In the 2 Phase 3 studies, several clinical measures of improvement including the primary 
efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, 
there appeared to be a greater dose response in subjects with high disease and serological 
activity than in subjects with lower activity. There was no apparent dose-response in the
safety profile of belimumab, with both doses being generally well-tolerated, further 
supporting the selection of 10 mg/kg belimumab as the recommended dose in 
combination with standard therapies.
The current study is designed to evaluate the efficacy (ie, induction and maintenance of 
renal remission) and safety of 10 mg/kg belimumab administered IV in combination with 
standard of care (including MMF, CYC, corticosteroids and AZA) in subjects with active 
lupus nephritis. 


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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 infections. Potential risks (i.e., 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, non 
opportunistic 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 dyspnea. However, infusion and hypersensitivity reactions can be severe 
and fatal. Infections were commonly reported events with belimumab and are expected 
due to the mechanism of action of belimumab and the SLE patient population.  
In the post-marketing setting with IV belimumab, delayed onset of symptoms of acute 
hypersensitivity reactions as well as recurrence of clinically significant reactions after 
initial appropriate treatment has been observed. Subjects will remain at the clinic for 
3 hours following the first 2 infusions for observation. Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment. Subjects should be made aware of the potential risk for severe or life-
threatening hypersensitivity reactions, the signs and symptoms of such reactions, the 
potential for delayed onset or recurrence of symptoms, and the importance of 
immediately seeking medical attention should they occur. Belimumab should be 
administered by a healthcare professional prepared to treat hypersensitivity reactions 
including anaphylaxis.
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. Delay 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.
Premedication including an antihistamine, 
with or without an antipyretic, may be 
administered before the infusion.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
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 placebo were nasopharyngitis, 
bronchitis, pharyngitis, cystitis, and 
gastroenteritis viral.  Serious infections 
occurred in 5% of patients receiving either 
belimumab or placebo.
Exclude patients who are 
currently on any suppressive 
therapy for acute or chronic 
infection, hospitalized for 
treatment of infection within 60 
days of Day 0, or who used 
parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-
fungals, or anti-parasitic agents) 
within 60 days prior to Day 0.,a 
history of or positive test at 
screening for HIV, Grade 3 or 4 
lymphopenia, Grade 3 or 4 IgG or 
IgA deficiency, serologic 
evidence of Hepatitis B viral 
(HBV) infection based on the 
results of testing for HBsAg and 
Anti-HBc including HBsAg 
positive, HBsAg negative but 
positive for Anti-HBc regardless 
of Anti-HBs antibody status 
requiring  clarification by HBV 
DNA, HBV DNA HCV positive at 
screening.
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately. 
Delay or withhold the dose of study agent, or 
discontinue study treatment when 
necessary.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Progressive 
multifocal 
leukoencephalopathy
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.
Exclude patients who have acute 
or chronic infection including 
PML.
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. Across all 
SLE trials as of 08 March 2013, the 
relative rate of malignant neoplasms per 
100-subject years (excluding non-
melanoma skin cancer [NMSC]) for 
belimumab was 0.527, 95% CI: 0.365-
0.736. This rate is consistent with the rate 
of malignant neoplasms, excluding NMSC, 
observed in the SLE international cohort 
(0.53, 95% CI: 0.48, 0.59); incidence ratio 
0.87 (0.59, 1.29) (Bernatsky et al, 2005). 
Incidence rates of malignancy for 
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.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
spontaneous SLE cases were not 
reported, as the number of cases is too 
few.
Immunogenicity
As with other monoclonal antibodies, 
treatment with belimumab could lead to 
the development of anti-drug antibodies 
(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.
Not applicable
Analyse anti-drug antibody laboratory values 
at the end of the study to further investigate 
clinical relevance.


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
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 immunizations. 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 
immunizations received prior to 
administration of belimumab. 
Exclude patients who have 
received a live vaccine within 
30 days of Day 0.
Live vaccines should not be given for 30 
days before or concurrently as clinical safety 
has not been established. Subjects who 
require a live vaccine during the study 
should have study agent discontinued prior 
to receiving the live vaccine.
Potential psychiatric 
events - Depression 
and suicidality
There have been reports of depression 
and suicidality in patients receiving 
belimumab. Based on an estimated 
current clinical trial exposure of 7117.3 
patient-years (PY) in belimumab studies 
(as of 08 March 2013), the rate of 
completed suicide in patients exposed to 
belimumab in clinical trials is estimated to 
be 4/7117.3 or 0.056/100 PY (0.015, 
0.144). The rate of suicidal behavior 
(completed suicide and attempt; including 
overdose) is 15/7117.3 or 0.211/100PY 
(0.118, 0.348). The rate of suicidal 
ideation (including all events of suicidality, 
Exclude patients 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 in the last 2 months or who 
in the investigator's judgment, 
pose a significant suicide risk.
Monitor patients for signs and symptoms of 
psychiatric events including depression and 
suicidality, request that patients report signs 
and symptoms.  Treat appropriately


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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
suicidal thoughts and behavior) is 
19/7117.3 or 0.267/100PY (0.161, 0.417).  
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).


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An Independent Data Monitoring Committee (IDMC) reviews unblinded safety data for
this Phase 3 study on an ongoing basis until the data are locked and analyzed through 
Week 104. At all times the sites and sponsor will remain blinded to treatment allocation. 
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 during the 
double-blind and open-label extension portions of the study. Investigators (and 
IRBs/IECs, as appropriate,) will be notified of the outcome of each IDMC meeting.
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 including those patients with renal manifestations 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. In a post hoc analysis of the pooled data in subjects 
with renal involvement at baseline, there were favorable trends of greater reduction in 
proteinuria, hematuria, pyuria, and lower renal flare rate with belimumab. These 
preliminary findings in patients with renal involvement support that belimumab may 
provide potential benefit to these patients (Dooley et al, 2013). 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; Dooley et al, 2013).  
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. In addition, the preliminary evidence suggests that patients with lupus 
nephritis may potentially benefit from belimumab.
2.
STUDY OBJECTIVES
•
To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV, or V using the 2003 ISN/RPS criteria.
•
To assess the safety and tolerability of belimumab plus standard of care versus 
placebo plus standard of care in adult subjects with lupus nephritis Class III, IV, or V 
using the 2003 ISN/RPS criteria.


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3.
STUDY DESIGN
3.1.
Basic Design Characteristics
This is a Phase 3, multi-center, multi-national, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of IV belimumab 10 mg/kg plus 
standard of care compared to placebo plus standard of care in adult subjects with active 
lupus nephritis. 
Subjects who meet the eligibility criteria during screening will be randomized to 1 of 2
treatment groups in a 1:1 ratio: 10 mg/kg belimumab plus standard of care or placebo 
plus standard of care. The randomization of all eligible subjects will be stratified by their 
induction regimen (high dose cortiocsteroids [HDCS] plus CYC vs HDCS plus MMF) 
and race (black race vs other). Subjects will be dosed with study agent on Days 0
(baseline), 14, 28, and then every 28 days thereafter through 100 weeks with a final 
evaluation for the double-blind treatment period at 104 weeks. At least 400 and up to 
approximately 464 lupus nephritis subjects will be randomized with a target of at least 
200 and up to approximately 232 subjects in each treatment group (belimumab or 
placebo). All subjects will receive background therapy consisting of one of the following 
standard of care regimens:
•
High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for induction 
therapy followed by Azathioprine (AZA) for maintenance therapy
OR
•
HDCS + Mycophenolate Mofetil (MMF) for induction followed by MMF for 
maintenance therapy
The standard of care medications are described in Section 5.5.1. 
All subjects should start the above induction therapy within 60 days prior to or on Day 0 
(baseline visit). This will allow subjects to be screened and potentially enrolled and will 
not be excluded on the basis of necessary acute management. The primary efficacy 
endpoint of a renal response will be a composite endpoint including changes in 
proteinuria and renal function at Week 104. For the renal function assessments at all 
study visits, the glomerular filtration rate (GFR) will be estimated using the simplified 
MDRD formula and the urinary protein: urinary creatinine ratio will be used for 
proteinuria. In addition, at baseline, Week 24, 48, 52, 76, 100 and 104, GFR will be 
calculated based on the mean value of 2 contiguous 24 hour urine collections and 2 serum 
creatinine measurements. The first serum creatinine will be collected at the initial visit 
which will take place within 3 days prior to or on the day of the scheduled visit. At the
initial visit, subjects will be provided with the materials for collecting the two 24 hour 
urine collections beginning the next morning following their initial clinic visit. On the 
third day following the initial visit, subjects will return to the clinic for the second serum 
creatinine sample. Urine collection may be postponed up to 14 days at the investigators 
discretion if menstrual bleeding or a genitourinary tract infection is present at any time 
during the 24 hour urine collection. 


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The primary endpoint will be measured using the Primary Efficacy Renal Response 
(PERR) based on study defined criteria (see Section 8.5). Week 104 PERR will be 
defined by a response at Week 100 that is confirmed by a repeat measurement at Week 
104. Likewise, for the relevant major secondary endpoints, complete and ordinal renal 
responses at Week 104 will be defined by the complete and ordinal renal response at 
Week 100 that is confirmed by a repeat measurement at Week 104.
All subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104. 
In the event that a subject withdraws consent from the study, an attempt should be made 
to obtain consent to collect follow-up safety data (at an exit visit approximately 4 weeks 
after the last dose of study agent as well as a follow-up visit approximately 8 weeks after 
the last dose of study agent) and to obtain survival status at Week 104. Any subject that 
withdraws consent for use and disclosure of research-related health information will be 
considered withdrawn from the study and will not be followed for mortality. 
Subjects who receive treatment with study agent through Week 100 and complete Week 
104 assessments in the double-blind period may enter into a 6-month open-label 
extension. The Week 104 visit of the double-blind period will serve as the Day 0 visit for 
subjects entering the 6-month open-label extension. In the open-label extension, all 
subjects will receive 10 mg/kg belimumab every 28 days until Week 24, with a final 
evaluation at Week 28 (4 weeks after the last dose). The first dose on the open-label 
extension will be given at the Week 104 visit of the double-blind period following the 
completion of all Week 104 assessments. Subjects participating in the open-label 
extension will continue to be monitored for efficacy and safety as per the study calendar 
(see Table 6-3). Subjects who complete the 104-week double-blind period, but do not 
enter the open-label extension will be required to return for an additional follow up visit 8 
weeks after the last dose of study agent. All subjects who enter the open-label extension 
period and withdraw early 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. 
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 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 if 
permissible according to local regulations. 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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4.
INCLUSION AND EXCLUSION CRITERIA
4.1.
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Males or females at least 18 years of age.
2. Have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology (ACR) criteria (Appendix 1).
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding 
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or 
pure Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy 
must be performed in the 6 months prior to the screening visit or during the screening 
period. The local biopsy report will be used to confirm subject eligibility. A tissue 
sample from the renal biopsy used to qualify the subject for randomization needs to 
be sent to a central reading center after Day 0 (baseline).
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an 
ANA titer ≥ 1:80 (based on Hep-2 immunofluorescence assay or equivalence by 
enzyme immunoassay assay) and/or a positive anti-dsDNA (≥30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results.
5. Have documentation of active renal disease at screening requiring induction therapy 
with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) or 
mycophenolate mofetil (MMF) or other oral forms of mycophenolate. The following 
factors will be used to define active renal disease at screening:

Urinary protein:creatinine ratio of ≥ 1.0 AND 

Active urinary sediment as defined by at least 1 of the following (in absence 
of menses and genitourinary tract infection).  

> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory 
reference range

> 5 white blood cell (WBC)/hpf or above the laboratory reference range.

Presence of cellular casts (RBC or WBC).

Subjects without active urinary sediment are eligible if they meet at least 1 of 
the following criteria: 

Have a confirmatory biopsy performed within 3 months prior to the 
screening visit or during the screening period meeting the criteria 
outlined in Inclusion Criterion 3.

Have proteinuria ≥ 3.5 grams/day (or urinary protein:creatinine ratio≥ 
3.5).
6. Have active renal disease defined as above which requires induction therapy with 
high dose corticosteroids (HDCS) with either intravenous (IV) cyclophosphamide 
(CYC) or mycophenolate mofetil (MMF) or other oral forms of mycophenolate:


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Induction therapy may begin before Screening but should be initiated within 60 days 
prior to or on Day 0 (baseline). Initiation of induction is when both HDCS and either 
MMF or CYC have been started.
The study recommended doses for induction therapy are as follows, adjustments may 
be made for tolerability issues (refer to Section 5.5.1 Standard of Care Medication for 
details): 
-
MMF 1-3g/day orally or Mycophenolate sodium 720 - 2160 mg/day orally 
-
corticosteroids: 0-3 IV pulses of methylprednisolone 500 -1000 mg/pulse 
followed by oral prednisone 0.5-1.0 mg/kg/day with total daily dose up to 60 
mg/day (or equivalence)
-
CYC 500 mg by IV infusion every 2 weeks (3 days) for 6 infusions 
Subjects who have been on MMF for SLE including lupus renal disease may be 
eligible if they have received, or will receive, the following induction therapy within 
60 days prior to or on Day 0 (baseline): 
-
initiation of HDCS with MMF dose increase to reach the target dose for induction 
in the subject (if the subject did not previously fail MMF induction based on the 
investigator’s opinion), OR 
-
initiation of HDCS with discontinuation of MMF and initiation of CYC.  
Note: It is recommended that subject eligibility should be discussed with the Medical 
Monitor if a subject initiated but did not complete an induction therapy within 6 
months prior to the initiation of current induction therapy for the study.
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 study, and for 
16 weeks after the last dose of study agent: 
◦
Implants of levonorgestrel or etonogestrel; 
◦
Ethinyl estradiol/Etonogestrel vaginal ring;


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◦
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 sterilisation with documentation of azoospermia prior to the 
female subject’s entry into the study, and this male is the sole partner for that 
subject. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
Note: If stricter female or male contraception requirements are specified in the 
country-specific label for induction and/or maintenance standard of care 
medications, they must be followed.
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. Subjects who have previously failed both CYC and MMF (or other forms of 
mycophenolate) induction therapies based on the investigator’s opinion. If a subject 
has failed only 1 of the 2 therapies for induction, they may be eligible for study 
inclusion if the other induction therapy is initiated within 60 days prior to or on Day 0 
(ie, a subject who failed MMF is eligible if newly initiating induction therapy with 
CYC or a subject who failed CYC is eligible if newly initiating induction therapy 
with MMF).
2. Subjects who received an induction therapy with CYC within 3 months prior to the 
planned initiation of the current induction for the study.
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 
based on the Adverse Event Severity Grading Tables (Appendix 7).
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, AZA, corticosteroids).
5. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins or monoclonal antibodies.
6. Have received treatment with belimumab within 364 days of baseline (Day 0). 
7. Received the following within 364 days of  baseline (Day 0):   


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
Nitrogen mustard

Chlorambucil

Vincristine

Procarbazine

Etoposide

Abatacept

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, or LY2127399 [anti-BAFF])

A biologic investigational agent (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.

Treatment with interleukin-6 targeted therapy (e.g., tocilizumab, sirukumab).
8. Received any of the following within 90 days of baseline (Day 0):  

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab, certolizumab, 
golimumab pegol)

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

Plasmapheresis.
9. Received a non-biological investigational agent within 60 days of baseline (Day 0).
10. Received a live vaccine within 30 days of baseline (Day 0).
11. 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 baseline (Day 0).
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant or are due to receive transplantation.
13. Subjects who have been on dialysis within 364 days of baseline (Day 0).
14. An estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit 
(using the simplified Modification of Diet in Renal Disease [MDRD] equation).
15. 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.
16. 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.
17. 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 
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18. Have acute or chronic infection requiring management, as follows:

Currently on any suppressive therapy for a chronic infection (such as 
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes 
zoster, or atypical mycobacteria).

Hospitalization for treatment of infection within 60 days of baseline (Day 0).

Have had infection requiring treatment with parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days 
of baseline (Day 0).
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to baseline (Day 0). 
20. Have a historically positive test or test positive at screening for HIV antibody.  
21. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:

Patients positive for HBsAg are excluded.

Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-
HBs antibody status, will require clarification of their status by testing for 
HBV DNA

o
if HBV DNA positive, patients will be excluded from participation

o
if HBV DNA negative, patients will be eligible to enrol.

NOTE: For those subjects randomised, additional ongoing assessment during 
the study is required (see Section 6.7.5).
22. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate. Subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing.
23. Have an IgA deficiency (IgA level < 10 mg/dL).
24. Have a Grade 3 or greater laboratory abnormality (including serum IgG level) based 
on the Adverse Event Severity Grading Tables (Appendix 7) except for the following 
that are allowed:

Urinalysis (eg, proteinuria)

Hematuria

Pyuria

Casts

Hypoalbuminemia due to lupus nephritis.

Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.


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
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant 
and not related to liver disease or anti-coagulant therapy.

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 the ALT and/or AST must be ≤ 
Grade 2.

Stable Grade 3 reduction in hemoglobin levels due to SLE

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count [with the 
exception of subjects receiving CYC who will be excluded if WBC is Grade 3 
or 4 per Exclusion Criterion 3]. Note that WBC count should be obtained 
immediately prior to starting induction therapy. If immediate pre-induction 
WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used. 

Hyperuricemia or blood urea nitrogen (BUN) elevation due to lupus nephritis 
or SLE.
25. 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) (Appendix 8) in the last 2 months 
or who, in the investigator's opinion, pose a significant suicide risk.
5.
STUDY TREATMENT REGIMEN
5.1.
Study Agent Name and Formulation
The common name of the study agent is BENLYSTA™. 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 4.8 mL 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.
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 
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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) using the subject’s current body weight in kilograms (kg) which should 
be obtained at each visit prior to dosing. 
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 for additional details), 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 
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 6.7 and Section 6.9). 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 


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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 include one active treatment arm of 10 mg/kg belimumab and a 
placebo arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over at least
1 hour. Once randomized, subjects will be dosed with study agent on Days 0, 14, and 28 
and every 28 days days thereafter through 100 weeks of double-blind treatment.
Following the final double-blind visit at Week 104, subjects who complete 100 weeks of 
treatment with study agent and complete Week 104 assessments, will have the option to 
continue in the 6-month open-label extension period (with first dose given at the Week 
104 visit).
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. 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 period and the open-label extension. 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 reaction, and monitor subjects closely.
Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment. In the event of a serious reaction, study agent administration must be 
discontinued immediately and the appropriate medical therapy administered. 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 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 the symptoms of such reactions, and the importance of immediately 
seeing medical attention.
5.4.
Alteration of Dose/Schedule Due to Toxicity
The dose of study agent administered may not be altered. The rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or 
infusion-associated symptoms. At later visits, these subjects may continue to be infused 
over a longer infusion period at the investigator’s clinical discretion. 


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If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to study agent and could potentially be 
exacerbated by the next dose, the investigator may delay 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 
study agent should be discontinued.  
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE 
that the investigator believes may be definitely, possibly or probably related to study 
agent, then treatment with study agent will be discontinued. The subject should be 
withdrawn from study agent, and followed at regularly scheduled study visits as specified 
by protocol and also until resolution of the AE(s) (whichever is longer). All subjects 
should be monitored closely for infection. Increased vigilance for infection is 
recommended in subjects whose serum IgG concentrations are < 250 mg/dL. Clinical 
judgment should be applied with respect to the appropriateness of continuing study 
therapy in these subjects. If a subject experiences IgG levels < 250 mg/dL, the dose of 
study agent must be withheld and the Medical Monitor must be consulted before 
administering any subsequent dose of study agent. Study agent will be discontinued in 
subjects with IgG levels < 250 mg/dL that are associated with a severe or serious 
infection.
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.
5.5.
Concurrent Medications During the Double-blind Treatment 
Period
This section reviews medications which are required or allowed provided the guidelines 
below are followed. Anytime the concurrent medication requirements are not followed, 
the subject will have study agent discontinued and will be considered a treatment failure 
(non-responder).
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, SLE 
Flare Index and PGA) and laboratory assessments (hematology, chemistry, urinalysis, 
anti-dsDNA, and complement) should be performed to document renal flare prior to 
instituting treatment that results in treatment failure designation.
Comprehensive education and guidance regarding the use of concurrent standard of care
medications (including escalations and tapers, as appropriate) must be provided to the 


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subject at baseline (Day 0) and each scheduled visit. Subject compliance with concurrent 
medications is essential and will be monitored and recorded in the eCRF. Guidance for 
subject education and instructions regarding monitoring subject compliance will be 
provided in the Study Procedures Manual.
Received doses for all systemic corticosteroids are considered as prednisone equivalent. 
As such, when “prednisone” is used throughout this protocol, it refers to prednisone dose 
or equivalent.
5.5.1.
Standard of Care Medication
This section reviews the required induction and maintenance standard of care regimens. 
All subjects should receive background standard of care therapy consisting of either CYC
plus HDCS for induction followed by AZA for maintenance or MMF plus HDCS for 
induction followed by MMF for maintenance. Each investigator must refer to the 
country-specific label for each required medication and heed appropriate warnings and 
precautions. If in the clinical judgment of the investigator, infection (including active or 
latent tuberculosis [TB] and active HBV infection) is suspected in a subject, screening 
examinations and appropriate management before initiating induction therapy should be 
considered following local guidelines.
The induction and maintenance regimens specified in this protocol are based on accepted 
clinical paradigms. Because the response of individual subjects to any given regimen 
cannot be predicted, it is important that the clinical course is monitored closely. If a 
subject fails to respond in an appropriate timeframe, or their renal function shows 
clinically significant deterioration, then appropriate rescue therapy should be instituted to 
minimize the risk of increasing renal damage. Once randomized, such subjects will be 
considered treatment failures for analysis, but should return for their scheduled visits
through Week 104. If any of the standard of care medications as induction and 
maintenance regimens is discontinued, the Medical Monitor should be consulted to assess 
the appropriateness of continuing study treatment in these subjects.
Cyclophosphamide and Azathioprine
Cyclophosphamide (CYC) used for induction therapy will consist of 500 mg by IV 
infusion every 2 weeks (3 days) for 6 infusions. Adjustments may be made for 
tolerability issues. If subjects previously received MMF for treatment of SLE including 
lupus renal disease and will receive CYC induction, MMF should be discontinued when 
CYC is initiated.
For the maintenance period, AZA will be started approximately 2 weeks after the last 
dose of CYC with a target dose of 2 mg/kg/day (not to exceed 200 mg/day) until study 
end. A prescribed total daily dose should be as close as possible to a target dose of 
2mg/kg/day, a total daily dose greater than 200 mg/day is prohibited and considered to 
constitute treatment failure. It is recommended that dosing commence at 50 mg/day and 
increase by no more than 50 mg/day every week until the target dose is achieved.
Adjustments may be made for tolerability issues. Subjects who develop Grade 3 or 4 
leucopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe


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gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above a 
switch to MMF will be permitted. The use of mesna and/or leuprolide (leuprorelin) is 
permitted with CYC dosing in accordance with the usual practice of the investigator.
Mycophenolate Mofetil
MMF used for induction and maintenance therapy is recommended at a dose from 1-3
g/day orally through study end.  The investigator should determine the appropriate dose 
within the dose range recommended for an individual subject based on the consideration 
of clinical benefit and side effects that may be expected. Dosing of MMF is 
recommended to start at 0.5 g twice a day (bid) for the first week, increase to 1 g bid for 
the second week, and then 1.5 g bid for the third and subsequent weeks, if appropriate. 
MMF should be taken morning and evening, before meals, with a glass of water. If 
tolerability issues are experienced with bid dosing, subjects may receive 1 g 3x/day (tid). 
If tid dosing is not tolerated, the MMF dose may be reduced to as low as 1 g/day. In 
addition, subjects who develop grade 3 or 4 neutropenia or any other side effects that are 
considered clinically significant by the investigator following initiation of MMF will be 
permitted to reduce the dose to no less than 1 g/day. A prescribed dose greater than 3
g/day is prohibited and considered to constitute treatment failure. 
After 6 months of MMF therapy, the dose of MMF may be reduced to 1 g/day or subjects 
may be switched to AZA (target dose 2 mg/kg/day) for tolerability reasons.
If MMF dose has to be temporarily reduced to less than 1g/day for safety reasons (eg. 
Serious Adverse Event), the Medical Monitor should be consulted to assess the 
appropriateness of continuing study treatment in the subject.
Mycophenolate sodium may be used in lieu of MMF for induction and/or maintenance 
therapy. A dose from 720 mg/day to 2160 mg/day orally is recommended. A dose greater 
than 2160 mg/day is prohibited and considered to constitute treatment failure.  
The use of IV forms of mycophenolate is prohibited.
High Dose Corticosteroids
All subjects must be on a daily corticosteroid regimen as part of the induction therapy.
The study recommended corticosteroid regimen includes 0-3 IV pulses of 
methylprednisolone 500
mg-1000
mg/pulse followed by oral prednisone at a 
recommended dose of 0.5-1.0 mg/kg/day with total daily dose up to 60 mg/day. 
Adjustments may be made for tolerability issues. It is recommended that oral 
corticosteroids be tapered according to Table 5-1. If necessary, it may take longer than 12 
weeks to complete the taper. 
Note: By Week 24, the dose of corticosteroids must be at 10 mg of prednisone/day or 
less (can be 0 mg) or subject will be considered a treatment failure. 


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Table 5-1
Recommended oral prednisone taper regimen
Study Week
Reduced Dose (mg/day)
0
60
2
50
3
45
4
40
5
35
6
30
7
25
8
20
9
17.5
10
15
11
12.5
12
10
5.5.2.
Immunosuppressives
The primary objective of this trial is to evaluate the efficacy of belimumab plus standard 
of care to reduce lupus nephritis disease activity. Other immunosuppressives (eg,
methotrexate [MTX]) will be allowed provided these are started prior to baseline and 
meet eligibility criteria. Dose alterations during the trial of these agents are permitted.
Subjects who newly initiate immunosuppressives (with the exception of topical agents) 
after the baseline visit outside the induction regimen will be considered treatment 
failures.
5.5.3.
Angiotension Pathway Antihypertensives
Drugs acting on the renin-angiotensin system are known to reduce proteinuria and are 
thought to have a renoprotective effect (Kanda et al, 2005). Therefore, it is strongly 
recommended that all subjects be receiving angiotensin pathway antihypertensive agents 
(angiotensin-converting 
enzyme 
[ACE] 
inhibitors 
or 
angiotensin 
receptor 
antagonists/blockers [ARBs]), or a combination therapy that includes these agents at 
screening/baseline and during the study. Since these medications may confound efficacy 
assessment by mimicking renal deterioration (eg, increased serum creatinine) or 
improving renal function (eg, beneficial remodeling of renal parenchyma), the following 
guidelines should be applied: 
•
Starting a new angiotensin pathway antihypertensive (ACE inhibitor, angiotensin 
receptor blocker) treatment after the Week 24 visit will cause the subject to be 
declared a treatment failure.
•
An angiotensin pathway antihypertensive will be considered new if the subject did 
not receive an angiotensin pathway antihypertensive at any time during the Day 0 to 
Week 24 treatment interval.
•
An angiotensin pathway antihypertensive may be replaced with another angiotensin 
pathway antihypertensive at any time during the study.


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•
Titration of dose to obtain therapeutic effect on blood pressure is allowed.
•
Initiation of new antihypertensive agents other than ACE inhibitors or ARBs is 
permitted.
5.5.4.
Anti-malarials
Hydroxycloroquine use in patients with lupus nephritis has been shown to delay the 
development of renal damage (Pons-Estel et al, 2009).  Therefore, it is strongly 
recommended that all subjects be receiving hydroxychloroquine at screening/baseline and 
during the study.
Since these medications may confound efficacy assessment by improving renal function, 
the following guidelines should be applied: 
•
a subject starting antimalarial treatment after the Week 24 visit will be declared a 
treatment failure.
•
an antimalarial medication may be replaced with another at anytime during the study.
•
dose change is allowed during the study if the antimalarial treatment was initiated by 
Week 24 visit
5.5.5.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin
The use of NSAIDs is not recommended during the study, although use would not 
constitute a treatment failure.  
5.5.6.
Corticosteroids
5.5.6.1.
Systemic Corticosteroids for Non-renal SLE-related Disease Activity
All subjects should be receiving a corticosteroid dose of 10 mg/day or less (can be 0 mg) 
by Week 24. Those who cannot be tapered to 10 mg/day or less by Week 24 will be 
declared treatment failures. No corticosteroid rescue treatment will be allowed from 
Week 76-104 because the treatment effect may confound the interpretation of study 
results and the subject will be declared a treatment failure. Outside of this window, there 
will be a limited number of corticosteroid rescue treatments allowed if clinically 
indicated for non-renal SLE-related disease activity as outlined below.
•
Up to 2 corticosteroid rescue treatments will be allowed.
•
At least a 3-month interval is required between each treatment. 
•
Each treatment course should be no longer than 14 days in duration with the steroid 
dose returning to ≤ 10 mg/day by Day 14.  
•
Up to a total of 20 mg/day (prednisone or prednisone equivalent) is permitted.
•
There can be no concurrent worsening of renal disease.
Any subjects who require corticosteroid rescue treatment exceeding the above criteria or 
who are unable to return to a dose ≤ 10 mg/day will be considered treatment failures.


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Additionally, any subjects who have not returned to ≤ 10 mg/day by Week 76 will be 
considered treatment failures.
5.5.6.2.
Systemic Corticosteroids for Renal SLE-related Disease Activity
All subjects should be receiving a corticosteroid dose of 10 mg/day or less (can be 0 mg) 
by Week 24. Those who cannot be tapered to 10 mg/day or less by Week 24 will be 
declared treatment failures.
The use of corticosteroids at a dose of > 10 mg/day for treatment of a renal flare (with or 
without concurrent non-renal SLE disease activity) is prohibited after Week 24 and the 
subject would be considered a treatment failure.
5.5.6.3.
Systemic Corticosteroids for Non-SLE Disease Activity
No corticosteroid rescue treatment will be allowed from Week 76-104 because the 
treatment effect may confound the interpretation of study results and the subject will be 
declared a treatment failure. Outside of this window, there will be a limited number of 
corticosteroid treatments allowed if clinically indicated for the treatment of non-SLE 
disease activity (eg, allergic reaction). 
•
Up to 3 corticosteroid treatments will be allowed.
•
At least a 3 month interval is required between each treatment. 
•
The maximum dose should be no longer than 3 days in duration with the steroid dose 
returning to ≤ 10 mg/day by Day 14.
•
Up to a total of 60 mg/day (prednisone or prednisone equivalent) will be permitted.
Any subjects who require corticosteroid rescue treatment exceeding the above criteria or 
who are unable to return to a dose no more than ≤ 10 mg/day will be considered 
treatment failures. Additionally, any subjects who have not returned to ≤ 10 mg/day by 
Week 76 will be considered treatment failures.
5.5.6.4.
Intraarticular Injections
Intraarticular injections will be allowed as clinically indicated. However, no intraarticular 
corticosteroid injections should be given from Week 96-104 although this use would not 
constitute a treatment failure.
5.5.6.5.
Inhaled and Topical Corticosteroids
Inhaled and topical steroids are allowed throughout the course of the study.
5.6.
Prohibited Medications and Non-Drug Therapies During the 
Double-Blind Treatment Period
Subjects who start the prohibited medications or therapies listed below at any time during 
the double-blind treatment period will be considered treatment failures for analysis (ie, 
non-responders). These subjects must discontinue treatment with study agent and should 


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return for scheduled visits through Week 104. The following medications and therapies 
are prohibited at any time during the double-blind treatment period:
•
New immunosuppressant agents (other than described in Section 5.5.1 as part of the
induction and maintenance regimens).
•
Corticosteroid use outside of the limits described in Section 5.5.6.
•
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. 
•
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).
•
Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra]).
•
Intravenous immunoglobulin (IVIG).   
•
Plasmapheresis.
Whenever a subject has worsening nephritis or SLE, a complete disease activity 
assessment (SELENA SLEDAI, SLE Flare Index, and PGA) and laboratory assessments 
(hematology, chemistry, urinalysis, urinary microscopy, spot urine, anti-dsDNA, and 
complement) should be performed to document disease activity prior to instituting 
treatment that results in treatment failure designation as defined in Section 5.5 and 
Section 5.6.
5.6.1.
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. These 
subjects should continue to return for the scheduled visits through Week 104.
5.7.
Prohibited Medications During Open-Label Extension
During the open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited 
medications during this phase are live vaccines, biological therapies, and other 
investigational agents.
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 
(Appendix 6) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject.


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Refer to the Study Calendar (Table 6-1, Table 6-2, and Table 6-3), Study Procedures 
Manual, and Central Laboratory Manual for additional information.
6.1.
Screening Procedures (Day -35 to Day 0)
The following assessments are required at screening:
•
Demographics.
•
Medical history.
•
Therapy History.
•
Complete physical examination (including vital signs).
•
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 5 – 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).

Autoantibodies (ANA and anti-dsDNA).

Biological markers (Complement C3, C4).

Serum immunoglobulin isotypes (IgG, IgM, IgA).

HIV antibody testing, serologic investigations for Hepatitis B (HB) infection 
(HBsAg, anti-HBc, and anti-HBs, HBV DNA, NOTE: if anti-HBc result is 
reactive, the sample drawn for HBV DNA will be tested for viral DNA; 
otherwise, the sample will be destroyed), and Hepatitis C antibody testing ± 
confirmatory HCV RNA-PCR testing. (NOTE: see Section 4.2, subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing). 

PT/PTT
•
Urine sample for:

Urinary protein: urinary creatinine ratio.

Locally performed urinary microscopy and routine urinalysis. Note: Urine 
collection may be postponed up to 14 days at the investigators discretion if 
menstrual bleeding or a genitourinary tract infection is present at the time of 
urinalysis.


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•
Renal biopsy result (should be from a renal biopsy obtained in the 6 months prior to 
the screening visit or during the screening period. The local biopsy reports will be 
used for the purposes of randomization. A tissue sample from the renal biopsy used to 
qualify the subject for randomization needs to be sent to a central reading center after 
Day 0 (baseline). 
•
Pre-flare GFR and/or serum creatinine – most recent GFR and/or serum creatinine 
values obtained prior to screening and before first manifestations of the current renal 
flare.
•
Suicidality assessment by using the Columbia-Suicide Severity Rating Scale (C-
SSRS) Screening assessment form (see Section 7.6 and Appendix 8).
•
For subjects in China, SAEs will be collected from the time a subject consents to 
participate in the study (see Section 7.2).
•
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 Response 
System (IWRS). Subjects will be randomized in a 1:1 ratio to treatment with either 10
mg/kg belimumab plus standard of care or placebo plus standard of care. Randomization 
of all eligible subjects will be stratified by their induction regimen (HDCS plus CYC vs 
HDCS plus MMF) and race (black race vs other). There is race stratification in this study 
because race may be an important factor related to outcomes in patients with lupus 
nephritis. Race should be self-designated.
6.3.
Double-Blind Treatment Period
Subjects will be evaluated during the scheduled study visits as outlined in the Study 
Calendar (Table 6-1 and Table 6-2). Time windows are provided for each study visit to 
allow flexibility in site and subject scheduling. All study visits should occur within the 
visit window of the scheduled study visit.
At baseline (Day 0), the subject will be randomized and receive the first dose of study 
agent. 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) through Week 104. All efforts should be made to retain subjects on schedule, based 
on the date of their Day 0 dose. During the double-blind treatment period, study agent is 
administered at every scheduled visit through Week 100. The final efficacy evaluation for 
the double-blind portion of the study will occur at Week 104. 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.  
Subjects who complete the double-blind period through Week 104 will be given the 
option to receive belimumab in the 6-month open-label extension.  


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•
Subjects who receive treatment with study agent through Week 100 and complete 
Week 104 assessments, but do not enter the open-label extension, will not have study 
agent administered at Week 104. Assessments should be completed for the Week 
104/Exit visit, and the subject should return in 4 weeks for the Follow-up visit.
•
Subjects who wish to continue in the open-label extension, will have study agent
administered at the Week 104 visit after all Week 104 assessments are performed 
(refer to Section 6.4 below). Subjects should remain under clinical supervision for 
3 hours after completion of the first 2 infusions.  
All subjects who discontinue treatment with study agent during the double-blind period
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104. 
In the event that a subject withdraws consent during the double-blind treatment period, an 
attempt should be made to obtain consent to collect follow-up safety data (at an exit visit 
approximately 4 weeks after the last dose of study agent as well as a follow-up visit 
approximately 8 weeks after the last dose of study agent) and to obtain survival status at 
Week 104. Any subject that withdraws consent for use and disclosure of research-related 
health information will be considered withdrawn from the study and will not be followed 
for mortality. 
Note that a urine pregnancy test is required at the 8-week follow-up visit for all women 
with an intact uterus, unless exempted from pregnancy testing (see Section 6.1). Women 
of child-bearing potential must be reminded of the requirement to report to the study 
investigator any pregnancy that occurs through 16 weeks following the last dose of study 
agent (see Section 7.7).


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Table 6-1
Study Calendar - Double-Blind Treatment Period (Screening to Week 52)
Screenin
g
Baseline
Double-Blind Treatment Period
Study Day
-35 days
Day 0
Day 3
14 ± 3 days
28 ± 3 days
56 ± 7 days
84 ± 7 days
112 ±7 days
140 ± 7 days
168 ± 7 days
196 ± 7 days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
Wk 
-5
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
WK 
20
Wk 
24
Wk 
24 
+ 
3d
Wk 
28
Wk 
32
Wk 
36
WK
40
Wk 
44
Wk 
48
Wk 
48 
+ 
3d
Wk 
52
Wk 
52 
+ 
3d
Written Informed Consent
x
Demographics (including race)
x
Medical History
x
SLE History
x
Therapy History
x
Eligibility Criteria
x
Biopsy ReportA
x
Pre-flare GFRB
x
Biopsy sample shipment for 
central evaluation 
After Day 
0
Clinical Assessments
SELENA SLEDAI, SLE Flare 
Index and PGA
x
x
x
x
x
SLICC Damage
x
x
x
C-SSRS Screening/Baseline 
x
C-SSRS Since Last VisitC
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Record Concurrent Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete Physical Exam
x
Symptom-driven Physical 
Exam
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
WeightD
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signsP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG
x
Record/Assess Adverse 
EventsE
xR
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology and chemistry 
(non-fasting)F
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum CreatinineG
x
x
x
x


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Screenin
g
Baseline
Double-Blind Treatment Period
Study Day
-35 days
Day 0
Day 3
14 ± 3 days
28 ± 3 days
56 ± 7 days
84 ± 7 days
112 ±7 days
140 ± 7 days
168 ± 7 days
196 ± 7 days
224 ± 7days
252 ± 7days
280 ± 7days
308 ± 7days
336 ± 7days
364 ± 7days
Study Week
Wk 
-5
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
WK 
20
Wk 
24
Wk 
24 
+ 
3d
Wk 
28
Wk 
32
Wk 
36
WK
40
Wk 
44
Wk 
48
Wk 
48 
+ 
3d
Wk 
52
Wk 
52 
+ 
3d
UrinalysisH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinary MicroscopyH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Spot urine 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
24-hour UrineG
X
x
x
x
Urine Biomarkers
x
x
x
x
BLyS protein (baseline only)
x
Pregnancy TestI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ANA
x
x
x
x
Complement (C3/C4), anti-
dsDNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
aCL (IgA, IgG, IgM isotypes) 
x
x
x
Anti-Sm, anti-C1qJ
x
x
x
Serum IgG
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum IgA & IgM
x
x
x
x
x
PT/PTT
x
x
x
x
x
HIV, Hep B and Hep C 
serology, and HBV DNAQ
x
Pharmacokinetic SamplingK
x
x
x
x
x
x
x
x
Immunogenicity (anti-
belimumab antibody)
x
x
x
x
Peripheral B lymphocytes
x
x
x
x
Pharmacogenetics Sampling 
(consenting subjects only)L
x
Protocol Treatments
Study Agent Administration
(Belimumab/Placebo)M,N
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Induction/Maintenance 
TherapyO
Throughout the Study
ABiopsy report indicating proliferative lupus nephritis. Should be from a renal biopsy obtained in the 6 months prior to the screening visit or during the screening period. A tissue sample from 
the renal biopsy used to qualify the subject for randomization needs to be sent to a central reading center after Day 0 (baseline).


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BMost recent GFR prior to the current renal flare.
C The Columbia-Suicidality Severity Rating Scale (C-SSRS) Since Last Visit form (see Appendix 9) will be used at Day 0 and all subsequent visits. The C-SSRS Baseline/Screening form 
(see Appendix 8) is only used at Screening. 
DThe weight at the current visit should be used to calculate dose.
EFor subjects who discontinue treatment with study agent during the double-blind period (for reasons other than withdrawal of consent), all adverse events will be collected through 8 weeks 
following the administration of the last dose of study agent. After this time, SAEs, regardless of relationship to study drug, will be collected through Week 104.
F Refer to Appendix 5 for a listing of laboratory assessments to be completed. 
GTwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  baseline, Weeks 24, 48 and 52.  Serum creatinine for these visits will be collected at 
the initial visit which will take place within 3 days prior to or on the day of the scheduled visit, and then 3 days after the initial visit. For urinary sediment assessments, both menstrual 
cycles and genitourinary tract infections may be confounders.  Urine collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract 
infection is present at time of urinalysis or anytime during the 24 hour urine collection.
HRoutine urinalysis and urinary microscopy will be performed locally.
IFor women of child-bearing potential, serum pregnancy test is required at screening. At subsequent visits, a urine pregnancy test is required. Results of the pregnancy test must be 
available prior to dosing.
JSamples will only be analyzed in subjects with positive results at baseline.
KFor PK sampling times, see Section 6.7.1.
LPharmacogenetic sampling informed consent must be obtained prior to any blood being taken for PGx research. Sample should be drawn prior to dosing.
MSubjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to follow the study calendar and have all 
assessments completed through Week 104 (with the exception of study agent administration).
N 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.
OInduction therapy may begin before Screening but should be initiated within 60 days prior to or on Day 0 (baseline).
P Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs are to be performed prior to dosing.
QNote: if anti-HBc result is reactive, the sample drawn for HBV DNA will be tested for viral DNA; otherwise, the sample will be destroyed. Subjects in China with positive hepatitis C 
screening results will be excluded without confirmatory hepatitis C RNA-PCR testing.
RNote: For subjects in China, SAEs will be collected from the time a subject consents to participate in the study (see Section 7.2).


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Table 6-2
Study Calendar - Double-Blind Treatment Period (Week 56 to 104)
Double-Blind Treatment Period
Study Day
392 ± 7days
420 ± 7days
448 ± 7days
476 ± 7days
504 ± 7days
532 ± 7days
560 ± 7days
588 ± 7days
616 ± 7days
644 ± 7days
672 ± 7days
700 ± 7days
Day 728/ Exit A
± 7days
(4  weeks after 
last dose)
Follow-up visitB
(8 week after 
last dose)
+7 days
Unscheduled 
VisitC
Study Week
Wk 
56
W
k6
0
Wk
64
Wk 
68
Wk 
72
Wk
76
Wk 
76 + 
3 d
Wk
80
Wk
84
Wk
88
Wk
92
Wk 
96
Wk 
100
Wk 
100
+ 3 d
Wk 
104 
Wk 
104 
+ 3 d
Clinical Assessments
SELENA SLEDAI, SLE Flare Index 
and  PGA
x
x
x
x
x
SLICC Damage
x
x
C-SSRS Since Last Visit
x
x
x
x
x
x
x
x
x
x
x
x
x
Record Concurrent Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom-driven Physical 
Examination
x
x
x
x
x
x
x
x
x
x
x
x
x
WeightD
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signsN
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Record/Assess Adverse EventsE
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Survival AssessmentF
x
Laboratory Assessments
Hematology and chemistry (non-
fasting)G
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum CreatinineH
x
x
x
UrinalysisI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinary MicroscopyI
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Spot urine 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
24-hour UrineH
x
x
x
Urine Biomarkers
x
Pregnancy TestJ
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complement (C3/C4), anti-dsDNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ANA, aCL (IgA, IgG, IgM isotypes)
x
x
Anti-Sm, anti-C1qK
x
x
Serum IgG
x
x
x
x
x
Serum IgA & IgM
x
x
PT/PTT
x
x
Pharmacokinetic SamplingL
x
x


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Double-Blind Treatment Period
Study Day
392 ± 7days
420 ± 7days
448 ± 7days
476 ± 7days
504 ± 7days
532 ± 7days
560 ± 7days
588 ± 7days
616 ± 7days
644 ± 7days
672 ± 7days
700 ± 7days
Day 728/ Exit A
± 7days
(4  weeks after 
last dose)
Follow-up visitB
(8 week after 
last dose)
+7 days
Unscheduled 
VisitC
Study Week
Wk 
56
W
k6
0
Wk
64
Wk 
68
Wk 
72
Wk
76
Wk 
76 + 
3 d
Wk
80
Wk
84
Wk
88
Wk
92
Wk 
96
Wk 
100
Wk 
100
+ 3 d
Wk 
104 
Wk 
104 
+ 3 d
Immunogenicity (anti-belimumab 
antibody)
x
x
x
Peripheral B lymphocytes
x
x
Protocol Treatments
Study Agent Administration
(Belimumab/Placebo)M
x
x
x
x
x
x
x
x
x
x
x
x
If entering 
extension
Induction/Maintenance Therapy
Throughout the Study
AFor subjects completing 100 weeks of treatment with study agent and continuing into the 6-month open-label extension, the Week 104 visit will also serve as the Day 0 visit of the 6-month 
open-label extension. Only subjects who continue in the open-label extension study will have study agent (belimumab) administered at the Week 104 visit after the completion of Week 104 
assessments. Subjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to follow the study calendar 
and have all assessments perfomed through Week 104 (with the exception of study agent administration).  For subjects who withdrew consent and agreed to have follow-up safety data 
collected or subjects who are not continuing into the open label extension, the Week 104/Exit visit will occur approximately 4 weeks after the last dose of study agent.
BThe 8-week follow-up visit is not required for subjects entering the open-label extension.
CAdverse events and concurrent medications should be assessed at each unscheduled visit.  When a subject has worsening nephritis or SLE, a complete disease activity assessment 
(SELENA SLEDAI, SLE Flare Index, and PGA), and laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, and complement) should be performed to document disease 
activity worsening (eg, renal flare/relapse) prior to instituting treatment that results in treatment failure designation as defined in Section 5.5 and Section 5.6. Other assessments should be 
performed as clinically indicated.
DThe weight at the current visit should be used to calculate dose.
EFor subjects who discontinue treatment with study agent during the double-blind period (for reasons other than withdrawal of consent), all adverse events will be collected through 8 weeks 
following the administration of the last dose of study agent. After this time, SAEs, regardless of relationship to study drug, will be collected through Week 104.
FIn the event that a subject withdraws consent from the study, an attempt should be made at the time of consent withdrawal to obtain consent to collect survival status at Week 104.
G Refer to Appendix 5 for a listing of laboratory assessments to be completed. 
HTwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  Weeks 76, 100 and 104. The serum creatinine for these visits will be collected on the 
day of the initial visit and then 3 days after the initial visit. For urinary sediment assessments, both menstrual cycles and genitourinary tract infections may be confounders.  Urine collection 
may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during the 24 hour urine collection.
I Routine urinalysis and urinary microscopy will be performed locally.
JFor women of child-bearing potential, a urine pregnancy test is required. Results of the urine pregnancy test must be available prior to dosing.
KSamples will only be analyzed in subjects with positive results at baseline.
LFor PK sampling times, see Section 6.7.1.
MSubjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to follow the study calendar and have all 
assessments completed through Week 104 (with the exception of study agent administration).
N Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs are to be performed prior to dosing.


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6.4.
Open-Label Extension
Subjects who receive treatment with study agent through Week 100 and complete the 
Week 104 assessments in the double-blind period may enter into a 6-month open-label 
extension. The Week 104 visit of the double-blind period will serve as the Day 0 visit for 
subjects entering the 6-month open-label extension. In the open-label extension, all 
subjects will receive 10 mg/kg belimumab approximately every 28 days until Week 24,
with a final evaluation at Week 28 (4 weeks after the last dose). The first dose on the 
open-label extension will be given at the Week 104 visit of the double-blind period after 
the completion of Week 104 assessments. Subjects participating in the open-label 
extension will continue to be monitored for efficacy and safety as per the study calendar 
(see Table 6-3). 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 who withdraw early from the open-label extension 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. 
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 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 if 
permissible according to local regulations. 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.
Note that a urine pregnancy test is required at the 8-week follow-up visit for all women 
with an intact uterus, unless exempted from pregnancy testing (see Section 6.1). 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 7.7).


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Table 6-3
Study Calendar- 6-Month Open-Label Extension
Open Label Extension
Study Day
Day 0A
Day 28
± 7 days
Day 56
± 7 days
Day 84
± 7 days
Day 112
± 7 days
Day 140
± 7 days
Day 168
± 7 days
Day 196/ExitB
± 7days 
(4 weeks 
after last dose) 
Follow-up visitC
(8 weeks after 
last dose)
+7 days
Study Week
Wk 4
Wk 
8
Wk 12
Wk 16
WK 20
Wk 24
Wk 
28
Clinical Assessments
See Week 104 Visit 
in Double-Blind Treatment Period
SELENA SLEDAI, SLE Flare Index and PGA
x
SLICC Damage
x
Record Concurrent Medications
x
x
x
x
x
x
x
x
Symptom-driven Physical Examination
x
WeightD
x
x
x
x
x
x
x
Vital signsL
x
x
x
x
x
x
x
x
Record/Assess Adverse Events
x
x
x
x
x
x
x
x
Laboratory Assessments 
Hematology and chemistry (non-fasting)E
x
x
x
x
UrinalysisF
x
x
x
x
Urinary MicroscopyF
x
x
x
x
Spot Urine
x
x
x
x
Pregnancy TestG
x
x
x
x
x
x
x
x
C3/C4, anti-dsDNA
x
x
Autoantibodies (aCL, ANA, anti-Sm, anti-C1q)H
x
x
Serum IgG
x
x
x
Serum IgA & IgM
x
x
Pharmacokinetic samplingI
x
Immunogenicity (anti-belimumab antibody)
x
x
Peripheral B lymphocytes
x
x
Protocol Treatments
Study Agent Administration (belimumab)K
x
x
x
x
x
x
x
Maintenance TherapyJ
Throughout the Study


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ADay 0 of the open-label extension is the Week 104 study visit of the double-blind treatment period, and represents the first belimumab administration for those subjects continuing on the 
6 month open-label extension.  
B For subjects who discontinue from the study, an Exit visit should be completed 4 weeks after the last dose of study agent.
C For subjects who discontinue from the study, a Follow-up visit should be completed 8 weeks after the last dose of study agent. The 8-week follow up visit is not required for subjects 
entering the separate continuation protocol.
D The weight at the current visit should be used to calculate dose.
ERefer to Appendix 5 for a listing of laboratory assessments to be completed. 
FRoutine urinalysis and urinary microscopy will be performed locally.
GFor women of child-bearing potential, a urine pregnancy test is required. Results of the urine pregnancy test must be available prior to dosing.
HSamples will only be analyzed for anti-Sm and anti-C1q in subjects with positive results at baseline.
IFor PK sampling times, see Section 6.7.1.
J AZA/MMF continued at the discretion of the investigator.
K 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.
L Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs are to be performed prior to dosing.


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6.5.
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 lupus nephritis symptoms, AE reporting, or follow-up to a previously 
reported AE.
When a subject has worsening nephritis or SLE, a complete disease activity assessment 
(SELENA SLEDAI, SLE Flare Index and PGA), and laboratory assessments 
(hematology, chemistry, urinalysis, urinary microscopy, spot urine, anti-dsDNA, and 
complement) should be performed to document disease activity worsening (eg, renal 
flare/relapse) prior to instituting treatment that results in treatment failure designation as 
defined in Section 5.5 and Section 5.6.
Refer to the Study Calendar (Table 6-2) for a list of procedures required at this visit. 
Other assessments should be performed as clinically indicated. 
6.6.
Renal Biopsies
The local biopsy reports will be used for the purposes of randomization. A tissue sample 
from the renal biopsy used to qualify the subject for randomization needs to be sent to a 
central reading center after Day 0 (baseline). Tissue from any renal biopsies performed as 
part of routine care anytime after baseline (Day 0) will also be collected, where possible, 
for a similar central reading. 
6.7.
Laboratory Tests
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): aCL (IgM, IgG, IgA isotypes), ANA, anti-Sm, anti-C1q, 
serum immunoglobulin isotypes IgM/IgA, and the results from the biological markers 
measured by FACS analysis listed below.
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis):
•
Peripheral 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 cells, and CD20-/138+ plasma cells.
For the renal function assessments at all study visits, the simplified MDRD formula 
(below) will be used to estimate GFR (Levey et al, 2006):


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eGFR = 175 x serum creatinine-1.154x Age-0.203 x [1.212 if Black] x [0.742 if Female]
The serum creatinine concentration is expressed in mg/dL.
In addition, at Baseline (Day 0), Week 24, 48, 52, 76, 100, and 104, the glomerular 
filtration rate (GFR) will be calculated based on creatinine clearance determined from the 
mean creatinine value of 2 contiguous 24 hour urine collections and 2 serum creatinine 
measurements (first serum creatinine collected at initial visit and the second sample taken 
3 days later at the follow-up visit). Subjects will be provided with the materials for 
collecting the two 24 hour urine collections beginning the next morning following their 
initial clinic visit. On the third day following the initial visit, subjects will return to the 
clinic for the second serum creatinine sample.  
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 sample (Ginsberg et al, 1983; Ruggenenti et al, 1998; KDOQI Clinical Practice 
Guidelines for Chronic Kidney Disease 2002; Price et al, 2005). Given this information, 
spot urinary protein: urinary creatinine ratio will be used for determining proteinuria in 
this study for renal response assessments and the SELENA SLEDAI (Appendix 3) 
disease activity indices.
For the urinary sediment assessments, both menstrual cycles and genitourinary tract 
infections may be confounders. The urine collection may be postponed up to 14 days at 
the investigators discretion if menstrual bleeding or a genitourinary tract infection is 
present at anytime during the 24 hour urine collection.
An exploratory analysis of urinary biomarkers related to lupus nephritis may be 
performed at baseline (pre-dose) and at selected timepoints thereafter. Data collection and 
analysis will be performed independently of the main study and will form the basis of a 
separate report. The biomarkers include, but are not limited to, MCP-1, hepcidin, NGAL, 
LFABP, Angiogenin, Angiopoietin 2, Angiostatin, IL-6r, Osteopontin, PAI-1, PF4, 
RAGE, RANK, Sgp130, Siglec 5, Siglec 9, Tgf-beta1, TIM1, TIMP-2, TLSP, TNFR-II, 
Trem1, VCAM-1, Vegf-C, and VEGF-R3.
Additional instructions regarding collection procedures are provided in the Study 
Procedures Manual and Central Laboratory Manual.
6.7.1.
Pharmacokinetics
All randomized subjects will be sampled for serum belimumab levels. A blood sample for 
pharmacokinetic analysis will be drawn according to the time schedule below.


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Table 6-4
PK Visit Days and Sample Times
Day (Week)
Time (Related to Dosing of Study Agent)
Day 0
Before the start of infusion
Day 3
Anytime during visit
Day 14 (Week 2)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 28 (Week 4)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 56 (Week 8)
Prior to dosing
Day 168 (Week 24)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 171 (Week 24 + 3 days)
Anytime during visit
Day 364 (Week 52)
Prior to dosing
Day 728/Exit (Week 104)
Anytime during visit (or prior to dosing if going into the open-label 
treatment period of the study)
8-week follow-up
Any time during visit
Open Label 8-week follow-up
Any time during visit 
On days study agent is administered and blood samples for pharmacokinetic analysis are 
obtained after infusion, blood samples for pharmacokinetic analysis should not be taken 
from the same arm used for the administration of study agent. Samples may be obtained 
by venipuncture.  
If a subject withdraws from treatment with study agent, a blood sample for 
pharmacokinetic analysis will be drawn any time during visit at 4 weeks and 8 weeks
after the last dose of study agent is administered. If a subject withdraws consent from the 
study, an attempt should be made to obtain a blood sample for pharmacokinetic analysis 
at the follow-up visits approximately 4 and 8 weeks after the last dose of study agent.
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.
6.7.2.
Liver Chemistry Stopping and Follow-up 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 [James, 2009; Le Gal, 2005].
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


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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).
6.7.2.1.
Required Actions and Follow up Assessments following ANY Liver 
Stopping Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the 
event also meets the criteria for an SAE (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)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 10).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return 
to within baseline

A specialist or hepatology consultation is recommended


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For All other criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up assessments within 24-72 hours

Monitor subjects weekly until liver chemistries resolve, stabilize or return to 
within baseline
FOLLOW UP ASSESSMENTS

Viral hepatitis serology (includes: Hepatitis A IgM antibody; Hepatitis B surface 
antigen and Hepatitis B Core Antibody (IgM) and HBV DNA (see Section 
6.7.5); 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)

Blood sample for pharmacokinetic (PK) analysis, obtained within approximately 
one to two weeks after last dose (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 SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of 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.


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6.7.3.
Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If 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
6.7.3.1.
Required Actions and Follow Up Assessments for Increased 
Monitoring with Continued Therapy

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 for Required Actions and Follow up Assessments following 
ANY Liver Stopping Event

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.
6.7.4.
Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than drug induced liver injury [DILI]) of the liver event 
(e.g. biliary obstruction, pancreatic events, hypotension,
acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity.
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, or possible study treatment-induced liver injury) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.


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
If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

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.
6.7.5.
Additional Hepatitis B Monitoring
Safety assessment for Hepatitis B during the trial will be as follows:
•
ALT and/or AST elevations of greater than 2.5 x ULN will require:
•
Sites to review laboratory results for anti-HBc from Screening visit:

If Screening anti-HBc result was reactive, then obtain HBV DNA.

If HBV DNA returns reactive, withdraw subject from further treatment and 
enter follow up visit schedule.  Investigator will determine the extent of 
required attention for proper follow up of potential hepatitis B re-activation.

If anti-HBc result from Screening visit was negative, then repeating hepatitis 
B testing is optional per investigator upon investigating for other causes.
•
Refer to the SPM for guidance on documenting the suspected reason for ALT and/or 
AST elevations of greater than 2.5 x ULN.
6.7.6.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at baseline (Day 0), and at any 
time on Week 8, Week 24, Week 52, Week 76 and Week 104 in the double-blind portion 
of the study. During the open-label extension, a sample will be collected at Week 24. 
Additionally, a sample will be collected at the 8-week follow-up visit. 


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6.8.
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 
treatment/study after receiving at least 1 dose of study agent will not be replaced. 
Subjects should be withdrawn from treatment with study agent for any of the following 
reasons:
•
Missing 3 or more consecutive doses of study agent
•
Prohibited concurrent medication or prohibited dose of concurrent medication 
(see Section 5.5 and Section 5.6).
•
Prohibited therapy.
•
Unacceptable toxicity (see Section 5.4).
•
Pregnancy.
•
Withdrawal of consent (including use and disclosure of research-related health 
information).
•
Subjects positive for Anti-HBc at Screening who develop elevated LFTs >2.5 x ULN 
during the study followed by an HBV DNA test that shows detectable viral load (see 
Section 6.7.5).
All subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104.
In the event that a subject withdraws consent during the double-blind period, an attempt 
should be made to obtain consent to collect follow-up safety data (at an exit visit 
approximately 4 weeks after the last dose of study agent as well as a follow-up visit 
approximately 8 weeks after the last dose of study agent) and to obtain survival status at 
Week 104. Any subject that withdraws consent for use and disclosure of research-related 
health information will be considered withdrawn from the study and will not be followed 
for mortality.
All subjects who discontinue treatment during the open-label extension should return for 
an 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. The follow-up visit is not required for subjects entering 
the separate continuation protocol.
6.9.
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 qualified designee, independent of the study (person responsible for 


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receiving and dispensing study agent). Except for a limited number of safety oversight 
personnel, all 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 (see Section 6.7). 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 
information is important for the safety of 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 (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction


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
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 (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
SERIOUS ADVERSE EVENT: A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation
NOTE:  In general, hospitalisation 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 hospitalisation are AEs.  
If a complication prolongs hospitalisation or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 


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vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific 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 hospitalisation but may jeopardise 
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 hospitalisation, 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. 
For subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent), all adverse events will be collected 
through 8 weeks following the administration of the last dose of study agent. After this 
time, all SAEs, regardless of relationship to study drug, will be collected through Week 
104.
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 event as described in 
the Study Procedures Manual. 


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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. 
For subjects in China, prior to study drug administration, SAE(s) regardless of 
relationship to study participation (eg, protocol mandated procedures, invasive tests) or 
study treatment will be reported from the time a subject consents to participate in the 
study.
SAEs that occur off study, after the follow-up period, that are assessed by the investigator 
as being definitely, possibly or probably related to study agent must be reported to the 
Sponsor as outlined in the Study Procedures Manual.
7.3.
Other Events Requiring Rapid Reporting (Protocol Specified 
Events)
Protocol Specified Events (PSEs) are additional events that must be reported in an 
expedited manner. A PSE may or may not be an SAE. PSEs are considered SAEs if they 
meet 1 or more of the criteria for an SAE (see Section 7.1). PSEs are recorded on the PSE 
page of the eCRF within 24 hours of site personnel becoming aware of the event. 
IgG < 250 mg/dL (Grade 4) is a protocol specified event for this protocol. 
7.4.
Laboratory Abnormalities as Adverse Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator 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). In addition, an IgG abnormality < 250 
mg/dL (Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 
mg/dl should also be reported as an SAE if it meets one or more of the SAE criteria in 
Section 7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be 
graded as mild, moderate, or severe as specified in Section 7.8.
7.5.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 


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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.
7.6.
Suicidality Assessment
Some autoimmune diseases have an increased risk of suicidal behaviour and/or ideation
(Bachen et al, 2009; Timonen et al, 2003; Stenager et al, 1992). In order to objectively 
assess suicidality in belimumab clinical programs the C-SSRS (Appendix 8 and
Appendix 9) 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 the 
double-blind portion of this study will be assessed for suicidality at every visit. 
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 question 3, 4 or 5 on the C-SSRS prompts the completion of the Possible 
Suicidality Related History Questionnaire (PSRHQ, only the first time this condition is 
met; refer to Appendix 11 for the PSRHQ) eCRF and a Possible Suicidality Related 
Questionnaire (PSRQ) eCRF (at all times this condition is met; refer to Appendix 12 for 
the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed 
during the blinded portion of this study using C-SSRS (refer to Appendix 8 and Appendix 
9 for C-SSRS).  The C-SSRS is a brief measure which is designed to assess severity and 
change of suicidality by integrating both behaviour 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 the study. 
Although assessment of suicidality using the C-SSRS will take place only during the 
blinded portion of the study, investigators are reminded of the importance to clinically 


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assess for suicidality at every visit given that SLE patients are at increased risk of suicidal 
behavior and/or ideation.
7.6.1.
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 behaviour 
or a “yes” response to suicidal ideation questions 3, 4 or 5 on the C-SSRS. Refer to 
Appendix 12 for the PSRQ. If the adverse event meets the definition of an SAE, which 
includes a “yes” answer to any suicidal behaviour 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. 
7.7.
Reporting a Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor within 24 hours of learning of its occurrence. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child.  Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the Sponsor.
7.8.
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 7) 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 (i.e., 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 Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.  The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
7.9.
Follow-up of Adverse Events
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. 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 For subjects in China, 
prior to study drug administration, SAE(s) regardless of relationship to study 


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participation (eg, protocol mandated procedures, invasive tests) or study treatment will be 
reported from the time a subject consents to participate in the study. For subjects who 
discontinue treatment with study agent during the double-blind period (for reasons other 
than withdrawal of consent), all SAEs, regardless of relationship to study drug, will be 
collected through Week 104.
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.
PSEs (see Section 7.3) that occur after Screening visit through 8 weeks after the date of 
last administration of study agent are reported and followed as described above for 
AEs/SAEs.
7.10.
Disease Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs
The following disease related events (DREs) (preferred terms; MedDRA v. 14.0) are 
common in subjects with SLE and can be serious/life-threatening:
Butterfly rash
Cutaneous lupus erythematosus
Glomerulonephritis membranoproliferative
Glomerulonephritis membranous
Glomerulonephritis proliferative
Lupus encephalitis
Lupus endocarditis
Lupus enteritis
Lupus hepatitis
Lupus myocarditis
Lupus nephritis
Lupus pancreatitis
Lupus pneumonitis
Lupus vasculitis
Nephritic syndrome
Nephritis
Neuropsychiatric lupus
Pericarditis lupus
Peritonitis lupus
SLE arthritis
Systemic lupus erythematosus
Systemic lupus erythematosus rash
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to the 
Sponsor (even though the event may meet the definition of a serious adverse event).  
These events will be recorded on the DRE page in the subject’s eCRF. However, if one 
or both of the following conditions apply, then the event should be reported as an SAE 
using the standard process:
•
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual subject, or
•
The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the study agent


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If either of the above conditions is met then record the DRE on the SAE page rather 
than the DRE page and report promptly (i.e., expedited reporting, see Section 7.2) to 
the Sponsor.
7.11.
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 (e.g., 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.
8.
ENDPOINTS AND STATISTICAL ANALYSIS
8.1.
General Statistical Considerations
Unless otherwise specified, all analyses will be performed on the intention to treat (ITT)
population defined as all subjects who are randomized and receive 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 the primary analysis after data through the Week 104
visit for all subjects have been collected, verified and validated. All subjects and study 
site personnel will remain blinded until the final database lock, which will occur after 
data have been collected, verified and validated for all subjects completing the 8 week 
follow-up after the open-label extension.
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. With this 
procedure, the primary and 4 major secondary efficacy endpoints will be evaluated for 
statistical significance based on a pre-specified sequence for interpretation: (1) primary 
efficacy renal response (PERR) at Week 104, (2) complete renal response (CRR) at Week 
104, (3) PERR at Week 52, (4) time to death or renal-related event, and (5) ordinal renal 
response (ORR) at Week 104. 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 


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endpoints in the sequence cannot be deemed statistically significant, although nominal p-
values may be reported and considered descriptive.
Analyses of other efficacy endpoints other than the major secondary efficacy endpoints 
will not be subject to any multiple testing procedure. All statistical tests will be 2-sided 
and performed at an overall significance level of 0.05.
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.
8.2.
Randomization Procedure and Assignment to Treatment 
Groups
This is a Phase 3, multi-center, multi-national, 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 baseline 
(Day 0) visit to be randomized in a 1:1 ratio (via an Interactive Web Response System) to 
1 of 2 treatment groups (10 mg/kg belimumab plus standard of care or placebo control 
plus standard of care. The randomization of all eligible subjects will be stratified by their 
induction regimen (HDCS plus CYC vs HDCS plus MMF) and race (black race vs other).
8.3.
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this Phase 3 program on an ongoing basis until the data are locked and analyzed
through Week 104 (after which monitoring may be assumed by an internal GSK/HGS 
committee). The IDMC will include physicians with expertise in infectious disease, 
rheumatology or nephrology and a statistician, none of whom are affiliated with the 
sponsor. The first review will occur 6 months after the first subject is randomized or after 
the first 20 subjects are randomized and have completed a Week 8 visit, whichever is 
sooner. Thereafter, the IDMC will review the data approximately every 6 months. At all 
times the sites and sponsor will remain blinded to treatment allocation. 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 and 
open-label extension portions of the study. 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 to the IDMC within 15 calendar days. In addition, the IDMC will receive 
information on all serious infections and all opportunistic infections, irrespective of 
relationship to study agent, within 15 calendar days.


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8.4.
Sample Size Rationale
The sample size was calculated using the ORR as the primary endpoint and assuming the 
endpoint proportions of complete, partial, and no renal response will be 25%, 25%, and 
50%, respectively, for subjects on placebo plus standard of care (Appel et al, 2009; 
Sinclair et al, 2007; Dooley et al, 2011) and 32.5%, 32.5%, and 35%, respectively, for
subjects on belimumab plus standard of care. Using these assumptions, simulations were 
performed using Van Elteren methods at the 5% significance level and a 1:1 
randomization allocation ratio, a target sample size of N=464 subjects is required (232 
per arm) to achieve at least 85% power to detect a treatment difference for the primary 
endpoint. 
In the event of recruitment challenges, randomization may be stopped as long as the 
number randomized is 400 subjects. The table below provides power estimates for 
sample sizes from 400 to 464 based on the original ORR assumptions.
Sample Size Total
Sample Size Per Arm
Power
400
200
80.13%
420
210
81.43%
440
220
83.40%
460
230
84.62%
464
232
85.60%
Assuming placebo response rates of 25%/25%/50%, the smallest response rates on 
belimumab 
resulting 
in 
a 
statistically 
significant 
difference 
range 
from 
30.3%/30.3%/39.4% (for N=400) to 30.0%/30.0%/40.0% (for N=464).
8.4.1.
Power for PERR Endpoint
PERR response rates are based on our assumptions for the Placebo+SOC responses 
assumed in the original ordinal endpoint (25% complete response and 25% partial 
response). Given the PERR endpoint is more stringent than a partial response but less 
stringent than the complete response, if one assumes a portion of the partial responders 
would meet the PERR criteria, then an expected response rate of approximately 40% for 
the Placebo+SOC arm is a reasonable estimate. Due to the lack of published data on the 
endpoint, there is a degree of uncertainty regarding the response rates; therefore a range 
of possible response rates and the associated power is provided.
For the new primary endpoint, PERR (Responder vs. Non-Responder), and the final 
sample size of N=448, there is 80% power to detect a 13.6% treatment difference and a 
minimum detectable difference of 9.7% for response rates spanning the 50% mark (40% 
vs. 53.6%) of the binomial distribution, the area of maximum variance. Given the 
achieved sample size of N=448, the table below provides the treatment difference 
required to achieve 80% power based on placebo response rates ranging from 20% to 
50% in 5% increments.


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Placebo (Pbo)
%Response
Belimumab (Bel)
%Response
Treatment Difference
(Bel – Pbo)
Minimum Detectable 
Difference
20
32.0
12.0
8.4
25
37.7
12.7
8.9
30
43.2
13.2
9.3
35
48.5
13.5
9.5
40
53.6
13.6
9.7
45
58.6
13.6
9.7
50
63.5
13.5
9.7
Based on methods for Fisher’s Exact Test using PASS 12.0 software.
8.5.
Efficacy
8.5.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is Primary Efficacy Renal Response (PERR) at Week 104, 
as follows:
•
Responder: Defined by a response at the Week 100 visit confirmed by a repeat 
measurement at the Week 104 visit, as follows:
Estimated glomerular filtration rate (GFR) is no more than 20% below the pre-flare 
value or ≥ 60 mL/min/1.73m2
AND
Urinary protein:creatinine ratio ≤0.7
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see Section 
5.5 and Section 5.6).
•
Non-responder: Not meeting criteria for the PERR.
The PERR at the Week 104 visit will be derived as below:
At Week 100 
At Week 104 
PERR at Week 104 
Responder
Responder
Responder
Responder
Non-Responder
Non-Responder
Non-Responder
Responder
Non-Responder
PERR at the Week 52 visit will be derived using a similar approach to that described 
above for the Week 104 visit, but using the Week 48 and Week 52 visits. 


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8.5.2.
Primary Efficacy Analyses
PERR (Responder vs. Non-Responder) at Week 104 will be compared between 
belimumab and placebo using logistic regression controlling for induction regimen (CYC 
vs. MMF), race (Black vs. Non-Black), baseline proteinuria and baseline eGFR.
Subjects who discontinue study agent should remain on study and undergo protocol 
required assessments through Week 104. Subjects who are withdrawn from the study 
agent prior to Week 104 will be imputed as a non-responder. 
8.5.2.1.
Missing Values
The following imputation method will be used to handle a missing visit related to 
the primary endpoint assessment:
•
If the Week 104 visit is missing, the primary endpoint will be determined using data 
from the Week 96 and the Week 100 visits.
•
If the Week 100 visit is missing, the primary endpoint will be determined using data 
from the Week 96 and the Week 104 visits.
•
If a subject misses both the Week 100 and the Week 104 visit, the subject will be 
defined as a non-responder. 
If only 1 laboratory component of the renal response endpoint is missing at only 1 visit, 
the following imputation method will be used for subjects missing a component of
the primary endpoint:
•
If this component is missing at the Week 104 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 100 visits.
•
If this component is missing at the Week 100 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 104 visits.
•
If this component is missing at both the Week 100 and the Week 104 the subject will 
be defined as a non-responder.
The parallel approach will be taken at Week 52 with the exception of the case with 
missing components at Week 48 and Week 52, in which case the subject will be defined 
as a non-responder.
8.5.2.2.
Sensitivity Analyses
The robustness of the primary efficacy results will be assessed by comparing PERR at the 
Week 104 visit between treatment groups in the completer population. The completer 
population is defined as all subjects who completed through Week 104 and were not 
permanently discontinued from treatment prior to Week 104. The analysis will be 
performed using the same method as the primary endpoint analysis. 
Other sensitivity analyses will be specified in the statistical analysis plan.


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8.5.2.3.
Subgroup Analysis
Subgroup analysis of the primary efficacy endpoint (ie, PERR at Week 104) will be 
performed in the following subgroups:
•
Induction regimen (HDCS plus CYC vs HDCS plus MMF).
•
Race (Black vs Non-Black).
•
Region (US/Canada, Europe/Australia/Israel, Asia, Americas excluding US and 
Canada).
•
Baseline anti-dsDNA (anti-dsDNA ≥ 30 IU/mL vs other).
•
Baseline complement (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).
•
Baseline Renal Biopsy Class (Class III or Class IV Only; Class V Only; Class V plus 
Class III or Class IV; Other).
8.5.3.
Secondary Efficacy Endpoints
8.5.3.1.
Major Secondary Efficacy Endpoints
•
Complete renal response (CRR) at Week 104 (see definition under ORR).
•
PERR at Week 52.
•
Time to death or renal-related event defined as any of the following: i) end stage renal 
disease (ESRD), ii) doubling of serum creatinine, iii) renal worsening as evidenced by 
increased proteinuria and/or impaired renal function, or iv) renal disease-related 
treatment failure. Further definition details will be provided in the analysis plan.
•
ORR (complete, partial or no response) at Week 104 defined as follows:
•
CRR:
Estimated glomerular filtration rate (GFR) is no more than 10% below the 
pre-flare value or within normal range 
AND
Urinary protein:creatinine ratio < 0.5 
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
Partial Renal Response (PRR):
Estimated GFR no more than 10% below the baseline value or within normal 
range 
AND


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≥ 50% decrease in the urine protein:creatinine ratio with one of the 
following:  

a urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0 
OR

a urine protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
No Renal Response (NRR):
Not meeting criteria for either CRR or PRR.
8.5.4.
Other Efficacy Endpoints
Disease activity
•
Change from baseline in SELENA SLEDAI score by visit. 
•
Proportion of subjects with SELENA SLEDAI score < 4 by visit.
•
Proportion of subjects with improvement in SELENA SLEDAI organ systems from 
baseline by visit.
•
Proportion of subjects with worsening in SELENA SLEDAI organ systems from 
baseline by visit
•
Change from baseline in SELENA SLEDAI excluding renal items by visit.
Note: Programmed analysis of these endpoints will apply SLEDAI-S2K proteinuria 
scoring.
Flares*
•
Time to first severe SFI flare.
•
Time to first severe SFI flare after Week 24.
*Severe SFI flare will be defined by using the modified SLE Flare Index (SFI) and will 
be described in the statistical analysis plan.
Renal Specific Measures
•
Individual components of PERR.  Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio 0.7.

Estimated GFR no more than 20% below the pre-flare value or ≥ 60 
mL/min/1.73m2. 

No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).


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•
Individual components of CRR.  Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio < 0.5.

Estimated GFR no more than 10% below the pre-flare value or within the 
normal range
•
Percent change in proteinuria by visit.
•
Change in proteinuria by visit.
•
Proportion of subjects with a doubling of the serum creatinine or progression to end 
stage renal disease (ESRD) as defined below:

Doubling of serum creatinine compared with baseline that is confirmed with a 
second measurement at least 3 weeks later.

Progression to ESRD defined as the need for chronic dialysis or renal 
transplantation.
•
Time to first PERR that is maintained through Week 52.
•
Time to the first PERR that is maintained through Week 104.
•
Time to the first CRR that is maintained through Week 52.
•
Time to the first CRR that is maintained through Week 104.
•
Proportion of subjects with PERR by visit.
•
Proportion of subjects with CRR by visit.
Corticosteroid Use
•
Proportion of subjects receiving ≤5 mg/day prednisone by visit.
•
Proportion of subjects receiving ≤7.5 mg/day prednisone by visit.
SLICC Damage Index (SDI)
•
SDI change from baseline at Week 104
•
Percent of patients with any SDI worsening (change >0) at Week 104 compared with 
baseline.
Biomarkers
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, aCL, anti-Sm, and anti-C1q).

Complement (C3, C4) levels.


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3. Percent of patients with normalized serological activity at Week 104 and over time

IgG, IgM and IgA (high to normal/low).

Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q) 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 treatment period. 
Other autoantibodies will be collected from all patients at baseline, then at regular 
intervals during the study.
Data collection and analysis of the exploratory renal biomarkers will be performed 
independently of the main study and will form the basis of a separate report. 
8.5.5.
Secondary Efficacy Analyses
8.5.5.1.
Major Secondary Efficacy Analyses
Time to death or renal-related event will be compared between belimumab vs. placebo
using a Cox proportional hazards model controlling for induction regimen (CYC vs. 
MMF), race (Black vs. Non-Black) baseline proteinuria, and baseline eGFR.
CRR at Week 104 and PERR at Week 52 will be compared between belimumab and 
placebo using logistic regression controlling for induction regimen (CYC vs. MMF), race 
(Black vs. Non-Black), baseline proteinuria, and baseline eGFR.
Analysis of ORR (complete, partial or no response) at Week 104 will be compared 
between belimumab vs. placebo using rank analysis of covariance (ANCOVA) 
controlling for induction regimen (CYC vs. MMF), race (Black vs. Non-Black), baseline 
proteinuria, and baseline eGFR. 
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 be graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 7) or the grades in Section 7.8, as appropriate. The frequency and 
incidence of AEs will be tabulated by MedDRA system organ class (SOC) and preferred 


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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 and incidence 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
(Appendix 7) 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 8 and Appendix 9)
•
Hypersensitivity reactions/anaphylaxis
•
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 Section 6.7.1.
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.


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9.
PHARMACOGENETICS (PGX)
In consenting subjects, a blood sample for PGx research should be drawn predose at 
baseline (Day 0) to better characterize genetic variability (eg, HLA typing) that may 
affect efficacy or safety endpoints. Information regarding PGx research is included in
Appendix 6.
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 
6). 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 development by GlaxoSmithKline Pharmaceuticals. Human Genome 
Sciences, Inc. a wholly owned subsidiary of GlaxoSmithKline Pharmaceuticals is the 
sponsor of this study.
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.


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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 
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 
CRFs 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 after 
every visit 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.


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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 disc (CD) containing the eCRFs for each of their subjects.
10.6.
Study Monitoring
The study sponsor or designee will monitor the study. Study monitors representing the 
sponsor will visit study sites routinely throughout the trial. The sponsor will review 
eCRFs 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 eCRFs 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 
promptly notify GlaxoSmithKline Pharmaceuticals / Human Genome Sciences of any 
audits they have scheduled with any regulatory authority.
10.7.
Drug Accountability
Upon receipt of the study agents, the designated 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.


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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 the sponsor 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 investigators 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.
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 the sponsor, 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 the sponsor 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.


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•
A decision on the part of the sponsor 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 the sponsor, 
study monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.


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11.
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on Renal Damage in Patients With Lupus Nephritis: LXV, Data From a Multiethnic US 
Cohort. Arthritis Rheum 2009;61(6):830–9.
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Price CP, Newall RG, Boyd JC. Use of Protein:Creatinine Ratio measurements on 
random urine samples for prediction of significant proteinuria: A Systematic Review. 
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Ruggenenti P, Gaspari F, Perna A, et al. Cross sectional longitudinal study of spot 
morning urine protein: creatinine ratio, 24 hour urine protein excretion rate, glomerular 
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controlled Aspreva Lupus Management Study (ALMS).  Lupus 2007;16:972-80. 


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Sobel ES, Mohan C, Morel L, et al. Genetic dissection of SLE pathogenesis: Adoptive 
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Stenager EM, Stenager E, Koch-Henriksen N, Brønnum-Hansen H, Hyllested K, Jensen 
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Räsänen P. Suicides in persons suffering from rheumatoid arthritis. Rheumatology.
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Touma Z, Gladman D, Urowitz M, Beyene J. Uleryk E, Shah P. Mycophenolate Mofetil 
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LIST OF APPENDICES
Appendix 1
American College of Rheumatology (ACR) Criteria for SLE.................101
Appendix 2
International Society of Nephrology/Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis.................................102
Appendix 3
SELENA SLEDAI Disease Assessment Scales ......................................103
Appendix 4
SLICC/ACR Damage Index ....................................................................106
Appendix 5
Laboratory Tests ......................................................................................108
Appendix 6
Pharmacogenetic Research ......................................................................109
Appendix 7
Adverse Event Severity Grading Tables..................................................113
Appendix 8
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening...................................................................................122
Appendix 9
Columbia- Suicide Severity Rating Scale (C-SSRS) Since Last Visit ....138
Appendix 10
Algorithm for Liver Chemistry Stopping and Follow-up Criteria...........149
Appendix 11
Possible Suicidality Related History Questionnaire (PSRHQ)................151
Appendix 12
Possible Suicidality Related Questionnaire (PSRQ)................................153
Appendix 13
Country-specific Requirements: Thailand...............................................155


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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 et al, 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. 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).
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
International Society of Nephrology/Renal 
Pathology Society (ISN/RPS) 2003 Classification of 
Lupus Nephritis
CLASS I
MINIMAL MESANGIAL LUPUS NEPHRITIS
Normal glomeruli by light microscopy, but mesangial immune deposits by 
immunofluorescence.
CLASS II
MESANGIAL PROLIFERATIVE LUPUS NEPHRITIS
Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light 
microscopy, with mesangial immune deposits.
May be a few isolated subepithelial or subendothelial deposits visible by 
immunofluorescence or electron microscopy, but not by light microscopy. 
CLASS III
FOCAL LUPUS NEPHRITIS
Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis 
involving < 50% of all glomeruli, typically with focal subendothelial immune deposits, 
with or without mesangial alterations.
Class III (A)
Active lesions: focal proliferative lupus nephritis
Class III (A/C)
Active and chronic lesions: focal proliferative and sclerosing lupus nephritis
Class III (C)
Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis
CLASS IV
DIFFUSE LUPUS NEPHRITIS
Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis 
involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, 
with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) 
lupus nephritis when ≥50% of the involved glomeruli have segmental lesions, and 
diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global 
lesions. Segmental is defined as a glomerular lesion that involves less than half of the 
glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or 
no glomerular proliferation. 
Class IV-S (A)
Active lesions: diffuse segmental proliferative lupus nephritis
Class IV-G (A)
Active lesions: diffuse global proliferative lupus nephritis
Class IV-S (A/C)
Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis
Class IV-G (A/C)
Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis
Class IV-S (C)
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis
Class IV-G (C)
Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis
CLASS V
MEMBRANOUS LUPUS NEPHRITIS
Global or segmental subepithelial immune deposits or their morphologic sequelae by 
light microscopy and by immunofluorescence or electron microscopy, with or without 
mesangial alterations. 
Class V lupus nephritis may occur in combination with class III or IV in which case both 
will be diagnosed.
Class V lupus nephritis may show advanced sclerosis.
CLASS VI
ADVANCED SCLEROSIS LUPUS NEPHRITIS
≥90% of glomeruli globally sclerosed without residual activity. 
Adapted from: Weening J, D’Agati V, Schwartz M, et al. The Classification of Glomerulonephritis in 
Systemic Lupus Erythematosus Revisited. J Am Soc Nephrol 2004; 15:241-150. 


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Appendix 3
SELENA SLEDAI Disease Assessment Scales
SELENA SLEDAI Score
Score if descriptor is present at time of visit or in the preceding 10 days.
Wgt.
Descriptor
Definition
8
Seizure
Recent onset (last 10 days). Exclude metabolic, infectious drug cause, 
or seizure due to past irreversible CNS damage.
8
Psychosis
Altered ability to function in normal activity due to severe disturbance in the 
perception of reality. Include hallucinations, incoherence, marked loose 
associations, impoverished thought content, marked illogical thinking, bizarre, 
disorganized, or catatonic behavior. Exclude uremia and drug causes.
8
Organic Brain 
Syndrome
Altered mental function with impaired orientation, memory or other intellectual function 
with rapid onset and fluctuating clinical features. Include clouding of consciousness with 
reduced capacity to focus and inability to sustain attention to environment, plus at least 
2 of the following: perceptual disturbance, incoherent speech, insomnia or daytime 
drowsiness, or increased or decreased 
psychomotor activity. Exclude metabolic, infectious, or drug causes.
8
Visual Disturbance
Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, 
serous exudate of hemorrhage in the choroid, optic neuritis, scleritis or 
episcleritis. Exclude hypertension, infection, or drug causes.
8
Cranial Nerve 
Disorder
New onset sensory or motor neuropathy involving cranial nerves. 
Include vertigo due to lupus.
8
Lupus Headache
Severe persistent headache: may be migrainous, but must be 
non-responsive to narcotic analgesia.
8
CVA
New onset of CVA(s). Exclude arteriosclerosis or hypertensive causes.
8
Vasculitis
Ulceration, gangrene, tender finger nodules, periungual infarction, 
splinter hemorrhages, or biopsy or angiogram proof of vasculitis.
4
Arthritis
More than 2 joints with pain & signs of inflammation 
(ie, tenderness, swelling or effusion).
4
Myositis
Proximal muscle aching/weakness associated with elevated creatine 
phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis.
4
UrinaryCasts
Heme-granular or red blood cell casts.
4
Hematuria
> 5 red blood cells/high power field. Exclude stone, infection, or other causes.
4
Proteinuria
New onset or recent increase of more than 0.5 g/24 hours.
4
Pyuria
> 5 white blood cells/high power field. Exclude infection.
2
Rash
New or ongoing inflammatory lupus rash.
2
Alopecia
New or ongoing abnormal, patchy or diffuse loss of hair due to active lupus.
2
Mucosal Ulcers
New or ongoing oral or nasal ulcerations due to active lupus.
2
Pleurisy
Classic and severe pleuritic chest pain or pleural rub or 
effusion or new pleural thickening due to lupus.
2
Pericarditis
Classic and severe pericardial pain or rub or effusion, 
or electrocardiogram confirmation.
2
Low Complement
Decrease in CH50, C3, or C4 below the lower limit of normal for testing laboratory.
2
Increased DNA
Binding
> 25% binding by Farr assay or above normal range for testing laboratory.
1
Fever
> 38°C. Exclude infectious cause.
1
Thrombocytopenia
< 100,000 platelets/mm3
1
Leukopenia
< 3,000 white blood cells/mm3. Exclude drug causes.
TOTAL SCORE
(Sum of weights next to descriptors marked present)
Adapted from: 
Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI: a disease activity index for 
lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35(6):630-40.


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SLE Flare Index
Mild or Moderate Flare
Severe Flare
Change in SELENA SLEDAI instrument score of 
3 points or more (but not to more than 12)
New/worse:
Discoid, photosensitive, profundus,
cutaneous vasculitis, bullous lupus
Nasopharyngeal ulcers
Pleuritis
Pericarditis
Arthritis
Fever (SLE)
Increase in prednisone, but not to > 0.5
mg/kg/day
Added NSAID or hydroxychloroquine for SLE
Activity
≥1.0 increase in PGA score, but not to more than
2.5
Change in SELENA SLEDAI instrument score to
greater than 12
New/worse:
CNS-SLE
Vasculitis
Nephritis
Myositis
Plt < 60,000
Hemolytic anemia:Hb < 70 g/L or decrease in
Hb > 30 g/L
Requiring: double prednisone, or prednisone
increase to > 0.5 mg/kg/day, or hospitalization
Increase in prednisone to > 0.5 mg/kg/day
New cyclophosphamide, azathioprine,
methotrexate, or mycophenolate for SLE activity
Hospitalization for SLE activity
Increase in PGA score to > 2.5
Adapted from:
Petri M, Buyon J, Kim M. Classification and definition of major flare in SLE clinical trials. Lupus 1999; 
8:685-91.
Petri M et al. Combined Oral Contraceptives in Women with Systemic Lupus Erythematosus. N Engl J 
Med 2005;353:2550-8.
Buyon JP et al. The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on 
Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial. Ann Internal Med 2005; 142 
(12 Pt 1):953-62.


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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 4
SLICC/ACR Damage Index
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology
Damage Index for Systemic Lupus Erythematosus*
Item 
Score
Ocular (either eye, by clinical assessment)
Any cataract ever 
1
Retinal change or optic atrophy 
1
Neuropsychiatric
Cognitive impairment (eg, memory deficit, difficulty with 
1
calculation, poor concentration, difficulty in spoken or written
language, impaired performance levels) or major psychosis
Seizures requiring therapy for 6 months 
1
Cerebrovascular accident ever (score 2 > 1) 
1(2)
Cranial or peripheral neuropathy (excluding optic) 
1
Transverse myelitis 
1
Renal
Estimated or measured glomerular filtration rate < 50% 
1
Proteinuria > 3.5 gm/24 hours 
1
Or
End-stage renal disease (regardless of dialysis or transplantation) 
3
Pulmonary
Pulmonary hypertension (right ventricular prominence, or loud P2) 
1
Pulmonary fibrosis (physical and radiograph) 
1
Shrinking lung (radiograph) 
1
Pleural fibrosis (radiograph) 
1
Pulmonary infarction (radiograph) 
1
Cardiovascular
Angina or coronary artery bypass 
1
Myocardial infarction ever (score 2 if > 1) 
1(2)
Cardiomyopathy (ventricular dysfunction)
1
Valvular disease (diastolic, murmur, or systolic murmur > 3/6) 
1
Pericarditis for 6 months, or pericardiectomy 
1
Peripheral vascular
Claudication for 6 months 
1
Minor tissue loss (pulp space) 
1
Significant tissue loss ever (eg, loss of digit or limb)(score 2 if > 1 site)
1(2)
Venous thrombosis with swelling, ulceration, or venous stasis 
1
Gastrointestinal
Infarction or resection of bowel below duodenum, spleen, liver, or 
1(2)
gall bladder ever, for cause any (score 2 if > 1 site)
Mesenteric insufficiency 
1
Chronic peritonitis 
1
Stricture or upper gastrointestinal tract surgery ever 
1


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Musculoskeletal
Muscle atrophy or weakness 
1
Deforming or erosive arthritis (including reducible deformities, excluding avascular necrosis)
1
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis)
1
Avascular necrosis (score 2 if > 1) 
1(2)
Osteomyelitis 
1
Skin
Scarring chronic alopecia 
1
Extensive scarring or panniculum other than scalp and pulp space 
1
Skin ulceration (excluding thrombosis) for > 6 months
1
Premature gonadal failure
1
Diabetes (regardless of treatment)
1
Malignancy (exclude dysplasia) (score 2 if > 1 site)
1(2)
*Damage (nonreversible change, not related to active inflammation) occuring since onset of lupus, 
ascertained by clinical assessment and present for at least 6 months unless otherwise stated.  Repeat 
episodes must occur at least 6 months apart to score 2.  The same lesion cannot be scored twice.
Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial 
validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363-9.


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Appendix 5
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)
Serum Pregnancy 
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Dysmorphic RBC
Casts (specified by type 
eg, RBC, WBC)
Urine Pregnancy
Spot urine
24-hour urine
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase
(GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
Infectious Disease Screening
HIV-1/2 antibody
Hepatitis C antibody
Hepatitis B surface antigen
Hepatitis B surface and core 
antibodies
Hepatitis B Viral DNA PCR 
Quantitative (HBV DNA)
Autoantibodies
ANA 
Anti-dsDNA
aCL (IgG, IgA and IgM isotypes)
Anti-Sm
Anti-c1q
Immunoglobulins
Serum immunoglobulin isotypes: IgG, 
IgM, IgA
Belimumab PK and Immunogenicity
*The urine microscopy and 
routine 
urinalysis 
will 
be 
performed locally. All other 
tests will be performed by a 
central laboratory. 
Biological Markers
BLyS protein 
Serum complement (C3 and C4) 
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)   Note: May be collected in selected sites/regions.
Urinary Biomarkers 
Include, but are not limited to, MCP-1, hepcidin, NGAL, LFABP, 
Angiogenin, Angiopoietin 2, Angiostatin, IL-6r, Osteopontin, PAI-1, 
PF4, RAGE, RANK, Sgp130, Siglec 5, Siglec 9, Tgf-beta1, TIM1, 
TIMP-2, TLSP, TNFR-II, Trem1, VCAM-1, Vegf-C and VEGF-R3.
Other:
Alcohol and drug screen


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Appendix 6
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 (~10 
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.


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Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator 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, 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.


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•
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.
•
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 study 
agent, 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 7
Adverse Event Severity Grading Tables
SKIN (INJECTION SITE)
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE1
SEVERE
POTENTIALLY LIFE-THREATENING
Induration
< 15mm 
15-30 mm
> 30mm
n/a
Erythema
< 15mm 
15-30 mm
> 30mm
n/a
Edema
< 15mm 
15-30 mm
> 30mm
n/a
Rash at Injection Site
< 15mm 
15-30 mm
> 30mm
n/a
Pruritus
slight itching at 
injection site
moderate itching at 
injection extremity
itching over entire body
n/a
1May be assessed as mild 
despite the size if event 
is transient (< 48 hours)
with mild discomfort; no 
medical 
intervention/therapy 
required
Modified from DMID Adult Toxicity Tables, 2007


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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
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
> 3 - < 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 8
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.


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
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.


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
Algorithm for Liver Chemistry Stopping and Follow-
up Criteria
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.7.2.1 and Section 6.7.3.1. 


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Liver Monitoring Event Algorithm with Continued Therapy for ALT≥3xULN 
but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.7.2.1 and Section 6.7.3.1
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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Appendix 11
Possible Suicidality Related History Questionnaire 
(PSRHQ)


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Appendix 12
Possible Suicidality Related Questionnaire (PSRQ)


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Appendix 13
Country-specific Requirements: Thailand
Protocol Amendment 02-Thailand, 16 August 2012
Summary of Modifications and Rationale:
The recommended duration of study agent infusion was changed from 1 hour to 
approximately 2-3 hours. This change was made to accommodate clinical practice in 
Thailand in which the normal IV infusion rate is generally between 80-150 mL/h; the 
volume of study agent to be infused IV (250 mL) was not changed.
Detailed Description of Changes
Section 5.3 Dose, Route of Administration, and Schedule
Formerly:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a 
placebo arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over 1 hour. 
Once randomized, subjects will be dosed with study agent on Days 0, 14, and 28 and 
every 28 days days thereafter through 100 weeks of double-blind treatment. Following 
the final double-blind visit at Week 104, subjects who complete 100 weeks of treatment 
with study agent and complete Week 104 assessments, will have the option to continue in 
the 6-month open-label extension period (with first dose given at the Week 104 visit).
Modified to:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a 
placebo arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over 
approximately 2 – 3 hours. Once randomized, subjects will be dosed with study agent
on Days 0, 14, and 28 and every 28 days days thereafter through 100 weeks of double-
blind treatment. Following the final double-blind visit at Week 104, subjects who 
complete 100 weeks of treatment with study agent and complete Week 104 assessments, 
will have the option to continue in the 6-month open-label extension period (with first 
dose given at the Week 104 visit).


 
 
 
 
CLINICAL PROTOCOL HGS1006-C1121 
 
Protocol Amendment: 00 
 
 
EudraCT Number: 2011-004570-28 
Date: 19 October 2011 
 
 
TITLE OF STUDY:  
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus Standard 
of Care in Adult Subjects with Active Lupus Nephritis 
 
 
 
 
STUDY SPONSOR: 
Human Genome Sciences, Inc. 
 
14200 Shady Grove Road 
 
Rockville, Maryland 20850 
 
U.S.A. 
 
 
 
 
 
 
Confidential and Proprietary 
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 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. 
 


Human Genome Sciences, Inc. 
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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-C1121 
Title of the Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus 
Standard of Care in Adult Subjects with Active Lupus Nephritis 
Clinical Development Phase: 3 
Objectives:  
• To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV or V using the 2003 ISN/RPS criteria. 
• To assess the safety and tolerability of belimumab plus standard of care versus  placebo 
plus standard of care in adult subjects with lupus nephritis Class III, IV or V using the 
2003 ISN/RPS criteria. 
 
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria: 
1. Males or females at least 18 years of age. 
2. Have a clinical diagnosis of SLE according to the American College of Rheumatology 
(ACR) criteria (Appendix 1). 
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV (excluding 
Class III(C), IV-S(C) and IV-G(C)) either with or without the presence of Class V, or pure 
Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy must be 
performed in the 6 months prior to baseline (Day 0). Whenever possible, a tissue sample 
from the renal biopsy used to qualify the subject will be collected and sent to a central 
reading center; however, the tissue sample will not be shipped prior to nor be used for the 
purposes of randomization. 
4. Have unequivocally positive ANA test results defined as an ANA titer ≥ 1:80 (based on 
Hep-2 immunofluorescence assay) and/or a positive anti-dsDNA (≥ 30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results. 
5. Have documentation of active renal disease at screening requiring initiation of induction 
therapy with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) 
or mycophenolate mofetil (MMF) or other oral forms of mycophenolate. Induction 
therapy should be started no more than 14 days prior to the baseline visit (Day 0). The 
following factors will be used to define active renal disease: 
 
Urinary protein:creatinine ratio of ≥ 1.0 AND active urinary sediment as defined by at 
least 1 of the following (in absence of menses and genitourinary tract infection).   


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 
> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory reference 
range. 
 
> 5 white blood cell (WBC)/hpf (or above the laboratory reference range). 
 
Presence of cellular casts (RBC or WBC). 
• Subjects without active urinary sediment are eligible if they meet at least 1 of the 
following criteria:  
 Have a confirmatory biopsy performed within 3 months prior to the baseline visit 
meeting the criteria outlined in criterion 3 
 Have proteinuria ≥ 3.5 grams/day. 
6. 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 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. 
7. 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).  
 


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Exclusion Criteria: Subjects will be excluded from participating in the study if they meet any 
of the following exclusion criteria: 
1. Subjects who have previously failed induction therapy with both CYC and MMF (or other 
forms of mycophenolate) based on the investigator’s opinion. If a subject has failed only 
1 of the 2 therapies for induction, they may be eligible for study inclusion if they are 
newly initiating the other induction therapy (ie, a subject who failed MMF is eligible if 
newly initiating induction therapy with CYC or a subject who failed CYC is eligible if 
newly initiating induction therapy with MMF). 
2. Subjects who have previously received an induction therapy within 6 months prior to the 
screening visit. 
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 based on 
the Adverse Event Severity Grading Tables (Appendix 7). 
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, azathioprine (AZA), 
corticosteroids). 
5. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies. 
6. Have received treatment with belimumab at anytime.  
7. Received any of the following within 364 days of baseline (Day 0):   
- 
Nitrogen mustard 
- 
Chlorambucil 
- 
Vincristine 
- 
Procarbazine 
- 
Etoposide 
- 
Abatacept 
- 
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, or LY2127399 [anti-BAFF]) 
- 
A biologic investigational agent (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. 
8. Received any of the following within 90 days of baseline (Day 0):   
- 
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab) 
- 
Interleukin-1 receptor antagonist (anakinra). 
- 
Intravenous immunoglobulin (IVIG). 
- 
Plasmapheresis. 
9. Received a non-biological investigational agent within 60 days of baseline (Day 0). 
10. Received a live vaccine within 30 days of baseline (Day 0). 
11. 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 baseline (Day 0). 
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic 
stem cell/marrow transplant or are due to receive transplantation. 
13. Subjects who have been on dialysis within 364 days of baseline (Day 0). 


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14. An estimated glomerular filtration rate < 30 ml/min at the screening visit (using the 
simplified Modification of Diet in Renal Disease [MDRD] equation). 
15. 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. 
16. 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. 
17. 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.   
18. 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 baseline (Day 0). 
- 
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of baseline (Day 0). 
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to baseline (Day 0).  
20. Have a historically positive test or test positive at screening for HIV antibody, hepatitis B 
surface antigen, or hepatitis C antibody.   
21. Have an IgA deficiency (IgA level < 10 mg/dL). 
22. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event Severity 
Grading Tables (Appendix 7) except for the following that are allowed: 
- 
Urinalysis (eg, proteinuria) 
- 
Hematuria 
- 
Pyuria 
- 
Casts 
- 
Hypoalbuminemia due to lupus nephritis 
- 
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 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 the ALT and/or AST must be ≤ Grade 2. 
- 
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. (Note that WBC 
count should be obtained immediately prior to starting induction therapy. If immediate 
pre-induction WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used).  
23. 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) (Appendix 8) in the last 2 months or who in the 
investigator's opinion, pose a significant suicide risk. 
 


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Study Design and Schedule:   
This is a Phase 3, multi-centre, multi-national, randomized, double-blind, placebo controlled 
study to evaluate the efficacy and safety of intravenous belimumab 10 mg/kg plus standard of 
care compared to placebo plus standard of care in adult subjects with active lupus nephritis. 
Subjects who meet the eligibility criteria during screening will be randomized to 1 of 2 
treatment groups in a 1:1 ratio: 10 mg/kg belimumab plus standard of care or placebo plus 
standard of care. The randomization of all eligible subjects will be stratified by their induction 
regimen (high dose cortiocsteroids [HDCS] plus CYC vs HDCS plus MMF) and race (black 
race vs other). Subjects will be dosed with study agent on Days 0 (baseline), 14, 28 and then 
every 28 days through 100 weeks with a final evaluation for the double-blind treatment period 
at 104 weeks. Approximately 464 lupus nephritis subjects will be randomized with a target of 
232 subjects in the belimumab treatment group and 232 in the placebo group. All subjects will 
receive background therapy consisting of one of the following standard of care regimens: 
• High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for induction therapy 
followed by Azathioprine (AZA) for maintenance therapy 
OR 
• HDCS + Mycophenolate Mofetil (MMF) for induction followed by MMF for maintenance 
therapy 
 
The standard of care medications are described in Section 5.5.1.  
All subjects will start the above induction therapy within 14 days prior to the baseline (Day 0) 
visit. This will allow subjects to be screened and potentially enrolled so they will not be 
excluded on the basis of necessary acute management. If an induction regimen has been 
received within 6 months prior to the screening visit, the subject will be excluded. The 
primary efficacy endpoint of a renal response (defined below) will be determined by changes 
in urinary sediment, proteinuria, and renal function at Week 104. For the renal function 
assessments at baseline, Week 24, 48, 52, 76, 100 and 104, the glomerular filtration rate 
(GFR) will be based on creatinine clearance determined from the mean creatinine value of 2 
contiguous 24 hour urine collections and 2 serum creatinine measurements (first serum 
creatinine collected at initial visit and the second sample taken 3 days later at the follow-up 
visit). Subjects will be provided with the materials for collecting the two 24 hour urine 
collections beginning the next morning following their initial clinic visit. On the third day 
following the initial visit, subjects will return to the clinic for the second serum creatinine 
sample. For all other study visits, GFR will be estimated using the simplified MDRD formula 
and the urinary protein: urinary creatinine will be used for proteinuria. 
For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections 
may be confounders. The urine collection may be postponed up to 14 days at the investigators 
discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during 
the 24 hour urine collection.  


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Renal response will be measured as complete, partial, or no response based on study defined 
criteria (see Section 8.5). Week 104 renal response will be defined by a response at Week 100 
that is confirmed by a repeat measurement at Week 104.   
All subjects who discontinue treatment during the double-blind period (for reasons other than 
receipt of prohibited medications or doses of medications that result in treatment-failure 
designation or withdrawal of consent) should return for the scheduled visits through 
Week 104. For subjects who discontinue study treatment due to receipt of prohibited  
medications, an Exit visit should be completed approximately 4 weeks after the last dose of 
study agent and a Follow-up visit approximately 8 weeks after the last dose of study agent. 
In the event that a subject withdraws consent from the study, an attempt should be made to 
obtain consent for mortality status at Week 104. Any subject that withdraws consent for use 
and disclosure of research-related health information will be considered withdrawn from the 
study and not followed for mortality.  
Subjects who successfully complete the initial 104-week double blind period may enter into a 
6-month open-label extension. The Week 104 visit of the double-blind period will serve as the 
Day 0 visit for subjects entering the open-label extension. In the open-label extension, all 
subjects will receive 10 mg/kg belimumab every 28 days until Week 24, with a final 
evaluation at Week 28 (4 weeks after the last dose). The first dose on the open-label extension 
will be given at the Week 104 visit of the double-blind period following the completion of all 
Week 104 assessments. Subjects participating in the open-label extension will continue to be 
monitored for efficacy and safety as per the study calendar (see Table 6-3). Subjects who 
complete the 104-week double-blind period, but do not enter the open label extension will be 
required to return for an additional follow up visit 8 weeks after the last dose of study agent. 
All subjects who enter the open-label extension period and withdraw early 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.  
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 belimumab. If belimumab is 
not commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under this protocol until belimumab becomes commercially available. 
Efficacy Endpoints and Analysis: 
The primary efficacy endpoint is renal response at Week 104 measured as an ordinal 
response - complete renal response, partial renal response, or no renal response. Renal 
response is determined by changes in urinary sediment, proteinuria, and renal function. Renal 
response at Week 104 will be defined by a response at Week 100 that is confirmed by a repeat 
measurement at Week 104. Renal response is defined as follows: 


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• Complete Renal Response 
 
Calculated glomerular filtration rate (GFR) is within normal range  
 
AND 
 
Inactive urinary sediment [(< 5 RBCs/hpf and < 5 WBCs/hpf (or within the reference 
range of the laboratory)]; and no cellular casts (no RBC or WBC casts)   
 
AND 
 
Urinary protein:creatinine ratio < 0.5  
 
(Note: For subjects with a normal urinary sediment and GFR at baseline and only the 
presence of proteinuria (≥ 3.5 grams/day), the urine protein:creatinine ratio should be 
< 0.5 to meet the primary endpoint) 
 
• Partial Renal Response  
 
Estimated or calculated GFR no more than 10% below the baseline value or within 
normal range  
 
AND 
 
RBCs/hpf ≥ 50% reduction from baseline or < 5 RBCs/hpf (or within the normal 
reference range for the central laboratory) and no RBC casts  
 
AND 
 
≥ 50% decrease in the urine protein:creatinine ratio with one of the following:   
 a urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0  
OR 
 a urine protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0 
 
• No Renal Response 
 
Not meeting criteria for either complete or partial renal response 
 
Major Secondary Endpoints:  
• Renal response (complete, partial or no response) at Week 52. 
• Proportion of subjects who achieve complete renal response at Week 104. 
 


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Sample Size Calculation: 
It is expected that approximately 50% subjects on placebo plus standard of care will have 
complete (10%) or partial renal response (40%) at the Week 104 visit (Appel et al, 2009; 
Sinclair, 2007). It is expected that renal response in subjects on belimumab plus standard of 
care will be approximately 65% (Complete = 15%, Partial = 50%). Approximately 
464 subjects will be randomized to achieve a target of 232 subjects in each treatment arm 
providing approximately 90% power to detect the difference in the primary endpoint, based 
on a 2-sided Van Elteren test at the 5% significance level (Zhao et al, 2008).  
Analysis of Primary Efficacy Endpoint: 
Renal response (complete, partial, or no renal response) at the Week 104 visit will be 
compared between the belimumab plus standard of care treatment group and placebo plus 
standard of care using the Van Elteren test, stratified by the baseline randomization factors. 
Any subject who receives a protocol-prohibited medication or protocol prohibited dose (as 
defined in Sections 5.5 and 5.6) will be considered a treatment failure (ie, non-responder) for 
the primary endpoint. 
Analysis of Major Secondary Efficacy Endpoints: 
Renal response (complete, partial or no response) at the Week 52 visit will be analyzed using 
the same method as for the primary endpoint. The proportion of subjects who achieve a 
complete renal response at the Week 104 visit, will be compared between the belimumab 
treatment group and placebo group using a logistic regression model. The independent 
variables in the model will include treatment group (ie, 10 mg/kg belimumab vs placebo) and 
the baseline randomization stratification factors.  
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 (Section 8.1).  
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 
the belimumab treatment group.  
An independent Data Monitoring Committee (DMC) will review unblinded safety data on an 
ongoing basis until data through Week 104 of the double-blind treatment period are locked 
and analyzed (after which time 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 DMC will review the data approximately every 4 months. At all times 
the sites and sponsor will remain blinded to treatment allocation. 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 


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abnormalities, opportunistic infections (serious and nonserious), malignancies, and 
hypersensitivity/anaphylactic reactions during the double-blind Week 104 and open-label 
extension portions of the study. Investigators and IRBs/IECs will be notified of the outcome 
of each DMC meeting.  
Pharmacokinetics 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 at the baseline visit (Day 0), 
Week 8, Week 24, Week 52, Week 76 and Week 104. During the 6 month open-label 
extension, samples will be obtained at Week 24. Additionally, a sample will be collected 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. 
Biological Markers and Autoantibodies:  
The following biomarkers will be measured from baseline (Day 0) and at selected timepoints 
thereafter: 
• Autoantibodies: ANA, anti-dsDNA, aCL (IgG, IgM, IgA isotypes), anti-Sm, and anti-C1q 
• Serum immunoglobulin isotypes: IgA, IgG, IgM  
• Serum complement (C3,C4) 
• BLyS protein (baseline only) 
 
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis) at baseline (Day 0) and at multiple time points thereafter: 
• Peripheral 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. 
 
Study Calendar: 
See Table 6-1, Table 6-2, and Table 6-3 for a calendar of study visits and assessments. 
Study Schematic:  See Figure 1-1. 
 


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Belimumab 
 
 
 
 
 
 
 
 
 
 
10mg/kg belimumab + 
Standard of Care 
 
 
10mg/kg belimumab +  
Standard of Care 
 
 
 
 
Placebo +  
Standard of Care 
 
 
10mg/kg belimumab +  
Standard of Care 
 
 
 
 
 
 
 
Figure 1-1  
Study schematic 
 
 
 
 
 
 
 
 
Baseline 
Week 52 
Major Secondary 
Endpoint:  Renal Response 
(CRR, PRR or NRR) 
Week 104 
Primary Endpoint:  Renal 
Response (CRR, PRR or NRR)  
 
Major Secondary Endpoint:  
Proportion of subjects with CRR  
Double-Blind Treatment Period  
104 Weeks 
Open-Label Extension 
28 Weeks 
SCREENING 
-28 days to Day 0 
Week 28  
End of study 


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Table of Contents 
Investigator Agreement .............................................................................................................. 2 
Study Synopsis ........................................................................................................................... 3 
Table of Contents...................................................................................................................... 13 
List of Tables ............................................................................................................................ 16 
List of Figures ........................................................................................................................... 17 
List of Abbreviations ................................................................................................................ 18 
1 
Background ................................................................................................................... 21 
1.1 Disease Background Relevant to Clinical Study .......................................................... 21 
1.2 Belimumab.................................................................................................................... 22 
1.2.1 
Mechanism of Action ................................................................................... 22 
1.2.2 
Clinical Experience with Belimumab ........................................................... 22 
1.3 Rationale for the Study ................................................................................................. 23 
2 
Study Objectives ........................................................................................................... 25 
3 
Study Design................................................................................................................. 25 
3.1 Basic Design Characteristics ........................................................................................ 25 
4 
Inclusion and Exclusion Criteria .................................................................................. 27 
4.1 Inclusion Criteria .......................................................................................................... 27 
4.2 Exclusion Criteria ......................................................................................................... 28 
5 
Study Treatment Regimen ............................................................................................ 31 
5.1 Study Agent Name and Formulation ............................................................................ 31 
5.2 Packaging, Labeling, Preparation, and Storage ............................................................ 31 
5.3 Dose, Route of Administration, and Schedule ............................................................. 32 
5.4 Alteration of Dose/Schedule Due to Toxicity .............................................................. 33 
5.5 Concurrent Medications ............................................................................................... 33 
5.5.1 
Standard of Care Medication ........................................................................ 34 
5.5.2 
Immunosuppressives .................................................................................... 35 
5.5.3 
Angiotension Pathway Antihypertensives .................................................... 35 
5.5.4 
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin .................. 36 
5.5.5 
Corticosteroids .............................................................................................. 36 
5.6 Prohibited Medications and Non-Drug Therapies ........................................................ 37 
6 
Study Procedures .......................................................................................................... 38 
6.1 Screening Procedures (Day -28 to Day 0) .................................................................... 38 
6.2 Study Enrollment Procedures ....................................................................................... 39 
6.3 Double-Blind Treatment Period ................................................................................... 39 
6.4 Open-Label Extension .................................................................................................. 45 


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6.5 Continuation Phase – For Subjects in Countries where Belimumab is not 
Commercially Available ......................................................................................... 45 
6.6 Exit Visit ....................................................................................................................... 48 
6.7 8-Week Follow-up Visit ............................................................................................... 48 
6.8 Unscheduled Visits ....................................................................................................... 48 
6.9 Renal Biopsies .............................................................................................................. 48 
6.10 
Laboratory Tests ..................................................................................................... 49 
6.10.1 
Pharmacokinetics .......................................................................................... 50 
6.10.2 
Immunogenicity ............................................................................................ 50 
6.11 
Withdrawal of Subjects from Treatment ................................................................ 50 
6.12 
Subject Unblinding ................................................................................................. 51 
7 
Adverse Event Reporting .............................................................................................. 52 
7.1 Definitions .................................................................................................................... 52 
7.2 Reporting Adverse Events to the Sponsor .................................................................... 53 
7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events) ....................... 53 
7.4 Laboratory Abnormalities as Adverse Events .............................................................. 53 
7.5 Progressive Multifocal Leukoencephalopathy ............................................................. 53 
7.6 Suicidality Assessment ................................................................................................. 54 
7.6.1 
Possible Suicidality Related Questionnaire (PSRQ) .................................... 55 
7.7 Reporting a Pregnancy .................................................................................................. 55 
7.8 Investigator Evaluation of Adverse Events .................................................................. 55 
7.9 Follow-up of Adverse Events ....................................................................................... 56 
7.10 
Post Study Serious Adverse Events ........................................................................ 56 
7.11 
Reporting Serious Adverse Events to Regulatory Authorities and Institutional 
Review Boards/Independent Ethics Committees ................................................... 57 
8 
Endpoints and Statistical Analysis ............................................................................... 58 
8.1 General Statistical Considerations ................................................................................ 58 
8.2 Randomization Procedure and Assignment to Treatment Groups ............................... 58 
8.3 Data Monitoring Committee (DMC) ............................................................................ 59 
8.4 Sample Size Rationale .................................................................................................. 59 
8.5 Efficacy ......................................................................................................................... 59 
8.5.1 
Primary Efficacy Endpoint ........................................................................... 59 
8.5.2 
Primary Efficacy Analysis ............................................................................ 61 
8.5.3 
Secondary Efficacy Endpoints ...................................................................... 63 
8.5.4 
Other Efficacy Endpoints ............................................................................. 63 
8.5.5 
Secondary Efficacy Analyses ....................................................................... 65 
8.5.6 
Other Efficacy Analyses ............................................................................... 65 
8.6 Safety ............................................................................................................................ 65 


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8.6.1 
Definition of Safety Variables ...................................................................... 65 
8.6.2 
Analysis of Safety Variables ........................................................................ 65 
8.7 Pharmacokinetics .......................................................................................................... 66 
8.7.1 
Definition of Pharmacokinetic Evaluation ................................................... 66 
8.7.2 
Analysis of Pharmacokinetics ...................................................................... 66 
9 
Pharmacogenetics (PGx) .............................................................................................. 66 
10 
Study Administration .................................................................................................... 67 
10.1 
Informed Consent ................................................................................................... 67 
10.2 
Institutional Review Board Review/Independent Ethics Committee Review and 
Approval ................................................................................................................. 67 
10.3 
Protocol Compliance .............................................................................................. 67 
10.4 
Protocol Revisions .................................................................................................. 68 
10.5 
Data Collection and Management .......................................................................... 68 
10.6 
Study Monitoring .................................................................................................... 69 
10.7 
Drug Accountability ............................................................................................... 69 
10.8 
Retention of Records .............................................................................................. 69 
10.9 
Financial Disclosure ............................................................................................... 69 
10.10 Publication Policy ................................................................................................... 69 
10.11 Study or Study Site Termination ............................................................................ 70 
11 
References .................................................................................................................... 71 
List of Appendices .................................................................................................................... 75 
 


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List of Tables 
Table 1-1  
Renal Endpoints at Week 52-Phase 3 Trials ................................................. 24 
Table 5-1  
Recommended oral prednisone taper regimen .............................................. 35 
Table 6-1  
Study Calendar - Double-Blind Treatment Period (Screen-Week 52) ......... 41 
Table 6-2  
Study Calendar - Double-Blind Treatment Period (Week 56-104) .............. 43 
Table 6-3  
Study Calendar- 6-Month Open-Label Extension ........................................ 46 
Table 6-4  
Study Calendar- Continuation Phase (For Subjects in Countries where 
Belimumab is not Commercially Available) ................................................ 47 
Table 6-5  
PK Visit Days and Sample Times ................................................................. 50 
 
 


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List of Figures 
Figure 1-1  
Study schematic ............................................................................................ 12 
 
 
 
 


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List of Abbreviations 
aCL 
anticardiolipin 
ACE 
angiotensin converting enzyme 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody  
ARB 
angiotensin receptor antagonists/blockers 
Anti-dsDNA anti-double-stranded DNA 
Anti-Sm 
anti-Smith antibody  
Anti-TNF 
anti-Tumor Necrosis Factor 
AST 
aspartate aminotransferase  
AUC 
area under the serum drug concentration-time curve 
AUCi 
area under the curve for an individual subject 
AZA 
Azathioprine 
bid 
twice a day 
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 
compact disc 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CRR 
complete renal response 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
CYC 
Cyclophosphamide 
CVA 
cerebrovascular accident 
dL 
deciliter 
DMC 
Data Monitoring Committee 
DMID  
Division of Microbiology and Infectious Diseases 
DNA 
deoxyribonucleic acid 
dsDNA 
double stranded DNA 
eCRF 
electronic case report form 
ECL 
electrochemiluminescence 
EDC 
electronic data capture 
ELISA 
Enzyme-linked immunosorobent assay 
ESRD 
end stage renal disease 
EU 
European Union 
FACS 
florescence activated cell sorting 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 


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GFR 
glomerular filtration rate 
GGT 
gamma glutamyl transferase 
GSK 
GlaxoSmithKline Pharmaceuticals 
HDCS 
High dose corticosteroids 
Hep-2 
Human Epithelial Cell Line 2 
HGS 
Human Genome Sciences, Inc. 
HIV 
human immunodeficiency virus 
hpf 
high power field 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IM 
intramuscular 
IRB 
Institutional Review Board 
ISN 
International Society for Nephrology 
ITT 
intention to treat 
IU 
international unit 
IUD 
intrauterine device 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
IWRS 
Interactive Web Response System  
KDOQI 
Kidney Disease Outcomes Quality Initiative 
kg 
kilogram 
LDH 
lactic dehydrogenase 
LOCF 
last observation carried forward 
MDD  
major depressive disorder 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MTX 
methotrexate 
μg 
microgram 
mg 
milligram 
mL 
milliliter 
mmHG 
millimeters of mercury 
NR 
no response 
NSAIDs 
non-steroidal anti-inflammatory drugs 
NWHIC 
National Women’s Health Information Center 
OMHRC  
Office of Minority Health Resource Center 
PGA 
Physician’s Global Disease Assessment 
PGx 
pharmacogenetics 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PRR 
partial renal response 
PSRHQ 
possible suicidality-related history questionnaire 
PSRQ 
possible suicidality related questionnaire 


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PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell 
RPS 
Renal Pathology Society 
SAE 
serious adverse event 
SAS 
statistical analysis system 
SC 
subcutaneous 
SELENA 
Safety of Estrogen in Lupus National Assessment trial 
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 
TACI-Fc 
transmembrane activator attached to Fc portion of an immunoglobulin  
tid 
three times daily 
TNF 
tumor necrosis factor 
ULN 
upper limits of normal 
USA 
United States of America 
USAN/INN 
United States adopted names/international nonproprietary name 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1 Background 
1.1 
Disease Background Relevant to Clinical Study 
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 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 (Jimenez et al, 
2003). In community-based studies among Asians, the prevalence (per 100,000) of SLE 
ranged from 3.2 to 70.4 (Thumboo and Wee, 2006). The disease onset is generally between 
the ages of 20 and 40. 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). 
Approximately 35% of all adult patients with SLE develop clinically significant lupus 
nephritis and despite improvements in both diagnosis and treatment over the last few decades 
it remains an indicator of poor prognosis (Gordon et al, 2009; Waldman and Appel, 2006). 
Manifestations of lupus nephritis include proteinuria, elevations in serum creatinine and the 
presence of urinary sediment. Alongside these clinical manifestations, morphological changes 
can be observed in renal biopsy specimens. In 1975 the WHO proposed a classification 
system for renal biopsies in SLE which was continually revised by them up until 1995. In 
2004 updated criteria jointly developed by the International Society of Nephrology and the 
Renal Pathology Society were published (Weening et al, 2004). Within the 5 overall classes, 
Classes I and II reflect disease restricted to mesangial abnormalities. Classes III and IV 
represent either focal (< 50% glomeruli involved - Class III) or diffuse (≥ 50% glomeruli 
involved - Class IV) segmental or global glomerulonephritis. Class V represents membranous 
disease with Class VI representing advanced sclerosis. Classes I and II are rarely accompanied 
by clinical manifestations and there is no activity in Class VI only damage, so therapy has 
traditionally focused on Classes III-V. 
Belimumab (BENLYSTA™) administered IV is approved in the United States (US), Canada, 
and the European Union (EU) for the treatment of adult patients with active autoantibody-
positive SLE who are receiving standard therapy; patients with severe active lupus nephritis 


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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 IV 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™; BENLYSTA™) 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 pharmacology, pharmacokinetic (PK), and toxicology data generated with 
belimumab are provided in the Investigator’s Brochure (IB).  
1.2.2 Clinical Experience with Belimumab 
Belimumab administered as an IV infusion has been studied in SLE patients in 1 Phase 1 trial 
(LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial (LBSL02) and 
2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 (HGS1006-C1057) 
and BLISS 76 (HGS1006-C1056)], and in RA patients in a Phase 2 double-blind, 
placebo-controlled trial (LBRA01).  
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the basis 
of the approval of IV 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 was also observed. 
Treatment with belimumab plus standard of care 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 of care 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. 


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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 subjects 
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.  
1.3 
Rationale for the Study 
Current standard of care treatment for lupus nephritis consists of corticosteroids and 
immunosuppressants. Several studies have now been conducted in lupus nephritis; however at 
this time no therapies have been approved for lupus nephritis. In the Euro-lupus trial, a low 
dose IV cyclophosphamide (CYC) regimen achieved similar clinical results with respect to 
treatment failures, renal remission and renal flares when compared to a high dose IV CYC 
regimen (Houssiau et al, 2002). A recent systematic review of recent trials in lupus nephritis 
concluded that MMF is as effective as CYC in inducing disease remission (Touma et al, 
2011). 
Belimumab treatment at a dose of 10 mg/kg in combination with standard SLE therapy 
demonstrated a statistically significant and clinically meaningful reduction in SLE disease 
activity vs placebo plus standard SLE therapy at week 52 in 2 Phase 3 clinical studies 
(C1056/BLISS76 and C1057/BLISS52) in subjects with active, autoantibody-positive SLE. 
While the 2 Phase 3 studies did explore the effect of belimumab on individual organ systems, 
these findings were limited for the renal organ domain as subjects were excluded if they had 
severe active lupus nephritis. However, 267 subjects (16%) included in the Phase 3 trials had 
renal involvement by SELENA SLEDAI (comprising hematuria, proteinuria, pyruia and/or 
urinary casts). In a post-hoc analysis of the pooled data (Table 1-1), there were trends towards 
SELENA SLEDAI renal organ domain improvement, especially in the subgroup of subjects 
who were anti-dsDNA positive and had low C3 and/or low C4 at baseline. There were 
favorable trends of greater reduction in proteinuria, hematuria, pyuria, and lower renal flare 
rate in the belimumab treatment groups versus placebo. Understanding whether belimumab 
plus standard of care can reduce the disease activity in subjects with active lupus nephritis 
subjects is of interest to prescribing physicians and health authorities.  


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Table 1-1  
Renal Endpoints at Week 52-Phase 3 Trials 
 
Phase 3 Studies Pooled 
 
Placebo  
N = 562 
1 mg/kg  
N = 559 
10 mg/kg  
N = 563 
SELENA SLEDAI Renal Improvement1 
In patients with the following at baseline: 
 
 
Renal involvement2 
39/92 (42.4%) 
43/90 (47.8%) 
42/85 (49.4%) 
Renal involvement + high activity3 
37/87 (42.5%) 
39/86 (45.3%) 
42/82 (51.2%) 
Renal involvement + anti-dsDNA+low C4  
21/62 (33.9%) 
24/60 (40.0%) 
28/60 (46.7%) 
Proteinuria 
(n = 116) 
(n = 110) 
(n = 112) 
Median % reduction5 
27.5 
48.3 
39.1 
Renal Flare  
 
 
 
Subjects with renal flare6 
16 (2.8%) 
14 (2.5%) 
8 (1.4%) 
Relevant Biomarkers 
 
 
 
Anti-dsDNA7 
 
 
 
Positive to Negative 
19/280 (6.8%) 
47/314 (15.0%) 
50/313 (16.0%) 
C38 
 
 
 
Low to Normal/High 
30/176 (17.0%) 
51/193 (26.4%) 
77/202 (38.1%) 
C49 
 
 
 
Low to Normal/High 
40/218 (18.3%) 
86/246 (35.0%) 
115/259 (44.4%) 
1 
SELENA SLEDAI renal domain includes hematuria, proteinuria, pyuria, and urinary casts. 
2 
In subjects with renal involvement at baseline (dropout=failure). 
3 
In subjects with renal involvement and SELENA SLEDAI score ≥ 7 at baseline (dropout=failure). 
4 
In subjects with renal involvement and anti-dsDNA+/low complement at baseline (dropout=failure). 
5 
In subjects with > 0.5 g at baseline (LOCF). 
6 
Censored at last assessment or start of rescue medications. 
7 
Anti-dsDNA: Positive (≥ 30 IU/mL); Negative (< 30 IU/mL). 
8 
C3: Normal/High (≥ 900 mg/L); Low (< 900 mg/L). 
9 
C4: Normal/High (≥ 16 mg/dL); Low (< 16 mg/dL). 
TE24.1, TE26.1, TE26.2 (C1056); TE24.1, TE26.1, TE26.2 (C1057);  
TA46.7, TAC790, TAC340, TAC397, TA1 (ISE) 
 
In the 2 Phase 3 studies, several clinical measures of improvement including the primary 
efficacy endpoint at Week 52 (SLE responder index or SRI), SELENA SLEDAI reductions, 
severe flare risk reduction, and complement normalization generally favored the 10 mg/kg 
dose. Trends toward clinically significant steroid reduction were present for both doses. 
Additionally, there appeared to be a greater dose response in subjects with high disease and 
serological activity than in subjects with lower activity. There was no apparent dose-response 
in the safety profile of belimumab, with both doses being generally well-tolerated, further 
supporting the selection of 10 mg/kg belimumab as the recommended dose in combination 
with standard therapies. 


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The current study is designed to evaluate the efficacy (ie, induction and maintenance of renal 
remission) and safety of 10 mg/kg belimumab administered IV in combination with standard 
of care (including MMF, CYC, corticosteroids and AZA) in subjects with active lupus 
nephritis.  
2 Study Objectives 
• To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV or V using the 2003 ISN/RPS criteria. 
• To assess the safety and tolerability of belimumab plus standard of care versus placebo 
plus standard of care in adult subjects with lupus nephritis Class III, IV or V using the 
2003 ISN/RPS criteria. 
 
3 Study Design 
3.1 
Basic Design Characteristics 
This is a Phase 3, multi-center, multi-national, randomized, double-blind, placebo controlled 
study to evaluate the efficacy and safety of intravenous belimumab 10 mg/kg plus standard of 
care compared to placebo plus standard of care in adult subjects with active lupus nephritis.  
Subjects who meet the eligibility criteria during screening will be randomized to 1 of 2 
treatment groups in a 1:1 ratio: 10 mg/kg belimumab plus standard of care or placebo plus 
standard of care. The randomization of all eligible subjects will be stratified by their induction 
regimen (high dose cortiocsteroids [HDCS] plus CYC vs HDCS plus MMF) and race (black 
race vs other). Subjects will be dosed with study agent on Days 0 (baseline), 14, 28 and then 
every 28 days through 100 weeks with a final evaluation for the double-blind treatment period 
at 104 weeks. Approximately 464 lupus nephritis subjects will be randomized with a target of 
232 subjects in the belimumab treatment group and 232 in the placebo group. All subjects will 
receive background therapy consisting of one of the following standard of care regimens: 
• High Dose Corticosteroids (HDCS) + Cyclophosphamide (CYC) for induction therapy 
followed by AZA for maintenance therapy 
OR 
• HDCS + Mycophenolate Mofetil (MMF) for induction followed by MMF for maintenance 
therapy 
 
The standard of care medications are described in Section 5.5.1.  
All subjects will start the above induction therapy within 14 days prior to the baseline (Day 0) 
visit. This will allow subjects to be screened and potentially enrolled so they will not be 
excluded on the basis of necessary acute management. If an induction regimen has been 
received within 6 months prior to the screening visit, the subject will be excluded. The 


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primary efficacy endpoint of a renal response will be a composite endpoint including changes 
in urinary sediment, proteinuria, and renal function at Week 104. For the renal function 
assessments at baseline, Week 24, 48, 52, 76, 100 and 104, the glomerular filtration rate 
(GFR) will be based on the mean value of 2 contiguous 24 hour urine collections and 2 serum 
creatinine measurements (first serum creatinine collected at initial visit and the second sample 
taken 3 days later at the follow-up visit). Subjects will be provided with the materials for 
collecting the two 24 hour urine collections beginning the next morning following their initial 
clinic visit. On the third day following the initial visit, subjects will return to the clinic for the 
second serum creatinine sample. For all other study visits, GFR will be estimated using the 
simplified MDRD formula and the urinary protein: urinary creatinine will be used for 
proteinuria. 
For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections 
may be confounders. The urine collection may be postponed up to 14 days at the investigators 
discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during 
the 24 hour urine collection.  
Renal response will be measured as complete, partial, or no response based on study defined 
criteria (see Section 8.5). Week 104 renal response will be defined by a response at Week 100 
that is confirmed by a repeat measurement at Week 104.   
All subjects who discontinue treatment during the double-blind period (for reasons other than 
receipt of prohibited medications or doses of medications that result in treatment-failure 
designation or withdrawal of consent) should return for the scheduled visits through 
Week 104. For subjects who discontinue study treatment due to receipt of prohibited 
medications, an Exit visit should be completed approximately 4 weeks after the last dose of 
study agent and a Follow-up visit approximately 8 weeks after the last dose of study agent. 
In the event that a subject withdraws consent from the study, an attempt should be made to 
obtain consent for mortality status at Week 104. Any subject that withdraws consent for use 
and disclosure of research-related health information will be considered withdrawn from the 
study and not followed for mortality.  
Subjects who successfully complete the initial 104-week double blind period may enter into a 
6-month open-label extension. The Week 104 visit of the double-blind period will serve as the 
Day 0 visit for subjects entering the 6-month open-label extension. In the open-label 
extension, all subjects will receive 10 mg/kg belimumab every 28 days until Week 24, with a 
final evaluation at Week 28 (4 weeks after the last dose). The first dose on the open-label 
extension will be given at the Week 104 visit of the double-blind period following the 
completion of all Week 104 assessments. Subjects participating in the open-label extension 
will continue to be monitored for efficacy and safety as per the study calendar (see Table 6-3). 
Subjects who complete the 104-week double-blind period, but do not enter the open label 
extension will be required to return for an additional follow up visit 8 weeks after the last dose 
of study agent. All subjects who enter the open-label extension period and withdraw early 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.  


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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 belimumab. If belimumab is 
not commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under this protocol until belimumab becomes commercially available. 
4 Inclusion and Exclusion Criteria 
4.1 
Inclusion Criteria 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Males or females at least 18 years of age. 
2. Have a clinical diagnosis of SLE according to the American College of Rheumatology 
(ACR) criteria (Appendix 1). 
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV (excluding 
Class III(C), IV-S(C) and IV-g(C)), either with or without the presence of Class V, or pure 
Class V membranoususing the 2003 ISN/RPS criteria (Appendix 2); the biopsy must be 
performed in the 6 months prior to baseline (Day 0). Whenever possible, a tissue sample 
from the renal biopsy used to qualify the subject will be collected and sent to a central 
reading center; however, the tissue sample will not be shipped prior to nor be used for the 
purposes of randomization. 
4. Have unequivocally positive ANA test results defined as an ANA titer ≥ 1:80 (based on 
Hep-2 immunofluorescence assay) and/or a positive anti-dsDNA (≥ 30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results. 
5. Have documentation of active renal disease at screening requiring initiation of induction 
therapy with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) 
or mycophenolate mofetil (MMF) or other oral forms of mycophenolate. Induction 
therapy should be started no more than 14 days prior to the baseline visit (Day 0). The 
following factors will be used to define active renal disease: 
 
Urinary protein:creatinine ratio of ≥ 1.0 AND active urinary sediment as defined by 
≥ at least 1 of the following (in absence of menses and genitourinary tract infection).   
 
> 5 red blood cell (RBC)/high power field (hpf) (or above the laboratory reference 
range) 
 
> 5 white blood cell (WBC)/hpf (or above the laboratory reference range). 
 
Presence of cellular casts (RBC or WBC). 
 
Subjects without active urinary sediment are eligible if they meet at least 1 of the 
following criteria:  
 Have a confirmatory biopsy performed within 3 months prior to the baseline visit 
meeting the criteria outlined in criterion 3. 
 Have proteinuria ≥ 3.5 grams/day. 


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6. 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 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. 
7. 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. Subjects who have previously failed induction therapy with both CYC and MMF (or other 
forms of mycophenolate) based on the investigator’s opinion. If a subject has failed only 1 
of the 2 therapies for induction, they may be eligible for study inclusion if they are newly 
initiating the other induction therapy (ie, a subject who failed MMF is eligible if newly 
initiating induction therapy with CYC or a subject who failed CYC is eligible if newly 
initiating induction therapy with MMF). 


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2. Subjects who have previously received an induction therapy within 6 months prior to the 
screening visit. 
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 based on 
the Adverse Event Severity Grading Tables (Appendix 7). 
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, AZA, corticosteroids). 
5. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies. 
6. Have received treatment with belimumab at anytime.  
7. Received the following within 364 days of  baseline (Day 0):    
- 
Nitrogen mustard 
- 
Chlorambucil 
- 
Vincristine 
- 
Procarbazine 
- 
Etoposide 
- 
Abatacept 
- 
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, or LY2127399 [anti-BAFF]) 
- 
A biologic investigational agent (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. 
8. Received any of the following within 90 days of baseline (Day 0):   
- 
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab) 
- 
Interleukin-1 receptor antagonist (anakinra). 
- 
Intravenous immunoglobulin (IVIG). 
- 
Plasmapheresis. 
9. Received a non-biological investigational agent within 60 days of baseline (Day 0). 
10. Received a live vaccine within 30 days of baseline (Day 0). 
11. 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 baseline (Day 0). 
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic 
stem cell/marrow transplant or are due to receive transplantation. 
13. Subjects who have been on dialysis within 364 days of baseline (Day 0). 
14. An estimated glomerular filtration rate < 30 ml/min at the screening visit (using the 
simplified Modification of Diet in Renal Disease [MDRD] equation). 
15. 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. 
16. 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. 


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17. 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.   
18. 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 baseline (Day 0). 
- 
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of baseline (Day 0). 
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to baseline (Day 0).  
20. Have a historically positive test or test positive at screening for HIV antibody, hepatitis B 
surface antigen, or hepatitis C antibody.   
21. Have an IgA deficiency (IgA level < 10 mg/dL). 
22. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event Severity 
Grading Tables (Appendix 7) except for the following that are allowed: 
- 
Urinalysis (eg, proteinuria) 
- 
Hematuria 
- 
Pyuria 
- 
Casts 
- 
Hypoalbuminemia due to lupus nephritis. 
- 
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 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 the ALT and/or AST must be ≤ Grade 2. 
- 
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. (Note that WBC 
count should be obtained immediately prior to starting induction therapy. If immediate 
pre-induction WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used).  
23. 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 C-SSRS 
(Appendix 8) in the last 2 months or who in the investigator's opinion, pose a significant 
suicide risk. 
 


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5 Study Treatment Regimen 
5.1 
Study Agent Name and Formulation 
The common name of the study agent is BENLYSTA™. 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. 
The placebo control is prepared as a sterile and lyophilized product.  Upon reconstitution with 
4.8 mL SWFI, each vial will contain 0.13 mg/mL citric acid, 2.8 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 
 


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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 body weight in kilograms 
(kg) at baseline (Day 0) of this study. If a subject’s weight increases or decreases by more 
than 5% from their baseline (Day 0) weight on this study, the current weight should be used to 
calculate the dose of study agent administered. 
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 
(see Section 5.1), 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 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 6.12). 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 include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over 1 hour. 
Once randomized, subjects will be dosed with study agent on Days 0, 14, and 28 and every 
28 days days thereafter through 100 weeks of double-blind treatment. Following the final 
double-blind visit at Week 104, subjects who will have the option to continue in the 6-month 
open-label extension period (with first dose given at Week 104 visit). 
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 reaction, and monitor subjects 
closely. In the event of a serious reaction, study agent administration must be discontinued 
immediately and the appropriate medical therapy administered.  Subjects should be monitored 


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during and for an appropriate period of time after 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 also be 
informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek 
medical care should a reaction occur.   
5.4 
Alteration of Dose/Schedule Due to Toxicity 
The dose of study agent administered may not be altered. The rate of infusion may be slowed 
or interrupted if the subject appears to develop signs of adverse reaction or infusion-associated 
symptoms. 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 
definitely, possibly or probably 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 definitely, possibly or probably 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 protocol and also 
until resolution of the AE(s) (whichever is longer). All subjects should be monitored closely 
for infection. Increased vigilance for infection is recommended in subjects who experience 
IgG levels < 250 mg/dL, especially for prolonged periods; clinical judgment should be applied 
with respect to the appropriateness of continuing study therapy in these subjects. The Medical 
Monitor must be consulted before administering subsequent doses of study agent in subjects 
with IgG levels < 250 mg/dL. Study agent will be discontinued in subjects with IgG levels 
< 250 mg/dL that are associated with a severe or serious infection.  
5.5 
Concurrent Medications 
This section reviews medications which are allowed during the course of the study provided 
the guidelines below are followed. Anytime the concurrent medication guidelines are not 
followed, the subject will have study agent discontinued and will be considered a treatment 
failure (non-responder). 
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, SLE Flare 
Index and PGA) and laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, 
and complement) should be performed to document renal flare prior to instituting treatment 
that results in treatment failure designation.  
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. 


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5.5.1 Standard of Care Medication 
This section reviews the required induction and maintenance standard of care regimens. All 
subjects will receive background standard of care therapy consisting of either CYC plus 
HDCS for induction plus AZA for maintenance or MMF plus HDCS for induction followed 
by MMF for maintenance. Each investigator must refer to the country-specific label for each 
required medication and heed appropriate warnings and precautions. 
Cyclophosphamide and Azathioprine 
Cyclophosphamide (CYC) used for induction therapy will consist of 500 mg by IV infusion 
every 2 weeks for 6 infusions. Adjustments may be made for tolerability issues. For the 
maintenance period, AZA will be started 2 weeks after the last dose of CYC with a target dose 
of 2 mg/kg/day (not to exceed 200 mg/day) until study end. A prescribed dose greater than 
2 mg/kg/day is prohibited and considered to constitute treatment failure. It is recommended 
that dosing commence at 50 mg/day and increase by no more than 50 mg/day every week 
until the target dose is achieved. Adjustments may be made for tolerability issues. Subjects 
who develop Grade 3 or 4 leucopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a 
severe gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above a switch to 
MMF will be permitted. The use of mesna and/or leuprolide (leuprorelin) is permitted with 
CYC dosing in accordance with the usual practice of the investigator. 
Mycophenolate Mofetil 
MMF used for induction and maintenance therapy is recommended at a dose from 1-3 g/day 
orally through study end.  Dosing of MMF will start at 0.5 g twice a day (bid) for the first 
week, increase to 1 g bid for the second week, and then 1.5 g bid for the third and subsequent 
weeks. MMF will be taken morning and evening, before meals, with a glass of water. If 
tolerability issues are experienced with bid dosing, subjects may receive 1 g 3x/day (tid). If tid 
dosing not tolerated, the MMF dose may be reduced to as low as 1g/day. Subjects who 
develop a grade 3 or 4 neutropenia, following initiation of MMF will be permitted to reduce 
the dose to no less than 1g/day. A prescribed dose greater than 3 g/day is prohibited and 
considered to constitute treatment failure.  
After 6 months of therapy, the dose of MMF may be reduced to 1 g/day or subjects may be 
switched to AZA (target dose 2 mg/kg) for tolerability reasons. 
Mycophenolate sodium may be used in lieu of MMF for induction and maintenance therapy. 
A dose from 720 mg/day to 2160 mg/day orally is recommended. A dose greater than 
2160 mg/day is prohibited and considered to constitute treatment failure.   
The use of IV forms of mycophenolate is prohibited. 


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High Dose Corticosteroids 
At the outset of the study, all subjects must be on a daily corticosteroid regimen. 
The study recommended corticosteroid regimen includes 0-3 IV pulses of methylprednisolone 
500 mg-1000 mg/pulse followed by an oral prednisone dose of up to 60 mg/day. It is 
recommended that oral corticosteroids be tapered according to the Table 5-1. If necessary, it 
may take longer than 12 weeks to complete the taper.  
Note: All subjects must be receiving 10 mg of prednisone/day or less by Week 24 or they will 
be considered a treatment failure.  
Table 5-1  
Recommended oral prednisone taper regimen 
Study Week 
Reduced Dose (mg/day) 
0 
60 
2 
50 
3 
45 
4 
40 
5 
35 
6 
30 
7 
25 
8 
20 
9 
17.5 
10 
15 
11 
12.5 
12 
10 
 
5.5.2 Immunosuppressives 
The primary objective of this trial is to evaluate the efficacy of belimumab plus standard of 
care to reduce lupus nephritis disease activity. Other immunosuppressives (eg, Methotrexate 
[MTX]) will be allowed provided these are started prior to baseline and meet eligibility 
criteria. Dose alterations during the trial of these agents are permitted. Subjects who newly 
initiate immunosuppressives (with the exception of topical agents) after the baseline visit 
outside the induction regimen will be considered treatment failures.  
5.5.3 Angiotension Pathway Antihypertensives 
Investigators are encouraged to consider whether the subject might benefit from angiotensin 
pathway antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors or 
angiotensin receptor antagonists/blockers [ARBs]), or a combination therapy that includes 
these agents, to treat hypertension or SLE-related nephropathy. ACE inhibitor and ARB use is 
allowed in this study as described in this section. Since these medications may confound 
efficacy assessment by mimicking renal deterioration (eg, increased serum creatinine) or 
improving renal function (eg, beneficial remodeling of renal parenchyma), the following 
guidelines should be applied.  


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• Starting a new angiotensin pathway antihypertensive (ACE inhibitor, angiotensin receptor 
blocker) treatment after the Week 24 visit will cause the subject to be declared a treatment 
failure. 
• An angiotensin pathway antihypertensive will be considered new if the subject did not 
receive an angiotensin pathway antihypertensive at any time during the Day 0 to Week 24 
treatment interval. 
• An angiotensin pathway antihypertensive may be replaced with another angiotensin 
pathway antihypertensive at any time during the study. 
• Titration of dose to obtain therapeutic effect on blood pressure is allowed. 
• Initiation of new antihypertensive agents other than ACE inhibitors or ARBs is permitted. 
 
5.5.4 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin 
The use of NSAIDs is not recommended during the study, although use would not constitute a 
treatment failure   
5.5.5 Corticosteroids 
5.5.5.1 
Systemic Corticosteroids for Non-renal SLE-related Disease Activity 
All subjects should be receiving a corticosteroid dose of 10 mg or less by Week 24. Those 
who cannot be tapered to 10 mg or less by Week 24 will be declared treatment failures. No 
corticosteroid rescue treatment will be allowed from Week 76-104. Outside of this window, 
there will be a limited number of corticosteroid rescue treatments allowed if clinically 
indicated for non-renal SLE-related disease activity as outlined below.  
• Up to 2 corticosteroid rescue treatments will be allowed. 
• At least a 3-month interval is required between each treatment.  
• Each treatment should be no longer than 7 days in duration with the steroid dose returning 
to ≤ 10 mg/day or no more than 5 mg above their Week 24 dose (whichever is higher) by 
Day 7.   
• Up to 20 mg/day (prednisone or prednisone equivalent) is permitted.  
• There can be no concurrent worsening of renal disease. 
 
Any subjects who require corticosteroid rescue treatment exceeding the above criteria or who 
are unable to return to a dose no more than ≤ 10 mg/day or no more than 5 mg above their 
Week 24 dose (whichever is higher) will be considered treatment failures. Additionally, any 
subjects who have not returned to ≤ 10 mg/day by Week 76 will be considered treatment 
failures. 
5.5.5.2 
Systemic Corticosteroids for Renal SLE-related Disease Activity 
All subjects should be receiving a corticosteroid dose of 10 mg or less by Week 24. Those 
who cannot be tapered to 10 mg or less by Week 24 will be declared treatment failures. 


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The use of corticosteroids at a dose of > 15 mg/day for treatment of a renal flare (with or 
without concurrent non-renal SLE disease activity) is prohibited and the subject would be 
considered a treatment failure. 
5.5.5.3 
Systemic Corticosteroids for Non-SLE Disease Activity 
No corticosteroid rescue treatment will be allowed from Week 76-104. Outside of this 
window, there will be a limited number of corticosteroid treatments allowed if clinically 
indicated for the treatment of non-SLE disease activity (eg, allergic reaction).  
• Up to 3 corticosteroid treatments will be allowed. 
• At least a 3 month interval is required between each treatment.  
• Each treatment should be no longer than 3 days in duration with the steroid dose returning 
to ≤ 10 mg/day or no more than 5 mg above their Week 24 dose  (whichever is higher) by 
Day 7.  
• Up to 100 mg/day (prednisone or prednisone equivalent) will be permitted. 
 
Any subjects who require corticosteroid rescue treatment exceeding the above criteria or who 
are unable to return to a dose no more than ≤ 10 mg/day or no more than 5 mg above their 
Week 24 dose (whichever is higher) will be considered treatment failures. Additionally, any 
subjects who have not returned to ≤ 10 mg/day by Week 76 will be considered treatment 
failures. 
5.5.5.4 
Intraarticular Injections 
Intraarticular injections will be allowed as clinically indicated. However, no intraarticular 
corticosteroid injections should be given from Week 96-104 although this use would not 
constitute a treatment failure 
5.5.5.5 
Inhaled and Topical Corticosteroids 
Inhaled and topical steroids are allowed throughout the course of the study. 
5.6 
Prohibited Medications and Non-Drug Therapies 
Subjects who start the prohibited medications or therapies listed below 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: 
• New immunosuppressant agents (other than described in Section 5.5.1 as part of the 
induction and maintenance regimens).  
• Corticosteroid use outside of the limits described in Section 5.5.5. 
• 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.  
• Anti-TNF therapy (eg, adalimumab, etanercept, infliximab). 


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• Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist [anakinra]). 
• Intravenous immunoglobulin (IVIG).    
• Plasmapheresis. 
 
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, PGA, and 
laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, and complement) 
should be performed to document renal flare prior to instituting treatment that results in 
treatment failure designation as defined in Sections 5.5 and 5.6. 
5.6.1.1 
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. These subjects 
should be followed according to the study protocol until the study endpoint is reached 
(Week 104 or until receipt of a prohibited medication or dose resulting in treatment failure 
designation). 
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 
(Appendix 6) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject. 
Refer to the Study Calendar (Table 6-1, Table 6-2, and Table 6-3), Study Procedures Manual 
and Central Laboratory Manual for additional information. 
6.1 
Screening Procedures (Day -28 to Day 0) 
The following assessments are required at screening: 
• Demographics. 
• Medical history. 
• Complete physical examination (including vital signs). 
• 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 5 – Laboratory Tests) 
- 
Hematology. 
- 
Modified Chem 20 (non-fasting). 


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- 
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). 
- 
Autoantibodies (ANA and anti-dsDNA). 
- 
Biological Markers (Complement C3, C4). 
- 
Serum Immunoglobulin isotypes (IgG, IgM, IgA). 
- 
HIV antibody, hepatitis B surface antigen, and hepatitis C antibody testing. 
- 
PT/PTT 
• Urine sample for: 
- 
Urinary protein: urinary creatinine ratio. 
- 
Locally performed urinary microscopy and routine urinalysis. 
• Renal biopsy result (should be from a renal biopsy obtained in the 6 months prior to 
baseline (Day 0). Whenever possible, a tissue sample from the renal biopsy used to qualify 
the subject will be collected and sent to a central reading center; however, the tissue 
sample will not be shipped prior to nor be used for the purposes of randomization. 
• Suicidality assessment by using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Screening assessment form (see Section 7.6 and Appendix 8). 
• 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 Response System 
(IWRS). Subjects will be randomized in a 1:1 ratio to treatment with either 10 mg/kg 
belimumab plus standard of care or placebo plus standard of care. Randomization of all 
eligible subjects will be stratified by their induction regimen (HDCS plus CYC vs HDCS plus 
MMF) and race (black race vs other). There is race stratification in this study because race 
may be an important factor related to outcomes in patients with lupus nephritis. Race should 
be self-designated.  
6.3 
Double-Blind Treatment Period 
Subjects will be evaluated at the study site during the scheduled study visits as outlined in the 
Study Calendar (Table 6-1 and Table 6-2). Time windows are provided for each study visit to 
allow flexibility in site and subject scheduling. All study visits should occur within the visit 
window of the scheduled study visit. 
At baseline (Day 0), the subject will be randomized and receive the first dose of study agent. 
Visits to the study sites for clinical evaluation, disease activity assessment, and laboratory 
sampling will occur every 28 days (calculated from the Day 0 dose) through Week 104. 
All efforts should be made to retain subjects on schedule, based on the date of their Day 0 
dose. During the double-blind treatment period, study agent is administered at every 


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scheduled visit through Week 100. The final efficacy evaluation for the double-blind portion 
of the study will occur at Week 104.  
Subjects who complete the double-blind period through Week 104 will be given the option to 
receive belimumab in the 6-month open-label extension.   
• Subjects who complete the 104-week double-blind period, but do not enter the open label 
extension, will not have study agent administered at Week 104. Assessments should be 
completed for the Week 104/Exit visit, and then the subject should return in 4 weeks for 
the Follow-up Visit. 
• Subjects who wish to continue in the open-label extension, will have study agent 
administered at the Week 104 visit after all Week 104 assessments are performed (refer to 
Section 6.4 below). 
 
All subjects who discontinue treatment during the double-blind period (for reasons other than 
receipt of prohibited medications or doses of medications that result in treatment-failure 
designation or withdrawal of consent) should return for the scheduled visits through 
Week 104. At a minimum, survival status should be collected at Week 104. 
For subjects who discontinue study treatment due to receipt of prohibited medications or 
doses of medications that result in treatment failure designation, and subjects who discontinue 
treatment and do not return for scheduled visits through Week 104, an Exit visit should be 
completed approximately 4 weeks after the last dose of study agent and a Follow-up visit 
completed approximately 8 weeks after the last dose of study agent.  
In the event that a subject withdraws consent during the double-blind treatment period, an 
attempt should be made at the time of consent withdrawal to obtain consent to collect survival 
status at Week 104. Any subject that withdraws consent for use and disclosure of research-
related health information will be considered withdrawn from the study and not followed for 
mortality.  


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Table 6-1  
Study Calendar - Double-Blind Treatment Period (Screen-Week 52) 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
 
Study Day 
 
 
-28 days 
 
0 
 
14±3  
days 
28±3  
days 
56±7  
days 
84± 7 days 
112±7 days 
140± 7 days 
168± 7 days 
 
196± 7 days 
224± 7days 
252± 7days 
280± 7days 
308± 7days 
336± 7days 
 
364± 7days 
 
Study Week 
Wk  
-4 
Wk  
0 
Wk 
0  
+ 
3d 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
WK 
20 
Wk 
24 
Wk 
24  
+ 
3d 
Wk 
28 
Wk 
32 
Wk 
36 
WK
40 
Wk 
44 
Wk 
48 
Wk 
48 
+ 
3d 
Wk 
52 
Wk 
52 
+ 
3d 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLE History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Therapy History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy ReportA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SELENA SLEDAI, SLE Flare 
Index and PGA 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
SLICC Damage 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
C-SSRS Screening/Baseline  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Since Last VisitB 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Record Concurrent Medications 
X 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-driven Physical Exam 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
WeightC 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Record/Assess Adverse Events 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Laboratory Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry 
(non-fasting)D 
X 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Serum CreatinineE 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
x 
UrinalysisF 
X 
x 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Urinary MicroscopyF 
X 
x 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Spot urine  
X 
x 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
24-hour UrineE  
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
BLyS protein (baseline only) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy TestG 
X 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
ANA 
X 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Complement (C3/C4), anti-
dsDNA 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
acL (IgA, IgG, IgM isotypes)  
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 


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Screening 
Baseline 
Double-Blind Treatment Period 
 
 
 
Study Day 
 
 
-28 days 
 
0 
 
14±3  
days 
28±3  
days 
56±7  
days 
84± 7 days 
112±7 days 
140± 7 days 
168± 7 days 
 
196± 7 days 
224± 7days 
252± 7days 
280± 7days 
308± 7days 
336± 7days 
 
364± 7days 
 
Study Week 
Wk  
-4 
Wk  
0 
Wk 
0  
+ 
3d 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
WK 
20 
Wk 
24 
Wk 
24  
+ 
3d 
Wk 
28 
Wk 
32 
Wk 
36 
WK
40 
Wk 
44 
Wk 
48 
Wk 
48 
+ 
3d 
Wk 
52 
Wk 
52 
+ 
3d 
Anti-Sm, antiC1qH 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Serum IgG 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
Serum IgA & IgM 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
PT/PTT 
x 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
HIV, HBsAg and hepatitis C 
antibody 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic SamplingI 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
x 
 
Immunogenicity (anti-
belimumab antibody) 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Peripheral B lymphocytes 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
Pharmacogenetics Sampling 
(consenting subjects only)J 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Agent Administration 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
ABiopsy report indicating proliferative lupus nephritis.  Should be from a renal biopsy obtained in the 6 months prior to baseline (Day 0).  Whenever possible, a tissue sample from the renal 
biopsy used to qualify the subject will be collected and sent to a central reading center; however, the tissue sample will not be shipped prior to nor be used for the purposes of randomization 
B The Columbia-Suicidality Severity Rating Scale (C-SSRS) Since Last Visit form (See Appendix 9) will be used at Day 0 and all subsequent visits. The C-SSRS Baseline/Screening form (See 
Appendix 8) is only used at Screening.  
CIf weight changes by more than 5% from baseline (Day 0) weight, the weight at the current visit should be used for calculating the dose. 
D Refer to Appendix 5 for a listing of laboratory assessments to be completed.  
ETwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  baseline, Weeks 24, 48 and 52.  The serum creatinine for these visits will be collected on 
the day of the initial visit and then 3 days after the initial visit. For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections  may be confounders.  The urine 
collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during the 24 hour urine collection. 
FRoutine urinalysis and urinary microscopy will be performed locally. 
GFor women of child-bearing potential, serum pregnancy test is required at screening. At subsequent visits, a urine pregnancy test is required. The results of the pregnancy test must be 
available prior to dosing. 
HSamples will be collected in all subjects at baseline (Day 0).  Thereafter, samples will only be collected in subjects with positive results at baseline. 
IFor PK sampling times, see Section 6.10.1. 
JPharmacogenetic sampling informed consent must be obtained prior to any blood being taken for PGx research. Sample should be drawn prior to dosing. 
 


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Table 6-2  
Study Calendar - Double-Blind Treatment Period (Week 56-104) 
 
 
Double-Blind Treatment Period 
 
 
 
Study Day 
392± 7days 
420± 7days 
448± 7days 
476± 7days 
504± 7days 
532± 7days 
 
560± 7days 
588± 7days 
616± 7days 
644± 7days 
672± 7days 
700± 7days 
 
Day 728/ Exit   
(4  weeks after 
last dose)A 
 
8 week follow-
up visit 
+7 daysB 
Unscheduled 
VisitC 
Study Week 
Wk 
56 
Wk
60 
Wk
64 
Wk 
68 
Wk 
72 
Wk 
76 
Wk 
76 + 
3 d 
Wk 
80 
Wk
84 
Wk
88 
Wk
92 
Wk 
96 
Wk 
100 
Wk 
100 
+ 3 d 
Wk  
104  
Wk 
104 + 
3 d 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SELENA SLEDAI, SLE Flare Index 
and  PGA 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
x 
SLICC Damage 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
C-SSRS Since Last Visit 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
Record Concurrent Medications 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
Symptom-driven Physical 
Examination 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
WeightC 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
Record/Assess Adverse Events 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry (non-
fasting)D 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
Serum CreatinineE 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
UrinalysisF 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
Urinary MicroscopyF 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
Spot urine  
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
24-hour UrineE  
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
x 
 
 
 
Pregnancy TestG 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
Complement (C3/C4), anti-dsDNA 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
ANA, acL (IgA, IgG, IgM isotypes) 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
Anti-Sm, antiC1qH 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
Serum IgG 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
x 
 
 
 
Serum IgA & IgM 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
PT/PTT 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
Pharmacokinetic SamplingI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
Immunogenicity (anti-belimumab 
antibody) 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
x 
 
Peripheral B lymphocytes 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
Study Agent  Administration 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
If 
entering 
extension 
 
 
 


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AFor subjects completing all 100 weeks of treatment and continuing into the 6-month open-label extension, the Week 104 visit will also serve as Day 0 visit of the 6-month open-label 
extension. For subjects discontinued from the double-blind study early or subjects who are not continuing into the open label extension, the Week 104/Exit visit will occur approximately 4 
weeks after the last dose of study agent. Only subjects who wish to continue in the open-label extension study will have study agent administered at the Week 104 visit after the completion of 
Week 104 assessments. 
BThe 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 
CIf weight changes by more than 5% from their Baseline (Day 0) weight, the weight at the current visit should be used for calculating the dose. 
D Refer to Appendix 5 for a listing of laboratory assessments to be completed.  
ETwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  Weeks 76, 100 and 104. The serum creatinine for these visits will be collected on the day 
of the initial visit and then 3 days after the initial visit. For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections may be confounders.  The urine 
collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during the 24 hour urine collection. 
F Routine urinalysis and urinary microscopy will be performed locally. 
GFor women of child-bearing potential, a urine pregnancy test is required. The results of the urine pregnancy test must be available prior to dosing. 
HSamples will only be collected in subjects with positive results at baseline. 
IFor PK sampling times, see Section 6.10.1. 
 


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6.4 
Open-Label Extension 
Subjects who successfully complete the initial 104-week double blind period and complete the 
Week 104 assessments may enter into a 6-month open-label extension. The Week 104 visit of 
the double-blind period will serve as the Day 0 visit for subjects entering the 6-month 
open-label extension. In the open-label extension, all subjects will receive 10 mg/kg 
belimumab every 28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the 
last dose). The first dose on the open-label extension will be given at the Week 104 visit of the 
double-blind period after the completion of Week 104 assessments. Subjects participating in 
the open-label extension will continue to be monitored for efficacy and safety as per the study 
calendar (see Table 6-3).  
During the open-label extension, the investigator may adjust concurrent medications (add, 
eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications and 
prohibited doses of medications as outlined in Sections 5.5 and 5.6 will still apply. 
All subjects who withdraw early from the open-label extension 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.  
6.5 
Continuation Phase – For Subjects in Countries where Belimumab 
is not Commercially Available 
Subjects who complete dosing in the 6-month open-label extension and 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 this protocol until belimumab becomes 
commercially available. The Day 168/Week 24 visit from the 6-month open-label extension 
will serve as the Day 0 visit for subjects entering the continuation phase. Subjects will 
continue to receive belimumab every 28 days until belimumab becomes commercially 
available. The schedule of assessments representing a 48 week treatment period is provided in 
Table 6-4.   
During the continuation phase, the investigator may adjust concurrent medications (add, 
eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications as 
outlined in Section 5.6 will still apply. 


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Table 6-3  
Study Calendar- 6-Month Open-Label Extension  
Open Label Extension 
 
 
 
Study Day 
 
Day 0A 
Day 28±3  
days 
Day 56±7  
days 
Day 84± 7 days 
Day 112±7 days 
Day 140± 7 days 
Day 168± 7 days 
Day 196± 
7days/Exit B 
(4 weeks  
after last dose)  
8 week follow-
up visit 
+7 daysC 
Study Week 
 
Wk 
4 
Wk  
8 
Wk 
12 
Wk 
16 
WK 
20 
Wk 
24 
Wk  
28 
 
Clinical Assessments 
See Week 104 Visit  
in Double-Blind Treatment Period 
 
 
 
 
 
 
 
 
SELENA SLEDAI, SLE Flare Index and  PGA 
 
 
 
 
 
 
x 
 
SLICC Damage 
 
 
 
 
 
 
x 
 
Record Concurrent Medications 
x 
x 
x 
x 
x 
x 
x 
x 
Symptom-driven Physical Examination 
 
 
 
 
 
 
x 
 
Weight 
x 
x 
x 
x 
x 
x 
x 
 
Record/Assess Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments  
 
 
 
 
 
 
 
 
Hematology and chemistry (non-fasting)D 
 
 
x 
 
 
x 
x 
x 
UrinalysisE 
 
 
x 
 
 
x 
x 
x 
Urinary MicroscopyE 
 
 
x 
 
 
x 
x 
x 
Spot Urine 
 
 
x 
 
 
x 
x 
x 
Pregnancy TestF 
x 
x 
x 
x 
x 
x 
x 
x 
C3/C4, anti-dsDNA 
 
 
 
 
 
x 
x 
 
Autoantibodies (acL, anti-Sm, ANA, antiC1q) 
 
 
 
 
 
x 
x 
 
Serum IgG 
 
x 
 
 
 
x 
x 
 
Serum IgA & IgM 
 
 
 
 
 
x 
x 
 
Pharmacokinetic samplingG 
 
 
 
 
 
 
 
x 
Immunogenicity (anti-belimumab antibody) 
 
 
 
 
 
x 
 
x 
Peripheral B lymphocytes 
 
 
 
 
 
x 
x 
 
Study Agent Administration 
x 
x 
x 
x 
x 
x 
x 
If entering 
continuation 
 
 
ADay 0 of the extension portion of the trial is the Week 104 study visit of the double-blind treatment period, and represents the first belimumab administration for those subjects continuing on 
the 6 month open-label extension. 
B For subjects who discontinue from the study, an Exit visit should be completed 4 weeks after the last dose of study agent. 
C The 8-week follow-up visit is to occur approximately 8 weeks after last dose of study agent for subjects withdrawing early from the open-label extension and for subjects who complete the 
open label extenstion and will not receive commercially available belimumab (in countries where available) or will not receive belimumab in the continuation phase (in countries where 
belimumab is not commercially available).   
DRefer to Appendix 5 for a listing of laboratory assessments to be completed.  
ERoutine urinalysis and urinary microscopy will be performed locally. 
FFor women of child-bearing potential, a urine pregnancy test is required. The results of the urine pregnancy test must be available prior to dosing 
GFor PK sampling times, see Section 6.10.1. 


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Table 6-4  
Study Calendar- Continuation Phase (For Subjects in Countries where Belimumab is not Commercially Available)  
Study Day 
Day 0A 
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 daysE 
ExitB 
8-week 
Follow-up  
+ 7 DaysC 
Study Week 
See Week 28 
Visit  
in Open-Label 
Extension 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
 
 
Record Concurrent Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record/Assess Adverse Events   
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy TestD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Immunogenicity (anti-belimumab antibody) 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Study Agent Administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ADay 0 of the extension portion of the trial is the Week 28 visit of the open-label extension, and represents the first belimumab administration for those subjects participating in the continuation 
phase. 
BAny 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 The 8-week follow-up visit is to occur approximately 8 weeks after last dose of study agent for subjects who withdraw from the continuation phase and will not be receive commercially 
available belimumab. 
DFor women of child-bearing potential, a urine pregnancy test is required. The results of the urine pregnancy test must be available prior to dosing 
 
This calendar represents a yearly (48 week) ongoing visit schedule until the subject terminates the study.  Week 4 of this calendar represents the next visit (after Week 28 from the 6-month 
open-label extension) for subjects continuing in this protocol where belimumab is not commercially available. Following completion of the Week 48 visit, for subjects in countries where 
belimumab is still not commercially available and wish to continue treatment, the study calendar will be repeated for subsequent years starting with the Week 4 visit. 
 


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6.6 
Exit Visit 
Subjects who drop out and do not complete the study must 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 104 visit will be 
performed for the Exit visit. During the open-label extension, the assessments for the Week 28 
visit will be performed for the Exit visit. 
Refer to the Study Calendar (Table 6-2 and Table 6-3) for a list of procedures required at this 
visit.   
6.7 
8-Week Follow-up Visit 
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent.  
Refer to the Study Calendar (see Table 6-2, Table 6-3 and Table 6-4) for a list of procedures 
required at this visit. 
6.8 
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 lupus nephritis symptoms, AE reporting, or follow-up to a previously reported 
AE. 
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, SLE Flare 
Index and PGA), and laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, 
and complement) should be performed to document disease activity worsening (eg, renal 
flare/relapse) prior to instituting treatment that results in treatment failure designation as 
defined in Sections 5.5 and 5.6. 
Refer to the Study Calendar (Table 6-2 and Table 6-3) for a list of procedures required at 
these visits. Other assessments should be performed as clinically indicated.  
6.9 
Renal Biopsies 
Whenever possible, a tissue sample from the renal biopsy used to qualify the subject will be 
collected and sent to a central reading center; however, the tissue sample will not be shipped 
prior to nor be used for the purposes of randomization. Tissue from any renal biopsies 
performed as part of routine care anytime after baseline (Day 0) will also be collected, where 
possible, for a similar central reading.  


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6.10 Laboratory Tests 
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2, and Table 6-3). 
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): aCL (IgM, IgG, IgA isotypes), ANA, anti-Sm, anti-C1q, and 
serum immunoglobulin isotypes IgM/IgA.  
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis): 
• Peripheral 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. 
For the renal function assessments at Baseline (Day 0), Week 24, 48, 52, 76, 100 and 104, the 
glomerular filtration rate (GFR) will be based on creatinine clearance determined from the 
mean creatinine value of 2 contiguous 24 hour urine collections and 2 serum creatinine 
measurements (first serum creatinine collected at initial visit and the second sample taken 
3 days later at the follow-up visit). Subjects will be provided with the materials for collecting 
the two 24 hour urine collections beginning the next morning following their initial clinic 
visit. On the third day following the initial visit, subjects will return to the clinic for the 
second serum creatinine sample. For all other study visits, the simplified MDRD formula 
(below) will be used to estimate GFR (Levey et al, 2000): 
 
eGFR = 186 x serum creatinine-1.154x Age-0.203 x [1.212 if Black] x [0.742 if Female] 
 
The serum creatinine concentration is expressed in mg/dL. 
 
 
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 
sample (Ginsberg et al, 1983; Ruggenenti et al, 1998; KDOQI Clinical Practice Guidelines for 
Chronic Kidney Disease 2002; Price et al, 2005). Given this information, spot urinary protein: 
urinary creatinine ratio will be used for determining proteinuria in this study for renal 
response assessments and the SELENA SLEDAI (Appendix 3) disease activity indices when a 
24-hour urine sample is not collected.  
For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections 
may be confounders. The urine collection may be postponed up to 14 days at the investigators 
discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during 
the 24 hour urine collection. 


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Additional instructions regarding collection procedures are provided in the Study Procedures 
Manual and Central Laboratory Manual.  
6.10.1 Pharmacokinetics 
All randomized subjects will be sampled for serum belimumab levels. A blood sample for 
pharmacokinetic analysis will be drawn according to the time schedule below. 
Table 6-5  
PK Visit Days and Sample Times 
Day (Week) 
Time (Related to Dosing of Study Agent) 
Day 0 
Before the start of infusion 
Day 3 
Anytime during visit 
Day 14 (Week 2) 
Prior to dosing, 0-4 hours after the end of infusion 
Day 28 (Week 4) 
Prior to dosing, 0-4 hours after the end of infusion 
Day 56 (Week 8) 
Prior to dosing 
Day 168 (Week 24) 
Prior to dosing, 0 - 4 hours after the end of infusion 
Day 171 (Week 24 + 3 days) 
Anytime during visit 
Day 364 (Week 52) 
Prior to dosing 
Day 728/Exit (Week 104) 
Anytime during visit (or prior to dosing if going into the open-label 
treatment period of the study) 
8-week follow-up 
Any time during visit  
 
On days study agent is administered and blood samples for pharmacokinetic analysis are 
obtained after infusion, blood samples for pharmacokinetic analysis should not be taken from 
the same arm as that used for the administration of study agent. Samples may be obtained by 
venipuncture.   
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.  
6.10.2 Immunogenicity 
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at baseline (Day 0), and at any time 
on Week 8, Week 24, Week 52, Week 76 and Week 104 in the double-blind portion of the 
study. During the open-label extension, a sample will be collected at Week 24. Additionally, a 
sample will be collected 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.  
6.11 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 


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withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of 
subjects should be avoided. Subjects who withdraw from treatment/ study after receiving at 
least 1 dose of study agent will not be replaced.  
Subjects may be withdrawn from treatment for any of the following reasons: 
• Prohibited concurrent medication or prohibited dose of concurrent medication 
(see Sections 5.5 and 5.6). 
• Prohibited therapy. 
• Unacceptable toxicity (see Section 5.4). 
• Pregnancy. 
• Withdrawal of consent (including use and disclosure of research-related health 
information). 
 
All subjects who discontinue treatment during the double-blind period (for reasons other than 
receipt of prohibited medications or doses of medication that result in treatment failure 
designation or withdrawal of consent) should return for all scheduled visits through 
Week 104. 
All subjects who discontinue treatment during the double-blind period for receipt of 
prohibited medications or doses of medication that result in treatment failure designation, or 
discontinue treatment during the open-label extension or continuation phase 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.  
In the event that a subject withdraws consent during the double-blind period, an attempt 
should be made at the time of consent withdrawal to obtain consent to obtain survival status at 
Week 104. Any subject that withdraws consent for use and disclosure of research-related 
health information will be considered withdrawn from the study and not followed for 
mortality.  
6.12 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 study site personnel, the 
subject, the sponsor and the Contract Research Organization (CRO) 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. 
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. Unless the medical emergency is deemed to be life-threatening, the Medical Monitor 


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must be consulted prior to unblinding. 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. 
7 Adverse Event Reporting 
7.1 
Definitions 
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 
preexisting 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 does not mean that the 
event is expected with the underlying disease(s) or concomitant medications. 


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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 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 
Procedures Manual. SAE Worksheets should be sent either via the EDC system, if SAE EDC 
functionality is available or by facsimile to the HGS Drug Safety designee using the fax 
number listed on the SAE Worksheet.  
7.3 
Other Events Requiring Rapid Reporting (Protocol Specified 
Events) 
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (See Section 7.1). PSEs are 
recorded on SAE Worksheets and sent to the Drug Safety designee within 24 hours of site 
personnel becoming aware of the event.  
IgG < 250 mg/dL (Grade 4) is a protocol specified event for this protocol.  
7.4 
Laboratory Abnormalities as Adverse Events 
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). In 
addition, an IgG abnormality < 250 mg/dL (Grade 4) should be recorded as an adverse event 
(and SAE if meeting the criteria in Section 7.1). 
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in the Appendix, the lab test should be graded 
mild, moderate, severe or life-threatening as specified in Section 7.8. 
7.5 
Progressive Multifocal Leukoencephalopathy 
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 SLE 


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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 
sponsor. 
7.6 
Suicidality Assessment 
Some autoimmune diseases have an increased risk of suicidal behaviour and/or ideation 
(Bachen, 2009; Timonen, 2003; Stenager, 1992). In order to objectively assess suicidality in 
belimumab clinical programs the C-SSRS (Appendix 8 and Appendix 9) 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, 2009). Since active SLE 
and MDD may increase the risk of suicidal ideation or behavior before or during clinical 
studies, subjects participating in the double-blind portion of this study will be assessed for 
suicidality at every visit.  
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 question 3, 4 
or 5 on the C-SSRS prompts the completion of the 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 blinded portion of this study using C-SSRS (Refer to Appendix 8 and Appendix 9 for 
C-SSRS).  The C-SSRS is a brief measure which is designed to assess severity and change of 
suicidality by integrating both behaviour and ideation (Posner, 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 the study.  
Although assessment of suicidality using the C-SSRS will take place only during the 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. 


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7.6.1 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 behaviour 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 behaviour 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.  
7.7 
Reporting a Pregnancy 
Pregnancies must be reported to the Drug Safety designee within 24 hours of the site 
becoming aware of a pregnancy in a 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 three 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 Section 7.2 
7.8 
Investigator Evaluation of Adverse Events 
The investigator will evaluate all adverse events with respect to seriousness, severity 
(intensity or grade), and causality (relationship to study agent). The criteria for serious 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 7. If an AE does not have Adverse Event Severity 
Grading in Appendix 7, 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; significant 
    medical intervention is required. 
 
*Note – a severity assessment of Life-threatening is not necessarily the same as the 
seriousness criterion of Life-threatening. (See “Serious” Criteria Section 7.1.) The former 
means that the event is a potential threat to life. The latter means that the event is an 
immediate threat to life. 


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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     
 
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 AE eCRF or SAE worksheet is completed. The initial causality assessment 
may be revised as new information becomes available. 
7.9 
Follow-up of Adverse Events 
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.  
7.10 Post Study Serious Adverse Events 
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 having as definitely, possibly or probably related to 
study agent must be reported to the Drug Safety designee on the SAE worksheet as described 
in Section 7.2. Post study SAEs will not be documented on the AE eCRF. 


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7.11 Reporting Serious Adverse Events to Regulatory Authorities and 
Institutional Review Boards/Independent Ethics Committees 
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 (ie, 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.  
All unexpected SAEs that are reported to the Sponsor as related to the study agent will be 
reported to investigators and IRBs/IECs irrespective of whether, upon unblinding by the 
Sponsor, the subject is known to have received belimumab or placebo.  This will insure that 
investigators and other investigational site staff do not become unblinded during the study.  
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). Regulatory authorities that receive such reports 
directly from the Sponsor will receive unblinded reports for those events where the subject 
was receiving belimumab. 
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 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 
Cutaneous lupus erythematosus 
Glomerulonephritis membranoproliferative  
Glomerulonephritis membranous  
Glomerulonephritis proliferative  
Lupus encephalitis 
Lupus endocarditis 
Lupus enteritis 
Lupus hepatitis 
Lupus myocarditis 
Lupus nephritis 
Lupus pancreatitis 
Lupus pneumonitis 
Lupus vasculitis 
Nephritic syndrome 
Nephritis 
Neuropsychiatric lupus 
Pericarditis lupus 
Peritonitis lupus 
SLE arthritis 
Systemic lupus erythematosus 
Systemic lupus erythematosus rash 
 


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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 receive 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 data through the Week 104 visit for all 
subjects have been collected, verified and validated. All subjects and study site personnel will 
remain blinded until the final database lock, which will occur after data have been collected, 
verified and validated for all subjects completing the 8 week follow-up after the open-label 
extension.  
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. With this 
procedure, the primary and 2 major secondary endpoints will be evaluated for statistical 
significance based on a pre-specified sequence for interpretation: (1) renal response 
(complete, partial or no response) at Week 104 (2) renal response (complete, partial or no 
response) at Week 52, and (3) complete renal response at Week 104. 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 may be reported and considered descriptive. 
Analyses of other efficacy endpoints other than the major secondary efficacy endpoints will 
not be subject to any multiple testing procedure. All statistical tests will be 2-sided and 
performed at an overall significance level of 0.05. 
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. 
8.2 
Randomization Procedure and Assignment to Treatment Groups 
This is a Phase 3, multi-center, multi-national, 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 baseline (Day 0) visit to be 
randomized in a 1:1 ratio (via an Interactive Web Response System) to 1 of 2 treatment 
groups (10 mg/kg belimumab plus standard of care or placebo control plus standard of care.  
The randomization of all eligible subjects will be stratified by their induction regimen (HDCS 
plus CYC vs HDCS plus MMF) and race (black race vs other). 


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8.3 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will review unblinded safety data for 
this Phase 3 program on an ongoing basis until the data are locked and analyzed through 
Week 104 (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 DMC will review the data approximately every 4 months. At all times the sites 
and sponsor will remain blinded to treatment allocation. 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 and open-label extension portions of the study. 
Investigators and IRBs/IECs 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 any IgG < 250 mg/dL and 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. In addition, the DMC will receive information on all serious 
infections and all opportunistic infections, irrespective of relationship to study agent, within 
15 calendar days. 
8.4 
Sample Size Rationale 
It is expected that approximately 50% subjects on placebo plus standard of care will have 
complete (10%) or partial renal response (40%) at the Week 104 visit (Appel et al, 2009; 
Sinclair et al, 2007). It is expected that renal response in subjects on belimumab plus standard 
of care will be approximately 65% (Complete=15%, Partial=50%). Approximately 464 
subjects will be randomized to achieve 232 subjects in each treatment arm providing 
approximately 90% power to detect the difference in the primary endpoint, based on a 2-sided 
Van Elteren test at the 5% significance level (Zhao et al, 2008).  
8.5 
Efficacy 
8.5.1 Primary Efficacy Endpoint  
The primary efficacy endpoint is renal response at Week 104 measured as an ordinal response 
- complete renal response, partial renal response, or no renal response. Renal response is 
determined by changes in urinary sediment, proteinuria, and renal function. Week 104 renal 
response will be defined by a response at the Week 100 visit that is confirmed by a repeat 
measurement at the Week 104 visit.  Renal response is defined as follows: 
• Complete Renal Response: 
 
Calculated glomerular filtration rate (GFR) is within normal range  
 
AND 
 


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Inactive urinary sediment [< 5 RBCs/hpf and < 5 WBCs/hpf (or within the reference range 
of the laboratory); and no cellular casts (no RBC or WBC casts)   
 
AND 
 
Urinary protein:creatinine ratio < 0.5  
 
(Note: For subjects with a normal urinary sediment and GFR at baseline and only the 
presence of proteinuria (≥ 3.5 grams/day), the urine protein:creatinine ratio should be 
< 0.5 to meet the primary endpoint) 
 
• Partial Renal Response: 
 
Estimated or calculated GFR no more than 10% below the baseline value or within normal 
range  
 
AND 
 
RBCs/hpf ≥ 50% reduction from baseline or < 5 RBCs/hpf (or within the normal reference 
range for the central laboratory) and no RBC casts  
 
AND 
 
≥ 50% decrease in the urine protein:creatinine ratio with one of the following: 
- 
a urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0 
OR 
- 
a urine protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0 
 
• No Renal Response: 
 
Not meeting criteria for either complete or partial renal response 
 
The renal response at the Week 104 visit will be derived as below: 
Week 100 Renal Response 
Week 104 renal Response 
Final Week 104 Renal 
Response 
Complete 
Complete 
Complete 
Complete 
Partial 
Partial 
Partial 
Complete 
Partial 
Partial 
Partial 
Partial 
Complete 
No Response 
No Response 
Partial 
No Response 
No Response 
No response 
Complete 
No Response 
No response 
Partial 
No Response 
 


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Renal response at the Week 52 visit will be derived using a similar approach to that described 
above for the Week 104 visit, but using the Week 48 and Week 52 visits.  
For a complete response to be declared at Week 104, a calculated GFR (using sequential 
24 hour urine collections as defined in Section 6.10) should be available for both of the 
Week 100 and 104 assessments. However, if a calculated GFR is only available for one of the 
timepoints, a complete response can be based on estimated GFR (MDRD, as defined in 
Section 6.10) for the missing calculated GFR assessment. If calculated GFR is missing for 
both assessments, then the best response possible will be partial response using estimated 
GFR.  The same approach will be taken at Week 52. 
At all other timepoints, complete and partial responses can be based on calculated or 
estimated GFRs.    
8.5.2 Primary Efficacy Analysis 
Renal response (complete, partial, or no renal response) at the Week 104 visit will be 
compared between the belimumab plus standard of care treatment group and placebo plus 
standard of care using the Van Elteren test, stratified by baseline randomization factors. 
Any subject who receives a protocol-prohibited medication or dose will be considered a 
treatment failure (ie, non-responder) for the primary endpoint. Subjects who do not receive 
protocol-prohibited medication/dose, but discontinue study agent should remain on study and 
undergo protocol required assessments through Week 104.  Subjects who are not treatment 
failures but are withdrawn from the study prior to the Week 104 visit will have the primary 
endpoint imputed as follows:   
• No Response: 
- 
If withdrawn before Week 52. 
- 
If withdrawn after Week 52, but had a response that was maintained < 24 weeks at the 
time of last contact. 
- 
If no response at the time of last contact. 
 
• Partial Response: 
- 
If withdrawn after the Week 52 visit and had a response that had been maintained for 
> 24 weeks at the time of last contact the patient will be considered to have a partial 
renal response.  Complete renal response will not be imputed.  
 
8.5.2.1 
Missing Values 
The following imputation method will be used to handle a missing visit related to the primary 
endpoint assessment: 
• If the Week 104 visit is missing, the primary endpoint will be determined using data from 
the Week 96 and the Week 100 visits. 


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• If the Week 100 visit is missing, the primary endpoint will be determined using data from 
the Week 96 and the Week 104 visits. 
• If a subject misses both the Week 100 and the Week 104 visit, the subject’s response will 
be imputed as follows. If the subject had a response at or after the Week 52 visit that was 
maintained for > 24 weeks at the time of last contact, the subject will be considered to 
have a partial renal response. Otherwise, the subject will be defined as a non-responder.  
 
If 2 or more components of the primary endpoint for a subject are missing at a visit 
(Week 100 or Week 104), all 3 components at this visit will be considered missing unless the 
subject has been determined as a non-responder based on the available data. If only 1 
component of the primary endpoint is missing at only 1 visit, the following imputation method 
will be used for subjects missing a component of the primary endpoint: 
• If this component is missing at the Week 104 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 100 visits. 
• If this component is missing at the Week 100 visit, the missing component will be 
determined using data on the component from the Week 96 and the Week 104 visits. 
• If this component is missing at both the Week 100 and the Week 104 the subject’s 
response will be imputed as follows. If the subject had a response on the missing 
component at or after the Week 52 visit that was maintained for > 24 weeks at the last 
contact, the subject will be considered to have a partial response on the missing 
component. Otherwise, the subject will be defined as a non-responder. 
 
The parallel approach will be taken at Week 52. 
8.5.2.2 
Sensitivity Analyses 
The robustness of the primary efficacy results will be assessed by comparing renal response 
(complete, partial or no renal response) at the Week 104 visit between treatment groups in the 
completer population. The completer population is defined as all subjects who are on 
treatment through the Week 100. The analysis will be performed using the Van Elteren test, 
stratified by baseline randomization factors. Any subject who receives a protocol-prohibited 
medication or dose will result into a treatment failure in this analysis.  
Other sensitivity analyses will be specified in the statistical analysis plan. 
8.5.2.3 
Subgroup Analysis 
Subgroup analysis of the primary efficacy endpoint (ie, renal response at Week 104) will be 
performed in the following subgroups: 
• Induction regimen (HDCS plus CYC vs HDCS plus MMF). 
• Race (black vs other). 
• Region (US/Canada, Europe/Australia/Israel, Asia, Americas excluding US and Canada). 
• Baseline anti-dsDNA (anti-dsDNA ≥ 30 IU/mL vs other). 


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• Baseline complement (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).  
 
8.5.3 Secondary Efficacy Endpoints 
8.5.3.1 
Major Secondary Efficacy Endpoints 
• Renal response measured by complete, partial or no response at Week 52. 
• Proportion of subjects who achieve complete renal response at Week 104. 
 
8.5.4 Other Efficacy Endpoints 
Disease activity 
• Mean and median percentage change from baseline in SELENA SLEDAI score by visit.  
• Proportion of subjects with a > 4 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 5 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 6 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 7 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with improvement and worsening in SELENA SLEDAI organ 
systems (Bombardier, 1992) from baseline by visit. 
• Mean and mean percent change from baseline in SELENA SLEDAI excluding renal items 
by visit. 
 
Flares* 
• Time to first renal flare and the rate of renal flare from Week 24 among subjects with PRR 
or CRR at Week 24. 
• Time to first renal flareand the rate of renal flare from Week 52 among subjects with PRR 
or CRR at Week 52. 
• Time to first severe flare. 
• Time to severe flare after Week 24. 
• Rate of severe flare per 100 subject years over 104 weeks. 
 
*Renal flare will be defined according to FDA Guidance (June 2010); Severe flare will be 
defined by using the modified SLE Flare Index.  Both definitions will be included in full in 
the statistical analysis plan. 


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Renal Specific Measures 
• Individual components of renal response.  Proportion of subjects  with the following by 
visit: 
- 
Inactive urinary sediment (< 5 RBCs/hpf and < 5 WBCs/hpf or within the reference 
range of the laboratory); and no cellular casts (no RBC or WBC casts).  
- 
RBCs/hpf ≥ 50% reduction from baseline and no RBC casts. 
- 
Urinary protein:creatinine ratio < 0.5.  
- 
≥ 50% improvement in the urine protein:creatinine ratio with one of the following:  a 
urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0 OR a urine 
protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0. 
- 
GFR within the normal range.  
- 
GFR no more than 10% below the baseline value.  
• Percent change in proteinuria by visit. 
• Proportion of subjects with a doubling of the serum creatinine or progression to end stage 
renal disease (ESRD) as defined below: 
- 
Doubling of serum creatinine compared with baseline that is confirmed with a second 
measurement at least 3 weeks later. 
- 
Progression to ESRD defined as the need for chronic dialysis or renal transplantation. 
• Duration of longest complete or partial renal response (CRR/PRR) in all subjects 
achieving at least 1 response. 
• Duration of CRR in all subjects achieving at least 1 CRR. 
• Time to first PRR/CRR that is maintained through Week 52. 
• Time to the first PRR/CRR that is maintained through Week 104. 
• Time to the first CRR that is maintained through Week 52. 
• Time to the first CRR that is maintained through Week 104. 
• Time to sustained (≥ 3months) complete or partial renal response (CRR/PRR) after 
Week 24. 
• Time to sustained (≥ 3months) CRR after Week 24. 
• Proportion of subjects with CRR by visit. 
• Proportion of subjects with CRR and/or PRR by visit. 
 
Corticosteroid Use 
• Proportion of subjects receiving ≤ 5 mg/day prednisone by visit. 
• Proportion of subjects receiving ≤ 10 mg/day prednisone by visit. 
 
Biomarkers 
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, 


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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, aCL, anti-Sm, and anti-C1q). 
- 
Complement (C3, C4) levels. 
3. Percent of patients with normalized serological activity at Week 104 and over time 
- 
IgG, IgM and IgA (high to normal/low). 
- 
Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q) 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 treatment period. Other 
autoantibodies will be collected from all patients at baseline, then at regular intervals during 
the study.  
8.5.5 Secondary Efficacy Analyses 
8.5.5.1 
Major Secondary Efficacy Analyses 
Renal response (complete, partial or no response) at the Week 52 visit will be analyzed using 
the same method as for the primary endpoint. The proportion of subjects who achieve a 
complete renal response at the Week 104 visit will be compared between the belimumab 
treatment group and placebo using a logistic regression model. The independent variables in 
the model will include treatment group (ie, 10 mg/kg belimumab vs placebo) and the baseline 
randomization stratification factors.  
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 7) or the grades in Section 7.8, 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 


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graded using Adverse Event Severity Grading Tables (Appendix 7) 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 8 and Appendix 9) 
• Hypersensitivity reactions/anaphylaxis 
• 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 Section 6.10.1. 
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 at baseline 
(Day 0) to better characterize genetic variability (eg, HLA typing) that may affect efficacy or 
safety endpoints. Information regarding PGx research is included in Appendix 6. 
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 6). 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 


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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 
GlaxoSmithKline Pharmaceuticals. Human Genome Sciences, Inc. is the sponsor of this 
study. 
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. 


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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 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 CRFs 
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 disc (CD) containing the eCRFs for each of 
their subjects. 


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10.6 Study Monitoring 
The study sponsor or designee will monitor the study. Study monitors representing the 
sponsor will visit study sites routinely throughout the trial. The sponsor will review eCRFs 
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 eCRFs 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 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority. 
10.7 Drug Accountability 
Upon receipt of the study agents, the designated 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 blinded 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 the sponsor 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 investigators 
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 


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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. 
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 the sponsor, 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 the sponsor 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 the sponsor 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 the sponsor, study 
monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 
 


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11 References 
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Buyon JP, Petri MA, Kim MY, et al. The Effect of Combined Estrogen and Progesterone 
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Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables, May 2001.  
Eibl MM and Rosen FS. Intravenous gamma globulin and plasmapheresis. In Frank MM et al 
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Goldfarb NS, Avery RK, Goormastic M, et al. Hypogammaglobulinemia in lung transplant 
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Jiménez S, Cervera R, Font J, et al. The epidemiology of systemic lupus erythematosus. Clin 
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Yamani MH, Avery RK, Mawhorter SD, et al. Hypogammaglobulinemia following cardiac 
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List of Appendices 
Appendix 1 
American College of Rheumatology (ACR) Criteria for SLE ...................... 76 
Appendix 2 
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 
2003 Classification of Lupus Nephritis ........................................................ 77 
Appendix 3 
SELENA SLEDAI Disease Assessment Scales ........................................... 78 
Appendix 4 
SLICC/ACR Damage Index ......................................................................... 81 
Appendix 5 
Laboratory Tests ........................................................................................... 83 
Appendix 6 
Pharmacogenetic Research ........................................................................... 84 
Appendix 7 
Adverse Event Severity Grading Tables ....................................................... 88 
Appendix 8 
Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline/Screening .... 97 
Appendix 9 
Columbia- Suicide Severity Rating Scale (C-SSRS) Since Last Visit ....... 114 
 
 


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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 et al, 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. 
 
5. Arthritis  
Nonerosive arthritis involving 2 or more peripheral joints characterized by 
tenderness. 
 
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/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). 
 
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 
International Society of Nephrology/Renal Pathology 
Society (ISN/RPS) 2003 Classification of Lupus 
Nephritis 
 
CLASS I 
MINIMAL MESANGIAL LUPUS NEPHRITIS 
Normal 
glomeruli 
by 
light 
microscopy, 
but 
mesangial 
immune 
deposits 
by 
immunofluorescence. 
CLASS II 
MESANGIAL PROLIFERATIVE LUPUS NEPHRITIS 
Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light 
microscopy, with mesangial immune deposits. 
May 
be 
a 
few 
isolated 
subepithelial 
or 
subendothelial 
deposits 
visible 
by 
immunofluorescence or electron microscopy, but not by light microscopy.  
CLASS III 
FOCAL LUPUS NEPHRITIS 
Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis 
involving < 50% of all glomeruli, typically with focal subendothelial immune deposits, with or 
without mesangial alterations.  
Class III (A) 
Active lesions: focal proliferative lupus nephritis 
Class III (A/C) 
Active and chronic lesions: focal proliferative and sclerosing lupus nephritis 
Class III (C) 
Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis 
CLASS IV 
DIFFUSE LUPUS NEPHRITIS 
Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis 
involving ≥ 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with 
or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus 
nephritis when ≥ 50% of the involved glomeruli have segmental lesions, and diffuse global 
(IV-G) lupus nephritis when ≥ 50% of the involved glomeruli have global lesions. Segmental 
is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class 
includes cases with diffuse wire loop deposits but with little or no glomerular proliferation.  
Class IV-S (A) 
Active lesions: diffuse segmental proliferative lupus nephritis 
Class IV-G (A) 
Active lesions: diffuse global proliferative lupus nephritis 
Class IV-S (A/C) 
Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis 
Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis 
Class IV-S (C) 
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis 
Class IV-G (C) 
Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis 
CLASS V 
MEMBRANOUS LUPUS NEPHRITIS 
Global or segmental subepithelial immune deposits or their morphologic sequelae by light 
microscopy and by immunofluorescence or electron microscopy, with or without mesangial 
alterations.  
Class V lupus nephritis may occur in combination with class III or IV in which case both will 
be diagnosed. 
Class V lupus nephritis may show advanced sclerosis. 
CLASS VI 
ADVANCED SCLEROSIS LUPUS NEPHRITIS 
≥90% of glomeruli globally sclerosed without residual activity.  
Adapted from:  
Weening J, D’Agati V, Schwartz M, et al. The Classification of Glomerulonephritis in Systemic Lupus 
Erythematosus Revisited. J Am Soc Nephrol 2004; 15:241-150.  


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Appendix 3 
SELENA SLEDAI Disease Assessment Scales 
 
SELENA SLEDAI Score 
 
Score if descriptor is present at time of visit or in the preceding 10 days. 
 
 
Wgt. 
 
Descriptor 
 
Definition 
 
8 
Seizure 
Recent onset (last 10 days). Exclude metabolic, infectious drug cause,  
or seizure due to past irreversible CNS damage. 
8 
Psychosis 
Altered ability to function in normal activity due to severe disturbance in the  
perception of reality. Include hallucinations, incoherence, marked loose  
associations, impoverished thought content, marked illogical thinking, bizarre, 
disorganized, or catatonic behavior. Exclude uremia and drug causes. 
8 
Organic Brain 
Syndrome 
Altered mental function with impaired orientation, memory or other intellectual function with 
rapid onset and fluctuating clinical features. Include clouding of consciousness with 
reduced capacity to focus and inability to sustain attention to environment, plus at least 2 of 
the following: perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, 
or increased or decreased  
psychomotor activity. Exclude metabolic, infectious, or drug causes. 
8 
Visual Disturbance 
Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages,  
serous exudate of hemorrhage in the choroid, optic neuritis, scleritis or  
episcleritis. Exclude hypertension, infection, or drug causes. 
8 
Cranial Nerve 
Disorder 
New onset sensory or motor neuropathy involving cranial nerves.  
Include vertigo due to lupus. 
8 
Lupus Headache 
Severe persistent headache: may be migrainous, but must be  
non-responsive to narcotic analgesia. 
8 
CVA 
New onset of CVA(s). Exclude arteriosclerosis or hypertensive causes. 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual infarction,  
splinter hemorrhages, or biopsy or angiogram proof of vasculitis. 
4 
Arthritis 
More than 2 joints with pain & signs of inflammation  
(ie, tenderness, swelling or effusion). 
4 
Myositis 
Proximal muscle aching/weakness associated with elevated creatine 
phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis. 
4 
UrinaryCasts 
Heme-granular or red blood cell casts. 
4 
Hematuria 
> 5 red blood cells/high power field. Exclude stone, infection, or other causes. 
4 
Proteinuria 
New onset or recent increase of more than 0.5 g/24 hours. 
4 
Pyuria 
> 5 white blood cells/high power field. Exclude infection. 
2 
Rash 
New or ongoing inflammatory lupus rash. 
2 
Alopecia 
New or ongoing abnormal, patchy or diffuse loss of hair due to active lupus. 
2 
Mucosal Ulcers 
New or ongoing oral or nasal ulcerations due to active lupus. 
2 
Pleurisy 
Classic and severe pleuritic chest pain or pleural rub or  
effusion or new pleural thickening due to lupus. 
2 
Pericarditis 
Classic and severe pericardial pain or rub or effusion,  
or electrocardiogram confirmation. 
2 
Low Complement 
Decrease in CH50, C3, or C4 below the lower limit of normal for testing laboratory. 
2 
Increased DNA 
Binding 
> 25% binding by Farr assay or above normal range for testing laboratory. 
1 
Fever 
> 38°C. Exclude infectious cause. 
1 
Thrombocytopenia 
< 100,000 platelets/mm3 
1 
Leukopenia 
< 3,000 white blood cells/mm3. Exclude drug causes. 
 
 
 
TOTAL SCORE 
 
(Sum of weights next to descriptors marked present) 
Adapted from:  
Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI: a disease activity index for lupus 
patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35(6):630-40. 
 


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SLE Flare Index 
 
Mild or Moderate Flare 
Severe Flare 
 
Change in SELENA SLEDAI instrument score of 3 
points or more (but not to more than 12) 
 
 
New/worse: 
Discoid, photosensitive, profundus, 
 cutaneous vasculitis, bullous lupus 
Nasopharyngeal ulcers 
Pleuritis 
Pericarditis  
Arthritis  
Fever (SLE) 
 
 
Increase in prednisone, but not to > 0.5 mg/kg/day 
 
 
Added NSAID or hydroxychloroquine for SLE 
Activity 
 
 
≥1.0 increase in PGA score, but not to more than 
2.5 
 
 
 Change in SELENA SLEDAI instrument score to 
greater than 12 
 
 New/worse:  
CNS-SLE  
Vasculitis  
Nephritis  
Myositis 
Plt < 60,000 
Hemolytic anemia:Hb < 70 g/L or decrease in 
Hb > 30 g/L 
 
Requiring: double prednisone, or prednisone 
increase to > 0.5 mg/kg/day, or hospitalization 
 
 Increase in prednisone to > 0.5 mg/kg/day 
 
 New cyclophosphamide, azathioprine, 
methotrexate, or mycophenolate for SLE activity 
 
 Hospitalization for SLE activity 
 
 Increase in PGA score to > 2.5 
 
Adapted from: 
 
 Petri M, Buyon J, Kim M. Classification and definition of major flare in SLE clinical trials. Lupus 1999; 
8:685-91. 
 
 Petri M et al. Combined Oral Contraceptives in Women with Systemic Lupus Erythematosus. N Engl J Med 
2005;353:2550-8. 
  
 Buyon JP et al. The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on 
Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial. Ann Internal Med 2005; 142  
 (12 Pt 1):953-62. 
 
 


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Physician’s Global Disease Assessment 
 
 
 
Adapted from:  
 Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. Lupus 
1999;8:685-91. 
 
 


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Appendix 4 
SLICC/ACR Damage Index 
 
Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index for Systemic Lupus Erythematosus* 
Item  
Score  
Ocular (either eye, by clinical assessment) 
Any cataract ever  
1 
Retinal change or optic atrophy  
1 
 
Neuropsychiatric 
Cognitive impairment (eg, memory deficit, difficulty with  
1 
calculation, poor concentration, difficulty in spoken or written 
language, impaired performance levels) or major psychosis 
Seizures requiring therapy for 6 months  
1 
Cerebrovascular accident ever (score 2 > 1)  
1(2) 
Cranial or peripheral neuropathy (excluding optic)  
1 
Transverse myelitis  
1 
 
Renal 
Estimated or measured glomerular filtration rate < 50%  
1 
Proteinuria > 3.5 gm/24 hours  
1 
Or 
End-stage renal disease (regardless of dialysis or transplantation)  
3 
 
Pulmonary 
Pulmonary hypertension (right ventricular prominence, or loud P2)  
1 
Pulmonary fibrosis (physical and radiograph)  
1 
Shrinking lung (radiograph)  
1 
Pleural fibrosis (radiograph)  
1 
Pulmonary infarction (radiograph)  
1 
 
Cardiovascular 
Angina or coronary artery bypass  
1 
Myocardial infarction ever (score 2 if > 1)  
1(2) 
Cardiomyopathy (ventricular dysfunction) 
1 
Valvular disease (diastolic, murmur, or systolic murmur > 3/6)  
1 
Pericarditis for 6 months, or pericardiectomy  
1 
 
Peripheral vascular 
Claudication for 6 months  
1 
Minor tissue loss (pulp space)  
1 
Significant tissue loss ever (eg, loss of digit or limb)(score 2 if > 1 site) 
1(2) 
Venous thrombosis with swelling, ulceration, or venous stasis  
1 
 
Gastrointestinal 
Infarction or resection of bowel below duodenum, spleen, liver, or  
1(2) 
gall bladder ever, for cause any (score 2 if > 1 site) 
Mesenteric insufficiency  
1 
Chronic peritonitis  
1 
Stricture or upper gastrointestinal tract surgery ever  
1 
 


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Musculoskeletal 
Muscle atrophy or weakness  
1 
Deforming or erosive arthritis (including reducible deformities, excluding avascular necrosis) 
1 
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis) 
1 
Avascular necrosis (score 2 if > 1)  
1(2) 
Osteomyelitis  
1 
 
Skin 
Scarring chronic alopecia  
1 
Extensive scarring or panniculum other than scalp and pulp space  
1 
Skin ulceration (excluding thrombosis) for > 6 months  
1 
 
Premature gonadal failure 
1 
 
Diabetes (regardless of treatment) 
1 
 
Malignancy (exclude dysplasia) (score 2 if > 1 site) 
1(2) 
 
 
 
*Damage (nonreversible change, not related to active inflammation) occuring since onset of lupus, ascertained 
by clinical assessment and present for at least 6 months unless otherwise stated.  Repeat episodes must occur at 
least 6 months apart to score 2.  The same lesion cannot be scored twice. 
Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial 
validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363-9. 
 


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Appendix 5 
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) 
Serum Pregnancy  
Protein 
Glucose 
Ketones 
Occult blood 
Microscopic examination 
including: 
WBC per hpf 
RBC per hpf 
Dysmorphic RBC 
Casts (specified by type 
eg, RBC, WBC) 
Urine Pregnancy 
Spot urine 
24-hour urine 
Electrolytes: 
 
Sodium 
 
Potassium 
 
Magnesium 
 
Chloride 
 
Carbon dioxide 
 
Calcium adjusted for Albumin 
 
Inorganic Phosphate 
Enzymes: 
 
SGOT (AST) 
 
SGPT (ALT) 
 
Alkaline Phosphatase 
 
Gamma glutamyl transferase (GGT) 
 
Lactic dehydrogenase (LDH) 
Other: 
 
Creatinine 
 
Blood urea nitrogen (BUN) 
 
BUN/creatinine ratio 
 
Bilirubin, total 
 
Protein, total  
 Albumin 
 
Uric acid 
 
Glucose 
  
 
Infectious Disease Screening 
HIV-1/2 antibody 
Hepatitis C antibody 
Hepatitis B surface antigen 
 
 
Autoantibodies 
ANA  
Anti-dsDNA 
aCL (IgG, IgA and IgM isotypes) 
Anti-Sm 
Anti-c1q 
*When 24 hour urines are 
collected, the calculated GFR 
will be based on the mean 
value of two 24 hour urine and 
serum creatinine collections. 
For 
all 
other 
visits, 
the 
simplified MDRD formula will 
be used to estimate GFR and 
the spot urine method will be 
used 
for 
the 
proteinuria 
assessments. 
The 
urine 
microscopy 
and 
routine 
urinalysis will be performed 
locally. All other tests will be 
performed 
by 
a 
central 
laboratory.  
Biological Markers 
BLyS protein  
Serum complement (C3 and C4)  
 
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)   Note: May be collected in selected sites/regions. 
 
 
Immunoglobulins 
Serum immunoglobulin isotypes: IgG, IgM, IgA 
 
Belimumab PK and Immunogenicity 
 


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Appendix 6 
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 (~10 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. 


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Screen and Baseline Failures 
If a blood sample for PGx research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the clinical study, then the investigator 
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, 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. 


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• 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. 
• 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 study agent, 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 7 
Adverse Event Severity Grading Tables 
 
 
 
SKIN (INJECTION SITE) 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE1 
SEVERE 
POTENTIALLY LIFE-THREATENING 
Induration 
< 15mm  
15-30 mm 
> 30mm 
n/a 
Erythema 
< 15mm  
15-30 mm 
> 30mm 
n/a 
Edema 
< 15mm  
15-30 mm 
> 30mm 
n/a 
Rash at Injection Site 
< 15mm  
15-30 mm 
> 30mm 
n/a 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire body 
n/a 
 
 
1May be assessed as 
mild despite the size if 
event is transient (< 48 
hours) with mild 
discomfort; no medical 
intervention/therapy 
required 
 
 
Modified from DMID Adult Toxicity Tables, 2007 
 


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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 
 
 
 
 
 
 
 
 
 
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 
> 3 - < 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 8 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening 
 


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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.


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 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit 


Human Genome Sciences, Inc. 
Confidential 
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Belimumab 
 
 
 
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.


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.


PPD
PPD
PPD
PPD
PPD