A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 104-Week Study to Evaluate the Efficacy and Safety of Belimumab Administered in Combination With Rituximab to Adult Subjects With Systemic Lupus Erythematosus (SLE)
Phase: PHASE3
Conditions: Systemic Lupus Erythematosus
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-
Controlled, 104-Week Study to Evaluate the Efficacy and Safety of Belimumab 
Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus 
Erythematosus (SLE)
Protocol Number: 205646 Amendment 04 (Global)
Short Title: A Phase 3 Study to Evaluate the Efficacy and Safety of Belimumab 
Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus 
Erythematosus (SLE) – BLISS-BELIEVE
Compound Number:
GSK1550188
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual.
Regulatory Agency Identifying Number(s):
United States Food and Drug Administration Identifying Number(s): IND 009970; 
EudraCT number: 2016-003050-32
Approval Date: 30-APR-2020
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4 (Global)
30-Apr-2020
Amendment 3 (Global)
15-Aug-2019
Amendment 2 / KOR-1
02-Feb-2019
Amendment 2 / ARG-1
11-Dec-2018
Amendment 2 / DEU-2
28-Nov-2018
Amendment 2 (Global)
17-Nov-2018
Amendment 1 /ARG-1
02-Jul-2018
Amendment 1/DEU-2
27-Nov-2017
Amendment 1/DEU-1
23-Oct-2017
Amendment 1/KOR-1
22-Jun-2017
Amendment 1 (Global)
17-Apr-2017
Original Protocol
16-Jan-2017
Amendment 04 (Global): 30-APR-2020
Rationale for the Amendment: In response to the COVID-19 pandemic, changes are 
being made in order to protect patient safety and data integrity. 1) Visit windows are 
being conditionally extended for all subject visits for the study. 2) Clarification that the 
independent blinded assessor can be called upon to perform the S2K efficacy assessment 
at an unscheduled visit. 3) In the event that subjects are unable to visit the site, it is 
acceptable for sites to supply investigational product (belimumab) to subjects by 
shipment to the subject. 4) Clarification regarding acceptable use and dosage of anti-
malarial treatments (e.g. hydroxychloroquine). 5) Change to the language describing the 
timing of the primary analysis. 6) Recommendations for safety contact with subjects in 
the event they cannot attend clinic visits. 7) Guidance for study treatment discontinuation 
if a subject has suspected or confirmed COVID-19 infection.
In addition, several corrections and clarifications have been made which are unrelated to 
the COVID-19 pandemic.
Section # and Name
Description of Change
Brief Rationale
1. Synopsis, Table of 
endpoints
Secondary endpoint “Time to 
clinical remission sustained to 
Week 64, defined as Clinical 
SLEDAI-2K score=0, achieved 
without immunosuppressants 
and with corticosteroids at a 
prednisone equivalent dose of 
0 mg/day.”
changed to 
Correction of error and 
alignment of the protocol with 
the reporting and analysis plan.

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Section # and Name
Description of Change
Brief Rationale
“Time to clinical remission 
sustained to Week 104, 
defined as Clinical SLEDAI-2K 
score=0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone 
equivalent dose of 0 mg/day.”
2: Schedule of Activities 
(SoA) Table 1,Table 2, Table 
3 and Table 4
Visit windows. Footnote a – if 
the COVID-19 pandemic is 
restricting the ability of sites to 
schedule subject visits within 
the protocol defined windows 
(±7 days), then it is permissible 
to use an expanded visit 
window (±28 days).
Unscheduled visit. The column 
for this visit in Table 1-Table 4 
has been changed to insert a 
cross in the box for the S2K 
blinded assessor. The footnote
in Table 1-Table 4 
corresponding to the 
unscheduled visit has also 
been amended to refer the 
reader to the relevant section 
of the protocol for more 
information. 
Post-treatment and exit 
interview. The footnote in Table
1-Table 4 corresponding to this 
interview has been amended to 
remove the requirement for the 
interview to be done prior to 
clinical assessments.
In light of the COVID-19 
pandemic, this allows increased 
flexibility for sites to schedule 
visits and collect key efficacy 
and safety data.
Provides greater flexibility to 
sites for obtaining the blinded 
assessor’s S2K assessment if 
subjects are unable to attend 
protocol defined visits.
Correction. It is not essential for 
the interviews to be conducted 
prior to clinical assessments.
4: Objectives and Endpoints
Secondary endpoint “Time to 
clinical remission sustained to 
Week 64, defined as Clinical 
SLEDAI-2K score=0, achieved 
without immunosuppressants 
and with corticosteroids at a 
prednisone equivalent dose of 
0 mg/day.”
Correction of error and 
alignment of protocol with 
reporting and analysis plan.

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Section # and Name
Description of Change
Brief Rationale
changed to 
“Time to clinical remission 
sustained to Week 104, 
defined as Clinical SLEDAI-2K 
score=0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone 
equivalent dose of 0 mg/day.”
7.3 Method of Treatment 
Assignment
Language added to clarify 
arrangements for direct supply 
of belimumab autoinjectors to 
subjects in the event subjects 
are unable to visit the site to 
collect them.
Allow subjects to continue 
treatment with belimumab if 
unable to visit the site, for 
example, as a consequence of 
the COVID-19 pandemic.
7.7.1 Allowable medications
Subsection 7.7.1.1 (Anti-
malarials) has been amended 
to include provision for subjects 
to have short term treatment 
with hydroxychloroquine for 
reasons other than lupus, for 
example, experimental 
treatment of COVID-19.
Response to potential change in 
use of anti-malarials as a 
consequence of the COVID-19 
pandemic.
8.2 Discontinuation of study 
treatment
Language added to provide 
guidance for investigators 
regarding treatment with 
investigational product should 
a subject have a suspected or 
confirmed COVID-19 infection.
Provision of guidance to assist 
investigators in response to the 
COVID-19 pandemic.
9.4 Assessments at 
Unscheduled Visits
Language added to help 
provide guidance to 
investigators for safety 
monitoring of subjects via 
telephone or video call if 
subjects are unable to attend 
protocol defined visits at the 
site,
Maintain investigator contact 
with and safety monitoring of 
subjects in response to the 
COVID-19 pandemic.
10. Statistical Considerations
Language has been added to 
sub-Section 10.1.1 and Section 
10.4 to clarify that the timing of 
w52 reporting and the planned 
estimands for the statistical 
analyses may be reviewed 
based upon the evolving 
impact of COVID-19.
Clarification that COVID-19 may 
impact upon the timing and the 
estimands of the statistical 
analysis.

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Section # and Name
Description of Change
Brief Rationale
A correction has been made in 
Section 10.4.1 to clarify that 
the MITT population (and not 
the ITT population) will be used 
to conduct the analysis of the 
primary and key secondary 
endpoints.
Correction and alignment of 
protocol with the reporting and 
analysis plan.
Appendix 9. Clinical 
Laboratory Tests
Language added to clarify that 
local laboratory tests are 
recommended if disruption as a 
consequence of COVID-19 
prevents or delays central 
laboratory tests.
Support continued safety and 
efficacy assessment in response 
to COVID-19.
Appendix 13. Protocol 
Amendment History
Has been fully updated with 
details of all global and country 
specific amendments.
Provide complete history of 
amendments.
Throughout protocol
Minor editorial revisions
Corrections of typographical 
errors and minor revisions for 
clarity.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................19
3.
INTRODUCTION....................................................................................................34
3.1.
Study Rationale ..........................................................................................34
3.2.
Background ................................................................................................34
3.3.
Benefit/Risk Assessment ............................................................................36
3.3.1.
Risk Assessment .........................................................................37
3.3.2.
Benefit Assessment.....................................................................44
3.3.3.
Overall Benefit: Risk Conclusion..................................................44
4.
OBJECTIVES AND ENDPOINTS...........................................................................44
5.
STUDY DESIGN ....................................................................................................50
5.1.
Overall Design ............................................................................................50
5.2.
Number of Participants ...............................................................................54
5.3.
Participant and Study Completion...............................................................54
5.4.
Scientific Rationale for Study Design ..........................................................54
5.4.1.
Selection of Controls....................................................................54
6.
STUDY POPULATION...........................................................................................55
6.1.
Inclusion Criteria.........................................................................................55
6.2.
Exclusion Criteria........................................................................................57
6.3.
Lifestyle Restrictions...................................................................................60
6.4.
Screen Failures...........................................................................................60
7.
TREATMENTS.......................................................................................................60
7.1.
Treatments Administered............................................................................61
7.1.1.
Medical Devices...........................................................................62
7.2.
Dose Modification .......................................................................................63
7.3.
Method of Treatment Assignment ...............................................................63
7.4.
Blinding.......................................................................................................63
7.5.
Preparation/Handling/Storage/Accountability..............................................64
7.6.
Treatment Compliance................................................................................65
7.7.
Concomitant Therapy..................................................................................66
7.7.1.
Allowable Medications .................................................................66
7.7.1.1.
Anti-malarials..............................................................67
7.7.1.2.
Corticosteroids ...........................................................67
7.7.1.3.
Corticosteroids for Reasons Other Than SLE 
Disease Activity..........................................................69
7.7.1.4.
Other Immunosuppressant Agents .............................69
7.7.1.5.
Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs), Aspirin, and Acetaminophen......................70
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................71
7.7.3.
Live Vaccines ..............................................................................71
7.7.4.
Additional SLE Therapy ...............................................................71

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7.8.
Treatment after the End of the Study ..........................................................72
8.
DISCONTINUATION CRITERIA.............................................................................73
8.1.
Withdrawal from the Study..........................................................................73
8.2.
Discontinuation of Study Treatment ............................................................73
8.2.1.
Liver Chemistry Stopping Criteria ................................................74
8.2.2.
Study Treatment Restart..............................................................76
8.3.
Temporary Discontinuation and Re-Start of Belimumab..............................76
8.4.
Withdrawal from the Study..........................................................................77
8.5.
Lost to Follow Up........................................................................................77
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................77
9.1.
Screening Assessments .............................................................................78
9.2.
Assessments at Baseline............................................................................80
9.3.
Assessments at Scheduled Visits ...............................................................80
9.4.
Assessments at Unscheduled Visits ...........................................................80
9.5.
Assessments at Early Withdrawal Visits and Follow-up Visits.....................81
9.6.
Efficacy Assessments.................................................................................81
9.6.1.
Patient-Reported Outcomes Assessments...................................82
9.7.
Adverse Events...........................................................................................83
9.7.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................84
9.7.2.
Method of Detecting AEs and SAEs.............................................84
9.7.3.
Follow-up of AEs and SAEs.........................................................84
9.7.4.
Regulatory Reporting Requirements for SAEs .............................84
9.7.5.
Cardiovascular and Death Events................................................85
9.7.6.
Pregnancy ...................................................................................85
9.7.7.
Medical Device Incidents .............................................................85
9.7.7.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................86
9.7.7.2.
Follow-up of Medical Device Incidents........................86
9.7.7.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................86
9.7.8.
Device Malfunction ......................................................................87
9.8.
Treatment of Overdose...............................................................................87
9.9.
Safety Assessments ...................................................................................88
9.9.1.
Physical Examinations.................................................................88
9.9.2.
Vital Signs....................................................................................88
9.9.3.
Electrocardiograms......................................................................88
9.9.4.
Clinical Safety Laboratory Assessments ......................................88
9.9.5.
Neurological Assessment ............................................................89
9.9.6.
Suicidal Risk Monitoring...............................................................89
9.10.
Pharmacokinetics .......................................................................................90
9.11.
Pharmacodynamics ....................................................................................90
9.12.
Genetics .....................................................................................................91
9.13.
Biomarkers .................................................................................................91
9.13.1.
Immunogenicity Assessments......................................................91
9.13.2.
RNA.............................................................................................91
9.13.3.
B Cell Receptors..........................................................................91
9.13.4.
BLyS Protein................................................................................91
9.14.
Medical Resource Utilization and Health Economics ..................................92

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10. STATISTICAL CONSIDERATIONS........................................................................92
10.1.
Hypotheses.................................................................................................92
10.1.1.
Analysis for Marketing Application ...............................................93
10.2.
Sample Size Determination ........................................................................93
10.3.
Populations for Analyses ............................................................................94
10.4.
Statistical Analyses.....................................................................................95
10.4.1.
Efficacy Analyses.........................................................................95
10.4.2.
Safety Analyses...........................................................................97
10.4.3.
Other Analyses ............................................................................97
10.4.4.
Interim Analyses ..........................................................................98
11. REFERENCES.......................................................................................................99
12. APPENDICES......................................................................................................101
12.1.
Appendix 1:Abbreviations and Trademarks...............................................101
12.2.
Appendix 2:Recommended Corticosteroid Taper Schedule ......................103
12.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................105
12.4.
Appendix 4:Study Governance Considerations.........................................108
12.5.
Appendix 5:Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................112
12.6.
Appendix 6:Liver Safety Study Treatment Restart Guidelines...................115
12.7.
Appendix 7:Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................116
12.8.
Appendix 8:Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................122
12.9.
Appendix 9:Clinical Laboratory Tests........................................................124
12.10. Appendix 10:Genetics...............................................................................127
12.11. Appendix 11: American College of Rheumatology (ACR) Criteria for 
SLE...........................................................................................................128
12.12. Appendix 12:Country-specific requirements..............................................129
12.13. Appendix 13: Protocol Amendment History...............................................131

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1.
SYNOPSIS
Protocol Title: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-
Controlled, 104-Week Study to Evaluate the Efficacy and Safety of Belimumab 
Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus 
Erythematosus (SLE)
Short Title: A Phase 3 Study to Evaluate the Efficacy and Safety of Belimumab 
Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus 
Erythematosus (SLE) - BLISS-BELIEVE
Rationale:
SLE is characterized by autoantibodies, including antibodies to double-stranded DNA 
(dsDNA), and by abnormal B cell activation and differentiation, indicating that therapies 
which deplete or modulate B cells could be beneficial in treating SLE. Belimumab and 
rituximab are monoclonal antibodies that achieve their expected pharmacology through 
different but complementary mechanisms; therefore, based on their mechanisms of 
action, synergistic effects when used in combination in the treatment of SLE are possible
compared to either treatment alone. Belimumab treatment increases peripheral memory B 
cells potentially by mobilization from tissues this may include the autoreactive B cell 
compartment. This mobilization would expose these cells to more efficient depletion by 
rituximab. Continuing belimumab after a single course of rituximab would then suppress 
the B-lymphocyte stimulator (BLyS) elevation observed after rituximab monotherapy, 
thus suppressing the signal which leads to rapid repopulation of B cells, including 
autoreactive B cells. This study will assess whether co-administration of belimumab and 
a single cycle of rituximab may optimize treatment with belimumab, resulting in 
improvements in clinical status with a favorable safety profile. 
Objectives and Endpoints: 
The key evaluations are based on comparing belimumab with or without a single cycle of 
rituximab (the combination arm vs. the control arm). There are limited analyses planned 
to compare the combination of belimumab with a single cycle of rituximab (combination 
arm) to belimumab with standard therapy (reference arm). Details of the analyses to be 
conducted will be described in the Reporting and Analysis Plan (RAP), including 
analysis of the combination arm vs. the control arm and the combination arm vs. the 
reference arm.
Objectives
Endpoints
Primary: Efficacy

To evaluate the efficacy of belimumab and 
a single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE.

Proportion of participants with a state of 
disease control defined as a Systemic 
Lupus Erythematosus Disease Activity 
Index (SLEDAI)- 2K score 2, achieved 
without immunosuppressants and with 

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Objectives
Endpoints
corticosteroids at a prednisone equivalent 
dose of 5 mg/day at Week 52. 
Secondary: Efficacy (Major)

Proportion of participants with a state of 
clinical remission defined as a Clinical 
SLEDAI-2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day at Week 64. (Serological 
activity score, i.e., anti-dsDNA positivity 
and/or hypocomplementemia, is excluded 
from the Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
disease control defined as a SLEDAI-2K
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day at Week 104. 
Secondary: Efficacy (Other)

Proportion of participants with a state of 
disease control, defined as a SLEDAI-2K 
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day, by visit.

Proportion of participants with a state of 
clinical remission, defined as a Clinical 
SLEDAI-2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit. (Serological 
activity score, i.e., anti-dsDNA positivity 
and/or hypocomplementemia, is excluded 
from the Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
complete remission, defined as SLEDAI-2K 
score=0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, sustained for at least 
24 weeks.

Proportion of participants with a state of 
clinical remission, defined as Clinical 
SLEDAI-2K score =0, achieved without 

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Objectives
Endpoints
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, sustained for at least 24 
weeks. (Serological activity score, i.e., anti-
dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
complete remission, defined as a SLEDAI-
2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit 

Time to first severe flare (as measured by 
the modified SLE Flare Index)

Time to first flare (as measured by the 
modified SLE Flare Index)

Time to disease control sustained to Week 
104, defined as SLEDAI-2K score 2, 
achieved without immunosuppressants and 
with corticosteroids at a prednisone 
equivalent dose of 5 mg/day.

Time to clinical remission sustained to 
Week 104, defined as Clinical SLEDAI-2K 
score=0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day. (Serological activity, i.e., 
anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)

Duration of disease control, defined as 
SLEDAI-2K score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day

Duration of clinical remission, defined as 
Clinical SLEDAI-2K score =0, achieved 
without immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day. (Serological activity, i.e., 
anti-dsDNA positivity and/or 

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Objectives
Endpoints
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)

Change from baseline in SLEDAI-2K score 
by visit

Proportion of participants with SLEDAI-2K 
organ improvement by visit

Proportion of participants with SLEDAI-2K 
organ worsening by visit

Change from baseline in Physician Global 
Assessment (PGA) by visit

Proportion of participants with any SLICC 
Damage Index worsening (change >0) 
compared with baseline at Week 52 and 
Week 104

Proportion of participants that meet the 
Lupus Low Disease Activity State (LLDAS) 
response criteria by visit. The LLDAS 
incorporates multiple measures of disease 
activity, specifically: (1) SLEDAI-2K 4, with 
no activity in major organ systems (renal, 
CNS, cardiopulmonary, vasculitis, fever) 
and no hemolytic anemia or gastrointestinal 
activity; (2) no new features of lupus 
disease activity compared with the previous 
assessment; (3) PGA (scale 0-3) 1; (4) 
current prednisolone (or equivalent) dose 
7.5 mg daily; and (5) well tolerated 
standard maintenance doses of 
immunosuppressive drugs and approved 
biological agents, excluding investigational 
drugs.

Proportion of participants with a state of 
disease control, defined as a SLEDAI-2K 
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day, by visit; using the 
Principal Investigators assessment of 
SLEDAI-2K.

Proportion of participants with a state of 
clinical remission, defined as a Clinical 
SLEDAI-2K score =0, achieved without 

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Objectives
Endpoints
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit; using the 
Principal Investigators assessment of 
SLEDAI-2K. (Serological activity score, i.e. 
anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)
Secondary: Safety

To assess the safety and tolerability of 
belimumab and a single cycle of rituximab 
administered in a combination regimen to 
adult participants with SLE

Incidence of adverse events (AEs) including 
serious AEs (SAEs) and AEs of special 
interest (AESIs)
Secondary: Patient Reported Outcomes 
(PROs)

To assess the impact of belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE on PROs

Change from baseline in Patient Global 
Assessment (PtGA) by visit

Change from baseline in LupusQoL domain 
summary scores (8 domains) by visit 

Change from baseline in FACIT-Fatigue 
score by visit 

Proportion of participants with improvement 
in FACIT-Fatigue score exceeding the 
Minimal Clinically Important Difference 
(MCID, 4) by visit
Exploratory: Pharmacokinetics and 
Biomarkers

To assess pharmacokinetics of and 
biomarker response to belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE
Belimumab and rituximab concentrations by 
visit
Change from baseline in autoantibodies by 
visit
Change from baseline in peripheral blood 
leukocytes including B cell subsets by visit
Change in BLyS levels from baseline by visit

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Objectives
Endpoints
Exploratory: Patient Reported Work 
Productivity

To explore the impact of belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE on patient experience and 
productivity 
Change from baseline in Work Productivity 
and Activity Impairment (WPAI): Lupus 
percent overall work productivity impairment 
by visit 
Change from baseline in WPAI: Lupus 
percent activity impairment score by visit
Overall Design:
This is a Phase 3, multi-center, 3-arm, randomized, double-blind, placebo-controlled, 
104 week superiority study to evaluate the efficacy and safety of belimumab administered 
in combination with a single cycle of rituximab to adult participants with SLE. 
Participants will be randomly assigned to 1 of 3 treatment arms; belimumab plus 
rituximab-placebo (Arm A, control), belimumab plus rituximab (Arm B, combination), or 
open-label belimumab plus standard therapy (Arm C, reference). Blinded independent 
assessors will conduct the SLEDAI-2K at key time points. An Independent Data 
Monitoring Committee (IDMC) will review the safety data on a regular basis.
Number of Participants:
A total of approximately 560 participants are expected to be screened, with a goal of 
randomizing at least 280 participants (50% screen failure rate).
The sample size may be increased up to a maximum of 320 participants if the dropout 
rate, missing data or number of major protocol deviations suggests further participants
are necessary to ensure robust conclusions can be drawn. The decision to increase the 
sample size will be made without unblinding the trial.
Treatment Groups and Duration:
Overview
At least 280 participants will be randomized in a 1:2:1 ratio to 1 of 3 arms: belimumab 
plus rituximab-placebo (Arm A, control, target N=70), belimumab plus rituximab (Arm 
B, combination, target N=140), or belimumab plus standard therapy (Arm C, reference, 
target N=70). Arms A and B are double-blind; participants will receive belimumab 200 
mg/week for 51 weeks. Arm C (reference) is an open-label arm with belimumab 
subcutaneous (SC) 200 mg/week and standard therapy for 104 weeks. Arm C (reference)
will provide a qualitative reference to assess the relative performance of Arm A (control) 
and Arm B (combination) vs. currently available standard SLE therapy (Arm C). The 
concomitant medication rules and definitions of treatment failure are the same for the 

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double-blind control and combination arms, Arms A and B, but differ from those for the 
open-label reference arm, Arm C.
Randomization and the first dose of belimumab should be completed within 35 days of 
initiation of screening procedures. Participants will be receiving stable standard therapy 
at entry. At randomization, participants will be stratified by their screening SLEDAI-2K 
score (9 vs. 10), by immunosuppressant use at screening (immunosuppressant use vs. 
no use) and by screening corticosteroid dose (prednisone equivalent 10 mg/day vs. 
>10 mg/day). Belimumab will be administered SC on Day 1 and then weekly (i.e., every 
7 days 1 day) through Week 51 for Arms A and B, and through Week 103 for Arm C. 
SC injections will be administered at alternating injection sites between the left or right 
thighs and the abdomen. Rituximab-placebo or rituximab will be administered by 
intravenous (IV) infusions at Weeks 4 and 6 for Arms A and B. Participants in Arms A 
and B will be administered a pre-medication regimen 30 minutes before each rituximab-
placebo or rituximab infusion on Weeks 4 and 6, including methylprednisolone 100 mg 
IV or equivalent, an antihistamine, and acetaminophen or equivalent.
Participants in any arm who are deemed treatment failures for efficacy endpoints at any 
time during the study will be encouraged to remain in the study and continue to have all 
efficacy and safety assessments.
Participants randomized to Arms A or B who enter the study on immunosuppressants will 
discontinue immunosuppressants prior to or on the day of the Week 4 visit. Continuing 
the stable immunosuppressant dose until Week 4 allows participants to receive 3 weeks 
of belimumab SC prior to discontinuing their immunosuppressants. Corticosteroids may 
be adjusted as necessary during this transition period. If participants in Arms A and B 
receive immunosuppressants after the Week 4 visit they will be deemed treatment 
failures. Participants in Arm C will continue their stable immunosuppressants throughout 
the study at the discretion of the investigator. If participants in Arm C require an 
increased dose of their stable immunosuppressant after Week 12 or addition of a new 
immunosuppressant they will be considered a treatment failure.
After the initial 12 weeks of study treatment, a protocol-specified corticosteroid taper will 
be initiated and conducted under the direction of the investigator for participants in all 
3 arms. The taper will proceed with a target of reaching a prednisone equivalent dose of 
5mg/day by Week 26. If the investigator believes the participant would benefit from 
continued steroid taper and, if tolerated, a prolonged corticosteroid taper should continue 
after Week 26 with the goal of corticosteroid discontinuation. Participants who are able to 
tolerate the final taper will be withdrawn from corticosteroids. If a participant is unable to 
tolerate the final stage of the corticosteroid taper, the investigator may reinitiate 
corticosteroids at a prednisone equivalent dose of up to and including 5 mg/day. If a 7-
day average prednisone equivalent dose of >5 mg/day is required at any time after 
Week 26 visit (i.e., beginning first day of Week 27), the participant will be considered a 
treatment failure for the efficacy endpoints. 
Anti-malarial therapies for SLE may not be initiated during the study, but may be 
continued or dose-adjusted during the study, and will be allowed within the definitions of 

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the efficacy endpoints.  Switching of anti-malarial due to toxicity or lack of availability is 
permitted
Non-Steroidal Anti-Inflammatory drugs (NSAIDs) (for 7 days) may not be initiated 
during the study, but may be continued and dose adjusted as clinically indicated until the 
Week 44 visit. After the Week 44 visit any increase in the NSAID dose above the 
baseline (Day 1) or Week 44 dose, whichever is higher, will declare the participant as a 
treatment failure unless the NSAID is given for <7 days.
During the 52-week double-blind portion of the study, participants in Arms A and B who 
cannot tolerate discontinuation of immunosuppressants or taper of corticosteroids or, in 
the opinion of the investigator, require added therapy, will be considered treatment 
failures for the efficacy endpoints. Blinding to the treatment assignments in Arms A and 
B will be maintained. At the investigator's discretion, these participants may continue 
treatment with belimumab, and/or be treated with additional SLE therapies as necessary, 
including corticosteroids and/or immunosuppressants. Participants in Arm C who are 
unable to tolerate the corticosteroid taper or, in the opinion of the investigator, require 
increased doses of their baseline immunosuppressants or addition of a new 
immunosuppressant will be considered treatment failures for the efficacy endpoints. 
Participants in Arms A and B will enter into the 52-week treatment-free, observational 
phase of the study after completing Week 52 (Weeks 53 through 104). “Treatment-free” 
refers to no active treatment with study treatment (i.e., belimumab and/or rituximab). 
Participants in Arm C will continue to receive belimumab SC and their stable 
immunosuppressants during Weeks 53 through 104. For participants in all three treatment 
arms, treatment with anti-malarials, NSAIDs, and/or corticosteroids with a prednisone 
equivalent dose of 5 mg/day will be allowed in Weeks 53 to 104. 
During Weeks 53 to 104, additional treatment may be given if the investigator believes 
the participant would benefit because he/she: a) responded to study treatment but did not 
meet the primary efficacy endpoint, or b) responded to study treatment but subsequently 
experienced increasing disease activity which requires additional therapy. Additional 
treatment may include open-label belimumab, corticosteroids (>5 mg/day), and/or 
immunosuppressants, and will be administered at the discretion of the investigator. 
Treatment with open-label rituximab is allowed within the protocol, but is not 
encouraged. Belimumab will be provided by the sponsor for those participants who 
reinitiate treatment with belimumab, but additional treatment with rituximab and/or other 
medications will not be provided by the sponsor. NOTE: These participants will be 
considered treatment failures for the Week 64 efficacy analyses if the additional 
treatment (see above) occurs before the Week 64 visit, and for the Week 104 efficacy 
analyses if the additional treatment occurs before the Week 104 visit. Participants who 
are deemed treatment failures will continue to be followed in the study and have all 
efficacy and safety assessments performed. 
In the event that a participant discontinues the study or withdraws consent early, an Early 
Withdrawal visit 1-4 weeks after last dose of study treatment and a Follow Up visit 8 
weeks after the last dose of study treatment should be scheduled. Additionally, an attempt 

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will be made to ascertain survival status at approximately 52 and 104 weeks after the first 
dose of study treatment.

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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Double-blind Treatment Phase Procedures: Year 1, Arms A and B
Double-Blind Treatment Phase 
Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before 
D1)
Treatment Period – Arms A and B (a)
Unsched-
uled Visit
Early 
Withdrawal
Visit (b)
Follow-
up visit 
(8 
weeks 
post 
last 
dose)
D1
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32,
W36
W40
W44, 
W48
W52
(l)
Informed consent
X
Inclusion and exclusion criteria
X
X (m)
Genetics Informed consent
X (r)
Randomization
X
Assessments: Clinic
Full physical exam including 
height and weight 
X
12-lead ECG
X
Demography
X
Medical history 
(includes substance usage)
X
Past and current medical 
conditions including 
cardiovascular medical history
X
Vital signs
X
Symptom-driven physical exam, 
vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
Assessments: Independent Assessor
SLEDAI-2K: Blinded Assessor (t)
X
X
X
X
X
X
X
Assessments: Principal Investigator
SLEDAI-2K: Investigator 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS Baseline/Screening
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Double-Blind Treatment Phase 
Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before 
D1)
Treatment Period – Arms A and B (a)
Unsched-
uled Visit
Early 
Withdrawal
Visit (b)
Follow-
up visit 
(8 
weeks 
post 
last 
dose)
D1
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32,
W36
W40
W44, 
W48
W52
(l)
Neurological Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLE Flare Index (n)
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC-ACR Damage Index
X
X
X
Physician Global Assessment 
(PGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival Assessment (d)
X
Assessments: Patient Reported Outcomes (PROs)
Patient Global Assessment (c)
X
X
X
X
X
X
X
FACIT-Fatigue (c)
X
X
X
X
X
X
X
Lupus QoL (c)
X
X
X
X
X
X
X
WPAI: Lupus (c)
X
X
X
X
X
X
X
Post-treatment interview (o)
X
X
Central Laboratory Tests
Drug and alcohol screen
X
HIV, Hep B and Hep C screen
X
Pregnancy test (WCBP) (e)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments (include 
liver chemistries)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum immunoglobulin 
(IgA, IgM, IgG)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-dsDNA/ANA, 
Complement C3/C4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Extractable nuclear antigens 
(ENAs)
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X

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Double-Blind Treatment Phase 
Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before 
D1)
Treatment Period – Arms A and B (a)
Unsched-
uled Visit
Early 
Withdrawal
Visit (b)
Follow-
up visit 
(8 
weeks 
post 
last 
dose)
D1
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32,
W36
W40
W44, 
W48
W52
(l)
Antiphospholipid antibodies (aCL, 
lupus anticoagulant, beta-2-
glycoprotein-1)
X
X
X
X
X
X
Labs and Biomarkers
B cells subsets
X
X
X
X
X
X
X
X
BLyS Protein
X
X
X
RNA for Interferon Signature
X
Immunogenicity: Belimumab
X
X(f)
X(f)
X
X
X
X
X
X
Immunogenicity: Rituximab
X
X(f)
X(f)
X
X
X
X
X
Pharmacokinetics: Belimumab
X(f)
X
X
X
X
X
X
Pharmacokinetics: Rituximab
X(g)
X(g)
X
X
X(h)
X
X
X
Genetic sample
X
Further Research
Blood Leukocyte Analysis 
(PBMC) (p)
X
X
X
B cell receptor (q)
X
X
X
B cells subsets (u)
X
X
X
X
Study Treatment
Training on use of Autoinjector
X
X
Dispense/Train or Collect 
Electronic Diary
X
X
Dispense Belimumab for weekly 
dosing (SC)
X (i)
X (s)
X
X
X
X
X
X
X
Rituximab or Rituximab-Placebo 
(IV)
X 
(j)
X 
(j)
X
(j)
Discontinue immunosuppressants
X
Initiate corticosteroid taper 
X (k)

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Double-Blind Treatment Phase 
Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before 
D1)
Treatment Period – Arms A and B (a)
Unsched-
uled Visit
Early 
Withdrawal
Visit (b)
Follow-
up visit 
(8 
weeks 
post 
last 
dose)
D1
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32,
W36
W40
W44, 
W48
W52
(l)
Target for steroid corticosteroid 
dose to reach prednisone 
equivalent 5 mg/day
X
Study Visit Review Procedures
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review 
(including SLE medications)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review HCRU and Patient Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Starting at Week 4 and throughout the study period including follow-up, a study visit time window 7 days is acceptable. Note: Every effort should be made to schedule the visit in 
this window, however if the COVID-19 pandemic situation affects the ability to achieve this then, for those COVID-19 specific instances, the visit window can be expanded to ±28 
days.
b.
Early Withdrawal Visit 1-4 weeks after last dose for participants that withdraw from the study.
c.
To be conducted prior to clinical assessments.
d.
Survival assessment at Week 52 for participants who withdraw before Week 52.
e.
Serum pregnancy test at Screening; Urine pregnancy test at all other visits, including pregnancy test 16 weeks after last dose of belimumab. The pregnancy test 16 weeks after 
the last dose of belimumab may be done at home, with the results reported by telephone call to the clinic. See Section 9 for pregnancy test requirements.
f.
At Week 4 and Week 6 pre-rituximab/ rituximab-placebo dose.
g.
At Week 4 post-rituximab/rituximab-placebo dose and at Week 6 pre- and post- rituximab/rituximab-placebo dose.
h.
At Week 32 only.
i.
The first dose of belimumab will be administered at the clinic and the subject needs to stay for 3 hours post dose for observation.
j.
Premedication administration will be given 30 minutes prior to each Rituximab / rituximab-placebo dose and the subject needs to stay in clinic for 1 hour post dose for observation
(i.e., Clinical monitoring including vital signs). If the subject misses the Week 4 dosing visit and dosing will take place during an unscheduled visit, the first dose of rituximab should 
be scheduled no later than 7 days after Week 4. The second dose of rituximab must be administered at least 2 weeks but not more than 3 weeks after the first rituximab dose. 
NOTE: Contact Medical Monitor if the date of a) first dose is more than 1 week past week 4, and b) if the date of the second dose of rituximab would exceed 3 weeks after the first
dose. During unscheduled visits, procedures for Immunogenicity and PK will follow the schedule for Week 4 and Week 6. 
k.
It is recommended that the steroid taper be initiated on Week 12 to reach the target prednisone equivalent of 5 mg/day at Week 26, but the taper schedule is at the discretion of 
the investigator.

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l.
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Please refer to Section 
9.4 and to the guidance provided in the Study Reference Manual.
m.
The interim medical history, including SLE medications, should be reviewed prior to randomization to assure that the participant's eligibility has not changed.
n.
Blood samples for a B cell receptor analysis should be obtained in the event of a suspected SLE Flare (refer to footnote q).
o.
To be conducted at US sites only. 
p.
To be conducted only at US study sites.
q.
To be conducted only at US study sites. B-cell receptor samples are also collected at US sites when subjects experience a suspected SLE Flare.
r.
Separate Genetics informed consent as needed per country specific requirements. Genetics informed consent and sample can be obtained any time after baseline.
s.
If a subject happens to be scheduled for an infusion (week 4 and/or 6) on the same day of the week as their normally scheduled belimumab injection, whenever possible, the day 
of the belimumab injection should be altered within the dosing window to separate the day of the injection from the day of the infusion to allow for appropriate safety monitoring of 
the infusion. If subject has already self-administered the belimumab dose on the day of IV infusion, contact study Medical Monitor for guidance prior to administering the 
rituximab/rituximab-placebo dose.
t.
Independent assessor will perform symptom-driven physical examination to include, at a minimum, assessments of eyes, mouth, skin, lungs, cardiovascular system, abdomen, 
and extremities (including joints). Independent assessors must have a source document (paper record in the study file) where the findings in the clinical exam and laboratory 
analyses supporting the scoring of S2K are described.
u.
To be conducted only at select European sites

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Table 2
Double-blind Observational Phase Procedures: Year 2, Arms A and B
Observational Period – Arms A and B (a)
Arms A and B 
Double-blind Observational Phase Procedures
(W=Week)
W60
W64
W72
W80
W88, 
W96
W104
Unscheduled 
Visit (e)
Early 
Withdrawal
Visit (f)
Follow-up visit 
(8 weeks post 
last dose) (j)
Assessments: Clinic
Symptom-driven physical exam, vital signs
X
X
X
X
X
X
X
X
X
Weight
X
X
Assessments: Independent Assessor
SLEDAI-2K: Blinded Assessor (m)
X
X
X
X
X
Assessments: Principal Investigator
SLEDAI-2K: Investigator 
X
X
X
X
X
X
X
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
Neurological assessment
X
X
X
X
X
X
X
X
X
SLE Flare Index (g)
X
X
X
X
X
X
X
X
SLICC-ACR Damage Index
X
X
Physician's Global Assessment (PGA)
X
X
X
X
X
X
X
X
Survival assessment (c)
X
Assessments: Patient Reported Outcomes (PROs)
Patient Global Assessment (b)
X
X
X
X
FACIT-Fatigue (b)
X
X
X
X
Lupus QoL (b)
X
X
X
X
WPAI: Lupus (b)
X
X
X
X
Exit Interview (h) 
X
X
Central Laboratory Tests
Urine pregnancy test (WCBP) (d)
X
X
X
X
X
X
X
X
X
Laboratory assessments 
(include liver chemistries) 
X
X
X
X
X
X
X
X
X
Serum immunoglobulin (IgA, IgM, IgG)
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Anti-dsDNA/ANA, Complement C3/C4
X
X
X
X
X
X
X
X
X
Extractable nuclear antigens (ENAs)
X
X
X
X
PT/PTT
X
X
X
X

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Observational Period – Arms A and B (a)
Arms A and B 
Double-blind Observational Phase Procedures
(W=Week)
W60
W64
W72
W80
W88, 
W96
W104
Unscheduled 
Visit (e)
Early 
Withdrawal
Visit (f)
Follow-up visit 
(8 weeks post 
last dose) (j)
Antiphospholipid antibodies (aCL, lupus 
anticoagulant, beta-2-glycoprotein-1)
X
X
X
X
X
Labs and Biomarkers
B cells subsets
X
X
X
X
X
BLyS Protein
X
X
X
X
X
X
X
Immunogenicity: Belimumab
X
X
X
X
X
Immunogenicity: Rituximab
X
X
Pharmacokinetics: Belimumab
X
X
X
X
X
X
X
Pharmacokinetics: Rituximab
X
X
X
Further Research
Blood Leukocyte Analysis (PBMC) (k)
X
X
X
B cell receptor (l)
X
X
X
B cell subsets (n)
X
X
X
X
X
Study Treatment
Collect Electronic Diary
X
X
Study Visit Review Procedures
AE/SAE review
X
X
X
X
X
X
X
X
X
Concomitant medication review (including SLE 
medications)
X
X
X
X
X
X
X
X
X
Review HCRU and Patient Diary (i)
X
X
X
X
X
X
X
X
a.
During this study period including follow-up, a study visit time window 7 days is acceptable. Note: Every effort should be made to schedule the visit in this window, however if the 
COVID-19 pandemic situation affects the ability to achieve this then, for those COVID-19 specific instances, the visit window can be expanded to ±28 days.
b.
To be conducted prior to clinical assessments.
c.
Survival assessment at Week 104 for participants who withdraw before Week 104.
d.
The pregnancy tests 12 months after the last dose of rituximab / rituximab-placebo (Week 58) and 16 weeks after the last dose of belimumab (Week 68) may be done at home, 
with the results reported by telephone call to the clinic. See Section 9 for pregnancy test requirements for participants that withdraw.(Argentina only: In addition to pregnancy 
testing at the specified clinic visits, a urine pregnancy test is to be performed at home at Week 56, Week 68, Week 76, Week 84, Week 92, and Week 100, with the results 
reported by telephone call to the clinic.)
e.
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Please refer to Section 

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9.4 and to the guidance is provided in the Study Reference Manual.
f.
Participants who withdraw from the study are required to complete an Early Withdrawal Visit 1-4 weeks after withdrawal from the study.
g.
Blood samples for a B cell receptor analysis should be obtained in the event of a suspected SLE Flare (refer to footnote l).
h.
To be conducted at US sites only. 
i.
Diary review is only necessary if the patient receive Belimumab rescue therapy. 
j.
Follow up visit is required only for subjects who receive belimumab rescue therapy at any time between Week 52 and Week 104.
k.
To be conducted only at US study sites.
l.
To be conducted only at US study sites. B-cell receptor samples are also collected when subjects at US sites experience a suspected SLE Flare.
m.
Independent assessor will perform symptom-driven physical examination to include, at a minimum, assessments of eyes, mouth, skin, lungs, cardiovascular system, abdomen, 
and extremities (including joints). Independent assessors must have a source document (paper record in the study file) where the findings in the clinical exam and laboratory 
analyses supporting the scoring of S2K are described.
n.
To be conducted at select European centers.

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Table 3
Open-Label Treatment Phase Procedures: Year 1, Arm C
Treatment Phase Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before D1)
Treatment Period – Arm C (a)
D1, 
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32, 
W36
W40
W44, 
W48
W52
Unsched-
uled Visit
(h)
Early 
Withdrawal
Visit (b)
Follow-up 
Visit (8 
weeks 
post last 
dose)
Informed consent
X
Inclusion and exclusion criteria
X
X (i)
Genetics Informed consent
X (m)
Randomization
X
Assessments: Clinic
Full physical exam including 
height and weight
X
12-lead ECG
X
Demography
X
Medical history 
(includes substance usage)
X
Past and current medical 
conditions including 
cardiovascular medical history
X
Vital signs
X
Symptom-driven physical 
exam, vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
Assessments: Independent Assessor
SLEDAI-2K: Blinded Assessor
(n)
X
X
X
X
X
X
X
Assessments: Principal Investigator
SLEDAI-2K: Investigator
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS Baseline/Screening
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLE Flare Index (j)
X
X
X
X
X
X
X
X
X
X
X
X
X

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Treatment Phase Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before D1)
Treatment Period – Arm C (a)
D1, 
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32, 
W36
W40
W44, 
W48
W52
Unsched-
uled Visit
(h)
Early 
Withdrawal
Visit (b)
Follow-up 
Visit (8 
weeks 
post last 
dose)
SLICC-ACR Damage Index
X
X
X
Physician Global Assessment 
(PGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival Assessment (d)
X
Assessments: Patient Reported Outcomes (PROs)
Patient Global Assessment (c)
X
X
X
X
X
X
X
FACIT-Fatigue (c)
X
X
X
X
X
X
X
Lupus QoL (c)
X
X
X
X
X
X
X
WPAI: Lupus (c)
X
X
X
X
X
X
X
Treatment Interview (k)
X
X
Central Laboratory Tests
Drug and alcohol screen
X
HIV, Hep B and Hep C screen
X
Pregnancy test (WCBP) (e)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments 
(include liver chemistries)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum immunoglobulin 
(IgA, IgM, IgG)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-dsDNA/ANA, 
Complement C3/C4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Extractable nuclear antigens 
(ENAs)
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
Antiphospholipid antibodies 
(aCL, lupus anticoagulant, 
beta-2-glycoprotein-1)
X
X
X
X
X
X
Labs and Biomarkers
B cells subsets
X
X
X
X
X
X
X
X

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Treatment Phase Procedures
(D=Day, W=Week)
Screening 
(35 to 
1 day(s) 
before D1)
Treatment Period – Arm C (a)
D1, 
(Base-
line)
W4
W6
W8
W12
W16
W20, 
W24
W26
W28, 
W32, 
W36
W40
W44, 
W48
W52
Unsched-
uled Visit
(h)
Early 
Withdrawal
Visit (b)
Follow-up 
Visit (8 
weeks 
post last 
dose)
BLyS Protein
X
X
X
RNA for interferon signature
X
Immunogenicity: Belimumab
X
X
X
X
X
X
X
X
X
Pharmacokinetics: Belimumab
X
X
X
X
X
X
X
Genetic sample
X
Further Research
B cell subsets (o)
X
X
X
X
B-cell Receptor (l)
X
X
X
Study Treatment
Training on use of Autoinjector
X
X
Dispense/Train or Collect 
Electronic patient diary
X
X
Dispense Belimumab for 
weekly dosing (SC)
X
(f)
X
X
X
X
X
X
X
X
X
Initiate corticosteroid taper
X 
(g)
Target for corticosteroid dose 
to reach prednisone equivalent 
5 mg/day
X
Study Visit Review Procedures
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review 
(including SLE medications)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review HCRU and Patient 
Diary
X
X
X
X
X
X
X
X
X
X
X
X
X

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a.
Starting at Week 4 and throughout the study period including follow-up, a study visit time window 7 days is acceptable. Note: Every effort should be made to schedule the visit in
this window, however if the COVID-19 pandemic situation affects the ability to achieve this then, for those COVID-19 specific instances, the visit window can be expanded to ±28
days.
b.
Early Withdrawal Visit 1-4 weeks after last dose for participants that discontinue and withdraw from the study.
c.
To be conducted prior to clinical assessments.
d.
Survival assessment at Week 52 for participants who withdraw before Week 52.
e.
For WOCBP Serum pregnancy test at Screening; Urine pregnancy test at all other visits, including pregnancy test 16 weeks after last dose of belimumab. The pregnancy test 16
weeks after the last dose of belimumab may be done at home, with the results reported by telephone call to the clinic. See Section 9 for pregnancy test requirements for
participants that withdraw.
f.
The first dose of belimumab will be administered at the clinic and the subject needs to stay for 3 hours post dose for observation.
g.
It is recommended that the steroid taper be initiated on Week 12 to reach the target prednisone equivalent of 5 mg/day at Week 26, but the taper schedule is at the discretion of
the investigator.
h.
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Please refer to Section
9.4 and to the guidance provided in the Study Reference Manual.
i.
The interim medical history, including SLE medications, should be reviewed prior to randomization to assure that the participant's eligibility has not changed.
j.
Blood samples for a B cell receptor analysis should be obtained in the event of a suspected SLE Flare (refer to footnote l).
k.
To be conducted at US sites only.
l.
To be conducted only at US study sites as part of further research. B-cell receptor samples are also collected at US sites when subjects experience a suspected SLE Flare.
m.
Separate Genetics informed consent as needed per country specific requirements. Genetics informed consent and sample can be obtained any time after baseline.
n.
Independent assessor will perform symptom-driven physical examination to include, at a minimum, assessments of eyes, mouth, skin, lungs, cardiovascular system, abdomen,
and extremities (including joints). Independent assessors must have a source document (paper record in the study file) where the findings in the clinical exam and laboratory
analyses supporting the scoring of S2K are described.
o.
To be conducted at select European centers.

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Table 4
Open-Label Treatment Phase Procedures: Year 2, Arm C
Treatment Period – Arm C (a)
Arm C
Treatment Phase Procedures
(W=Week)
W60
W64
W72
W80
W88, 
W96
W104
Unscheduled 
Visit (e)
Early 
Withdrawal
Visit
Follow-up 
Visit (8 weeks 
post last 
dose)
Assessments: Clinic
Symptom-driven physical exam, 
vital signs
X
X
X
X
X
X
X
X
X
Weight
X
X
Assessments: Independent Assessor
SLEDAI-2K: Blinded Assessor (i)
X
X
X
X
X
Assessments: Principal Investigator
SLEDAI-2K: Investigator
X
X
X
X
X
X
X
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
Neurological assessment
X
X
X
X
X
X
X
X
X
SLE Flare Index (f)
X
X
X
X
X
X
X
X
SLICC-ACR Damage Index
X
X
Physician Global Assessment (PGA)
X
X
X
X
X
X
X
X
Survival assessment (c)
X
Assessments: Patient Reported Outcomes (PROs)
Patient Global Assessment (b)
X
X
X
X
FACIT-Fatigue (b)
X
X
X
X
Lupus QoL (b)
X
X
X
X
WPAI: Lupus (b)
X
X
X
X
Exit Interview (g)
X
X
Central Laboratory Tests
Urine pregnancy test (WCBP) (d)
X
X
X
X
X
X
X
X
X
Laboratory assessments 
(include liver chemistries) 
X
X
X
X
X
X
X
X
X
Serum immunoglobulin (IgA, IgM, IgG)
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Anti-dsDNA/ANA, Complement C3/C4
X
X
X
X
X
X
X
X
X

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Treatment Period – Arm C (a)
Arm C
Treatment Phase Procedures
(W=Week)
W60
W64
W72
W80
W88, 
W96
W104
Unscheduled 
Visit (e)
Early 
Withdrawal
Visit
Follow-up 
Visit (8 weeks 
post last 
dose)
Extractable nuclear antigens (ENAs)
X
X
X
X
PT/PTT
X
X
X
X
Antiphospholipid antibodies (aCL, lupus 
anticoagulant, beta-2-glycoprotein-1)
X
X
X
X
X
Labs and Biomarkers
B cells subsets
X
X
X
X
X
Immunogenicity: Belimumab
X
X
X
X
X
Pharmacokinetics: Belimumab
X
X
X
X
X
Further Research
B cell receptor (h)
X
X
X
Study Treatment
Collect Electronic Diary 
X
X
Dispense Belimumab for weekly dosing 
(SC)
X
X
X
X
X
Study Visit Review Procedures
AE/SAE review
X
X
X
X
X
X
X
X
X
Concomitant medication review 
(including SLE medications)
X
X
X
X
X
X
X
X
X
Review HCRU and Patient Diary
X
X
X
X
X
X
X
X

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a.
During this study period including follow-up, a study visit time window ± 7 days is acceptable. Note: Every effort should be made to schedule the visit in this window, however if the 
COVID-19 pandemic situation affects the ability to achieve this then, for those COVID-19 specific instances, the visit window can be expanded to ±28 days.
b.
To be conducted prior to clinical assessments.
c.
Survival assessment at Week 104 for participants who withdraw before Week 104.
d.
The pregnancy test 16 weeks after the last dose of belimumab may be done at home, with the results reported by telephone call to the clinic. .(Argentina only: In addition to 
pregnancy testing at the specified clinic visits, a urine pregnancy test is to be performed at home at Week 56, Week 68, Week 76, Week 84, Week 92, and Week 100, with the 
results reported by telephone call to the clinic.)
e.
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Please refer to Section 
9.4 and to the guidance provided in the Study Reference Manual.
f.
Blood samples for a B cell receptor analysis should be obtained in the event of a suspected SLE Flare (refer to footnote h).
g.
To be conducted at US sites only.
h.
To be conducted only at US study sites. B-cell receptor samples are also collected at US sites only when subjects experience a suspected SLE Flare.
i.
Independent assessor will perform symptom-driven physical examination to include, at a minimum, assessments of eyes, mouth, skin, lungs, cardiovascular system, abdomen, and 
extremities (including joints). Independent assessors must have a source document (paper record in the study file) where the findings in the clinical exam and laboratory analyses 
supporting the scoring of S2K are described.

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3.
INTRODUCTION
3.1.
Study Rationale
Systemic Lupus Erythematosus (SLE) is characterized by autoantibodies, including 
antibodies to double-stranded DNA (dsDNA), and by abnormal B cell activation and 
differentiation [Davidson, 2001], indicating that therapies which deplete or modulate 
B cells could be beneficial in treating SLE. Belimumab and rituximab are monoclonal 
antibodies that achieve their expected pharmacology through different but 
complementary mechanisms; therefore, based on their mechanisms of action, synergistic 
effects in the treatment of SLE are possible. Belimumab treatment increases peripheral 
memory B cells potentially by mobilization from tissues this may include the autoreactive 
B cell compartment. This study will assess whether co-administration of belimumab and 
a single cycle of rituximab may optimize treatment with belimumab, resulting in 
improvements in clinical status with a favorable safety profile, by comparing participants 
randomized to belimumab plus rituximab vs. belimumab plus rituximab-placebo. An 
open-label arm is included to provide a qualitative reference to standard therapy.
3.2.
Background
Belimumab is an important treatment option for patients with SLE, but significant 
numbers of patients do not achieve a state of low disease activity, and are still left with 
moderate level of residual disease activity. There is a large unmet medical need for 
additional effective treatment which could meaningfully reduce disease-related morbidity 
and mortality and limit the toxicity associated with traditional treatment regimens such as 
corticosteroids and immunosuppressants.
Rituximab treatment results in nearly complete depletion of CD20+ B cells in the 
peripheral blood within hours of treatment. In contrast, relatively high numbers of CD20+ 
B cells persist in the bone marrow following initial treatment with rituximab [Boumans, 
2011]. Belimumab treatment increases peripheral memory B cells potentially by 
mobilization from tissues this may include the autoreactive B cell compartment from 
tissues into the periphery. This mobilization would expose these cells to more efficient 
depletion by rituximab. Continuing belimumab after a single course of rituximab would 
suppress the B-lymphocyte stimulator (BLyS) elevation observed after rituximab 
monotherapy, thus suppressing the signal which leads to potential repopulation of 
autoreactive B cells.
A treatment regimen which could reliably and effectively achieve and maintain low 
disease activity or remission, including patients with earlier and potentially more 
reversible disease prior to the development of permanent disability or end-organ damage, 
would change the paradigm by which SLE is treated today. This patient population has a 
large unmet medical need as 50% of SLE patients develop end-organ damage within the 
first 5 years of diagnosis [Urowitz, 2012]. Recent scientific research suggests that a 
combination treatment with anti-BLyS and anti-CD20 may potentially address this need. 
Anti-BLyS and anti-CD20 therapeutics operate through different but complementary 
mechanisms and the addition of a single cycle of rituximab treatment may optimize the 
effect of belimumab treatment in SLE.

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Synergy may emerge through the following mechanisms:

Belimumab may cause redistribution of memory and germinal center B cells 
from lymphoid tissue into blood, where they are exposed to higher rituximab 
concentrations in the absence of local tissue factors that protect the B cells in 
their niches, which is likely to increase B cell depletion.

Neutralization of serum BLyS level increases seen after rituximab monotherapy, 
preventing rapid B cell repopulation which is associated with SLE disease flares.

Increased stringency of B cell reconstitution in the presence of anti-BLyS 
therapy with belimumab, resulting in fewer auto-reactive cells being formed 
after B cell depletion with rituximab.
Preclinical data supporting the hypothesis that a combination of belimumab and 
rituximab may provide additional efficacy over either agent alone were generated in a 
human-CD20 expressing mouse model. Experiments using this model demonstrated 
relative resistance of the marginal zone (MZ) B cell compartment to anti-CD20 antibody 
monotherapy. Approximately 50% of these cells remained following anti-CD20 mAb as 
compared to complete depletion of circulating mature B cells. MZ B cells were rendered 
sensitive to anti-CD20 mAb depletion when they were effectively mobilized from tissues 
into the vasculature with anti-L and anti-4 integrand mAbs. Thus, the tissue B cells 
were not inherently resistant to anti-CD20 mAb treatment: treatment response was 
enhanced by prior mobilization of the MZ B cells into the vasculature [Gong, 2005]. 
Additionally, when mouse BLyS receptor (BR3)-Fc and anti-hCD20 were combined in 
this model, there was more effective tissue B cell depletion of MZ B cells and follicular 
(FO) B cells than with either agent alone. Similar observations were made in murine SLE 
models [Lin, 2015] in which dual targeting resulted in greater efficacy with increased 
tissue B cell depletion, greater reduction in a range of auto-antibody levels, and 
significant decreases in total IgG1, IgG2b, IgG3, IgM, and IgA when compared to BLyS 
inhibition and CD20 B cell depletion alone.
There have been 4 recent case reports of patients with SLE and Sjogren’s Syndrome 
demonstrating the ability of the combination to induce remission or states of disease 
control for prolonged periods [Kraaij, 2014; De Vita, 2014; Simonetta, 2016]. In one case 
a 32-year-old woman with a 3 year history of lupus nephritis who previously failed 
2 induction regimens was treated with rituximab which led to a partial response. When
there was still B cell depletion but as B cells began to repopulate, the patient was started 
on belimumab at which point the patient entered remission on no steroids or 
immunosuppressants. Remission persisted after 18 months. The second case involved a 
42-year-old man with lupus nephritis who likewise had failed standard therapy and 
induction regimens. Initiation of rituximab led to only partial response and a full relapse 
occurred while the patient was still B cell depleted but B cells began to repopulate, at 
which point belimumab was started. The patient entered a prolonged (>12 months) state 
of disease control on no steroids or immunosuppressants but on belimumab. The third 
case involved a 23-year-old woman with refractory lupus nephritis who failed standard 
therapy and the addition of belimumab only resulted in transient partial reduction of 
proteinuria. Belimumab was stopped and the patient received one cycle of rituximab with 
no significant or sustained effects on disease activity, and a rebound increase in serum B-

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cell activating factor of the TNF ligand family (BAFF) levels was detected. Belimumab 
was reintroduced and the patient experienced “rapid and dramatic” improvements in 
clinical and biological parameters including proteinuria. After more than 18 months no 
disease flares or proteinuria relapses were observed. In the fourth case, a patient with 
severe, refractory (including to prior courses of rituximab) Sjogren’s Syndrome with 
associated Mucosa associated lymphoid tissue (MALT) lymphoma and cryglobulinemic 
vasculitis was treated with belimumab. The patient did not respond and so, as a last 
resort, rituximab was tried again, while there was still ongoing exposure to belimumab. 
This was followed by complete and persistent regression of the lymphoma, skin ulcers 
and vasculitis. Cryoglobulins and rheumatoid factor became persistently negative and the 
patient is in remission after three and a half years.
A detailed description of the chemistry, pharmacology, efficacy and safety of belimumab 
is provided in the most recent version of the Belimumab Investigator’s Brochure. Refer to 
the local rituximab approved product label for description of the chemistry, 
pharmacology, efficacy, and safety of rituximab.
3.3.
Benefit/Risk Assessment
More detailed information about the established benefits and risks of belimumab and 
rituximab, including expected adverse events (AEs), may be found in the Belimumab 
Investigator’s Brochure and local rituximab approved product label, respectively.
There are no published clinical trial data for the co-administration of belimumab with 
rituximab; however, the following data were reviewed and no new safety risks beyond 
what would be expected for either agent alone is suggested from the limited data 
available from patients who may have had overlapping exposures to belimumab and 
rituximab:

The GSK Safety Database of AEs from clinical trials and post-marketing 
experience

An insurance claims database (Safety Works)

In-stream, blinded data from an ongoing GSK study of belimumab in subjects 
with vasculitis who were induced with high dose corticosteroids and either 
rituximab or cyclophosphamide

In stream, blinded data from an ongoing GSK study of belimumab co-
administered with rituximab in the treatment of primary Sjögren’s syndrome
Given that the experience of co-administration of anti-CD20 and anti-BLyS therapies to 
date is very limited, robust safety monitoring and stopping rules are being implemented 
to safeguard subject safety. The key risk assessment and mitigation strategy for this 
protocol is outlined below and in Section 8.2.

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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
Infections:
Prolonged B cell suppression and more complete 
B cell depletion expected; potential for more 
profound hypogammaglobulinemia with 
increased risk for serious infections including 
opportunistic infections (OIs), Progressive 
multifocal leukoencephalopathy (PML), and 
Hepatitis B virus (HBV) reactivation. 
Rituximab: The rate of serious infections with 
rituximab in the rheumatoid arthritis (RA)
population is 4% per year.
Reactivation of hepatitis B has also been very 
rarely reported in RA patients receiving 
rituximab.
Late onset neutropenia occurs rarely in patients 
treated with rituximab.
Belimumab: The rate of serious infections for 
SLE is 5% of subjects receiving either 
belimumab or placebo.
Belimumab and Rituximab Coadministration:
Infections are expected events for both 
belimumab and rituximab. Cases of PML have 
been very rarely reported, including fatal events, 
for both rituximab and belimumab in autoimmune 
diseases.
There is preclinical evidence for prolonged B cell 
suppression and more complete B cell depletion 
as well as effect on IgG1+ plasma cells in the 
long-lived bone marrow niche thought to be less 
Exclusions based on significant infection history, 
serologic evidence of past or present HBV or 
Hepatitis C virus (HCV) infection; IgG 
<250 mg/dL (note: <400mg/dL for Germany), IgA 
deficiency (IgA level <10 mg/dL), neutrophils 
<1.5X109/L.
A PML management plan including neurologic 
questionnaire, patient alert card, and stopping 
criteria will be utilized. An independent PML 
Panel is also available for consultations.
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 reported to the 
Medical Monitor within 24 hrs. The 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
sensitive to immunotherapy [Lin, 2015] with dual 
B cell immunotherapy. Assessment of the 
translatability of the IgG reductions to humans is 
difficult to make due to species differences in B 
cell biology and different treatments; however, 
the mouse data raises the hypothetical risk that 
immunoglobulin levels may reduce more with 
coadministration treatment.
Neutropenia:
SLE disease related neutropenia and Rituximab 
induced neutropenia may result in further
reduction in circulating neutrophils and/or 
influence timing of this neutropenia onset as 
compared to when Rituximab is administered 
alone.
appropriateness of continuing study agent, while 
the case is being assessed, should be 
discussed.
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request that 
patients report signs of infection. Treat infections 
immediately and appropriately.
Neutropenia:
Individual subject’s treatment with belimumab 
and rituximab/rituximab-placebo will be 
discontinued for (a) life threatening infection; (b) 
IgG <400 mg/dL if associated with a serious 
infection. 
Subjects should be monitored for neutropenia 
throughout the study. Neutropenia should be 
managed appropriately according to local 
practice and clinical judgement should be applied 
with regard to the appropriateness of continuing 
study treatment in these subjects.
•
Study treatment with rituximab/rituximab-
placebo (infusions Week 4 and/or Week 
6) must be temporarily withheld and the 
GSK medical monitor consulted about 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
continued dosing if a subject 
experiences a neutrophil count <1x109/L.
•
Study treatment with belimumab (Arms 
A/B and C) must be temporarily withheld 
and the GSK medical monitor consulted 
about continued dosing if a subject 
experiences a neutrophil count 
<0.5x109/L.
Systemic Infusion / Injection-Related Reactions, Hypersensitivity Reactions and Immunogenicity:
Serum Sickness: Serum sickness has been 
associated with rituximab in autoimmune 
indications [Meijer, 2010].
There is a potential risk for increased 
immunogenicity due to cross reactivity which 
could lead to increased frequency of 
hypersensitivity reactions, particularly of the 
delayed type.
Rituximab: The incidence of serum sickness 
associated with rituximab in pSS studies has 
ranged from 6-38% [Carubbi, 2014].
Administration of belimumab and rituximab may 
result in infusion and hypersensitivity reactions, 
which can be severe and can be fatal. Delay in 
the onset of serious hypersensitivity reactions 
can occur. Both rituximab and belimumab have 
been associated with delayed type non-acute 
Hypersensitivity reaction (HSR)/serum sickness, 
although no relationship to Anti-drug Antibody 
(ADA) has been established.
Belimumab and Rituximab Coadministration: 
Incidences of hypersensitivity and infusion 
reactions have been noted to be higher with co-
administration vs. mono-biologic therapy but no 
Immunogenicity will be evaluated with periodic 
assessment over the course of the study. 
A pre-medication regimen will be given before 
each rituximab/rituximab placebo infusion: 
methylprednisolone 100 mg IV, an antihistamine
and acetaminophen or equivalent. 
Subjects should remain under clinical 
supervision for 3 hours after completion of the 
first belimumab injection and the 
rituximab/placebo infusions. Should symptoms of 
acute hypersensitivity occur, an extended period 
of monitoring may be appropriate, based on 
clinical judgement. If subjects are to receive 
belimumab after 4 consecutive weeks of not 
receiving belimumab, the first belimumab dose 
must be administered in the clinic and subject 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
association with ADA has been established 
[Weinblatt, 2006].
should remain under clinical supervision for 3 
hours after the completion of the dose. 
Patients will be given an alert card for HSR and 
delayed HSR/serum sickness.
Malignancy:
There is an increased risk of malignancy, 
including Non-Hodgkin’s lymphoma, in SLE.
There is a theoretical increased risk of 
malignancy with combination 
immunosuppressive mechanisms.
Belimumab and Rituximab: Immunomodulatory 
drugs like rituximab and belimumab may 
increase the risk of malignancy. To date, no 
causal relationship between belimumab or 
rituximab and malignancy, including B cell 
lymphoma, has been detected, both of which 
have been administered long term and in 
combination with other immunosuppressants of 
various mechanisms.
Subjects with a history of malignancy in the 5 yrs 
prior to randomization, except for adequately 
treated basal or squamous cell cancers of the 
skin, or carcinoma in situ of the uterine cervix, 
will be excluded.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, request 
that patients report signs and symptoms. Treat 
appropriately.
Interaction with Vaccinations:
There is a risk of reduced antibody titers with 
mono and dual B cell immunotherapy. The 
potential synergistic effect of rituximab and 
belimumab may result in a prolonged B cell 
depletion that could have a similar inhibitory 
impact on vaccine responses as administering 
repeated doses of rituximab.
Rituximab: As described in the label [Rituxan
package insert, 2016], the response to 
pneumococcal vaccination (a T cell independent 
antigen) as measured by an increase in antibody 
titers to at least 6 of 12 serotypes was lower in 
patients treated with rituximab plus methotrexate 
(MTX) as compared to patients treated with MTX 
alone (19% vs. 61%). Additionally, a lower 
proportion of patients in the rituximab plus MTX 
Immunization with live vaccines is prohibited 
from 30 days prior to Day 1 and during 
belimumab use.
Subjects’ vaccination status should be assessed 
and current immunization guidelines followed; all 
necessary vaccinations should be administered if 
possible no later than 30 days prior to Day 1.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
group developed detectable levels of anti-
keyhole limpet hemocyanin antibodies (a novel 
protein antigen) after vaccination compared to 
patients on MTX alone (47% vs. 93%).
In a combination study, median antibody titers 
(tetanus, diphtheria, pneumococcus) at Week 32 
were reduced from baseline in atacicept 
(recombinant fusion protein which inhibits BLyS 
and APRIL) but not placebo-treated patients who 
had been previously treated with rituximab. 
However, these values recovered close to 
baseline by Week 16 of the follow-up, there were 
few shifts to below protective titers, and no 
between group differences with respect to the 
frequency of shifts.
Belimumab: The efficacy of concurrent 
vaccination in patients receiving belimumab is 
not known; however, in the belimumab 
vaccination trial, evaluation of the impact of 
belimumab treatment on response to on-
treatment vaccination with 23-valent 
pneumococcal vaccine revealed that immune 
responses to the different serotypes were similar 
in SLE patients receiving belimumab compared 
with those not receiving treatment at the time of 
vaccination.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
Psychiatric Events:
There is an identified risk of psychiatric events 
with belimumab and rituximab.
Rituximab: Depression and anxiety were 
common AEs in rituximab RA trials.
Belimumab: There have been reports of 
depression and suicidality in patients receiving 
belimumab. 
Subjects who, in the investigator’s opinion, pose 
a significant suicide risk will be excluded.
The Columbia-Suicide Severity Rating Scale (C-
SSRS) will be completed at each visit 
Subjects will be monitored closely for signs and 
symptoms of psychiatric illness including 
depression and suicidal ideation. Subjects 
displaying such signs and symptoms will be 
treated appropriately and referred as necessary 
to specialty psychiatric care.
Cardiac Disorders:
Rituximab: Angina pectoris, cardiac arrhythmias 
such as atrial flutter and fibrillation, heart failure 
and/or myocardial infarction have occurred in 
patients treated with rituximab. There is no data 
on the safety of rituximab in patients with 
moderate to severe heart failure or severe, 
uncontrolled Cardiovascular (CV) disease.
Belimumab and Rituximab: Hypotension may 
accompany infusion/postinjection systemic 
reactions with both rituximab and belimumab.
Exclude subjects with severe heart failure (New 
York Heart Association, Class IV) or other 
severe, uncontrolled cardiac disease.
Closely monitor any patients with cardiac history 
or those who have experienced prior 
cardiopulmonary adverse reactions during 
administration of rituximab/rituximab placebo. 
Consider withholding antihypertensive 
medications 12 hours prior to rituximab/rituximab 
placebo infusion.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP): Belimumab (GSK1550188), Rituximab, and Belimumab and Rituximab Coadministration
Severe Skin reactions:
Rituximab: Severe skin reactions such as Toxic 
Epidermal Necrolysis and Stevens-Johnson 
syndrome; some with fatal outcome, have been 
reported with rituximab.
Permanently discontinue treatment in the case of 
such an event with suspected relationship to 
treatment.
Posterior Reversible Encephalopathy Syndrome (PRES):
Rituximab: Cases of Posterior reversible 
encephalopathy syndrome (PRES) / reversible 
posterior leukoencephalopathy syndrome 
(RPLS) have been reported. Signs and 
symptoms included visual disturbance, 
headache, seizures and altered mental status, 
with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation 
by brain imaging. The reported cases had 
recognized risk factors for PRES/RPLS, 
including the patients’ underlying disease, 
hypertension, immunosuppressive therapy 
and/or chemotherapy.
Medical monitor will be notified of any new 
neurologic symptoms. Medical monitor and 
investigator will consider the possibility of PRES 
in differential diagnosis.

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3.3.2.
Benefit Assessment
The primary data supporting efficacy of intravenous (IV) belimumab were the Phase 3 
trials (C1056 and C1057) in which 1684 subjects were treated for up to 52 weeks 
(C1057) or 76 weeks (C1056) (Belimumab Investigator’s Brochure, Section 5.3.1.2). 
Belimumab produced significant improvements in the SLE Responder Index as well as in 
the individual component Safety of Estrogen in Lupus National Assessment Trial 
(SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score in 
both studies. Pooled analyses demonstrated steroid sparing and decreased risk of severe 
flares over 52 weeks. Clinical trial data for belimumab since approval continue to show 
efficacy in the treatment of SLE through decreased SLE flares and decreased disease 
activity across multiple organ systems (Belimumab Investigator’s Brochure, Section 
5.3.1.3). Similar results were observed in the pivotal Phase 3 trial of belimumab SC 200 
mg/week (BEL112341), with significant improvements in the SLE Responder Index and 
time to first severe flare endpoints. The inclusion of rituximab provides an opportunity 
for subjects with active SLE despite standard lupus therapy to benefit from potentially 
disease modifying regimen that may include induction of disease control or clinical 
remission and a reduction in or complete discontinuation of corticosteroids and 
immunosuppressant therapy.
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures that will be implemented to minimize risk to subjects 
participating in this study, the potential risks associated with co-administration of 
belimumab and rituximab are justified by the anticipated benefits that may be afforded to 
patients with SLE who choose to participate in this trial.
4.
OBJECTIVES AND ENDPOINTS
The key evaluations are based on comparing belimumab with or without a single cycle of 
rituximab (the combination arm vs. the control arm). There are limited analyses planned 
to compare the combination of belimumab with a single cycle of rituximab (combination 
arm) to belimumab with standard therapy (reference arm). Details of the analyses to be 
conducted will be described in the Reporting and Analysis Plan (RAP), including 
analysis of the combination arm vs. the control arm and the combination arm vs. the 
reference arm.
Objectives
Endpoints
Primary: Efficacy

To evaluate the efficacy of belimumab and 
a single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE.

Proportion of participants with a state of 
disease control defined as a SLEDAI- 2K 
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5mg/day at Week 52. (Serological 
activity, i.e., anti-dsDNA positivity and/or 

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Objectives
Endpoints
hypocomplementemia, is scored in the 
SLEDAI-2K endpoint.)
Secondary: Efficacy (Major)

Proportion of participants with a state of 
clinical remission defined as a Clinical 
SLEDAI-2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day at Week 64. (Serological 
activity score, i.e., anti-dsDNA positivity 
and/or hypocomplementemia, is excluded 
from the Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
disease control defined as a SLEDAI-2K 
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day at Week 104. 

Secondary: Efficacy (Other)

Proportion of participants with a state of 
disease control, defined as a SLEDAI-2K 
score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day, by visit.

Proportion of participants with a state of 
clinical remission, defined as a Clinical 
SLEDAI-2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit. (Serological 
activity score, i.e., anti-dsDNA positivity 
and/or hypocomplementemia, is excluded 
from the Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
complete remission, defined as SLEDAI-
2K=0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, sustained for at least 24 
weeks.

Proportion of participants with a state of 
clinical remission at Week 104, defined as 

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Objectives
Endpoints
Clinical SLEDAI-2K score=0, achieved 
without immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, sustained for at least 24 
weeks. (Serological activity score, i.e., anti-
dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)

Proportion of participants with a state of 
complete remission, defined as a SLEDAI-
2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit 

Time to first severe flare (as measured by 
the modified SLE Flare Index)

Time to first flare (as measured by the 
modified SLE Flare Index)

Time to disease control sustained to Week 
104, defined as SLEDAI-2K score 2, 
achieved without immunosuppressants and 
with corticosteroids at a prednisone 
equivalent dose of 5 mg/day 

Time to clinical remission sustained to 
Week 104, defined as Clinical SLEDAI-2K 
score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day. (Serological activity, i.e., 
anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.) 

Duration of disease control, defined as 
SLEDAI-2K score 2, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 5 mg/day

Duration of clinical remission, defined as 
Clinical SLEDAI-2K score =0, achieved 

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Objectives
Endpoints
without immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day. (Serological activity, i.e., 
anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)

Change from baseline in SLEDAI-2K score 
by visit

Proportion of participants with SLEDAI-2K 
organ improvement by visit

Proportion of participants with SLEDAI-2K 
organ worsening by visit

Change from baseline in Physician Global 
Assessment (PGA) by visit

Proportion of participants with any SLICC 
Damage Index worsening (change >0) 
compared with baseline at Week 52 and 
Week 104

Proportion of participants that meet the 
Lupus Low Disease Activity State (LLDAS) 
response criteria by visit. The LLDAS 
incorporates multiple measures of disease 
activity, specifically: (1) SLEDAI-2K 4, with 
no activity in major organ systems (renal, 
CNS, cardiopulmonary, vasculitis, fever) 
and no hemolytic anemia or gastrointestinal 
activity; (2) no new features of lupus 
disease activity compared with the previous 
assessment; (3) PGA (scale 0-3), 1; (4) 
current prednisolone (or equivalent) dose 
7.5 mg daily; and (5) well tolerated 
standard maintenance doses of 
immunosuppressive drugs and approved 
biological agents, excluding investigational 
drugs.

Proportion of participants with a state of 
disease control, defined as a SLEDAI-2K 
score 2, achieved without 
immunosuppressants and with 

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Objectives
Endpoints
corticosteroids at a prednisone equivalent 
dose of 5 mg/day, by visit; using the 
Principal Investigators assessment of 
SLEDAI-2K.

Proportion of participants with a state of 
clinical remission, defined as a Clinical 
SLEDAI-2K score =0, achieved without 
immunosuppressants and with 
corticosteroids at a prednisone equivalent 
dose of 0 mg/day, by visit; using the 
Principal Investigators assessment of 
SLEDAI-2K. (Serological activity score, i.e. 
anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the 
Clinical SLEDAI-2K endpoint.)
Secondary: Safety

To assess the safety and tolerability of 
belimumab and a single cycle of rituximab 
administered in a combination regimen to 
adult participants with SLE

Incidence of adverse events (AEs) including 
serious AEs (SAEs) and AEs of special 
interest (AESIs)

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Objectives
Endpoints
Secondary: Patient Reported Outcomes 
(PROs)

To assess the impact of belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE on PROs

Change from baseline in Patient Global 
Assessment (PtGA) by visit

Change from baseline in LupusQoL domain 
summary scores (8 domains) by visit

Change from baseline in FACIT-Fatigue 
score by visit 

Proportion of subjects with improvement in 
FACIT-Fatigue score exceeding the Minimal 
Clinically Important Difference (MCID, 4) 
by visit
Exploratory: Pharmacokinetics and 
Biomarkers

To assess pharmacokinetics of and 
biomarker response to belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE

Belimumab and rituximab concentrations by 
visit

Change from baseline in autoantibodies by 
visit

Change from baseline in peripheral blood 
leukocytes including B cell subsets by visit

Change in BLyS levels from baseline by
visit
Exploratory: Patient Reported Work 
Productivity

To explore the impact of belimumab and a 
single cycle of rituximab administered in a 
combination regimen to adult participants 
with SLE on patient experience and 
productivity 

Change from baseline in Work Productivity 
and Activity Impairment (WPAI): Lupus 
percent overall work productivity impairment 
score by visit 

Change from baseline in WPAI: Lupus 
percent activity impairment score by visit

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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase 3, multi-center, 3-arm, randomized, double-blind, placebo-controlled, 
104 week superiority study to evaluate the efficacy and safety of belimumab administered 
in combination with a single cycle of rituximab to adult participants with SLE. 
Participants will be randomly assigned to 1 of 3 treatment arms; belimumab plus 
rituximab-placebo (Arm A, control), belimumab plus rituximab (Arm B, combination), or 
belimumab plus standard therapy (Arm C, reference). Arms A and B are double-blind; 
Arm C is open-label. In order to minimize bias given that Arm C is open-label, blinded 
independent assessors will conduct SLEDAI-2K evaluations at key time points, including 
the primary and key secondary efficacy endpoints. An Independent Data Monitoring 
Committee (IDMC) will review the safety data periodically to ensure external medical 
and statistical review of safety issues (Section 10.4.4).
Randomization and the first dose of belimumab should be completed within 35 days of 
initiation of screening procedures. Participants will be receiving stable standard therapy 
at entry. At randomization, participants will be stratified by their screening SLEDAI-2K 
score (9 vs. 10), by immunosuppressant use at screening (immunosuppressant use vs. 
no use), and by screening corticosteroid dose (prednisone equivalent 10 mg/day vs. 
>10 mg/day). Belimumab will be administered subcutaneously (SC) on Day 1 and then 
weekly (i.e., every 7 days 1 day) through Week 51 for Arms A and B, and through 
Week 103 for Arm C. SC injections will be administered at alternating injection sites 
between the left or right thighs and the abdomen. Rituximab-placebo or rituximab will be 
administered by IV infusions at Weeks 4 and 6 for Arms A and B. Participants in Arms A 
and B will be administered a pre-medication regimen 30 minutes before each rituximab-
placebo or rituximab infusion on Weeks 4 and 6, including methylprednisolone 100 mg 
IV or equivalent, an antihistamine, and acetaminophen or equivalent. The primary 
efficacy endpoint will be measured at Week 52.
Participants from any arm who are deemed treatment failures at any time during the study 
will be encouraged to remain in the study and continue to have all efficacy and safety 
assessments.
Participants randomized to Arms A and B who enter the study on immunosuppressants 
will discontinue immunosuppressants at or prior to the Week 4 visit. Continuing the 
stable immunosuppressant dose until Week 4 allows participants to receive 3 weeks of 
belimumab SC prior to discontinuing their immunosuppressants. Corticosteroids may be 
adjusted as necessary during this transition period. If participants in Arms A and B 
receive immunosuppressants after the Week 4 visit they will be deemed treatment failures 
for the efficacy endpoints. Participants in Arm C who enter the study on stable 
immunosuppressants may continue their stable immunosuppressants throughout the study 
at the discretion of the investigator. If participants in Arm C require an addition of a new 
immunosuppressant after Week 12 they will be considered a treatment failure. See 
Section 7.7.1.4 for additional details on management of immunosuppressants.

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After the initial 12 weeks of study treatment, a protocol-specified corticosteroid taper will 
be initiated and conducted under the direction of the investigator for participants in all 
3 arms. The taper will proceed with a target of reaching a prednisone equivalent dose of 
5 mg/day by Week 26. If the investigator believes the participant would benefit from 
continued steroid taper and, if tolerated, a prolonged corticosteroid taper should continue 
after Week 26 with the goal of corticosteroid discontinuation. Participants who are able to 
tolerate the final taper will be withdrawn from corticosteroids. If a participant is unable to 
tolerate the final stage of the corticosteroid taper, the investigator may reinitiate 
corticosteroids at a prednisone equivalent dose of up to and including 5 mg/day. If a 7-
day average prednisone equivalent dose of >5 mg/day is required at any time after Week 
26, the participant will be considered a treatment failure for the efficacy endpoints. The 
recommended corticosteroid taper scheme is described in Appendix 2.
Anti-malarial therapies for SLE may not be initiated during the study, but may be 
continued or dose-adjusted during the study, and will be allowed within the definitions of 
the efficacy endpoints. 
During the 52-week double-blind phase, participants in Arms A and B who cannot
tolerate discontinuation of immunosuppressants or taper of corticosteroids or, in the 
opinion of the investigator, require added therapy, will be considered treatment failures 
for the efficacy endpoints. Blinding to the treatment assignments in Arms A and B will be 
maintained. At the investigator's discretion, these participants may continue treatment 
with belimumab, and/or be treated with additional SLE therapies as necessary, including 
corticosteroids and/or immunosuppressants. Participants in Arm C who are unable to 
tolerate the corticosteroid taper or, in the opinion of the investigator, require increased 
doses of their baseline immunosuppressants or addition of a new immunosuppressant will 
be considered treatment failures for the efficacy endpoints.
Participants in Arms A and B will enter into the 52-week treatment-free, observational 
phase of the study after completing Week 52 (Weeks 53 through 104). “Treatment-free” 
refers to no active treatment with study treatment (i.e., belimumab and/or rituximab).
Participants in Arm C will continue to receive belimumab SC and their stable 
immunosuppressants during Weeks 53 through 104. Treatment with anti-malarials, 
NSAIDs, and/or corticosteroids with a prednisone equivalent dose of 5 mg/day will be 
allowed in Weeks 53 through 104 in all three arms. 
During Weeks 53 to 104, additional treatment may be given if the investigator believes 
the participant would benefit because he/she: a) responded to study treatment but did not 
meet the primary efficacy endpoint; or b) responded to study treatment but subsequently 
experienced increasing disease activity which requires additional therapy. Additional 
treatment may include open-label belimumab, corticosteroids (>5 mg/day), and/or 
immunosuppressants, and will be administered at the discretion of the investigator. 
Additional treatment with rituximab is allowed, but not encouraged. Belimumab will be 
provided by the sponsor to those participants who reinitiate treatment with belimumab, 
but additional treatment with rituximab and/or other SLE medications will not be 
provided by the study. These participants will be considered treatment failures for the 
Week 104 efficacy analyses. Participants who are deemed treatment failures will be 
encouraged to continue in the study and to have all efficacy and safety assessments.

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Additional information on management of participants who receive open-label 
belimumab and/or rituximab, including the schedule for obtaining immunogenicity 
samples, is provided in the Study Reference Manual (SRM).
Participants who discontinue study therapy but remain in the study will follow the study 
visit schedule.
Participants who discontinue study treatment and withdraw from the study up to Week 52 
are required to complete an Early Withdrawal Visit and a Follow-up Visit; the Early 
Withdrawal Visit is scheduled 1 to 4 weeks after the last dose of belimumab and the 
Follow-up Visit is scheduled 8 weeks after the last dose of belimumab. Participants in 
Arms A or B who withdraw from the study after Week 52 are required to complete an 
Early Withdrawal Visit 1-4 weeks after withdrawal from the study. Participants in Arm C 
who discontinue study treatment and withdraw from the study after Week 52 are required 
to complete an Early Withdrawal Visit and a Follow-up Visit; the Early Withdrawal Visit 
is scheduled 1 to 4 weeks after the last dose of belimumab and the Follow-up Visit is 
scheduled 8 weeks after the last dose of belimumab. 
Female participants of child bearing potential will have a urine pregnancy test 16 weeks 
after the last dose of belimumab and/or or monthly for 1 year after the last dose of 
rituximab or rituximab-placebo, whichever is later. 
In the event that a participant withdraws from the study or withdraws consent, an attempt 
will be made to ascertain survival status at approximately 52 weeks and 104 weeks after 
the first dose of study treatment.
A study schematic is provided in Figure 1.

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Figure 1
Study Schematic

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5.2.
Number of Participants
A total of approximately 560 participants are expected to be screened, with a goal of 
randomizing at least 280 participants (50% screen failure rate).
The sample size may be increased up to a maximum of 320 participants if the dropout 
rate, missing data or number of major protocol deviations suggests further participants
are necessary to ensure robust conclusions can be drawn. The decision to increase the 
sample size will be made without unblinding the trial.
See Section 10.2, Sample size determination.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study, including the Week 104 Visit, as defined in the SoA (Section 2).
Participants who discontinue study therapy but remain in the study will follow the study 
visit schedule. 
Participants who discontinue study treatment and withdraw from the study up to Week 52 
are required to complete an Early Withdrawal Visit and a Follow-up Visit; the Early 
Withdrawal Visit is scheduled 1 to 4 weeks after the last dose of belimumab and the 
Follow-up Visit is scheduled 8 weeks after the last dose of belimumab. Participants in 
Arms A or B who withdraw from the study after Week 52 are required to complete an 
Early Withdrawal Visit 1-4 weeks after withdrawal from the study. Participants in Arm C 
who discontinue study treatment and withdraw from the study after Week 52 are required 
to complete an Early Withdrawal Visit and a Follow-up Visit; the Early Withdrawal Visit 
is scheduled 1 to 4 weeks after the last dose of belimumab and the Follow-up Visit is 
scheduled 8 weeks after the last dose of belimumab. 
Women of child bearing potential are required to have a urine pregnancy test 16 weeks 
after the last dose of belimumab and/or monthly until 12 months after the last dose of 
rituximab or rituximab-placebo, whichever is later.
Participants who are deemed to meet treatment failure criteria at any time in the study 
will be encouraged to remain in the study and continue to have all efficacy and safety 
assessments.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
5.4.1.
Selection of Controls
The belimumab plus rituximab-placebo arm (Arm A) will be used as the study control 
arm because belimumab has demonstrated efficacy in 4 large, controlled, Phase 3 
controlled clinical trials, HGS1006-C1056 (referred to hereafter as C1056), HGS1006-

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C1057 (C1057), BEL113750, and BEL112341, and remains the only biologic approved 
for the treatment of SLE. An open-label reference arm of belimumab plus standard 
therapy, including immunosuppressants (Arm C) is included to provide a qualitative 
reference to assess the relative performance of Arm A (control) and Arm B (combination) 
vs. belimumab plus standard SLE therapy in current practice (Arm C, reference).
Belimumab SC 200 mg weekly will be dosed for 51 weeks for Arms A and B since this 
was the dose and duration of therapy for the primary endpoint in the positive Phase 3 
study of SC belimumab (BEL112341). The SC 200 mg weekly dose was selected for 
study BEL112341 because it provides steady-state average belimumab concentrations 
similar to those in the 10 mg/kg every 4 weeks dose groups, which were positive for the 
primary endpoint in the pivotal Phase 3 studies of IV belimumab (C1056 and C1057). 
Arm B will explore the combination of rituximab (2 doses of 1000 mg IV at Weeks 4 and 
6) and 51 weeks of belimumab SC dosing. In Arms A and B, a pre-medication regimen 
will be given before each rituximab or rituximab-placebo infusion, including 
methylprednisolone 100 mg IV or equivalent, an antihistamine, and an acetaminophen or 
equivalent.
As rituximab is not approved for the treatment of patients with SLE, no standard dosing 
regimen is established. In this study, rituximab dosing will follow 1 cycle of the approved 
dosing recommendation for rheumatoid arthritis (RA) which is 2 IV doses of 1000 mg 
given in a 2-week interval. This rituximab regimen demonstrated rapid B cell depletion of 
CD19-positive cells (<5 cells/L) in approximately 90% of subjects by 2 weeks after the 
infusions in a large Phase 3 SLE trial [Merrill, 2010].
Rituximab or rituximab-placebo will be dosed at Weeks 4 and 6, after initiation of 
belimumab and discontinuation of baseline immunosuppressants. Participants who enter 
the study on immunosuppressants will have these medications discontinued at or prior to 
the Week 4 visit. The justification for dosing at Week 4 and Week 6 includes: 1) 
separation of start times for belimumab and rituximab, thereby allowing for observation 
of safety events which may be attributable to starting treatment with the individual 
agents, and b) evidence that belimumab may mobilize B cells into the periphery making 
them available targets for anti-CD20 treatment, thus starting belimumab prior to 
rituximab may allow more efficient peripheral B cell depletion by rituximab [Stohl, 
2012].
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 years of age at the time of signing the informed consent.

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Type of Participant and Disease Characteristics
Participants who:
2.
Have a clinical diagnosis of SLE based on 4 or more of the 11 American College of 
Rheumatology (ACR) criteria (see Appendix 11).
3.
Have a screening SLEDAI-2K score 6 (This refers to the total score. Serological 
activity, i.e., anti-double stranded deoxyribonucleic acid [dsDNA]) positivity and/or 
hypocomplementemia is not required to be present in SLEDAI-2K assessment, but 
are scored if present).
4.
Have unequivocally positive autoantibody test results defined as an anti-nuclear 
(ANA) titer 1:80 and/or a positive anti-dsDNA (30 IU/mL) serum antibody test 
from 2 independent time points as follows:

Positive test results from 2 independent time points within the study screening 
period. Screening results must be based on the study's central laboratory results
OR

One positive historical test result and 1 positive test result during the screening 
period.
NOTE: Historical documentation of a positive test of ANA (e.g., ANA by HEp-2 
titer) and anti-dsDNA (e.g., anti-dsDNA by Farr assay) that must include the 
date and type of the test, the name of the testing laboratory, and numerical 
reference range, whenever available. Only unequivocally positive values as 
defined in the laboratory's reference range are acceptable; borderline values 
will not be accepted.
Concomitant Medications
5.
Are on a stable SLE treatment regimen consisting of any of the following 
medications (alone or in combination) for a period of at least 30 days prior to Day 1
(i.e., day of first dose of study treatment) with the exception that switching one agent 
for another of the same class for tolerability or availability reasons, which will be 
allowed within 30 days of Day 1.

Corticosteroids (prednisone or prednisone equivalent)

For those subjects on alternating daily doses of steroids, use the average of 2 
daily doses to calculate the average daily steroid dose.

Any immunosuppressant or immunomodulatory agents including methotrexate, 
azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, 
mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin 
inhibitors (e.g. tacrolimus, cyclosporine), sirolimus, cyclophosphamide, 6-
mercaptopurine, mizoribine, or thalidomide. (Note: oral cyclophosphamide use 
is exclusionary in Germany)

Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine).

Non-steroidal anti-inflammatory drugs (NSAIDs).

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NOTES:

Corticosteroids may be added as a new medication or their doses adjusted up to 
30 days prior to Day 1.

New SLE therapy other than corticosteroids must not be added within 60 days 
prior to Day 1.
6.
Male and/or female
A female participant is eligible to participate if she is not pregnant (see Appendix 3), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 3
during the treatment period and for at least 16 weeks after the last dose of 
belimumab, or at least 12 months after the last dose of rituximab or rituximab-
placebo, whichever is later.
Informed Consent
7.
Capable of giving signed informed consent as described in Appendix 4 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Symptomatic herpes zoster within 3 months prior to screening. 
2.
Evidence of active or latent tuberculosis (TB). Documentation may include medical 
history and examination, chest X-rays (posterior, anterior, and lateral), and TB 
testing: either a positive tuberculin skin test (TST; defined as a skin induration ≥5 
mm at 48 to 72 hours, regardless of Baccillus Calmette-Guerin (BCG) or other 
vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold Plus
test.
NOTE: The choice to perform a TST or a QuantiFERON-TB Gold Plus test will be 
made by the investigator according to local licensing and standard of care. The 
QuantiFERON-TB Gold Plus test can only be used in countries where it is 
licensed, and the use of this test is dependent on previous treatment(s). This 
test may not be suitable if previous treatment(s) produced significant 
immunosuppression.
3.
Significant allergies to humanized monoclonal antibodies.
4.
History of hypersensitivity to belimumab and/or rituximab or known to have titers of 
human anti-mouse antibody or history of hypersensitivity reactions when treated 
with other diagnostic or therapeutic monoclonal antibodies. 

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5.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years.
6.
Alanine transferase (ALT) >2x upper limit of normal (ULN).
7.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
8.
IgA deficiency (IgA level < 10 mg/dL).
9.
IgG < 250 mg/dL. (Note: <400 mg/dL for Germany only)
10. Neutrophils < 1.5 x 109.
11. Current unstable liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, persistent jaundice, or cirrhosis.
12. Severe heart failure (New York Heart Association Class IV) or other severe, 
uncontrolled cardiac disease.
13. QTc >450 msec or QTc >480 msec in participants with bundle branch block. 
NOTES: 

The QTc is the QT interval corrected for heart rate according to Bazette's 
formula (QTcB), Fridericia's formula (QTcF), and/or another method. It is either 
machine-read or manually overread. 
14. Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant.
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, 
gastrointestinal, hepatic, renal, neurological, psychiatric, 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 an acute or chronic infection requiring management as follows: 

Currently on any suppressive therapy for a chronic infection such as 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical 
mycobacteria. 

Hospitalization for treatment of infection within 60 days of Day 1. 

Have had infection requiring treatment with parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of 
Day 1. Prophylactic anti-infective treatment is allowed.
17. Have severe lupus kidney disease (defined by proteinuria >6 g/24 hour or equivalent 
using spot urine protein to creatinine ratio, or serum creatinine >2.5 mg/dL), or have 
severe active nephritis requiring induction therapy not permitted by protocol (e.g., IV 
cyclophosphamide), or have required hemodialysis or high dose prednisone or 
equivalent (>100 mg/day) within 90 days of Day 1.

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18. Have severe active central nervous system (CNS) lupus (including seizures, 
psychosis, organic brain syndrome, cerebrovascular accident (CVA), cerebritis, or 
CNS vasculitis) requiring therapeutic intervention within 60 days of Day 1.
19. Have a planned surgical procedure, laboratory abnormality, or condition (e.g., poor 
venous access) that, in the opinion of the principal investigator, makes the subject 
unsuitable for the study.
20. 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 in the 
last 2 months or who, in the investigator's opinion, pose a significant suicide risk.
21. Have a history of an anaphylaxis reaction to parenteral administration of contrast 
agents, human or murine proteins, or monoclonal antibodies.
Prior/Concomitant Therapy
22. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines 
during the screening period or during the study.
23. Have received any of the following within 364 days of Day 1:

Belimumab. 

Rituximab. 

Abatacept. 

Any B cell targeted therapy (anti-CD20 agents other than rituximab, anti CD22 
[epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], 
TACI Fc, anti-BAFF (LY2127399), anti-Interferon alpha agents or anti-BLyS 
other than belimumab). 

A biologic investigational agent other than B cell targeted therapy (e.g., 
abetimus sodium, anti CD40L antibody [BG9588/ IDEC 1311]). (Investigational 
agent applies to any drug not approved for sale in the country in which it is 
being used.)
24. Have required 3 or more courses of systemic corticosteroids (e.g., IV pulse therapy 
or high dose oral treatment) within 364 days of Day 1. (Topical or inhaled steroids 
are permitted.)
25. Have received any of the following within 90 days of Day 1: 

Anti-TNF therapy (e.g., adalimumab, etanercept, infliximab) 

Interleukin-1 receptor antagonist (anakinra) 

Intravenous immunoglobulin (IVIG) 

High dose prednisone or equivalent (>100 mg/day) 

Plasmapheresis.
26. Have received any of the following within 60 days of Day 1: 

A non-biologic investigational agent (Investigational agent applies to any drug 
not approved for sale in the country in which it is being used.)

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
Intravenous (IV) cyclophosphamide and, for Germany only, oral 
cyclophosphamide

Any steroid injection (e.g., intramuscular [IM], intraarticular, or IV).
NOTE: New inhaled and topical steroids and new topical immunosuppressive agents 
(e.g., eye drops, topical creams) are allowed. Any NSAID use for <1 week is 
allowed.
Diagnostic assessments
27. Positive immunodeficiency virus (HIV) antibody test.
28. Positive serology for Hepatitis B, defined as (i) HB surface antigen positive 
(HBsAg+) OR (ii) HB core antibody positive (HBcAb+).
29. Positive Hepatitis C (HCV) antibody test.
Other Exclusions
30. Have current drug or alcohol dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to Day 1.
31. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator, contraindicates participation in the 
study.
32. Unable to administer study treatment (belimumab) by SC injection and has no other 
reliable resource to administer the injection.
6.3.
Lifestyle Restrictions
No restrictions are required.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, and eligibility criteria. SAEs are collected 
during screening if they are related to study participation.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened one time; all screening procedures must be repeated. 
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.

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7.1.
Treatments Administered
Study Treatment Name:
Belimumab 
(GSK1550188)
Rituximab
Rituximab-placebo
Dosage formulation:
Sterile, liquid 
product.
Sterile, liquid 
concentrate.
Unit dose 
strength(s)/Dosage 
level(s):
200 mg/mL; 1mL 
(deliverable)
500 mg/50 mL
(single-use vial)
Route of Administration 
SC injection
IV infusion
IV infusion
Dosing instructions:
Once weekly SC 
injection via 
autoinjector in thigh 
or abdomen
1000 mg IV 
infusion at Week 4 
and Week 6
IV infusion at Week 4 
and Week 6
Packaging and Labeling:
Belimumab will be 
provided in cartons 
(5 auto-
injectors/carton). 
Each carton will be 
labeled as required 
per country 
requirement.
Rituximab will be 
provided as a 
single 50 mL vial in 
its original carton. 
Each carton will be 
labeled as required 
per country 
requirement.
Placebo is saline in 
250 mL bags, sourced 
locally

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Study Treatment Name:
Belimumab 
(GSK1550188)
Rituximab
Rituximab-placebo
Manufacturer:
Prefilled syringe:
Prefilled syringe 
components are 
procured from 
Becton Dickinson. 
Prefilled syringe is 
filled with drug 
product and 
assembled at GSK, 
Barnard Castle, 
UK.
Autoinjector: The 
autoinjector 
components are 
manufactured by 
Scandinavian 
Health Limited 
(SHL) and 
assembled with the 
prefilled syringe at 
GSK, Barnard 
Castle, UK.
Single-Use Vial:
Refer to local 
rituximab approved 
label.
Device:
Single-use 
autoinjector
Not applicable
Not applicable
7.1.1.
Medical Devices

The GSK manufactured medical devices (or devices manufactured for GSK by a 
third party) provided for use in this study are injection devices: a prefilled syringe 
contained within an autoinjector device.

Instructions for medical device use are provided to the participant upon enrollment. 

GSK medical device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout 
the study. (See Section 9.7).

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7.2.
Dose Modification
No dose modifications of belimumab or rituximab/rituximab-placebo are allowed.
7.3.
Method of Treatment Assignment
All participants will be assigned to study treatment in accordance with the randomization 
schedule and randomization must occur before any investigational product is 
administered. Participants will be centrally randomized using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log in information and 
directions for the IWRS will be provided to each site. A participant will be assigned a 
subject number at the time the informed consent is signed. Once a subject number has 
been assigned to a participant, it cannot be re-assigned to another participant.
A randomization schedule will be generated with the following treatment assignments:
Arm
Treatment Description
A
Belimumab SC for 52 weeks + Rituximab IV Placebo at Weeks 4 and 6
B
Belimumab SC for 52 weeks + Rituximab IV 1000 mg at Weeks 4 and 6
C
Belimumab SC plus standard therapy for 104 weeks 
Study treatment will be dispensed at the study visits summarized in the SoA (Section 2). 
Returned study treatment should not be re-dispensed to the participants. In the event that 
a subject is unable to attend their planned study visit (see Section 2) to receive their 
carton of belimumab autoinjectors, if allowable under local regulations and approved by 
the sponsor, the investigator may with the agreement of the subject arrange to have the 
autoinjectors dispensed and shipped directly to the subject.
At least 280 participants will be randomized in a 1:2:1 ratio to 1 of 3 treatment groups: 
belimumab plus rituximab-placebo (Arm A, target N=70), belimumab plus rituximab 
(Arm B, target N=140), or belimumab plus standard therapy (Arm C, target N=70). 
Randomization of participants will be stratified by screening SLEDAI-2K score (9 vs. 
10), immunosuppressant use at screening (immunosuppressant use vs. no use), and 
screening corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day).
7.4.
Blinding
The study is double-blind with regard to whether participants are randomized to Arm A 
(belimumab plus rituximab-placebo) or Arm B (belimumab plus rituximab). 
Randomization to Arm C will not be blinded. In order to minimize bias given that Arm C 
is open-label, independent assessors blinded to treatment group (A, B, or C) will conduct 
the SLEDAI-2K assessments at selected visits, including those that are components of the 
primary and major secondary endpoints, on the schedule provided in the SoA (Section 2).

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Investigators and the Sponsor/Study Team will remain blinded to the results of the B cells 
subsets because those data could potentially unblind whether or not the participant 
received rituximab.
An unblinded pharmacist will be used at each study site to prepare rituximab and its 
placebo for IV administration. Unblinded monitors will be assigned to review all 
pharmacy records, storage, and procedures.
The IWRS will be programmed with blind-breaking instructions. In case of emergency, 
the investigator has the sole responsibility for determining if unblinding a participant’s 
treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If a participant’s treatment assignment is 
unblinded, GSK must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and 
electronic Case Report Form (eCRF), as applicable.
An unblinded pharmacist at each site will be assigned to use the IWRS randomization 
software, to order and to receive all drug shipments and notifications.
A participant may continue in the study if that participant’s treatment assignment is 
unblinded by the investigator or treating physician. The event or condition which led to 
the unblinding will be recorded in the eCRF.
An Independent Data and Monitoring Committee (IDMC) will conduct periodic reviews 
of unblinded data to ensure external objective and/or statistical review of safety issues 
(see Section 10.4.4). The composition, remit, and procedures of the IDMC are provided 
in the IDMC Charter.
Review and adjudication of treatment failures, AEs of special interest and protocol 
deviations will be performed by blinded individuals in preparation for the Week 52 and 
end of study data base locks (DBLs). Subject level data will not be shared with site 
personnel until after the end of study reporting is complete. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with a Serious Adverse Event (SAE) for 
purposes of regulatory reporting. If the SAE requires that an expedited regulatory report 
be sent to one or more regulatory agencies, a copy of the report, identifying the 
participant’s treatment assignment, may be sent to investigators in accordance with local 
regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 

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automated) area in accordance with the labeled storage conditions with access 
limited to authorized unblinded site staff, e.g., unblinded pharmacist. 
3.
The investigator, institution, the head of the medical institution or delegate (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance

The first dose of belimumab will be administered by the participant at the clinical 
site under medical supervision. (Participants may be assisted in administration of 
their SC dose of belimumab at this first dose and with subsequent doses.) 
Participants will remain in the clinic for at least 3 hours for observation. The date 
and time of the dose administered in the clinic will be recorded in the Patient Diary.
NOTE-1: If a participant misses a dose of belimumab on the scheduled day of 
administration, instruct the participant to self-administer the missed dose as soon as 
possible during that dosing week. If subject did not self-administer the dose by end 
of the weekly dosing period, SKIP that dose. The participant should not administer 
two doses on the same day and two doses should not be administered to make up for 
a dose missed for a full 7 day dosing window. Thereafter, the subject can resume 
self-administering belimumab weekly on their usual day of administration.
NOTE-2: If a participant has administered a partial dose or was unable to completely 
self-administer a dose of belimumab due to malfunction of the autoinjector or user 
error, instruct the subject to SKIP additional attempts and not re-inject for that 
week’s belimumab dose. Thereafter, the subject should resume self-administering 
belimumab weekly on their usual day of administration during the following weekly 
dosing period. The participant should not self-administer 2 doses on the same day, 
even if they believe that they did not receive any medication from the first 
administration attempt. (See Section 9.7.8 - Device Malfunction).
NOTE 3: Participants who miss 4 or more consecutive doses of belimumab must 
receive the next dose of belimumab in the clinic and remain in the clinic for at least 
3 hours for observation as with the initial belimumab dose.
The site should contact the Medical Monitor if participants miss 8 or more 
consecutive doses of belimumab to evaluate continuation in the study.

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
When participants self-administer study treatment at home, compliance with 
belimumab will be assessed through review of the self-injection patient diary with 
each participant during site visits and documented in the source. A record of the 
number of belimumab autoinjectors dispensed to and taken by each participant must 
be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays will also be 
recorded in the eCRF.

Rituximab or rituximab-placebo will be administered IV to participants at the site or 
infusion center, following administration of the premedication regimen. 
Administration of the premedication regimen and the rituximab or rituximab-placebo 
will be documented in the source documents and reported in the eCRF, including 
whether the full infusion was administered and over what period of time. Study 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.
7.7.
Concomitant Therapy
This section reviews the medications and the doses allowed and prohibited during the 
course of the study.
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving from the start of 
treatment until the follow-up visit at the time points specified in the SoA must be 
recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Allowable Medications
Participants must be on a stable SLE treatment regimen for at least 30 days prior to Day 1 
(see Section 6.1). These medications may include corticosteroids, anti-malarial agents, 
immunosuppressant agents and nonsteroidal anti-inflammatory agents (NSAIDs).
New SLE therapy other than corticosteroids must not be added within 60 days of Day 1.
Once a participant is randomized and receives the 1st dose of study agent on Day 1, the 
investigator may adjust concurrent medications (add, eliminate, change dose 
level/frequency) as clinically required; however, changes in certain medications (as 
outlined below) may result in the participant being defined as a treatment failure. Rules 
regarding declaring a participant as a treatment failure may vary according to timing and 
are handled differently in Arms A and B vs. Arm C. Participants declared treatment 

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failures are encouraged to remain in the study and receive all efficacy and safety 
assessments through Week 104.
7.7.1.1.
Anti-malarials
Anti-malarial therapies for SLE may be continued or dose adjusted during the study, and 
will be allowed within the definitions of the efficacy endpoints. A new anti-malarial (e.g., 
hydroxychloroquine, chloroquine, quinacrine) may not be started during the course of the 
study for SLE. Starting any new anti-malarial treatment for SLE after Day 1 will declare 
the participant a treatment failure.
For non-SLE reasons (e.g., for the experimental treatment of COVID-19) an anti-malarial 
may be initiated for a subject not previously on an anti-malarial, or dose increased above 
the common allowable maximum doses (defined below) according to the following 
guidelines, for short-term treatment:

< 21 days treatment duration

Not during the intervals within 8 weeks before the key efficacy visits (actual visit 
date) at Weeks 52, 64, and 104.
An anti-malarial may be replaced by another anti-malarial due to documented toxicity or 
lack of availability at any time during the study.
The common allowable maximum doses of anti-malarial drugs are:

Hydroxychloroquine – 400 mg/day

Chloroquine – 500 mg/day

Quinacrine – 100 mg/day
For compounded anti-malarials, no individual component may exceed the maximum dose 
above.
Clinical loading dose is permitted for initiation or replacement.
NOTE: The use of anti-malarials for anti-malarial prophylaxis is permitted.
7.7.1.2.
Corticosteroids
Received dose for all systemic corticosteroids will be converted to prednisone equivalent 
dose. As such, when “prednisone” is used throughout this protocol, it refers to prednisone 
dose or equivalent.
Total systemic corticosteroid dose is defined as the average daily dose of all 
corticosteroids taken SC, IV, IM, intradermally, and orally for both SLE and non-SLE 
reasons.
At baseline, the average daily dose of corticosteroids is the sum of corticosteroid dose 
over 7 consecutive days up to, but not including Day 1, divided by 7. While on study 

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treatment, the average daily dose of corticosteroids is the sum of all corticosteroid doses 
over 7 consecutive days up to and including the day of interest, divided by 7, unless 
otherwise specified. 
Participants may enter the study on any prescribed dose of corticosteroids. If a participant 
is not receiving corticosteroid therapy on study Day 1, once the subject is randomized 
and receives the 1st dose of study agent on Day 1, the investigator may add corticosteroid 
medication as clinically required (for example, in order to manage the transition period 
for discontinuing immunosuppressants by Week 4). Dosage of corticosteroids may be 
adjusted as clinically necessary until Week 12. After the initial 12 weeks of the study, a 
protocol specified corticosteroid taper is recommended to begin and should be initiated 
and conducted under the direction of the investigator. The taper will proceed with a target 
of reaching a prednisone equivalent dose of 5 mg/day by Week 26. The recommended 
corticosteroid taper scheme is described in Appendix 2. Corticosteroids may be adjusted 
as clinically necessary through Week 26, participants will not be declared treatment 
failures unless they are not able to successfully taper to a 7-day average prednisone 
equivalent dose of 5 mg/day after Week 26. For purposes of defining treatment failure, 
after Week 26, the average daily dose of corticosteroids is the sum of corticosteroid dose 
on the 7 days immediately following the Week 26 visit, divided by 7 (the corticosteroid 
dose on the day of the Week 26 visit is not included in the calculation). After Week 26, if 
a participant’s average daily dose of corticosteroid exceeds a prednisone equivalent dose 
of 5 mg/day at any time the participant will be declared a treatment failure. (The date of 
treatment failure will be the end of the 7-day interval which meets the treatment failure 
rule.)
If the investigator believes the participant would benefit from continued corticosteroid 
taper after Week 26, and if it is tolerated, a prolonged corticosteroid taper should 
continue with the goal of discontinuing corticosteroids. Recommendations for the 
schedule of this taper are included in Appendix 2. Participants who are able to tolerate the 
final taper will be withdrawn from corticosteroids. If a participant is unable to tolerate the 
final stage of the corticosteroid taper, the investigator may reinitiate corticosteroids at a 
prednisone equivalent dose of up to and including 5 mg/day. If a 7-day average 
prednisone equivalent dose of >5 mg/day is required at any time after Week 26, the 
participant will be considered a treatment failure for the efficacy endpoints. Participants 
who are declared treatment failures are encouraged to remain in the study through Week 
104 and receive all safety and efficacy assessments.
For purposes of assessing the major secondary endpoint at Week 64 (the proportion of 
participants with a state of clinical remission, defined as a Clinical SLEDAI-2K score = 
0), achieved without immunosuppressants and with corticosteroids at a prednisone 
equivalent dose of 0 mg/day at Week 64), participants must be on a dose of 0 mg/day on 
the 7 days immediately following the Week 64 visit (the corticosteroid dose on the day of 
the Week 64 visit is not included in the calculation).
Intraarticular Injections:

Participants may receive intraarticular injections during the study with the exception 
of within 8 weeks prior to the key efficacy endpoints (i.e., Weeks 52, 64, and 104). A 

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participant who receives any intraarticular injection(s) within 8 weeks before the 
Week 52, 64, and/or 104 visits will be defined as a treatment failure.
7.7.1.3.
Corticosteroids for Reasons Other Than SLE Disease Activity
Corticosteroids for non-SLE reasons (e.g., asthma, contact dermatitis, etc) may be given 
short-term at higher doses than 5 mg/day according to the following guidelines:

Up to 750 mg (prednisone) for 1 day,
and/or

Up to 60 mg/day (prednisone) for 2-3 days ,
and/or

Up to 40 mg/day (prednisone) for 4-7 days.
After Week 26, the duration of high dose corticosteroids use for reasons other than SLE 
must not exceed 7 days, after which time, tapering should begin. The total corticosteroid 
dose must be tapered to 5 mg/day within 21 days of the 1st dose of a course of high 
dose corticosteroids given for non-SLE reasons. In addition no new high dose 
corticosteroids for reasons other than SLE are allowed that result in an average
corticosteroid dose of >5 mg/day during the intervals starting 8 weeks before the key 
efficacy visits at Weeks 52, 64, and 104. During the intervals of 8 weeks before these 
efficacy endpoints, any new high dose corticosteroid use will declare the participant as a 
treatment failure. The day of the Week 44, 56, and 96 visits will count as the start of 
these 3 intervals.
NOTE: Inhaled and topical corticosteroids are allowed throughout the course of the 
study.
7.7.1.4.
Other Immunosuppressant Agents
Belimumab SC 200 mg/week will be initiated in all treatment arms on Day 1 of the study. 
Participants who enter the study on immunosuppressant therapy in Arms A and B will 
continue their stable immunosuppressant regimen until up to Week 4. At or prior to the 
Week 4 visit, immunosuppressants will be discontinued. Corticosteroids may be adjusted 
as necessary during this transition period. Participants in Arm C may continue their 
immunosuppressant agents throughout the study.
Starting any new immunosuppressant agent after Day 1 for increased lupus disease 
activity will cause the participant to be declared a treatment failure. An 
immunosuppressant agent may however be replaced with one of the agents listed below 
due to documented toxicity or lack of availability.
For participants in Arms A and B, the dose of existing immunosuppressant agents may be 
adjusted, as clinically required, up to the Week 4 visit. Any existing immunosuppressant 
agents will be discontinued at or prior to the Week 4 visit for Arms A and B.

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Participants in Arm C may continue their existing immunosuppressant agents throughout 
the course of the study. Dosage of existing immunosuppressant agents may be increased 
as clinically necessary until Week 12. After the Week 12 visit, any increase in dose over 
the baseline (Day 1) or Week 12 visit dose, whichever is higher, will cause the participant 
to be declared a treatment failure.
The common allowable maximum doses for immunosuppressant agents at baseline (Day 
1) and during the study are listed below:

Azathioprine – 300 mg/day

6-mercaptopurine – 300 mg/day

Mycophenolate mofetil (PO)/ mycophenolate mofetil hydrochloride (IV) –
4 g/day

Mycophenolate sodium (PO) – 2.88 g/day

Methotrexate – 25 mg/week

Oral cyclophosphamide – 2.5 mg/kg/day (Note: use not permitted in Germany)

Cyclosporine – 4 mg/kg/day*

Tacrolimus – 0.2 mg/kg/day*

Sirolimus – 2 mg/kg/day*

Thalidomide – 200 mg/day

Leflunomide – 40 mg/day*

Mizoribine – 150 mg/day
*Clinical loading dose is permitted when replacing immunosuppressant agents. 
Monitor blood levels as clinically indicated.
An immunosuppressant agent may be replaced with one of the agents above due to 
documented toxicity or lack of availability. For other immunosuppressant agents not 
listed above, the investigator must contact the Medical Monitor for approval.
New topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed after 
Day 1.
7.7.1.5.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Aspirin, and 
Acetaminophen
Since NSAIDs and aspirin may affect efficacy parameters (e.g., arthritis) and may affect 
renal function (NSAID nephropathy), the use of these agents should be initiated and 
stabilized prior to entry into the trial.
NSAIDs may be continued and dose adjusted as clinically indicated until 8 weeks before 
efficacy visits, i.e., Weeks 52, 64, and 104. During the intervals of 8 weeks before these 
efficacy endpoints, any increase in the NSAID dose above the dose at Day 1 or the visit 
day starting the interval of 8 weeks prior to these key efficacy visits, whichever is higher, 
will declare the participant as a treatment failure unless the NSAID is given for <7 days.
The day of the Week 44, 56, and 96 visits will count as the start of these 3 intervals.

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New NSAIDs may not be added after Day 1 unless given for <7 days. Initiation of an 
NSAID after Day 1 that is given 7 days will declare the participant as a treatment 
failure.
An NSAID may be replaced with another NSAID due to documented toxicity or lack of 
availability.
Daily doses of aspirin up to 1000 mg/day are allowed at any time during the study. Daily 
doses of aspirin above 1000 mg/day may be initiated at any time up to the Week 44 visit 
and may continue through the end of the study. For participants who never received an 
aspirin regimen at a dose >1000 mg/day between the Day 1 and Week 44 visit, starting a 
new aspirin regimen at a dose >1000 mg/day after the Week 44 visit will declare the 
participant a treatment failure unless the aspirin is given for <7 days.
Acetaminophen (paracetamol) is primarily an analgesic and lacks the anti-inflammatory 
properties of other NSAIDs. The use of acetaminophen is recommended when possible to 
treat non-SLE related conditions, in the absence of a pre-existing hepatic function 
deficiency.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Participants who start prohibited medications or therapies at any time during the study 
will be considered treatment failures for analysis (i.e., non-responders). The Medical 
Monitor must be contacted to discuss the appropriateness of continuing study treatment.
The following medications and therapies are prohibited at any time during the study:

Other investigational agents (biologic or non-biologic). Investigational applies to any 
drug not approved for sale in the country in which it is being used.

Co-enrollment into another study of a different investigational agent or that may 
interfere with the conduct of this protocol.

Anti-TNF therapy (e.g., adalimumab, etanercept, infliximab).

Other biologics with effects on the immune system (e.g., abatacept, interleukin-1 
receptor antagonist [anakinra]).

IVIG.

IV cyclophosphamide and for Germany only, oral cyclophosphamide

Plasmapheresis.
7.7.3.
Live Vaccines
Live vaccines are not permitted in the study. Participants who require a live vaccine 
during the study should have study agent discontinued prior to receiving the live vaccine.
7.7.4.
Additional SLE Therapy
In the 52-week, double-blind treatment phase, participants in Arms A or B who fail to 
adequately respond to study treatment or in the medical judgment of the investigator 

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cannot meet the corticosteroid taper rules, tolerate immunosuppressant withdrawal at 
Week 4, or who will require additional therapy will be considered treatment failures. 
Participants who are treatment failures will be encouraged to remain in the study and 
receive all safety and efficacy assessments through Week 104. At the discretion of the 
investigator, the participant may continue to receive belimumab SC 200 mg/week. If 
additional medical treatment is necessary it will also be at the discretion of the 
investigator and may include corticosteroids and/or immunosuppressants. 
In the 52-week observational phase (Weeks 53 to 104), participants in Arms A and B 
may continue or reinitiate open-label belimumab SC 200 mg weekly treatment if (a) they 
responded clinically in the 52-week treatment phase of the study but did not meet the 
primary efficacy endpoint, or (b) responded clinically but subsequently experienced an 
increase in disease activity requiring treatment. If a participant requires rescue therapy in 
addition to the re-initiation of treatment with belimumab, corticosteroids >5 mg/day of a 
prednisone equivalent and/or immunosuppressants may be given at the discretion of the 
investigator. Reason for rescue therapy and medication dosing requirements should be 
documented in source records. Treatment with open-label rituximab is allowed, but not 
encouraged. Belimumab will be provided by the study, but other SLE treatments, 
including rituximab, will not be provided by the sponsor. In these situations the 
participants in Arms A or B would be considered treatment failures for the efficacy 
endpoints. Participants who are declared treatment failures will be encouraged to remain 
in the study and continue to receive all safety and efficacy assessments. Additional 
information on management of participants who receive open-label belimumab and/or 
rituximab, including the schedule for obtaining immunogenicity samples, is provided in 
the SRM.
Participants in Arm C will continue to receive belimumab during Weeks 53 to 104. 
Participants in Arm C who, in the opinion of the investigator, require additional 
treatment, may receive rescue therapy including corticosteroids >5 mg/day of a 
prednisone equivalent and/or new, additional or increased immunosuppressants at the 
investigator's discretion. Treatment with open-label rituximab is allowed, but not 
encouraged. Other SLE treatments, including rituximab, will not be provided by the 
study. In these situations, the participants in Arm C would be considered treatment 
failures for the efficacy endpoints. Participants who are declared treatment failures will 
be encouraged to remain in the study and continue to receive all safety and efficacy 
assessments.
Management of additional SLE therapy, including required laboratory tests and other 
procedures, is described in the SRM.
7.8.
Treatment after the End of the Study
At the end of the study, participants who wish to continue treatment with belimumab may 
do so by being prescribed commercially available belimumab.

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8.
DISCONTINUATION CRITERIA
8.1.
Withdrawal from the Study
Participants are free to withdraw from the study at any time, for any reason. Participants 
may withdraw consent, including use and disclosure of research-related health 
information at any time, for any reason. Participants may be withdrawn/removed, if 
necessary, by the investigator or the sponsor for safety, behavioral, administrative, or 
other reasons. It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of participants should 
be avoided.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken, and the investigator must document this in the site study records.
In addition, for participants who are WOCBP who receive rituximab or rituximab-
placebo at the Week 4 visit, or at both the Weeks 4 and 6 visits, but who discontinue the 
study prior to the Week 60 visit, maintenance of contraception and monthly telephone 
calls for urine pregnancy test results will be required until 12 months after the last dose of 
rituximab or rituximab-placebo was administered.
8.2.
Discontinuation of Study Treatment
Participants who discontinue study treatment should be encouraged to continue to 
participate in study visits in accordance with the SoA (Section 2), especially all 
remaining safety evaluations.
If a participant experiences a clinically significant AE that the investigator believes may 
be definitely, possibly, or probably related to study treatment and could potentially be 
exacerbated by the next dose, the investigator may delay study treatment dosing by up to 
one week or withhold one 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 or rituximab (or rituximab-placebo) should be 
postponed further or discontinued.
Participants may be withdrawn from study treatment for any of the following reasons:

Prohibited concurrent medication or therapy or prohibited dose of concurrent 
medication or therapy (see Section 7.7.2).

Unacceptable toxicity.

Pregnancy will require withdrawal from study treatment, belimumab and/or 
rituximab when the pregnancy is recognized. Maintenance of contraception and 
monthly telephone calls for urine pregnancy test results will be required until 
12 months after the last dose of rituximab or rituximab-placebo was 
administered. Participants who become pregnant during the study will be 
encouraged to remain in the study to be followed for all efficacy and safety 
assessments including the course and outcome of the pregnancy. If the outcome 
of the pregnancy occurs after a subject completes or leaves the study, attempts 

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will be made to obtain follow up information, including the outcome of the 
pregnancy.
NOTE: (Germany only): Whether rituximab is excreted in human milk is not 
known. However, because maternal IgG is excreted in human milk, and 
rituximab was detectable in milk from lactating monkeys, women should not 
breastfeed while treated with rituximab and for 12 months following rituximab 
treatment.
All participants should be monitored closely for infection. Participants who develop IgG 
<250 mg/dL confirmed by repeat test 1 week (>2 days) after the initial result, will have 
study treatment withheld, and the investigator must contact the Medical Monitor to 
determine if study treatment should be continued. In addition, increased vigilance for 
infection is recommended in participants who develop IgG <550 mg/dL. Those with a 
decrease in IgG below 400 mg/dL that is associated with a serious infection (i.e., an 
infection reported as an SAE) will be withdrawn from study treatment. In addition, if any 
participant develops a life-threatening infection regardless of IgG status, the investigator 
must contact the Medical Monitor to determine whether study treatment should be 
continued. 
Severe skin reactions such as Toxic Epidermal Necrolysis and Stevens-Johnson 
syndrome, some with fatal outcome, have been reported with the use of rituximab. In 
case of such an event, treatment should be permanently discontinued.
A participant will be withdrawn from study treatment if he or she meets liver stopping 
criteria (defined in Section 8.2.1), presents with suicidal ideation of type 4 or 5 on the 
C-SSRS, or in the investigator's judgment, the participant is at risk for a suicide attempt. 
Participants who are withdrawn from study treatment will remain in the study for 
observation and continue to have all safety and efficacy assessments.
For any study participants exhibiting symptoms consistent with COVID-19, please 
consider holding dosing of investigational product (IP) and consult with the Medical 
Monitor. If a participant tests positive for COVID-19, or if no testing is available, hold 
dosing of IP until symptoms resolve and contact the Medical Monitor. If a positive 
COVID-19 test result is reported, please consult with the Medical Monitor on whether 
resolution of symptoms alone, without retesting, is enough to resume dosing of the 
investigational product.
8.2.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment is required when:

a participant meets one of the conditions outlined in Algorithm A or Algorithm B
OR

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
when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation it is in the 
best interest of the participant.
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
See Appendix 5 for liver safety required actions and follow-up assessments.

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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
See Appendix 5 for liver safety required actions and follow-up assessments.
8.2.2.
Study Treatment Restart
If participant meets liver chemistry stopping criteria do not restart participant with study 
treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the participant
Refer to Appendix 6 for full guidance. 
8.3.
Temporary Discontinuation and Re-Start of Belimumab
Study treatment with belimumab (Arms A/B and C) must be temporarily withheld and 
the GSK medical monitor consulted about continued dosing if a subject experiences a 
neutrophil count <0.5x109/L.
Withdrawal of study treatment does not require withdrawal from the study; participants 
who discontinue study treatment should be encouraged to continue the study with all 
safety and efficacy assessments. Participants who miss 4 consecutive doses of belimumab 
must have the next dose of belimumab in the clinic and stay for observation for 3 hours.

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8.4.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator or the 
sponsor for safety, behavioral, compliance, administrative or other reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA (Section 2) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.
8.5.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

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
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the two 
year duration of the study for study related assessments, including any extra 
assessments that may be required, will not exceed 1100 mL, with the exception 
of additional blood required for the Blood Leukocyte analysis as specified 
below.

Additional blood (2 samples of 40 mL each in Year 1 and 2 samples of 40 
mL each in Year 2) for the Blood Leukocyte analysis will be collected from 
participants from US study sites. If a participant in the Blood Leukocyte 
analysis withdraws from the study and completes an Early Withdrawal Visit, 
a 40 mL sample will be collected at the Early Withdrawal Visit.

Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
9.1.
Screening Assessments
Information collected during the screening phase assessments represent key data that 
identify and define participant baseline status. This information is critical for the 
evaluation and comparison of subsequent safety and efficacy assessments.
Informed Consent 
Informed consent will be obtained from the participant prior to the initiation of any study 
procedures or study-specific data collection.
Participants who give written consent will enter a screening period of up to 35 days. A 
participant may be randomized when all screening procedures have been completed and 
eligibility criteria confirmed. 
Screening Assessments
During the screening period the following assessments will be performed:
Demographic parameters will be captured: year of birth, sex, race, and ethnicity.
Medical history/medication will be assessed as related to the exclusion criteria listed in 
Section 6.2. A complete medical history will be taken at the Screening Visit. Information 
from the medical history is important to establish the baseline condition of the 
participant, and will impact the safety monitoring assessments during the study. Any 
significant medical conditions affecting the participant in the past 5 years should be 

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recorded on the Medical conditions page of the eCRF. The history should include the 
following:

Past or current conditions

Prior surgical procedures

Pharmacotherapy and chronic or current use of any medication or herbal 
preparation

Prior use of belimumab and/or rituximab

Allergies and significant allergic reactions

Significant infections, or history of recurrent infection, including urinary and 
respiratory tract infections

Smoking history (current or previous smoker, number of cigarettes smoked per 
day)

Cardiovascular medical history/risk factors (as detailed in the eCRF).
Pregnancy Test 
A serum pregnancy test will be performed for women of child-bearing potential at the 
Screening Visit and a urine pregnancy test will be performed during each subsequent 
clinic visit. Refer to the pregnancy section (Section 9.7.6). (Argentina only: Additional 
urine pregnancy tests will be performed at specified study weeks (i.e., non visit weeks) 
during study year 2 (see SoA in Section 2).
Full physical examination
The full physical examination will include complete assessment of all organ systems 
including assessments of the head and neck (including eyes, ears, nose, throat, and 
thyroid gland), skin, musculoskeletal (including evaluation of both small and large 
joints), neurological, respiratory, and cardiovascular systems, gastrointestinal system, and 
abdomen (including liver and spleen), lymph nodes and extremities.
Electrocardiogram
A single 12-lead ECG will be obtained at screening using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
Laboratory tests
The following laboratory tests will be performed at screening, as related to the eligibility 
criteria described in Section 6.2.

Autoantibodies and complement

HIV, hepatitis B and Hepatitis C screen

Immunoglobulin (IgG, IgA, IgM)

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
Urinalysis

Hematology and blood chemistry

Drug and alcohol screen

PT/PTT
Repeat samples may be taken for retesting for technical issues with the samples. If the 
investigator decides to repeat a laboratory test of an abnormal (exclusionary) value, it is 
recommended that the investigator contact the study team for additional consultation. 
Sharing the relevant medical history and current findings with the GSK Medical Monitor 
would help to determine if re-testing is warranted.
SLEDAI-2K
The SLEDAI-2K is a clinical index for measuring SLE disease activity in the previous 
10 days.
9.2.
Assessments at Baseline
Procedures at the Baseline Visit are listed in the SoA (Section 2). They include clinical 
and efficacy assessments, patient reported outcome (PRO) assessments, laboratory tests, 
pharmacokinetics, pharmacogenetics, biomarkers and blood samples for immunogenicity. 
The interim medical history, including SLE medications, should be reviewed to assure 
that the participant's eligibility for the study has not changed. Additional information 
about these procedures are provided in Section 9.6 (clinical and efficacy), Section 9.6.1
(patient reported outcome assessments), Section 9.9.4 (laboratory tests), Section 9.10
(pharmacokinetics), Section 9.11 (pharmacodynamics), Section 9.12 (genetics), Section 
9.13 (biomarkers) and blood samples for immunogenicity (Section 9.13.1) and in the
SRM.
9.3.
Assessments at Scheduled Visits
Procedures at the Scheduled Visits are listed in the SoA (Section 2). They include clinical 
and efficacy assessments, patient reported outcome assessments, laboratory tests, 
pharmacokinetics, biomarkers, and blood samples for immunogenicity. Time windows 
are provided for each study visit to allow flexibility in site and participant scheduling. All 
study visits should occur within the visit window of the scheduled study visit. Additional 
information about these procedures are provided in Section 9.6 (clinical and efficacy), 
Section 9.6.1 (patient reported outcome assessments), Section 9.9.4 (laboratory tests), 
Section 9.10 (pharmacokinetics), Section 9.11 (pharmacodynamics), Section 9.13
(biomarkers) and blood samples for immunogenicity (Section 9.13.1) and in the SRM. 
Participants who are deemed treatment failure and/or discontinue study treatment, but 
remain in the study, will follow the study visit schedule.
9.4.
Assessments at Unscheduled Visits
Unscheduled visits may be performed for a variety of reasons, including safety. The
specific procedures to be performed at an Unscheduled Visit depend on the reason for the 

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Unscheduled Visit. Additional information on the procedures to be performed at an 
Unscheduled Visit is provided in the SRM.
Note: if a subject is unable to attend their scheduled visit, for example as a consequence 
of restrictions related to the COVID-19 pandemic, for continued safety monitoring, the 
investigator should contact the subject by telephone or video call to review adverse 
events (including suicidal ideation/behavior and neurological symptoms), concomitant 
medications and ongoing SLE treatments including belimumab. These reviews will be 
documented in the source records and the eCRF. Such telephone/video contacts may be 
recorded as unscheduled visits. No attempt should be made to perform efficacy 
assessments at these telephone/video contacts.
9.5.
Assessments at Early Withdrawal Visits and Follow-up 
Visits
Participants who discontinue study treatment and withdraw from the study up to Week 52 
are required to complete an Early Withdrawal Visit and a Follow-up Visit; the Early 
Withdrawal Visit is scheduled 1 to 4 weeks after the last dose of belimumab and the 
Follow-up Visit is scheduled 8 weeks after the last dose of belimumab. Participants in 
Arms A or B who withdraw from the study after Week 52 are required to complete an 
Early Withdrawal Visit 1-4 weeks after withdrawal from the study. Participants in Arm C 
who discontinue study treatment and withdraw from the study after Week 52 are required 
to complete an Early Withdrawal Visit and a Follow-up Visit; the Early Withdrawal Visit 
is scheduled 1 to 4 weeks after the last dose of belimumab and the Follow-up Visit is 
scheduled 8 weeks after the last dose of belimumab. Procedures at the Early Withdrawal
Visits and Follow-up Visits are listed in the SoA (Section 2).
9.6.
Efficacy Assessments
Overview
Planned time points for all efficacy assessments are listed in the SoA (Section 2). At 
selected time points, the SLEDAI-2K is performed by independent assessors who are 
blinded with regard to the treatment group assignment. Time windows are provided for 
each study visit to allow flexibility in site and participant scheduling. All study visits 
should occur within the visit window of the scheduled study visit. Details regarding the 
conduct of the efficacy assessments described below are provided in the SRM. In 
addition, information from the SLEDAI-2K, PGA, laboratory tests, use and doses of SLE 
medications, and clinical evaluations will be used to calculate the Lupus Low Disease 
Activity State (LLDAS) [Franklyn, 2016].
SLEDAI-2K
The SLEDAI-2K is a clinical index for measuring SLE disease activity in the previous 
10 days.

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Physician's Global Assessment
The Physician's Global Assessment (PGA) is a physician-reported visual analogue scale 
that provides an overall measure of the participant's current disease activity. 
SLICC-ACR Damage Index
The Systemic Lupus International Collaborating clinics (SLICC) -American College of 
Rheumatology (ACR) Damage Index measures irreversible changes occurring since the 
diagnosis of SLE.
SLE Flare Index
The SLE Flare Index identifies whether a participant has experienced a mild/moderate or 
severe flare.
Lupus Low Disease Activity State 
The Lupus Low Disease Activity State (LLDAS) incorporates multiple measures of 
disease activity, specifically:

SLEDAI-2K 4, with no activity in major organ systems (renal, CNS, 
cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal 
activity

No new features of lupus disease activity compared with the previous assessment

PGA (scale 0-3) 1

Current prednisolone (or equivalent) dose 7.5 mg daily

Well tolerated standard maintenance doses of immunosuppressive drugs and 
approved biological agents, excluding investigational drugs.
9.6.1.
Patient-Reported Outcomes Assessments
Patient-Reported Outcome (PRO) questionnaires will be completed by participants at 
clinic visits on the schedule outlined in the SoA (Section 2). PRO questionnaires should 
be completed by participants, whenever possible before the investigator’s safety
evaluation and efficacy assessment (e.g., SLEDAI-2K) at a clinic visit, in the order 
specified in the SRM. Patient interviews (post-treatment and exit interviews) will be 
conducted in a subgroup of participants, as described below.
Patient Global Assessment
The Patient Global Assessment (PtGA) asks participants to rate the severity of their SLE 
between 0 (
) and 10 (
) that best represents their current level of 
disease activity. (“Considering all of the ways your systemic lupus erythematosus (lupus) 
affects you, how do you feel your lupus is today?”)
CCI
CCI

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FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) 
version 4.0 includes 13 fatigue-related items that ask patients to rate fatigue during the 
previous 7 days, yielding an overall score from 0 to 52, with lower scores representing 
worse fatigue (www.facit.org). The use of the FACIT-fatigue scale in SLE patients has 
been validated by Lai et al [Lai, 2011] and together with results from other studies 
including Cella and colleagues [Cella, 2005], an MCID of ≥4 was concluded [Lai, 2011].
LupusQoL
The LupusQoL is a valid SLE-specific health related qualify of life (HRQOL) instrument 
with 34 questions across 8 domains. Questions are related to the patient experience in the 
prior 4 weeks, and a 5-point Likert response format is used, ranging from 0 (
 to 4 (
). A LupusQoL summary score for each domain is reported on a 0 to 100 
scale, with greater values indicating better HRQOL [McElhone, 2007].
WPAI: Lupus
The Work Productivity and Activity Impairment Questionnaire (WPAI) is a measure of 
overall work impairment that discerns time missed from work and impairment of work 
and regular activities due to a specific disease or health problem. WPAI outcomes include 
work time missed, impairment while working, overall work productivity impairment and 
activity impairment expressed as impairment percentages with higher percentages 
implying greater impairment and less productivity [Reilly, 1993]. The WPAI: Lupus 
reflects the impairments due to lupus. 
Patient Interviews
Patient interviews will provide a qualitative summary of participants' experience of 
treatment benefits, treatment satisfaction, and experience as a study participant. Adverse 
events will not be solicited during the interview however, if an SAE is described by the 
participant, it will be collected and processed according to GSK required timelines and 
procedures. These interviews will be conducted in a subgroup of participants in the US at 
the Week 52 and Week 104 study visits (or upon early withdrawal after Week 12).
Interview questions designed to fully assess a participant's experience with a study 
medication will be administered in a semi-structured format by a trained interviewer. 
Participant feedback will be captured in a data collection sheet as well as being audio-
taped for subsequent transcription and qualitative analysis. The interview technique and 
questions will be described in the SRM.
9.7.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 7.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
CCI
CCI
CCI

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9.7.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2). However, any SAEs assessed as 
related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study.

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 7. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in study 
participants after completion of their participation in the study. However, if the 
investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator 
must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 7.
9.7.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.7.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious and serious AEs of 
special interest (AESI) (i.e., infections, malignancies, and depression/suicidality/self-
injury) will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.5). Further information on follow-
up procedures is given in Appendix 7.
9.7.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 

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participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.7.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 7 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.7.6.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 16 weeks after the last dose of belimumab or 12 months
(i.e., Week 58) after the last dose of rituximab/rituximab-placebo, whichever is later.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.7.7.
Medical Device Incidents
Medical devices (i.e., belimumab autoinjector) are provided for use in this study for the 
purposes of self-administration of study treatment. In order to fulfill regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and 

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documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 8.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.7.1 and Appendix 7 of the protocol. 
Also see Section 7.6 regarding instructions to subjects in the event of a device 
malfunction.  
9.7.7.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in 
which the medical device is used. 

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify the 
sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 
8.
9.7.7.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE or SAE will be followed and 
reported in the same manner as other AEs (see Section 9.7.1). This applies to all 
participants, including those who discontinue study treatment or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
9.7.7.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after 
the investigator determines that the event meets the protocol definition of a 
medical device incident.

The Medical Device Incident Report Form will be sent to the sponsor by via the 
SAE- coordinator. Regulatory Reporting Requirements for Medical Device 
Incidents.

The Device Malfunction/Failure Reporting Form will be sent to the sponsor 
along with the Medical Device Incident Form (see Section 9.7.8).

The investigator will promptly report all incidents occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal 

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responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.7.8.
Device Malfunction
Medical devices (Belimumab Autoinjector) that are provided for use in this study for the 
purposes of self-administration of study treatment may malfunction during use (e.g., parts 
missing, device leaking, needle bent). The information provided in this section applies to 
occurrence and reporting of device malfunctions that are NOT associated with an 
AE/SAE.
If when using an autoinjector, the subject experiences a device malfunction, the 
participant should stop using the device and SKIP additional attempts and not re-inject 
for that week’s belimumab dose. (See NOTE-1 in Section 7.6 for additional instruction 
regarding administration of study treatment following a device malfunction). 
The subject should record the malfunction in the Smartphone and contact the site the 
same day or as soon as possible to report the device malfunction. The study site should 
record the malfunction on the Device Malfunction/Failure Reporting Form (see form in 
the SRM) and forward the information to GSK as described on the form by the next 
business day. The subject should return that malfunctioned device to the study site at the 
next scheduled visit for shipment back to GSK for evaluation.
9.8.
Treatment of Overdose
For this study, any dose of belimumab greater than 200 mg per week will be considered 
an overdose. 
There is limited experience with overdosage of belimumab. Adverse reactions reported in 
association with cases of overdose have been consistent with those expected for 
belimumab.
Two doses up to 20 mg/kg administered 21 days apart by IV infusion have been given to 
humans with no increase in incidence or severity of adverse reactions compared with 
doses of 1, 4, or 10 mg/kg.
GSK does not recommend specific treatment for an overdose of belimumab.
For this study, any dose of rituximab in excess of 1000 mg IV within a 24 hour period 
will be considered an overdose. There has been no experience of overdosage with 
rituximab. GSK does not recommend specific treatment for an overdose of rituximab.
In the event of a belimumab and/or rituximab overdose, the investigator should:
1.
Contact the Medical Monitor immediately.

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2.
Closely monitor the participant for AEs/SAEs
3.
Document the quantity of the excess dose as well as the duration of the overdosing.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.9.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.9.1.
Physical Examinations

The full physical examination at screening will include complete assessment of 
all organ systems including assessments of the head and neck (including eyes, 
ears, nose, throat, and thyroid gland), skin, musculoskeletal (including 
evaluation of both small and large joints), neurological, respiratory, and 
cardiovascular systems, gastrointestinal system, and abdomen (including liver 
and spleen), lymph nodes and extremities.

A symptom-driven physical examination at the scheduled and unscheduled 
clinic visits will include, at a minimum, assessments of eyes, mouth, skin, lungs, 
cardiovascular system, abdomen and extremities (including joints).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.9.2.
Vital Signs

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available.

Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse. 
9.9.3.
Electrocardiograms

A single 12-lead ECG will be obtained during screening using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.
9.9.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 9 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

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
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 60 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 9, must be 
conducted in accordance with the laboratory manual and the SoA.
9.9.5.
Neurological Assessment
A questionnaire-based neurological examination to detect any signs or symptoms 
consistent with the diagnosis of Progressive Multifocal Leukoencephalopathy (PML) will 
be conducted by the investigator or designated site staff at each visit. If a question is 
answered 'yes' and the reason for the symptom is unknown (i.e., is not definitively 
explained by other known cause), the participant will be referred to a neurologist for 
evaluation and the medical monitor contacted within 24 hours. An MRI with gadolinium 
enhancement (pending renal function evaluation) and/or cerebrospinal fluid (CSF) JCV 
PCR is recommended to be performed to confirm the diagnosis of PML, if suspected. 
9.9.6.
Suicidal Risk Monitoring
There have been some reports of suicidal ideation or behavior symptoms, as reported in 
the product label in some patients being treated with belimumab for SLE. GSK considers 
it important to monitor for such events before and during clinical studies with compounds 
such as this.
Participants being treated with belimumab should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in 
behavior. Consideration should be given to discontinuing belimumab in participants who 
experience signs of suicidal ideation or behavior. 
Families and caregivers (where appropriate and at the discretion of the participant) of 
participants being treated with belimumab should be alerted about the need to monitor 
participants for the emergence of unusual changes in behavior, as well as the emergence 
of suicidal ideation and behavior and to report such symptoms immediately to the study 
investigator.
Baseline assessment of suicidal ideation and behavior AND treatment emergent suicidal 
ideation and behavior will be assessed during Study 205646 using C-SSRS. It is 

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recommended that the Investigator consider mental health consultation or referral for 
subjects who experience signs of suicidal ideation or behavior. The Medical Monitor 
should be notified when these events occur. In addition, a “yes” to any suicidal behavior 
or ideation question on the C-SSRS prompts the completion of the Possible Suicidality 
Related Questionnaire (PSRQ). Details of the C-SSRS and PSRQ questionnaires will be 
provided in the SRM.
9.10.
Pharmacokinetics

Blood samples of approximately 2 mL each will be collected for measurement of 
serum concentrations of belimumab or rituximab, respectively, as specified in the 
SoA. Instructions for the collection and handling of biological samples will be 
provided by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the pharmacokinetics (PK) of belimumab or 
rituximab. For each belimumab and rituximab PK sample collection the following 
is required: collect 2 mL whole blood into a 2 mL serum blood collection tube. 
Specimen will be allowed to clot and the tube then centrifuged at approximately 
1600 g for 15 minutes at room temperature to separate the clot from the serum. 
The resultant serum will be transferred to appropriately labeled 1.8 mL 
polypropylene tubes.

Samples collected for analyses of belimumab or rituximab serum concentrations 
may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

Genetic analyses will not be performed on these serum samples.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.11.
Pharmacodynamics
Blood Leukocyte Analysis
Blood samples for B cell analysis will be collected as indicated in the SoA (Section 2). B
cell flow cytometry panels will be used to measure changes over the course of therapy in 
blood cells, B cells and B cell subsets including but not limited to: the transitional, naive, 
memory, activated and plasma B cell compartments. For subsets of interest, absolute 
numbers of cells and proportions relative to all B cells will be determined.
Further Research
Further research samples are optional and will be reported separate from the Clinical 
Study Report (CSR) including but not limited to:
Additional blood samples for further B cell research will be collected from subjects at 
select European study sites as indicated in the SoA (Section 2).

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Peripheral blood mononuclear cells (PBMCs) may be collected only at US study sites to 
allow for examination of additional selected leukocyte populations to support further 
evaluation of the mechanisms of action of study treatment.
9.12.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 10 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM. 
9.13.
Biomarkers
Biomarker analyses are specified in the following sections. 
Biomarker assessments designated as “further research” require an additional further 
research consent and will be reported separate from the CSR.
Remaining aliquots of any biomarker samples collected as part of this protocol may be 
utilized for future analyses as permitted by consent and local regulations.
9.13.1.
Immunogenicity Assessments
Serum samples will be collected for belimumab (Arms A, B, and C) and rituximab 
(Arms A and B) immunogenicity assessments as indicated in the SoA (Section 2).
9.13.2.
RNA
Blood samples will be drawn before dosing on Day 1 (Baseline) for analysis of interferon 
signature.
9.13.3.
B Cell Receptors
Blood samples for further research B cell receptor analysis will be drawn as indicated in 
the SoA (Section 2). Blood samples for B cell receptor analysis will also be drawn if the 
participant experiences a suspected SLE Flare, as defined by the SLE Flare Index.
9.13.4.
BLyS Protein
Blood samples will be collected for quantification of BLyS protein levels as indicated in 
the SoA (Section 2).

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9.14.
Medical Resource Utilization and Health Economics
Health care resource utilization (HCRU) data will be collected for all participants 
throughout the study. Participants will be asked to record medical encounters each week
(see SoA, Section 2). Protocol-mandated medical resource utilization is excluded. The 
investigator and clinical site staff will review the reported HCRU at each visit. The data 
will be used to conduct exploratory economic analyses and will include:

Number of outpatient/hospital clinic visits

Number of emergency room/urgent care facility visits

Number and duration of in-patient hospitalizations (total nights, including 
duration by wards [intensive care unit vs. general ward])

Use of over the counter (non-prescription) medication.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of the study is to demonstrate superiority (improvement in 
response rate) of co-administration of belimumab plus rituximab (Arm B: Combination) 
over belimumab monotherapy (Arm A: Control), when comparing the primary efficacy 
endpoint at Week 52 in subjects with SLE. An exploratory assessment of the relative 
performance of Arm A (control) and Arm B (combination) vs. standard SLE therapy 
(Arm C) will also be conducted.
The primary efficacy endpoint is defined as: the proportion of participants with a state of 
disease control defined as a SLEDAI-2K score 2, achieved without 
immunosuppressants and with corticosteroids at a prednisone equivalent dose of 
5mg/day at Week 52.
Null Hypothesis (H0):
There is no difference between Arm B 
(combination) and Arm A (control) in terms of the 
primary endpoint at Week 52.
Alternative Hypothesis (H1):
There is a difference between Arm B (combination) 
and Arm A (control) in terms of the primary 
endpoint at Week 52.
A step-down sequential testing procedure will be used to control the overall type 1 error 
rate for comparing Arm B (combination) vs Arm A (control). With this procedure, the 
primary endpoint will be evaluated first and then the two major secondary endpoints (i.e., 
Clinical SLEDAI 2K score =0 at Week 64 next and then SLEDAI-2K score 2 at Week 
104) for statistical significance based on the pre-specified sequence for interpretation. 
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 

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sequence statistical significance is not met, then subsequent endpoints in the sequence 
cannot be deemed statistically significant. Analyses of other efficacy endpoints will not 
be subject to any multiple comparison procedure.
10.1.1.
Analysis for Marketing Application
Primary Analysis
A statistical analysis will be completed once all participants have completed 52 weeks of 
the study, if feasible. If the Week 52 database freeze is delayed due to COVID-19 
pandemic, the timing of the Week 52 reporting may be reviewed and changes will be 
documented in the RAP.
End of Study Analysis
After the initial 52 week double-blind phase, participants in Arms A and B will enter into 
the 52-week double blind treatment-free, observational phase of the study (Weeks 53 
through 104). Participants in Arm C will continue to receive belimumab SC and standard 
therapy, which may include their stable immunosuppressants, during Weeks 53 through 
104. A final analysis will be conducted following the completion of Week 104.
10.2.
Sample Size Determination
In order to ensure adequate exposure for evaluation of safety, the study is designed with a 
target of 140 participants to be randomized into the combination arm. At least 
280 participants will be randomised in this study, with a target of 70 participants in 
Arm A, 140 participants in Arm B and 70 participants in Arm C. This sample size 
provides at least 98% power (for the comparison of Arm B to Arm A at Week 52) at the 
5% level of significance assuming the underlying response in the control arm is 10% and 
the true population effect is 25% with treatment Arm B (combination assumed response 
rate of 35%). The primary endpoint will be based on assuming study dropouts = 
treatment failures, and so the assumed responder rates for treatment Arms A and B 
already account for participant dropout rates. However, the sample size may be increased 
up to a maximum of 320 participants if the dropout rate, missing data or number of major 
protocol deviations suggests further participants are necessary to ensure robust 
conclusions can be drawn. Sample size was calculated using PASS 12 and is based in the 
Likelihood ratio test. No inferential tests are planned between Arm C and Arm A or Arm 
B; therefore no adjustment for multiplicity is required. 
There are limited clinical data with therapies including both belimumab and rituximab. 
Based on elicitation of opinion from external experts, as well as the rarity of remission or 
disease control seen in published external studies and internal GSK review of previous 
belimumab data, a rate of 35% achieving a state of disease control (i.e., Arm B) is 
considered to be highly significant in SLE care. The assumed 10% responder rate in 
Arm A (control) at 52 weeks was estimated based on exploration of historical data from 
three comparable belimumab Phase 3 trials (IV: C1056 [BLISS-76] and C1057 
[BLISS-52] and SC: BEL112341) in patients with SLE, albeit with some significant 
differences from this study in protocol inclusion criteria, control of background therapy 
for SLE, SLEDAI-2K derivation and treatment failure rules. The estimated Arm A 

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(control) response rates based on data from previous belimumab Phase 3 studies ranged 
from 3.3% (C1056), 7.3% (C1057), and 8.3% (BEL112341). It is appreciated that these 
rates are derived from studies that did not include a forced steroid or immunosuppressant 
taper. Due to the limitations of the historical data and therefore the likely imprecision of 
the estimated responder rates, a more conservative estimate of the assumed belimumab 
monotherapy arm of 10% is being used for sample size calculations.
Assuming a 10% control responder rate and 70 participants in Arm A and 
140 participants in Arm B, the minimum detectable effect (MDE) at p-value <0.05 is a 
11% improvement (i.e., an observed improvement with the combination of 11% or more 
would give a p-value <0.05).
Sample Size Sensitivity
A sample size sensitivity analysis was conducted on the primary endpoint, to investigate 
the impact on power if the assumed underlying control response rate deviates from 10% 
or the treatment difference deviates from 25%. The results of these analyses are displayed 
in Table 5. 
Table 5
Power if the Underlying Response Rates Vary from 10% (Control) 
and 35% (Combination)a
Control Rate (Arm A)
Combination Rate (Arm B)
Power
5%
30%
99%
15%
40%
97%
10%
25%
75%
10%
30%
93%
10%
40%
99%
a.
All calculations assume a 5% level of significance, N=70 (control), N=140 (combination).
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF.
Randomized
All participants who are randomized. This population will be comprised of 
participants according to the treatment that a participant was randomized to 
receive, regardless of the actual treatment received.
Intent-To-Treat 
(ITT)
All randomized participants who received at least one dose of study treatment. 
This population will be comprised of participants according to the treatment that 
a participant was randomized to receive, regardless of the actual treatment 
received.
Modified Intent-
Arm A&B: All randomized participants who received at least one dose of study 

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Population
Description
To- Treat (MITT)
treatment will be included.
Arm C: All randomized participants who received at least one dose of study 
treatment and for whom their independent blinded assessor was not potentially 
unblinded (i.e., enrolled after 07SEPT 2018) will be included.
This population will be comprised of participants according to the treatment that 
a participant was randomized to receive, regardless of the actual treatment
received.
Per-Protocol 
(PP)
All randomized participants who receive at least one dose of study treatment 
excluding participants with major protocol deviations with potential to impact 
efficacy assessments.
All further populations to be used for the assessment of health outcomes, biomarkers and 
pharmacokinetics data will be defined in the RAP.
10.4.
Statistical Analyses
Following an assessment of the impact of COVID-19 on the planned estimands, it may be 
necessary to update existing estimands or add new estimands. Where required, details of 
these analyses will be included in the RAP.
10.4.1.
Efficacy Analyses
Unless otherwise stated, the primary and key secondary efficacy endpoints will be 
conducted using the:

MITT population

Blinded independent assessors SLEDAI-2K data
Endpoint
Statistical Analysis Methods
Primary
Endpoint: The proportion of participants with a state of disease control defined 
as a SLEDAI 2K-score ≤2, achieved without immunosuppressants and with 
corticosteroids at a prednisone equivalent dose of 5mg/day at Week 52. (Arm B: 
combination vs Arm A control)
Analysis: The proportion of subjects achieving a treatment response (as defined 
for the primary endpoint) at Week 52 will be compared between Arm B 
(combination) vs Arm A (control) using a logistic regression model. The 
independent variables in the model will include treatment group, baseline 
SLEDAI-2K score (9 vs. 10 mg/day), immunosuppressant use at baseline 
(immunosuppressant use vs. no use), and baseline corticosteroid dose 

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Endpoint
Statistical Analysis Methods
(prednisone equivalent 10 mg/day vs. 10 mg/day). If any factor fails to 
converge it will be removed from the logistic model. If the logistic model fails to 
converge, e.g., due to a small number of responders, the primary endpoint will be 
analyzed using a Fishers exact test. 
Missing data for the primary endpoint will be handled as follows:

The study is designed to continue to collect data for participants who 
prematurely discontinue from their randomized treatment. All data on the 
primary endpoint collected for these participants will be included in the 
primary analysis, irrespective of whether they are classified as ‘on-treatment ‘ 
or not. For participants who withdraw prematurely from study treatment and 
for whom subsequent collection of data is not possible, it will be assumed for 
the primary analysis that they are treatment failures. A dropout/treatment 
failure = non-responder (DO/TF=NR) analysis will be used, therefore no 
missing data will be assumed as all participants will be classed as either a 
non-responder or responder. The basic premise of the DO/TF=NR analysis is 
that a participant meeting any of treatment failure criteria defined below (prior 
to Week 52), will be considered a treatment failure and thus counted as a 
non-responder in the statistical analysis:

Received protocol prohibited medication, including non-study rituximab, 
prior to Week 52;

Received immunosuppressants after Week 4;

Received a prednisone equivalent corticosteroid dose of >5 mg/day after 
Week 26;

Withdrew from the study prior to Week 52.
Sensitivity Analysis: Sensitivity analyses will be defined in the RAP and will 
explore the impact of missing data and treatment failure imputation. 
Secondary
(First Major)
Endpoint: The proportion of participants with a state of clinical remission defined 
as a Clinical SLEDAI-2K score =0, achieved without immunosuppressants and 
corticosteroids at a prednisone equivalent dose of 0 mg/day at Week 64. (Arm B: 
combination vs Arm A control)
Note: For purposes of the Major Secondary Endpoint, Clinical SLEDAI-2K is 
scored similar to the SLEDAI-2K but excludes serological activity scores, i.e., anti-
dsDNA positivity and/or hypocomplementemia.
Analysis: The proposed statistical analyses planned for the primary endpoint will 
be repeated for the first major secondary endpoint. The following treatment failure 
criteria (prior to Week 64) will be used:
1.
Received protocol prohibited medication, including non-study rituximab, prior 
to Week 64;
2.
Received immunosuppressants after Week 4;

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Endpoint
Statistical Analysis Methods
3.
Received a prednisone equivalent corticosteroid dose of >5 mg/day after 
Week 26;
4.
Received open-label belimumab in the Week 52 to Week 64 period;
5.
Withdrew from the study prior to Week 64.
Secondary
(Second 
Major)
Endpoint: The proportion of participants with a state of disease control defined 
as a SLEDAI-2K score 2, achieved without immunosuppressants and with 
corticosteroids at a prednisone equivalent dose of 5mg/day at Week 104.
Analysis: The proposed statistical analyses planned for the primary endpoint will 
be repeated. The following treatment failure criteria will be used:
1.
Received protocol prohibited medication, including non-study rituximab, prior 
to Week 104;
2.
Received immunosuppressants after Week 4;
3.
Received a prednisone equivalent corticosteroid dose of >5 mg/day after 
Week 26;
4.
Received open-label belimumab after Week 52;
5.
Withdrew from the study prior to Week 104;
Exploratory
An exploratory assessment, using descriptive statistics, of the relative 
performance of Arm A (control) vs standard SLE therapy (Arm C) and Arm B 
(combination) vs. standard SLE therapy (Arm C) will also be conducted using the 
primary and key secondary endpoints. Details, including treatment failure rules for 
Arm C, will be described in the RAP.
10.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
Endpoint
Statistical Analysis Methods
Secondary
Descriptive statistics will be used to summarize AEs, SAEs, AEs of special 
interest (AESI), changes in laboratory parameters, and immunogenicity (both anti-
belimumab and anti-rituximab antibodies will be assessed). The frequency of 
laboratory abnormalities will be tabulated by treatment group. The frequency of 
AEs will be tabulated by MedDRA system organ class (SOC) and preferred term 
and compared between treatment arms.
10.4.3.
Other Analyses
Secondary Efficacy (Other), PK, pharmacodynamic, biomarker, and PRO exploratory 
analyses will be described in the RAP. 

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10.4.4.
Interim Analyses
There are no formal planned interim analyses.
An independent data monitoring committee (IDMC) will review unblinded safety data on 
an ongoing basis until all participants have completed the 104 week study (after which 
monitoring may be assumed by an internal GSK committee). The IDMC will include 
physicians with relevant clinical expertise and a statistician, none of whom is affiliated 
with the sponsor. The 1st IDMC data review meeting will occur after approximately 
60 participants have been randomized (approximately 15 in each of Arms A and C and 
approximately 30 in Arm B) and completed 12 weeks of study treatment OR 
approximately 6 months after the treatment of the 1st participant, whichever is earlier.
After the initial review, the IDMC will review the data approximately every 6 months. 
For coordination with other ongoing IDMC activities, the initial meeting may be 
scheduled prior this milestone, and then will resume the above described schedule 
(approximately every 6 months). Ad hoc meetings of the IDMC can also be requested as 
needed to review urgent safety information or AEs. Events to be monitored during the 
safety review will include at a minimum all SAEs (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 treatment phase (Year 1) 
and double-blind observational phase (Year 2) for Arms A & B and open-label treatment 
phase (Years 1 and 2) for Arm C. Investigators and IRBs/IECs will be notified of the 
outcome of each IDMC meeting. In addition, the IDMC will receive information within 
72 hours of all SAEs that are life threatening or result in death. Other SAEs, all 
opportunistic infections, irrespective of relationship to study treatment, and protocol 
specified events (i.e., IgG <250 mg/dL) will be provided to the IDMC bi-weekly for 
review.

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Boumans MJH, Thurlings RM, Gerlag DM, Vos K, Tak PP. Response to rituximab in 
patients with rheumatoid arthritis in different compartments of the immune system. 
Arthritis Rheum 2011;63(11):3187-94.
Carubbi F, Alunno A, Cipriani P, Bartoloni E, Ciccia F, Triolo G,et al. Rituximab in 
primary Sjögren's syndrome: a ten-year journey. Lupus 2014;23(13):1337-49.
Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. Validation of the 
Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other 
instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005: 32(5): 811-9.
Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345(5):340-50.
De Vita S, Quartuccio L, Salvin S, Picco L, Scott CA, Rupolo M,et al. Sequential therapy 
with belimumab followed by rituximab in Sjögren's syndrome associated with B-cell 
lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin 
Exp Rheumatol 2014;32(4):490-4.
Franklyn K, Lau CS, Navarra SV, Louthrenoo W, Lateef A, Hamijoyo L, et al for the 
Asia-Pacific Lupus Collaboration. Definition and initial validation of a Lupus Low 
Disease Activity State (LLDAS). Ann Rheum Dis. 2016 Sep;75(9):1615-21.
GlaxoSmithKline Document Number 2011N128591_04. Belimumab Investigator’s 
Brochure. 12 June 2017.
Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L,et al. Importance of cellular 
microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 
2005;174:817-26. 
Hochberg MC. Updating the American College of Rheumatology revised criteria for the 
classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
Kraaij T, Huizinga TW, Rabelink TJ, Teng YK. Belimumab after rituximab as 
maintenance therapy in lupus nephritis. Rheumatology (Oxford) 2014;53(11):2122-4.
Lai J-S, Beaumont JL, Ogale S, Brunetta P, Cella D. Validation of the Functional 
Assessment of Chronic Illness Therapy-Fatigue Scale in patients with moderately to 
severely active systemic lupus erythematosus, participating in a clinical trial. J 
Rheumatol 2011;38:672-9.
Lin W, Seshasayee D, Lee WP, Caplazi P, McVay S, Suto E, et al. Dual B cell 
immunotherapy is superior to individual anti-CD20 depletion or BAFF blockade in 
murine models of spontaneous or accelerated lupus. Arthritis Rheum 2015;67(1) 215-24.
McElhone K, Abbott J, Shelmerdine J, Bruce IN, Ahmad Y, Gordon C, et al. 
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the LupusQol, for adults with systemic lupus erythematosus. Arthritis Rheum 2007: 
15;57(6): 972-9.
Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, et al. 
Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, 
double-blind, placebo-controlled trial. Arthritis Rheum 2010:62(4):960-8.
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy 
and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: 
the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of 
rituximab trial. Arthritis Rheum 2010;62(1):222-33.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65.
Rituxan [package insert]. South San Francisco, CA: Genentech, Inc.; 2016.
Simonetta F, Allali D, Roux-Lombard P, Chizzolini C. Successful treatment of refractory 
lupus nephritis by the sequential use of rituximab and belimumab. Joint Bone Spine. 
2016: pii: S1297-319X(16)30020-3. doi: 10.1016/j.jbspin.2016.01.008. [Epub ahead of 
print].
Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, et al. Belimumab 
reduces autoantibodies, normalizes low complement levels, and reduces select B cell 
populations in patients with systemic lupus erythematosus. Arthritis Rheum 
2012;64(7):2328-37.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 
revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 
1982;25(11):1271-7.
Urowitz MB, Gladman DD, Ibañez D, Fortin PR, Bae SC, Gordon C, et al. Evolution of
disease burden over five years in a multicenter inception systemic lupus erythematosus 
cohort. Arthritis Care Res 2012;64:132-7.
Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E, et al. Safety of 
the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving 
background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year 
randomized, placebo-controlled study. Arthritis Rheum 2006;54(9):2807-16.

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12.
APPENDICES
12.1.
Appendix 1:Abbreviations and Trademarks
ACR
American College Of Rheumatology
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANA
Anti-Nuclear Antibody
APRIL
A Proliferation-Inducing Ligand
BAFF
B-cell Activating Factor Of The TNF Ligand Family
BLyS
B-Lymphocyte Stimulator
BR3
BLyS Receptor 3
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
Cardiovascular
DBL
Data Base Lock
DMC
Data Monitoring Committee
dsDNA
Double Stranded Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
FDA
US Food and Drug Administration
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HBC
Hepatitis C Virus
HBV
Hepatitis B Virus
HCRU
Health care resource utilization
HGS
Human Genome Sciences
HSR
Hypersensitivity Reaction
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
Ig
Immunoglobulin
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IM
Intramascular
IP
Investigational Product
IRB
Institutional Review Boards
ITT
Intent-to-Treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
mAb
Monoclonal Antibody
MALT
Mucosa Associated Lymphoid Tissue
MDE
Minimum detectable effect

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MedDRA
Medical Dictionary for Regulatory Activities
MITT
Modified Intent-to-Treat
MTX
Methotrexate
MZ
Marginal Zone
NSAID
Non-Steroid Anti-Inflammatory Drug
OI
Opportunistic Infection
PBMC
Peripheral Blood Mononuclear Cell
PK
Pharmacokinetic(s)
PML
Progressive Multifocal Leukoencephalopathy
PP
Per-Protocol
PRES
Posterior Reversible Encephalopathy Syndrome
PRO
Patient Reported Outcomes
pSS
Primary Sjögren’s Syndrome
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
RA
Rheumatoid Arthritis
RAP
Reporting And Analysis Plan
RPLS
Reversible Posterior Leukoencephalopathy Syndrome
SC
Subcutaneous(ly)
SELENA
Safety of Estrogen in Lupus National Assessment Trial
SHL
Scandinavian Health Limited
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SLICC
Systemic Lupus International Collaborating Clinics
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reactions
TNF
Tumor Necrosis Factor
US
United States
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BENLYSTA
MedDRA
QuantiFERON-TB Gold or QuantiFERON-
TB Gold Plus
Rituxan

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12.2.
Appendix 2:Recommended Corticosteroid Taper Schedule
A two-phase corticosteroid taper will be employed in the study. 
Taper Phase 1 will occur under the direction of the investigator between study Weeks 12 
and 26 with a target prednisone equivalent corticosteroid dose of 5 mg/day by study 
Week 26. Participants who cannot tolerate prednisone equivalent corticosteroid dose of 
5 mg/day after Week 26 will be considered treatment failures. Participants who are 
deemed treatment failures will be encouraged to remain in the study and continue to have 
all efficacy and safety assessments. The recommended corticosteroid taper schedule for 
Phase 1 is outlined in Table 6. Common corticosteroid doses and prednisone equivalents 
are presented in Table 7. Adjustments may be made for tolerability at the investigator’s 
discretion.
Table 6
Recommended Oral Corticosteroid Taper 
(Prednisone equivalent dosing)
Study Week
Prednisone equivalent dose 
(mg/day)
12
60
13
55
14
50
15
45
16
40
17
35
18
30
19
25
20
20
21
17.5
22
15
23
12.5
24
10
25
7.5
26
5
Taper Phase 2 will occur starting at Week 26 after subjects have been successfully 
tapered to prednisone equivalent corticosteroid dose of 5 mg/day. In order to attempt to 
discontinue participants’ corticosteroids a prolonged prespecified taper will be employed. 
A decrease of 1 mg/day on one day per week is recommended until a participant is 
decreased to 0 mg/day. For example, the first week of this taper a participant who was 
receiving a prednisone equivalent corticosteroid dose of 5 mg/day will receive 4 mg on 
Monday and 5 mg/day from Tuesday through Sunday. In the second week of the taper the 
participant will receive 4 mg on Monday and Tuesday and then 5 mg/day from 
Wednesday through Sunday, etc until the participant is on 0 mg/day. Thus, the 
discontinuation of 5 mg/day would take 35 weeks to accomplish.

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Table 7
Common Corticosteroid Equivalent Approximate Dose (mg) and 
Prednisone- Equivalent Multiplier Factor
Corticosteroids
Equivalent Dose (mg)
Prednisone-Equivalent 
Multiplier Factor
Prednisone
5
NA
Prednisolone
5
1
Triamcinolone
4
1.25
Cortisone
25
0.2
Hydrocortisone
20
0.25
Methylprednisolone
4
1.25
Betamethasone 
0.6 - 0.75
8.3 – 6.7
Dexamethasone 
0.75
6.7
References:
Dixon JS (ed). Second-line agents in the treatment of rheumatic diseases. Informa Health Care, 1991. (456).
Meikle AW, Tyler FH. Potency and duration of action of glucocorticoids. Effects of hydrocortisone, prednisone and 
dexamethasone on human pituitary-adrenal function. Am J Med 1977;63;200-7.
Singer M, Webb AR. Oxford Handbook of Critical Care. 2nd ed. New York: Oxford University Press, 2005.

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12.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 8.

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Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the standard of care medications, which may 
reduce the efficacy of the contraceptive method. In this case two highly effective methods of contraception should 
be utilized during the treatment period and for at least 16 weeks after the last dose of belimumab and/or monthly 
until 12 months after the last dose of rituximab or placebo, whichever is later. 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.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test.

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
Additional pregnancy testing during the treatment period per the SoA and at 
16 weeks after the last dose of belimumab and/or monthly until 12 months after the 
last dose of rituximab or placebo, whichever is later, and as required locally.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Pregnancy testing using a serum sample, with a sensitivity of 5 mIU/mL will be 
performed and assayed in the central laboratory at the Screening Visit. Urine 
pregnancy test kits provided by the central laboratory will be used for all other 
scheduled pregnancy tests and in accordance with instructions provided in its 
package insert.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any participant who becomes pregnant while participating will discontinue study 
treatment or be withdrawn from the study. Participants who discontinue study treatment 
should be encouraged to continue to participate in study visits in accordance with the 
SoA (Section 2), especially all remaining safety evaluations.
Breast-feeding (Germany only): Whether rituximab is excreted in human milk is not 
known. However, because maternal IgG is excreted in human milk, and rituximab was 
detectable in milk from lactating monkeys, women should not breastfeed while treated 
with rituximab and for 12 months following rituximab treatment.

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12.4.
Appendix 4:Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 

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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
An Independent Data Monitoring Committee (IDMC) will conduct periodic reviews of 
unblinded data to ensure external objective and/or statistical review of safety issues. The 
composition, remit, and procedures of the IDMC are provided in the IDMC Charter (see 
Section 10.4.4).
An Independent Adjudication Team, including representatives from Clinical, 
Biostatistics, and Data Management, will be established before the Week 52 data are 
unblinded. This team will participate in the review and adjudication of treatment failures, 
AEs of special interest, and protocol deviations in preparation for the Week 52 and end of 
study data base locks (DBLs). After unblinding, only members of the Independent 
Adjudication Team will continue to participate in the review and adjudication of 
treatment failures, AEs of special interest, and protocol deviations in preparation for the 
end of study DBL (unblinded team members will no longer participate in adjudication).
Members of the Independent Adjudication Team remain blinded until the End of Study
Data Base Freeze (DBF).

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Dissemination of Clinical Study Data
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate. GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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12.5.
Appendix 5:Liver Safety: Required Actions and Follow-up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (refer to Appendix 6)

If restart is not granted, permanently 
discontinue study treatment and continue 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and Hepatitis 
delta antibody5.

Belimumab and rituximab pharmacokinetic 
(PK) within 8 weeks after last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 

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participant in the study for any protocol 
specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
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 high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). NOTE: not required in 
China 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant 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 participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)

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4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If Hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants 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 PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment 

Participant 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 participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute liver failure. Drug Metab Dispos 2009;37:1779-84.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of 
hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients. J 
Clin Microbiol. 2005;43(5):2363–69. 

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12.6.
Appendix 6:Liver Safety Study Treatment Restart Guidelines
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcoholic hepatitis.
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).

Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has a 
confirmed genetic marker associated with liver injury, the presence of the marker 
should be excluded. 

There is no evidence of alcoholic hepatitis.

IRB/IEC approval of study treatment restart has been obtained.
If restart of study treatment is approved by GSK in writing: 

The participant 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 participant must also provide signed informed consent specifically for the restart 
of study treatment. Documentation of informed consent must be recorded in the 
study file. 

Study treatment must be administered at the dose specified by GSK

Participants approved by GSK for restart of study treatment must return to the clinic 
twice a week for liver function tests until stable liver function tests have been 
demonstrated and then standard laboratory monitoring may resume as per protocol.

If the participant meets protocol-defined liver function stopping criteria after study 
treatment restart, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the IRB/IEC, must be informed of the outcome for the 
participant following study treatment restart. 

GSK must be notified of any adverse events, as per Appendix 7. 

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12.7.
Appendix 7:Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

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 study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 

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the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 

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requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in 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 in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 

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assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the SAE coordinator by telephone.

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SAE Reporting to GSK via Paper CRF

If the electronic system is unavailable for more than 24 hours, then facsimile 
transmission of the SAE paper CRF is the preferred method to transmit this 
information to the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

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12.8.
Appendix 8:Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 7.1.1 for the list of GSK 
medical devices). 
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects

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Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 7.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence.

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12.9.
Appendix 9:Clinical Laboratory Tests

The tests detailed in Table 9 will be performed by the central laboratory. 

Local laboratory results are required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation and for those patients at select sites participating in the 
further research B-cell analyses. In addition, local laboratory results are 
recommended if central laboratory results cannot be obtained (perhaps as a 
consequence of disruption associated with the COVID-19 pandemic).

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 9
Protocol Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MPV
MCHC
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
RDW
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose -
Nonfasting
Calcium 
(corrected)
Alkaline 
phosphatase
eGRF
Routine
Urinalysis

Standard Urinalysis Macro and Urinalysis Micro (microscopic examination if 
blood or protein is abnormal)

Specific gravity

pH, Glucose, Protein, Blood, Ketones, Occult Blood, Bilirubin, Nitrite, 

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Laboratory 
Assessments
Parameters
Leukocyte Esterase by dipstick

Spot Urine (protein:creatinine ratio)
Immunoglobulins

Serum isotypes: IgG, IgM, IgA
Autoantibodies

ANA titer

Anti-dsDNA

aCL 

Beta-2-glycoprotein

Lupus anticoagulant

Extractable nuclear antigens (ENAs)
Serum 
Complement

Complement C3

Complement C4
Urine Drug 
Screen

Amphetamines, Barbiturates, Benzodiazepines, Cocaine Metabolites, 
Marijuana Metabolites, Methadone, Opiates, Phencyclidine, Propoxyphene, 
Ethanol
Genetics

Blood sample collection
Belimumab PK

Blood sample collection
Rituximab PK

Blood sample collection
RNA Interferon 
Signature

Blood sample collection
PBMC

Blood sample collection
Immunogenicity

Blood sample collection
B Cell Subset

Blood sample collection
B-Cell Receptor

Blood sample collection
BLyS Protein

Blood sample collection
Other Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)

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Laboratory 
Assessments
Parameters

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)

PT/PPT
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.2 and Appendix 5. All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).
Lab data that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.

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12.10.
Appendix 10:Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples may be used for research related to belimumab, rituximab, or any 
concomitant medicines, or systemic lupus erythematosus (SLE) and related diseases. 
They may also be used to develop tests/assays including diagnostic tests related to 
belimumab, rituximab, or any concomitant medicines, and SLE. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate)

DNA samples may be analyzed if it is hypothesized that this may help further 
understand the clinical data or the disease under study. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to belimumab, rituximab, or study treatments of these drug 
classes. The results of genetic analyses may be reported in the clinical study report or 
in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on belimumab, rituximab or SLE 
continues but no longer than 15 years after the last subject last visit or other period as 
per local requirements.

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12.11.
Appendix 11: American College of Rheumatology (ACR) 
Criteria for SLE
The ACR Criteria for the Classification of Systemic Lupus Erythematosus* 
[Tan, 1982; Hochberg, 1997]
Criterion
Definition
*
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.
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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12.12.
Appendix 12:Country-specific requirements
South Korea Investigational Product Labels
Belimumab
Box
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.
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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Rituximab
Box
Vial
Korea Subjects: In regards to Inclusion criteria 1, only adult participants as per local 
laws at the time of signing the informed consent will be eligible for inclusion in this 
study.
South Korea: 
Amendment 01/KOR-1: see GlaxoSmithKline Document Number 2016N272781_02.
Germany:
Amendment 01/DEU-1: see GlaxoSmithKline Document Number 2016N272781_03.
Amendment 01/DEU-2: see GlaxoSmithKline Document Number 2016N272781_04.
Argentina:
Amendment 01/ARG-1: see GlaxoSmithKline Document Number 2016N272781_05.
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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12.13.
Appendix 13: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 03 (Global)  15-AUG-2019
Overall rationale for the Amendment: 1) To define dosing interruptions based on 
neutrophil count, 2) Incorporate country-specific changes for S. Korea, Germany and 
Argentina into Global Amendment 03 protocol, 3) define an MITT population for 
analysis, and 4) provide clarification of changes and updates on wording related to study 
conduct.
Section # and Name
Description of Change
Brief Rationale
2: Schedule of Activities 
(SoA) Table 1, Table 2, Table
3 and Table 4
Listed sample analysis that are 
for exploratory further research
Add clarity for sites so as not to 
confuse protocol required 
samples with further research 
samples
2: Schedule of Activities 
(SoA) Table 1 and Table 3
Footnote a – corrected visit 
week that 7 day window begins
Footnote b – corrected early 
withdrawal only for patient who 
discontinue study
Footnote u (Table 1) and 
footnote o (Table 3) – indicated 
samples are optional and for 
further research purposes from 
select European centers
Incorrect in previous version
Incorrectly indicated this applied 
to patients discontinuing IP as 
well in previous version
Clarification for sites regarding 
sample collection for further 
research
2: Schedule of Activities 
(SOA), Table 1, Table 2,
Table 3, and Table 4
Footnotes n and q (Table 1) 
and footnotes g and I (Table 2), 
footnotes j and l (Table 3) and 
footnotes f and h (Table 4) 
updated text to “suspected “ 
SLE flare
Clarification to sites that B-cell 
samples should be collected any 
time flare is suspected.
2 SoA Table 2 and Table 4
Footnote d (Table 2) and 
footnote f (Table 4) Include 
Argentina specific requirement 
for monthly pregnancy testing 
during study year 2 testing
Footnote n (Table 2) indicated 
samples are optional and for 
further research purposes from 
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
Clarification for sites regarding 
sample collection for further 
research

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Section # and Name
Description of Change
Brief Rationale
select European centers
2 Table 2: SoA
Add Further Research 
collection of B-cell subsets at 
Year 2 Unschedued Visit
Allow for further research 
sample collection for patients 
who restart belimumab in Year 2
3: Benefit/Risk Assessment
Removed text indicating there 
are no published clinical 
research data on use of 
belimumab and rituximab
Published literature is available
3.3.1: Risk Assessment: 
Infections
Included Germany specific 
change: for subjects with 
hypogammaglobulinemia -
changed from IgG <250 mg/dL 
to IgG <400 mg/dL
Neutropenia language updated 
to reflect new value for 
interrupting belimumab 
treatment and potential for 
continued dosing
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
To allow flexibility to continue 
dosing with belimumab in 
instances of neutropenia if 
clinically appropriate
4 and Study Synopsis:
Objectives and Endpoints
Added two additional 
secondary efficacy (Other) 
endpoints added based on 
principal investigator 
assessment of SLEDAI-2K
Changed to aid assessment of 
difference between the blinded 
assessor and principal 
investigator
5.1: Overall Design 
Removed text indicating 
participants who discontinued 
IP but remained in the study 
may have to perform 
unscheduled visit
Corrected error in text
5.3: Participant and Study 
Completion
Removed text indicating 
participants who discontinued 
IP but remained in the study 
may have to perform 
unscheduled visit
Corrected error in text
6.1: Inclusion criteria
Included Germany specific 
change that oral 
cyclophosphamide is not an 
allowed medication in the list of 
concomitant medications
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
6.2: Exclusion Criteria
Included Germany specific 
changes:
Incorporation of country specific 
amendments into Amendment 

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Section # and Name
Description of Change
Brief Rationale
exclusion of subjects with 
hypogammaglobulinemia -
changed from IgG <250 mg/dL 
to IgG <400 mg/dL added to 
the relevant prior/concomitant 
therapy exclusion criterion 
and
exclusion of subjects who had 
oral cyclophosphamide within 
60 days of Day 1 
03 Global Protocol
7.7.1.4: Other 
Immunosuppressant Agents
Included Germany specific 
change: Deleted oral 
cyclophosphamide, 
2.5 mg/kg/day from the list of 
common allowable maximum 
doses at baseline and during 
the study
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
7.7.2: Prohibited Medications 
and Non-Drug Therapies
Text added to clarify when 
medical monitor must be 
contacted.
Included Germany specific 
change: Added oral 
cyclophosphamide to list of 
medications prohibited at any 
time during the study
Statement added for clarity.
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
7.7.4 Additional SLE Therapy
Added that rescue medications 
should be documented.
Ensure collection of this 
information in the source 
documentation.
8.2: Discontinuation of Study 
Treatment and 12.3 
Appendix 3: Contraception 
Guidance and Collection of 
Pregnancy Information
Included Germany specific 
change:  Clarification that 
women should not breastfeed 
while treated with rituximab 
and for 12 months following 
rituximab treatment.
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
8.3: Temporary 
Discontinuation and Restart 
of Belimumab
Language regarding temporary 
belimumab discontinuation and 
potential
restart 
due 
to 
neutropenia added
To describe action to be taken in 
instances of neutropenia 
9.1: Screening Assessment -
Pregnancy Test
Included Argentina specific 
change: reference to additional  
pregnancy tests during study 
year 2.
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol

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Section # and Name
Description of Change
Brief Rationale
Laboratory tests
Added text regarding repeat 
samples.
Statement added for clarity.
9.4: Assessments at 
Unscheduled Visits
Removed text indicating 
participants who discontinued 
IP but remained in the study 
may have to perform 
unscheduled visit
Corrected error in text
9.6.1 Patient-Reported 
Outcomes Assessments –
Patient Interviews
Removed reference to the 
Patient Interview 
Communication Plan as plan is 
not implemented by the site.
Corrected text.
9.9.6 Suicidal Risk 
Monitoring
Added wording to monitoring 
statement regarding informing 
families and caregivers 
Wording added to address 
privacy concerns
9.11 Pharmacodynamics
Added text for exploratory 
research performed on 
additional blood samples for 
future B cell research
Added for conduct of future B 
cell research in newly enrolled 
participants at selected sites.
9.13 Biomarkers
Added statement on remaining 
sample use
Aligned with further research 
intent in ICF
9.13.3: B Cell Receptors
Added “further research” 
Highlight these analyses are 
part of further research
10.3 Populations for 
Analyses
Modified Intent-to-Treat 
population added 
Additional population excluding 
subjects for whom their 
independent blinded assessor 
was potentially unblinded, to 
facilitate analysis excluding 
these subjects.
12.1 Trademarks
Added trademarks.
Added trademarks
12.4 Appendix 4: Study 
Governance Considerations
Changed wording to clarify the 
adjudication process 
Corrected text.
12.9 Appendix 9: Clinical 
Laboratory tests
Added wording indicating local 
labs are required for 
participants consented into 
exploratory further B cell 
research
Inadvertenly not included in 
previous version.
12.12 Appendix 12: Country-
specifc requirements 
Korea specific label and 
enrolment criteria language 
added
Incorporation of country specific 
amendments into Amendment 
03 Global Protocol
Throughout protocol
Minor editorial revisions
Corrections of typographical 
errors and minor revisions for 

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Section # and Name
Description of Change
Brief Rationale
clarity.
Amendment 02 (KOR-1)  02-FEB-2019
Overall Rationale for the Amendment: To add changes specific for South Korea from 
previously approved KOR-1 (shown in the table below) to the Global Amendment 02 
Protocol.
Section # and Name
Description of Change
Brief Rationale
Appendix 12: Country-
Specific requirments, 
following addition of new 
appendix in Amendment 02 
(Global), the country-specific 
requirements previously 
found in Appendix 11 in 
Amendment 01/KOR-1 are 
now located in Appendix 12.
Include IP label, additional 
clarification about the inclusion 
criteria age as per local 
regulations, provide details of 
IPs supplied for South Korea
Country specific requirement for 
South Korea
Amendment 02 (ARG-1)  11-DEC-2018
Overall Rationale for the Amendment: To add changes specific for Argentina from 
previously approved ARG-1 (shown in the table below) to the Global Amendment 02 
Protocol:
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities (SoA), Table 2 and 
Table 4
Include requirement for 
monthly pregnancy testing 
during study year 2.
Country specific requirement for 
Argentina
Section 9.1: Screening 
Assessment - Pregnancy 
Test
Include reference to additional  
pregnancy tests during study 
year 2.
Country specific requirement for 
Argentina
Amendment 02 (DEU-2)  28-NOV-2018
Overall Rationale for the Amendment: To add changes specific for Germany from 
previously approved DEU-1 and DEU-2 (shown in the table below) to the Global 
Amendment 02 Protocol:
Section # and Name
Description of Change
Brief Rationale
3.3.1 Risk Assessment, 
Mitigation Strategy
Exclusion criterion for subjects 
with hypogammaglobulinemia 
Country specific requirement for 
Germany

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Section # and Name
Description of Change
Brief Rationale
6.2 Exclusion criteria
changed from IgG <250 mg/dL 
to IgG <400 mg/dL
8.2 Discontinuation of Study 
Treatment
Appendix 3, Contraceptive 
Guidance and Collection of 
Pregnancy Information
Clarification that women should 
not breastfeed while treated 
with rituximab and for 
12 months following rituximab 
treatment.
Consistent with recommendation 
from rituximab EU SmPC
6.1 Inclusion criteria
Deleted oral 
cyclosphosphamide as an 
allowed medication in the list of 
concomitant medications
Country specific requirement for 
Germany
7.7.1.4 Other 
Immunosuppresant Agents
Deleted oral 
cyclophosphamide, 
2.5 mg/kg/day from the list of 
common allowable maximum 
doses at baseline and during 
the study
6.2 Exclusion criteria
Added oral cyclophosphamide 
within 60 days of Day 1 to the 
relevant prior/concomitant 
therapy exclusion criterion 
Country specific requirement for 
Germany
7.7.2 Prohibited Medications 
and Non-Drug Therapies
Added oral cyclophosphamide 
to list of medications prohibited 
at any time during the study
Amendment 02 (Global)  17-NOV-2018
Rationale for the Amendment: 1) To change the timing of the initial analysis from 
Study Week 64 to Study Week 52 to support an earlier submission to regulatory 
authorities, 2) Recruit additional 80 participants into the study to ensure adequate number 
of evaluable participants, and 3) provide clarification of changes and updates on wording 
related to study conduct.
Section # and Name
Description of Change
Brief Rationale
1 Synopsis
1) Objectives and 
Endpoints;
2) Number of 
Participants
1) Removed reference to 
timing of analysis from 
this section.
2) Changed the number 
of participants  
Changed for consistency.

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Section # and Name
Description of Change
Brief Rationale
1, Synopsis; 3.3.1 Risk 
Management; 5.1 Overall 
Design; 5.4.1, Selection of 
Controls; 6.1 Inclusion 
Criteria IC #5, 
Removed reference to “oral” 
antihistamine 
Increase flexibility to administer 
pre-medication for 
rituximab/rituximab placebo 
treatment arms A or B)
2 Schedule of Activities 
(Table 1-Table 4)
1) Added a new row “Vital 
Signs” for Screening phase
2) Deleted select sample 
collection times for “B Cell 
Receptor”
3) Added new footnote for 
Dispense Belimumab for 
weekly dosing (SC)” 
advising that if Week 4 and 
6 belimumab dosing 
should happen to be 
scheduled for the day of 
the rituximab/rituximab 
placebo infusions, 
whenever possible, the day 
of belimumab dosing 
should be altered within 
the dosing window to occur 
on a day other than that of 
the infusion.
4) Added information to 
monitor subjects including 
vital signs during IV 
Rituximab/ rituximab 
placebo infusion.
5) Updated footnote for “Urine 
Pregnancy Test (WCBP)” 
6) Added footnote to 
“SLEDAI-2K: Blinded 
Assessor” row to 1) clarify 
the need to perform 
Symptom-driven physical 
exam, vital signs same as 
primary or sub investigator 
and 2) indicate the need to 
maintain source 
documentation for the 
physical exam and lab 
report analysis supporting 
Added for clarity and 
consistency with study 
procedures, added missing 
information. 
Rationale for #2: These samples 
were not part of central lab 
sample collection procedures. 
Samples at the deleted time 
points for B Cell Receptor have 
not been collected since the 
sites were informed of this 
change at study start.

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Section # and Name
Description of Change
Brief Rationale
the S2K scoring.
7) Added clarification to 
footnotes regarding PBMC 
blood sample collection 
and SLE flares
8) Added footnote regarding 
future B cell research
9) Remove additional text at 
end of Table 4.
Rationale for #9: This text 
applies only to GSK early phase/ 
Pharmacokinetic studies and 
was not applicable to this study.
4 Objectives and Endpoints
Removed reference to timing of 
analysis from this section.
Changed for consistency.
5.1 Overall Design, Figure 1
Updated number of participants 
in study schematic 
Changed for consistency.
5.2 Number of Participants
1) Changed number of 
participants screened: 400 to 
560;
Changes number of 
participants randomized: 200 to 
280
2) Changed number of added 
due to dropout/missing 
data/major protocol deviations: 
300 to 320
During the early conduct of the 
study some participants in Arm 
C (n=29) were inappropriately 
identified on the lab report which 
could have unblinded the 
independent blinded assessors. 
Blinding of Arms A and B was 
not compromised. The increase 
in the overall sample size from 
200 to 280 randomized 
participants under the same 
randomization ratio (1:2:1) 
increases the number of 
participants enrolled in Arm C 
from 50 to 70, with 41 of these 
unaffected by the unblinding 
issue. The number of 
participants in Arms A and B are 
also increased from 50 to 70 
and 100 to 140, respectively. 
This increase allows improved 
sensitivity to detect treatment 
effects and assessment of 
safety.
Assumes approx. 10%-15% 
dropout rate.
6.1 Inclusion criteria
IC #2 - Added minimum 
number of criteria required for 
SLE diagnosis (4 or more of 
Added for clarity and 
consistency with study 
procedures, add missing 

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Section # and Name
Description of Change
Brief Rationale
11)
IC #3 – Added clarification on 
presence and scoring of 
serological activity
IC #4 – Removed “key on 
historical lab report” that 
explaines positive/negative lab 
results.
information.
Note to IC #4: Use serum 
antibody threshold described in 
IC #4 (i.e., ANA titer ≥1:80 and 
anti-dsDNA ≥30 IU/mL) 
6.2 Exclusion Criteria
EC #2 - Revised text
EC #2 – Replaced 
QuantiFERON-TB Gold with 
QuantiFERON-TB Gold Plus 
assay
EC #4 – Revised text 
EC #24 – Added examples
Added for clarity and 
consistency; 
Qiagen has recently developed 
an improved version of its 
Quantiferon-TB Gold assay and 
as a result this assay is being 
discontinued. Quantiferon-TB 
Gold assay is being replaced by 
“Quantiferon-TB Gold Plus” 
assay that is more specific and 
sensitive. 
7.3 Method of Treatment 
Assignment
1) Changed ≥10 mg/day 
to >10 mg/day
2) Changed the number 
of participants
1) Corrected information
2) Updated for consistency
7.4 Blinding
Changed timing from Week 64 
to Week 52
SAEs will only be unblinded by 
GCSP for regulatory reporting 
purposes.
Removed text requiring 
investigator to contact Medical 
Monitor before unblinding a 
subject
Change for consistency
Added for clarity
Removed text as per change to 
the GSK SOP_54827 for 
emergency unbliding
7.6 Treatment Compliance
Added information and 
instruction if any one dose of 
belimumab is missed.
Added information if subject did 
not administer the full dose of 
belimumab due to autoinjector 
malfunction.
Revised text on missed 
Added for clarity and 
consistency

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Section # and Name
Description of Change
Brief Rationale
4 doses of belimumab.
7.7.1.2 Corticosteroids
Added information about 
corticosteroid dose=0 mg/day 
at study Day 1
Added for clarity and 
consistency
8.1 Withdrawal from the 
Study
Changed 52 weeks to 12 
months
Changed for consistency
8.2 Discontinuation of Study 
Treatment
Changed 52 weeks to 12 
months
Remove Duplicate pregnancy 
language 
Changed for clarity and 
consistency
9.3 Assessment of 
Scheduled Visits
Added “deemed treatment 
failure”
Added for clarity and 
consistency
9.6.1 Patient-Reported 
Outcomes Assessments
And
Patient Interviews
Added information on timing of 
PRO assessments
Added information on 
managing SAEs described 
during “Patient Interview”
Added for clarity and 
consistency
9.7.6 Pregnancy
Added “e.g., Week 58” 
Added for clarity
9.7.7. Medical Device 
Incidents (Including 
Malfunctions) 
Added “autoinjector” 
Added cross-reference to 
Section 7.6 Patient Compliance
Added for clarity and 
consistency
9.7.7.3 Prompt Reporting of 
Medical Device Incidents to 
Sponsor
Added information regarding 
forms
Added for clarity
9.7.8 Device Malfunction 
(NEW)
Added a new section for 
reporting Device Malfunction
Added to align with GSK 
procedures.
9.9.6 Suicidal Risk 
Monitoring
Removed “Adverse Event” and 
changed PSRAE to PSRQ
Changed for consistency
9.11 Pharmacodynamics
Added text for collection of 
additional blood samples for 
future B cell research
Added for conduct of future B 
cell research in newly enrolled 
participants at selected sites.
10.1.1 Analysis for Marketing 
Application
Initial database lock (DBL) has 
been changed to after Week 
52. 
The first DBL will include the 
initial 52 week double-blind 
phase (Primary Endpoint)
10.2 Sample Size 
Determination
Added text to reflect changes 
in the sample population
Changed for consistency
11 References
Added references for new 
Added new references

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Section # and Name
Description of Change
Brief Rationale
appendix 
12 Appendices
Removed text in Table 7 in 
Appendix: Recommended 
Corticosteroid Taper Schedule 
Updated timing from Week 64 
to Week 52 in Appendix: Study 
Goverance, Committee 
Structure
Added ACR Criteria for SLE 
Update appendix for Country-
specific Requirements. 
Removed text added in error
Changed for consistency
Added new appendix for clarity.
Adedd cross-reference for 
country-specific amendments for 
Korea, Germany, and Argentina.
Throughtout protocol
Minor editorial and document 
formatting revisions
Added for clarity
Amendment 01/ARG-1 -02-JUL-2018
Overall Rationale for the Amendment: The purpose of this amendment is to support 
country-specific requirements and amendments for Argentina.
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities (SoA), Table 2 and 
Table 4
Include requirement for 
monthly pregnancy testing 
during study year 2.
Country specific requirement for 
Argentina
Section 9.1: Screening 
Assessment - Pregnancy 
Test
Include reference to additional  
pregnancy tests during study 
year 2.
Country specific requirement for 
Argentina
Amendment 01/DEU-2 27-NOV-2017
Overall Rationale for the Amendment: The purpose of this amendment is to support 
country-specific requirements for Germany.
Section # and Name
Description of Change
Brief Rationale
6.1 Inclusion criteria
Deleted oral 
cyclosphosphamide as an 
allowed medication in the list of 
concomitant medications
Country specific requirement for 
Germany
7.7.1.4 Other 
Immunosuppresant Agents
Deleted oral 
cyclophosphamide, 
2.5 mg/kg/day from the list of 
common allowable maximum 

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Section # and Name
Description of Change
Brief Rationale
doses at baseline and during 
the study
6.2 Exclusion criteria
Added oral cyclophosphamide 
within 60 days of Day 1 to the 
relevant prior/concomitant 
therapy exclusion criterion 
Country specific requirement for 
Germany
7.7.2 Prohibited Medications 
and Non-Drug Therapies
Added oral cyclophosphamide 
to list of medications prohibited 
at any time during the study
Amendment 01/DEU-1 23-OCT-2017
Overall Rationale for the Amendment: The purpose of this amendment is to support 
country-specific requirements for Germany.
Section # and Name
Description of Change
Brief Rationale
3.3.1 Risk Assessment, 
Mitigation Strategy
6.2 Exclusion criteria
Exclusion criterion for subjects 
with hypogammaglobulinemia 
changed from IgG <250 mg/dL 
to IgG <400 mg/dL
Country specific requirement for 
Germany
8.2 Discontinuation of Study 
Treatment
Appendix 3, Contraceptive 
Guidance and Collection of 
Pregnancy Information
Clarification that women should 
not breastfeed while treated 
with rituximab and for 
12 months following rituximab 
treatment.
Consistent with recommendation 
from rituximab EU SmPC
Amendment 01/KOR-1 22-JUN-2017
Overall Rationale for the Amendment: The purpose of this amendment is to support 
country-specific requirements and amendments for South Korea.
Section # and Name
Description of Change
Brief Rationale
Appendix 11
Include IP label, additional 
clarification about the inclusion 
criteria age as per local 
regulations, provide details of 
IPs supplied for South Korea
Country specific requirement for 
South Korea
Amendment 01 (Global) 17-APR-2017

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Overall Rationale for the Amendment: GSK received additional comments and 
feedback from EMA and FDA and incorporated the recommendations in
Amendment 1. In addition, further changes and updates were identified by the 
study team and incorporated in Amendment 1.
Section # and Name
Description of Change
Brief Rationale
1 Synopsis Number of 
Participants
5.2 Number of Participants
Adding language to allow for 
randomization of additional 
subjects
Account for early dropout rate 
and provide sufficient exposure 
in Arms A and B for safety 
assessment
6.2 Exclusion Criteria
New criterion: History of 
anaphylactic reaction to 
parenteral administration of 
contrast agents, human or 
murine proteins or monoclonal 
antibodies 
Consistent criteria in subjects 
receiving biological products
7.4 Blinding
Updated text for unblinding by 
the Investigator
For consistency with updates to 
GSK required language
7.4 Blinding 
10.1.1 Analysis for Marketing 
Application
Initial database lock (DBL) has 
been changed to week 64 
Address the data analysis 
request by EMA. DBL will 
include the initial 52 week 
double-blind phase (Primary 
Endpoint)
8.2 Discontinuation of Study 
Treatment
Updated the third bullet –
Pregnancy will require study 
treatment withdrawal and 
requirement for pregnancy 
testing for rituximab 52 week 
post last dose.  
Clarification
7.7.1.3 Corticosteroids for 
Reasons Other Than SLE 
Disease Activity
Change corticosteroid dose 
from 100 mg/day to 60 mg/day 
for 2-3 days 
FDA recommendation to 
minimize confounding effects of 
high dose corticosteroids
2 Schedule of Activities 
(Table 1-Table 4)
Update definition and 
organization of the tables
Add clarity and consistency with 
study procedures, add missing 
information
9.6.1 Patient-Reported 
Outcomes Assessments
Update information about the 
assessment scales.
Add clarifying information 
regarding the scales
9.13.3 B Cell Receptors
Add more blood sample 
collection times to match those 
for the B Cell analysis
Required in order to obtain 
absolute numbers of B Cell 
subsets and relative values to all 
B Cells.
10.4.1 Efficacy Analyses
Definition of Clinical SLEDAI-
2K
Clarification

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Section # and Name
Description of Change
Brief Rationale
10.4.3 Other Analyses
Reference to Efficacy Analysis 
(Other)
Add missing information
10.4.4 Interim Analyses
Update safety review timeline 
and processes
Review processes consistent 
with other belimumab studies 
and per changes approved by 
IDMC
12 Appendices
Common corticosteroid dose 
and prednisone-equivalent 
multiplier table
Add supporting information 
Liver safety study treatment 
restart text updated as per 
updates to GSK guidelines
Change made as per updates to 
GSK guidelines
11 Reference
References for new appendix 
Add new references
Global changes
Change naming convention of 
‘Exit’ visit to ‘Early Withdrawal’ 
visit; 
Replace rituximab 
premedication “analgesia” with 
“acetaminophen or equivalent”;  
More accurate description