Clinical trial NCT03312907
Conditions: Systemic Lupus Erythematosus
Keywords: immunosuppressants Systemic Lupus Erythematosus Disease Activity Index Belimumab Lupus Low Disease Activity State Systemic Lupus Erythematosus
Sponsor: GlaxoSmithKline
Start date: 2018-03-01; Completion date: 2021-07-07
Enrollment: 292 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess whether co-administration of belimumab and a single cycle of rituximab will optimize treatment with belimumab, which will result in improvements of clinical status with a favorable safety profile, by comparing subjects randomized to belimumab plus rituximab versus belimumab plus rituximab-placebo. Approximately 292 subjects will be randomized in a 1:2:1 ratio 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). Belimumab will be administered as subcutaneous (SC) and rituximab-placebo or rituximab will be administered by intravenous (IV) infusions. The total duration of the study is for 104 weeks.

Detailed description:

Arms: arm 1: Eligible subjects will receive Belimumab 200 milligrams (mg) to be administered subcutaneously (SC) on Day 1 and then weekly (i.e., every 7 days) through Week 52. Subjects will also receive rituximab-placebo to be administered by intravenous (IV) infusions at Weeks 4 and 6 in double blind manner. Subjects will receive standard therapy excluding Immunosuppressants and including anti-malarials, non-steroidal anti-inflammatory drugs (NSAIDs), and/or corticosteroids tapered down to prednisone equivalent of less than or equal to (\<=) 5 mg/day until Week 104. Subjects will not receive treatment after 52 weeks and will be in observation until Week 104. arm 2: Eligible subjects will receive Belimumab 200 mg to be administered SC on Day 1 and then weekly (i.e., every 7 days) through Week 52. Subjects will also receive rituximab 1000 mg to be administered by IV infusions at Weeks 4 and 6 in double blind manner. Subjects will receive standard therapy excluding Immunosuppressants and including anti-malarials, NSAIDs, and/or corticosteroids tapered down to prednisone equivalent of \<= 5 mg/day until Week 104. Subjects will not receive treatment after 52 weeks and will be in observation until Week 104. arm 3: Eligible subjects will receive open-label Belimumab 200 mg administered SC on Day 1 and then weekly (i.e., every 7 days) until Week 104. Subjects will also receive standard therapy including immunosuppressant, anti-malarials, NSAIDs, and/or corticosteroids tapered down to prednisone equivalent of \<= 5 mg/day until Week 104.
Interventions: intervention 1: Belimumab intervention 2: Rituximab intervention 3: Rituximab-placebo intervention 4: Standard therapy (Including Immunosuppressants) intervention 5: Standard therapy (Excluding Immunosuppressants) intervention 6: Steroid Taper
Intervention descriptions: intervention 1: Belimumab will be administered as SC injection once weekly via autoinjector in thigh or abdomen intervention 2: Rituximab will be administered as IV infusion of 1000mg at Week 4 and Week 6 intervention 3: Saline will be administered as IV infusions at Week 4 and Week 6 intervention 4: Standard therapy will contain stable SLE medications including immunosuppressant to be administered from baseline through Week 104. intervention 5: Standard therapy excluding Immunosuppressant will contain anti-malarials, NSAIDs, and/or corticosteroids with prednisone dose equivalent to \<= 5 mg/day will administered through Week 104. intervention 6: Steroid taper will include prednisone doses equivalent to =\< 5 mg/day in all Arms through Week 104.

Protocol documents:
Prot_000.pdf: 
2016N272781_11
CONFIDENTIAL
GlaxoSmithKline group of companies
205646
1
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


2016N272781_11
CONFIDENTIAL
205646
3
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.


2016N272781_11
CONFIDENTIAL
205646
4
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.


2016N272781_11
CONFIDENTIAL
205646
5
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.


2016N272781_11
CONFIDENTIAL
205646
6
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.


2016N272781_11
CONFIDENTIAL
205646
7
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


2016N272781_11
CONFIDENTIAL
205646
8
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


2016N272781_11
CONFIDENTIAL
205646
9
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


2016N272781_11
CONFIDENTIAL
205646
10
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 


2016N272781_11
CONFIDENTIAL
205646
11
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 


2016N272781_11
CONFIDENTIAL
205646
12
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 


2016N272781_11
CONFIDENTIAL
205646
13
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 


2016N272781_11
CONFIDENTIAL
205646
14
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


2016N272781_11
CONFIDENTIAL
205646
15
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 


2016N272781_11
CONFIDENTIAL
205646
16
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 


2016N272781_11
CONFIDENTIAL
205646
17
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 


2016N272781_11
CONFIDENTIAL
205646
18
will be made to ascertain survival status at approximately 52 and 104 weeks after the first 
dose of study treatment.


2016N272781_11
CONFIDENTIAL
205646
19
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


2016N272781_11
CONFIDENTIAL
205646
20
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


2016N272781_11
CONFIDENTIAL
205646
21
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)


2016N272781_11
CONFIDENTIAL
205646
22
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.


2016N272781_11
CONFIDENTIAL
205646
23
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


2016N272781_11
CONFIDENTIAL
205646
24
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


2016N272781_11
CONFIDENTIAL
205646
25
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 


2016N272781_11
CONFIDENTIAL
205646
26
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.


2016N272781_11
CONFIDENTIAL
205646
27
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


2016N272781_11
CONFIDENTIAL
205646
28
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


2016N272781_11
CONFIDENTIAL
205646
29
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


2016N272781_11
CONFIDENTIAL
205646
30
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.


2016N272781_11
CONFIDENTIAL
205646
31
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


2016N272781_11
CONFIDENTIAL
205646
32
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


2016N272781_11 
CONFIDENTIAL
205646
33 
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.


2016N272781_11
CONFIDENTIAL
205646
34
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.


2016N272781_11
CONFIDENTIAL
205646
35
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-


2016N272781_11
CONFIDENTIAL
205646
36
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.


2016N272781_11
CONFIDENTIAL
205646
37
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 


2016N272781_11
CONFIDENTIAL
205646
38
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 


2016N272781_11
CONFIDENTIAL
205646
39
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 


2016N272781_11
CONFIDENTIAL
205646
40
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.


2016N272781_11
CONFIDENTIAL
205646
41
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.


2016N272781_11
CONFIDENTIAL
205646
42
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.


2016N272781_11
CONFIDENTIAL
205646
43
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.


2016N272781_11
CONFIDENTIAL
205646
44
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 


2016N272781_11
CONFIDENTIAL
205646
45
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 


2016N272781_11
CONFIDENTIAL
205646
46
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 


2016N272781_11
CONFIDENTIAL
205646
47
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 


2016N272781_11
CONFIDENTIAL
205646
48
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)


2016N272781_11
CONFIDENTIAL
205646
49
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


2016N272781_11
CONFIDENTIAL
205646
50
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.


2016N272781_11
CONFIDENTIAL
205646
51
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.


2016N272781_11
CONFIDENTIAL
205646
52
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.


2016N272781_11
CONFIDENTIAL
205646
53
Figure 1
Study Schematic


2016N272781_11
CONFIDENTIAL
205646
54
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-


2016N272781_11
CONFIDENTIAL
205646
55
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.


2016N272781_11
CONFIDENTIAL
205646
56
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).


2016N272781_11
CONFIDENTIAL
205646
57
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. 


2016N272781_11
CONFIDENTIAL
205646
58
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.


2016N272781_11
CONFIDENTIAL
205646
59
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.)


2016N272781_11
CONFIDENTIAL
205646
60

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.


2016N272781_11
CONFIDENTIAL
205646
61
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


2016N272781_11
CONFIDENTIAL
205646
62
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).


2016N272781_11
CONFIDENTIAL
205646
63
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).


2016N272781_11
CONFIDENTIAL
205646
64
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 


2016N272781_11
CONFIDENTIAL
205646
65
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.


2016N272781_11
CONFIDENTIAL
205646
66

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 


2016N272781_11
CONFIDENTIAL
205646
67
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 


2016N272781_11
CONFIDENTIAL
205646
68
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 


2016N272781_11
CONFIDENTIAL
205646
69
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.


2016N272781_11
CONFIDENTIAL
205646
70
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.


2016N272781_11
CONFIDENTIAL
205646
71
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 


2016N272781_11
CONFIDENTIAL
205646
72
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.


2016N272781_11
CONFIDENTIAL
205646
73
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 


2016N272781_11
CONFIDENTIAL
205646
74
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


2016N272781_11
CONFIDENTIAL
205646
75

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.


2016N272781_11
CONFIDENTIAL
205646
76
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.


2016N272781_11
CONFIDENTIAL
205646
77
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.


2016N272781_11
CONFIDENTIAL
205646
78

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 


2016N272781_11
CONFIDENTIAL
205646
79
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)


2016N272781_11
CONFIDENTIAL
205646
80

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 


2016N272781_11
CONFIDENTIAL
205646
81
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.


2016N272781_11
CONFIDENTIAL
205646
82
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


2016N272781_11
CONFIDENTIAL
205646
83
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


2016N272781_11
CONFIDENTIAL
205646
84
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 


2016N272781_11
CONFIDENTIAL
205646
85
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 


2016N272781_11
CONFIDENTIAL
205646
86
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 


2016N272781_11
CONFIDENTIAL
205646
87
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.


2016N272781_11
CONFIDENTIAL
205646
88
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. 


2016N272781_11
CONFIDENTIAL
205646
89

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 


2016N272781_11
CONFIDENTIAL
205646
90
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).


2016N272781_11
CONFIDENTIAL
205646
91
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).


2016N272781_11
CONFIDENTIAL
205646
92
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 


2016N272781_11
CONFIDENTIAL
205646
93
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 


2016N272781_11
CONFIDENTIAL
205646
94
(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 


2016N272781_11
CONFIDENTIAL
205646
95
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 


2016N272781_11
CONFIDENTIAL
205646
96
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;


2016N272781_11
CONFIDENTIAL
205646
97
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. 


2016N272781_11
CONFIDENTIAL
205646
98
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.


2016N272781_11
CONFIDENTIAL
205646
99
11.
REFERENCES
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. 
Development and validation of a disease-specific health-related quality of life measure, 


2016N272781_11
CONFIDENTIAL
205646
100
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.


2016N272781_11
CONFIDENTIAL
205646
101
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


2016N272781_11
CONFIDENTIAL
205646
102
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


2016N272781_11
CONFIDENTIAL
205646
103
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.


2016N272781_11
CONFIDENTIAL
205646
104
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.


2016N272781_11
CONFIDENTIAL
205646
105
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.


2016N272781_11
CONFIDENTIAL
205646
106
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.


2016N272781_11
CONFIDENTIAL
205646
107

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.


2016N272781_11
CONFIDENTIAL
205646
108
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 


2016N272781_11
CONFIDENTIAL
205646
109
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).


2016N272781_11
CONFIDENTIAL
205646
110
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 
written notification to the sponsor. 


2016N272781_11
CONFIDENTIAL
205646
111
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


2016N272781_11
CONFIDENTIAL
205646
112
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 


2016N272781_11
CONFIDENTIAL
205646
113
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)


2016N272781_11
CONFIDENTIAL
205646
114
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. 


2016N272781_11
CONFIDENTIAL
205646
115
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. 


2016N272781_11
CONFIDENTIAL
205646
116
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 


2016N272781_11
CONFIDENTIAL
205646
117
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


2016N272781_11
CONFIDENTIAL
205646
118
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 


2016N272781_11
CONFIDENTIAL
205646
119
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 


2016N272781_11
CONFIDENTIAL
205646
120
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.


2016N272781_11
CONFIDENTIAL
205646
121
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.


2016N272781_11
CONFIDENTIAL
205646
122
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


2016N272781_11
CONFIDENTIAL
205646
123
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.


2016N272781_11
CONFIDENTIAL
205646
124
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, 


2016N272781_11
CONFIDENTIAL
205646
125
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)


2016N272781_11
CONFIDENTIAL
205646
126
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.


2016N272781_11
CONFIDENTIAL
205646
127
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.


2016N272781_11
CONFIDENTIAL
205646
128
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.


2016N272781_11
CONFIDENTIAL
205646
129
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.


2016N272781_11
CONFIDENTIAL
205646
130
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.


2016N272781_11
CONFIDENTIAL
205646
131
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


2016N272781_11
CONFIDENTIAL
205646
132
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 


2016N272781_11
CONFIDENTIAL
205646
133
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


2016N272781_11
CONFIDENTIAL
205646
134
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 


2016N272781_11
CONFIDENTIAL
205646
135
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


2016N272781_11
CONFIDENTIAL
205646
136
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.


2016N272781_11
CONFIDENTIAL
205646
137
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.


2016N272781_11
CONFIDENTIAL
205646
138
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 


2016N272781_11
CONFIDENTIAL
205646
139
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


2016N272781_11
CONFIDENTIAL
205646
140
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


2016N272781_11
CONFIDENTIAL
205646
141
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 


2016N272781_11
CONFIDENTIAL
205646
142
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


2016N272781_11
CONFIDENTIAL
205646
143
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


2016N272781_11
CONFIDENTIAL
205646
144
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

SAP_001.pdf: 
0 
 
 
 
Statistical Analysis Plan 
Study ID:  205646 
Official Title of Study:  Reporting and Analysis Plan Addendum 2 for 205646, 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) 
Date of Document: 22-JUL-2021 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205646 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan Addendum 2 
Title 
: Reporting and Analysis Plan Addendum 2 for 205646, 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) 
Compound Number  
: GSK1550188 
Effective Date  
: Refer to Document Date 
Description: 
• This second RAP addendum is supplemental to the RAP (Dated: 
05/AUG/2020), and the first RAP addendum (Dated: 08/OCT/2020). 
• It is based on protocol amendment 04 (Dated: 30/APR/2020) of study 205646. 
• The main purpose of this addendum is to list an abridged set of outputs that will 
be produced for the final study report.  These changes are being made following 
the first database lock and primary analyses at the end of Year 1 of the study.  
 
 
Author(s) 
Author  
Approval Method 
Principal Statistician (Immunology Biostatistics) 
eTMF 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
PPD


 
CONFIDENTIAL 
 
 
 
205646 
2 
 
RAP Team Confirmations: 
Reviewer 
Approval Method 
E-mail filed in eTMF 
Statistics Leader (Immunology Biostatistics) 
E-mail filed in eTMF 
Programming Leader (Immunology Programming) 
E-mail filed in eTMF 
Medical Monitor (Immunology Clinical Development) 
 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Approval Method 
eTMF 
Statistics Leader (Immunology Biostatistics) 
Programming Leader (Immunology Programming) 
eTMF 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205646 
3 
 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ........................................................................................................... 4 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
CHANGES/CLARIFICATIONS TO THE RAP ........................................................... 5 
2.1. 
Modifications to the planned list of outputs for the end of study 
analyses ....................................................................................................... 5 
2.1.1. 
Study Population Tables ................................................................ 6 
2.1.2. 
Study Population Figures ............................................................... 8 
2.1.3. 
Study Population Listings ............................................................... 8 
2.1.4. 
Efficacy Tables .............................................................................. 9 
2.1.5. 
Efficacy Figures ........................................................................... 13 
2.1.6. 
Efficacy Listings ........................................................................... 14 
2.1.7. 
Safety Tables ............................................................................... 14 
2.1.8. 
Safety Figures ............................................................................. 19 
2.1.9. 
Safety Listings ............................................................................. 19 
2.1.10. 
Health Outcomes Tables ............................................................. 21 
2.1.11. 
Health Outcomes Figures ............................................................ 21 
2.1.12. 
Health Outcomes Listings ............................................................ 22 
2.1.13. 
Biomarkers Tables ....................................................................... 22 
2.1.14. 
Biomarkers Figures ...................................................................... 24 
2.1.15. 
Biomarkers Listings ..................................................................... 24 
2.1.16. 
Pharmacokinetic Tables ............................................................... 25 
2.1.17. 
Pharmacokinetic Figures ............................................................. 25 
2.1.18. 
Pharmacokinetic Listings ............................................................. 25 
2.2. 
New ‘Intent-to-Treat Year 2’ Population ...................................................... 26 
2.3. 
Biomarker and Pharmacokinetic (PK) ......................................................... 26 
2.3.1. 
Specifications in the original RAP ................................................ 26 
2.3.2. 
Clarifications for the Year 2 reporting ........................................... 26 
 


 
CONFIDENTIAL 
 
 
 
205646 
4 
 
ABBREVIATIONS 
 
 
Abbreviation 
Description 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
anti-dsDNA 
Anti-double-stranded DNA 
ATC 
Anatomical, Therapeutic, Clinical 
BLyS 
B-Lymphocyte Stimulator 
COVID-19 
Coronavirus Disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue Scale 
GSK 
GlaxoSmithKline 
IBA 
Independent Blinded Assessor 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
IV 
Intravenous 
LLDAS 
Lupus Low Disease Activity State 
LSLV 
Last Subject Last Visit 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-To-Treat 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PISR 
Post-Injection Systemic Reactions 
PK 
Pharmacokinetic 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
RAP 
Reporting and Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SLE 
Systemic Lupus Erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
SOC 
System Organ Class 
TF 
Treatment Failure 
WPAI 
Work Productivity and Activity Impairment Questionnaire 


 
CONFIDENTIAL 
 
 
 
205646 
5 
 
1. 
INTRODUCTION 
This RAP addendum is supplemental to the RAP (Dated: 05/AUG/2020), and the first 
RAP addendum (Dated: 08/OCT/2020).  It is based on protocol amendment 04 (Dated: 
30/APR/2020) of study 205646. 
The main purpose of this addendum is to list an abridged set of outputs that will be 
produced for the final study report.  These changes are being made following the first 
database lock and primary analyses at the end of Year 1 of the study.  
 
2. 
CHANGES/CLARIFICATIONS TO THE RAP 
2.1. 
Modifications to the planned list of outputs for the end of 
study analyses 
As specified in the original RAP (Section 3.2), there are two database locks for this study, 
corresponding to the primary analyses and the end of study analyses.   
• The primary analyses would include data up to the 52 week visit for the primary 
endpoint. 
• The final analyses would be conducted following the last subject completion of 
year 2 (including all 8 week-follow-up visits). 
The original RAP (Section 3.2) had the following text: “This RAP details the planned 
analysis for both database locks, with the expectation of an observed treatment benefit at 
Week 52.  If the Week 52 reporting does not identify a treatment benefit, an abridged set 
of analysis may be conducted at the end of the study, which will be detailed in a RAP 
amendment or RAP addendum.”. 
Following the results of the primary analyses, an abridged set of outputs will be produced 
and these are detailed below. 
 


CONFIDENTIAL 
 
 
205646 
6 
 
2.1.1. 
Study Population Tables 
Study Population Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Subject Disposition 
21.01.  
21.01 
Screened 
Study Populations (Year 1&2) 
 
21.02.  
21.02 
ITT 
Subject Status (Year 1&2) 
 
21.03.  
21.04 
ITT 
Subject Status and Reason for Study Withdrawal (Year 1&2) 
 
21.04.  
21.05 
ITT 
Time to Withdrawal from the Study (Year 1&2) 
 
21.05.  
21.06 
ITT 
Treatment Status and Reasons for Discontinuing Belimumab SC 
Study Treatment (Year 1&2) 
 
21.06.  
21.07 
ITT 
Time to Belimumab SC Study Treatment Discontinuation [1] (Year 
1&2) 
 
Protocol Deviations 
21.07.  
21.09 
ITT Year 2 
Important Protocol Deviations after Week 52 (Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
Concomitant Medications 
21.08.  
21.11 
ITT Year 2 
Concomitant Medications by ATC Level 1 and ATC Level 4 Term 
(Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
21.09.  
21.13 
ITT 
First Medication Usage Resulting in Treatment Failure Designation  
(Year 1&2) 
 
Extent of Exposure 
21.10.  
21.14 
ITT 
Exposure to Belimumab SC (Study Treatment and Re-start [1]) 
(Year 1&2) 
 


CONFIDENTIAL 
 
 
205646 
7 
 
Study Population Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
21.11.  
21.15 
ITT Year 2 
Exposure to Belimumab SC [1] (Arms A&B: Re-start; Arm C: Study 
Treatment) (Year 2) 
• Belimumab doses that occur up to and 
including the Week 52 visit date are included 
as Year 1 doses.  Belimumab doses that 
occur after the Week 52 visit date are 
included as Year 2 doses.  This was 
incorrect in the original RAP Section 6.5. 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
Coronavirus Disease 2019 (COVID-19) Pandemic 
21.12.  
NEW 
ITT 
COVID-19 Pandemic Visit Impacts (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
21.13.  
NEW 
ITT 
Reason for Study Withdrawal by Relationship to COVID-19 
Pandemic (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
21.14.  
NEW 
ITT 
Reasons for Discontinuing Belimumab SC Study Treatment by 
Relationship to COVID-19 Pandemic (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
21.15.  
NEW 
ITT 
Important Protocol Deviations by Relationship to COVID-19 
Pandemic (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
 


CONFIDENTIAL 
 
 
205646 
8 
 
2.1.2. 
Study Population Figures 
Study Population Figures 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Subject Disposition 
21.01.  
21.01 
ITT 
Time to Withdrawal from Study (Year 1&2) 
 
21.02.  
21.02 
ITT 
Time to Belimumab SC Study Treatment Discontinuation (Year 1&2)  
COVID-19 Pandemic 
21.03.  
NEW 
ITT 
Visits Impacted by COVID-19 Pandemic (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
 
2.1.3. 
Study Population Listings 
Study Population Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Subject Disposition 
21.01.  
21.01 
Randomized 
Subject Disposition (Year 1&2) 
 
21.02.  
21.02 
Randomized 
Reasons for Study Withdrawal (Year 1&2) 
 
21.03.  
21.03 
Randomized 
Reasons for Belimumab SC Study Treatment Discontinuation (Year 
1&2) 
 
Protocol Deviations 
21.04.  
21.04 
Randomized 
Important or COVID-19 Protocol Deviations (Year 1&2) 
 
Concomitant Medications 
21.05.  
21.06 
Randomized 
Concomitant Medications (Year 2) 
 


CONFIDENTIAL 
 
 
205646 
9 
 
Study Population Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
21.06.  
21.07 
Randomized 
Medications that Result in Treatment Failure Designation (Year 2) 
 
Extent of Exposure 
21.07.  
21.08 
Randomized 
Study Treatment Administration (Year 1&2) 
 
COVID-19 Pandemic 
21.08.  
21.09 
Randomized 
Country Level Listing of Dates of Waves of COVID-19 Pandemic 
Measures 
 
21.09.  
NEW 
Randomized 
All Subjects with Visits and Assessments Impacted by COVID-19 
Pandemic (Year 1&2) 
• New output (recommended in GSK COVID-
19 guidance document) 
 
2.1.4. 
Efficacy Tables 
Efficacy Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Clinical Remission 
22.01.  
22.01 
MITT 
Clinical Remission (IBA) at Week 64 (Hybrid) 
 
22.02.  
22.02 
MITT 
Logistic Regression Analysis of Clinical Remission (IBA) at Week 64 
(Hybrid) 
 
22.03.  
22.03 
MITT 
Disposition of Clinical Remission (IBA) at Week 64 (Hybrid) 
 
22.04.  
NEW 
MITT 
Disposition of Clinical Remission (IBA) by First Reason for Non-
Response at Week 64 (Hybrid) 
• New output (omission in original RAP) 


CONFIDENTIAL 
 
 
205646 
10 
 
Efficacy Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
22.05.  
22.04 
MITT 
Clinical Remission (IBA) and its Components at Week 64 (Hybrid) 
• The planned component for ‘Corticosteroid 
>0 to <=5mg/day’ has been modified to 
match the actual component of the endpoint, 
i.e. “Corticosteroids at a prednisone 
equivalent dose of 0 mg/day” 
22.06.  
NEW 
MITT 
Clinical Remission (IBA) and its Components by Baseline C3/C4 
Level & Anti-dsDNA at Week 64 (Hybrid) 
• New output (key subgroup of interest) 
• The planned component for ‘Corticosteroid 
>0 to <=5mg/day’ has been modified to 
match the actual component of the endpoint, 
i.e. “Corticosteroids at a prednisone 
equivalent dose of 0 mg/day” 
22.07.  
22.08 
MITT 
Clinical Remission (IBA) by Visit (Hybrid) (Year 2) 
 
22.08.  
22.09 
MITT 
Clinical Remission (PI) by Visit (Hybrid) (Year 2) 
 
22.09.  
22.25 
MITT 
Duration of Clinical Remission (PI) (Hybrid) (Year 1&2) 
 
22.10.  
22.20 
MITT 
Clinical Remission (PI) Sustained for at least 24 Weeks by Visit 
(Hybrid) (Year 2) 
 
22.11.  
22.33 
MITT 
Time to Clinical Remission (PI) Sustained for at least 24 weeks and 
maintained through to Week 104 [1] (Hybrid) 
 
Disease Control 
22.12.  
22.10 
MITT 
Disease Control (IBA) at Week 104 (Hybrid) 
 
22.13.  
22.11 
MITT 
Logistic Regression Analysis of Disease Control (IBA) at Week 104 
(Hybrid) 
 
22.14.  
22.12 
MITT 
Disposition of Disease Control (IBA) at Week 104 (Hybrid) 
 
22.15.  
NEW 
MITT 
Disposition of Disease Control (IBA) by First Reason for Non-
Response at Week 104 (Hybrid) 
• New output (omission in original RAP) 


CONFIDENTIAL 
 
 
205646 
11 
 
Efficacy Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
22.16.  
22.13 
MITT 
Disease Control (IBA) and its Components at Week 104 (Hybrid) 
 
22.17.  
NEW 
MITT 
Disease Control (IBA) and its Components by Baseline C3/C4 Level 
& Anti-dsDNA at Week 104 (Hybrid) 
• New output (key subgroup of interest) 
22.18.  
22.17 
MITT 
Disease Control (IBA) by Visit (Hybrid) (Year 1&2) 
 
22.19.  
22.18 
MITT 
Disease Control (PI) by Visit (Hybrid) (Year 1&2) 
 
22.20.  
NEW 
MITT 
Duration of Disease Control (PI) (Hybrid) (Year 1&2) 
• New output (omission in orginal RAP) 
22.21.  
22.24 
MITT 
Time to Disease Control (PI) Sustained for at least 24 weeks and 
maintained through to Week 104 [1] (Hybrid) 
 
Complete Remission 
22.22.  
22.21 
MITT 
Complete Remission (PI) by Visit (Hybrid) (Year 2) 
 
22.23.  
22.19 
MITT 
Complete Remission (PI) Sustained for at Least 24 Weeks by Visit 
(Hybrid) (Year 2) 
 
Flares 
22.24.  
22.22 
MITT 
Time to First Severe Flare (Treatment Policy, TF=Severe Flare) 
(Year 1&2) (Modified SLE Flare Index) 
 
22.25.  
NEW 
MITT 
Time to First Severe Flare (Treatment Policy) (Year 1&2) (Modified 
SLE Flare Index) 
• New output (of interest following post SAC 
request for Year 1) 
• Treatment Failures are not included as 
severe flares 
22.26.  
22.23 
MITT 
Time to First Flare (Treatment Policy, TF=Flare) (Year 1&2) 
(Modified SLE Flare Index) 
 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) 
22.27.  
22.26 
MITT 
SLEDAI-2K (PI) - Change from Baseline by Visit (Hypothetical) 
(Year 1&2) 
 


CONFIDENTIAL 
 
 
205646 
12 
 
Efficacy Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
22.28.  
22.27 
MITT 
SLEDAI-2K (PI) - Organ System Improvement by Organ System 
and Visit Among Subjects with Organ System Involvement at 
Baseline [1] (Treatment Policy) (Year 1&2) 
 
22.29.  
22.28 
MITT 
SLEDAI-2K (PI) - Organ System Worsening by Organ System and 
Visit Among Subjects with No Organ System Involvement at 
Baseline [1] (Observed) (Year 1&2) 
 
Physician Global Assessment (PGA) 
22.30.  
22.29 
MITT 
Physician Global Assessment (PGA) - Change from Baseline by 
Visit (Hypothetical) (Year 1&2) 
 
Systemic Lupus International Collaborating Clinics (SLICC) 
22.31.  
22.30 
MITT 
SLICC/ACR Damage Index Worsening (Change>0) Compared with 
Baseline at Week 104 (Treatment Policy, WOCF) 
 
Lupus Low Disease Activity State (LLDAS) 
22.32.  
22.31 
MITT 
Lupus Low Disease Activity State (LLDAS) (PI) by Visit (Treatment 
Policy) (Year 1&2) 
 
22.33.  
22.32 
MITT 
Lupus Low Disease Activity State (LLDAS) (PI) and its Components 
at Weeks 52, 64 and 104 (Treatment Policy) (Year 1&2) 
 
Modified Disease Control 
22.34.  
22.39 
MITT 
SLEDAI-2K Score <=2 (IBA), Without Current 
Immunosuppressants, Without Current Belimumab dosing (Arms A 
& B) and Corticosteroids dose <=5mg/day at Week 104 (COVID-19 
Modified, Treatment Policy) 
 
Proteinuria 
22.35.  
NEW 
ITT 
Proteinuria Shifts from Baseline by Visit (Observed) (Year 1&2) 
• New output (of interest following post SAC 
request for Year 1) 


CONFIDENTIAL 
 
 
205646 
13 
 
2.1.5. 
Efficacy Figures 
Efficacy Figures 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Efficacy Figures 
22.01.  
22.01 
MITT 
Clinical Remission (IBA) at Week 64 (Hybrid) 
 
22.02.  
22.03 
MITT 
Clinical Remission (PI) by Visit (Hybrid) (Year 2) 
 
22.03.  
22.04 
MITT 
Disease Control (IBA) at Week 104 (Hybrid) 
 
22.04.  
22.06 
MITT 
Time to First Severe Flare (Treatment Policy, TF=Severe Flare) 
(Year 1&2) (Modified SLE Flare Index) 
 
22.05.  
22.07 
MITT 
Time to First Flare (Treatment Policy, TF=Flare) (Year 1&2) 
(Modified SLE Flare Index) 
 
22.06.  
22.10 
MITT 
SLEDAI-2K (PI) - Change from Baseline by Visit (Observed) (Year 
1&2) 
 
22.07.  
22.11 
MITT 
Physician Global Assessment (PGA) - Change from Baseline by 
Visit (Observed) (Year 1&2) 
 
22.08.  
NEW 
ITT 
Proteinuria Shifts from High at Baseline to Normal by Visit 
(Observed) (Year 1&2) 
• New output (of interest following post SAC 
request for Year 1) 
 


CONFIDENTIAL 
 
 
205646 
14 
 
2.1.6. 
Efficacy Listings 
Efficacy Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Efficacy Listings 
22.01.  
22.01 
ITT 
Disease Control, Clinical Remission, and Complete Remission by 
Visit (Year 1&2) 
 
 
2.1.7. 
Safety Tables 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Adverse Events 
23.01.  
23.01 
ITT Year 2 
Adverse Events Summary - On Study (Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
23.02.  
23.02 
ITT 
Adverse Events Summary - On Study (Year 1&2) 
 
23.03.  
23.03 
ITT Year 2 
Adverse Events by SOC and PT - On Study (Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
23.04.  
23.04 
ITT 
Adverse Events by SOC and PT - On Study (Year 1&2) 
 
23.05.  
23.05 
ITT 
Adverse Events by PT - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.06.  
23.06 
ITT 
Study Treatment Related Adverse Events by SOC and PT – 
Belimumab Only [1] – On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.07.  
23.07 
ITT 
Study Treatment Related Adverse Events by SOC and PT – 
Rituximab Only [1] – On Study (Year 1&2) 
• Now presents data for Year 1&2 


CONFIDENTIAL 
 
 
205646 
15 
 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
23.08.  
23.08 
ITT 
Study Treatment Related Adverse Events by SOC and PT – Both 
Belimumab & Rituximab [1] – On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.09.  
NEW 
ITT 
Study Treatment Related Non-Serious Adverse Events by PT – 
Belimumab Only [1] – On Study (Year 1&2) 
• New output (required for Plain Language 
Summary) 
23.10.  
NEW 
ITT 
Study Treatment Related Non-Serious Adverse Events by PT – 
Rituximab Only [1] – On Study (Year 1&2) 
• New output (required for Plain Language 
Summary) 
23.11.  
NEW 
ITT 
Study Treatment Related Non-Serious Adverse Events by PT – 
Both Belimumab & Rituximab [1] – On Study (Year 1&2) 
• New output (required for Plain Language 
Summary) 
23.12.  
23.09 
ITT 
Adverse Events by SOC, PT and Maximum Severity – On Study 
(Year 1&2) 
• Now presents data for Year 1&2 
23.13.  
23.11 
ITT 
Adverse Events by SOC and PT and Race - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.14.  
23.13 
ITT 
Adverse Events by SOC and PT and Baseline C3/C4 Levels and 
Anti-dsDNA – On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.15.  
23.22 
ITT 
Adverse Events Leading to Permanent Discontinuation of Study 
Treatment by SOC and PT – Belimumab – On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.16.  
23.23 
ITT 
Common [1] Non-Serious Adverse Events by SOC and PT - On 
Study (Year 1&2) 
• Now presents data for Year 1&2 
Deaths and Serious Adverse Events 
23.17.  
23.18 
ITT 
Death by Category and PT - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.18.  
23.19 
ITT Year 2 
Serious Adverse Events by SOC and PT - On Study (Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
23.19.  
23.20 
ITT 
Serious Adverse Events by SOC and PT - On Study (Year 1&2) 
 
23.20.  
23.24 
ITT 
Study Treatment Related Serious Adverse Events by SOC and PT - 
Belimumab Only [1] - On Study (Year 1&2) 
• Now presents data for Year 1&2 


CONFIDENTIAL 
 
 
205646 
16 
 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
23.21.  
23.25 
ITT 
Study Treatment Related Serious Adverse Events by SOC and PT - 
Rituximab Only [1] - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.22.  
23.26 
ITT 
Study Treatment Related Serious Adverse Events by SOC and PT – 
Both Belimumab and Rituximab [1] - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.23.  
NEW 
ITT 
Study Treatment Related Serious Fatal and Non-Fatal Adverse 
Events by PT – Belimumab Only [1] - On Study (Year 1&2) 
• New output (required for Plain Language 
Summary) 
23.24.  
NEW 
ITT 
Study Treatment Related Serious Fatal and Non-Fatal Adverse 
Events by PT - Rituximab Only [1] - On Study (Year 1&2) 
• New output (required for Plain Language 
Summary) 
23.25.  
NEW 
ITT 
Study Treatment Related Serious Fatal and Non-Fatal Adverse 
Events by PT – Both Belimumab and Rituximab [1] - On Study 
(Year 1&2) 
• New output (required for Plain Language 
Summary) 
Survival Staus 
23.26.  
23.29 
ITT 
Survival Status at Week 104 
 
Adverse Events of Special Interest (AESI) 
23.27.  
23.30 
ITT Year 2 
Adverse Events of Special Interest by Category - On Study (Year 2) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
23.28.  
NEW 
ITT 
Adverse Events of Special Interest by Category - On Study (Year 
1&2) 
• New output (omission in original RAP) 
23.29.  
23.31 
ITT 
Malignant Neoplasm Adverse Events of Special Interest by 
Category and PT - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.30.  
23.32 
ITT 
Post Belimumab SC Injection Systemic Reactions Adverse Events 
of Special Interest by Category and PT - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.31.  
23.33 
ITT 
Serious Post Belimumab SC Injection Systemic Reactions Adverse 
Events of Special Interest by Category and PT - On Study (Year 
1&2) 
• Now presents data for Year 1&2 


CONFIDENTIAL 
 
 
205646 
17 
 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
23.32.  
23.34 
ITT 
Infection Adverse Events of Special Interest by Category and PT - 
On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.33.  
23.35 
ITT 
Infection Adverse Events of Special Interest Leading to Belimumab 
SC Study Treatment Discontinuation by Category and PT - On 
Study (Year 1&2) 
• Now presents data for Year 1&2 
23.34.  
23.36 
ITT 
Depression/Suicide/Self-injury Adverse Events of Special Interest 
by Category and PT - On Study (Year 1&2) 
• Now presents data for Year 1&2 
23.35.  
23.41 
ITT 
Adverse Events of Special Interest including Exposure-Adjusted 
Incidence Rates by Category – On Study (Year 1&2) 
• Now presents data for Year 1&2 
COVID-19 Pandemic Adverse Events 
23.36.  
23.42 
ITT 
Exposure Adjusted Incidence Rates of Adverse Events Over Time 
in Relation to COVID-19 Pandemic – On Study (Year 1&2) 
• Now presents data for Year 1&2 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
23.37.  
23.45 
ITT 
C-SSRS Suicidal Ideation or Behavior during On Study Period (Year 
1&2) 
• Now presents data for Year 1&2 
23.38.  
23.46 
ITT 
Treatment-Emergent C-SSRS Suicidal Ideation or Behavior On 
Study Relative to Pre-treatment (Year 1&2) 
• Now presents data for Year 1&2 
Laboratory Results 
23.39.  
23.50 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Hematology (Year 
1&2) 
• Now presents data for Year 1&2 
23.40.  
23.51 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Hematology (Year 1&2) 
• Now presents data for Year 1&2 
23.41.  
23.54 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Liver Function 
(Year 1&2) 
• Now presents data for Year 1&2 


CONFIDENTIAL 
 
 
205646 
18 
 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
23.42.  
23.55 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Liver Function (Year 1&2) 
• Now presents data for Year 1&2 
23.43.  
23.58 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Electrolytes (Year 
1&2) 
• Now presents data for Year 1&2 
23.44.  
23.59 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Electrolytes (Year 1&2) 
• Now presents data for Year 1&2 
23.45.  
23.62 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Other Chemistries 
(Year 1&2) 
• Now presents data for Year 1&2 
23.46.  
23.63 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Other Chemistries (Year 1&2) 
• Now presents data for Year 1&2 
23.47.  
23.65 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Urinalysis (Year 
1&2) 
• Now presents data for Year 1&2 
23.48.  
23.66 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Urinalysis (Year 1&2) 
• Now presents data for Year 1&2 
23.49.  
23.69 
ITT 
Worst Post-Baseline Laboratory Toxicity Grade: Immunoglobulins 
(Year 1&2) 
• Now presents data for Year 1&2 
23.50.  
23.70 
ITT 
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline: Immunoglobulins (Year 1&2) 
• Now presents data for Year 1&2 
23.51.  
23.71 
ITT 
Laboratory Reference Range Shifts from Baseline by Visit: 
Immunoglobulins (Year 1&2) 
• Now presents data for Year 1&2 
Immunogenicity 
23.52.  
23.76 
ITT 
Immunogenic Response to Belimumab SC by Visit (Year 1&2) 
• Now presents data for Year 1&2 
Vital Signs 
23.53.  
23.78 
ITT 
Vital Signs Change from Baseline by Visit (Observed) (Year 1&2) 
• Now presents data for Year 1&2 


CONFIDENTIAL 
 
 
205646 
19 
 
Safety Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Serious Adverse Events (additional outputs) 
23.54.  
NEW 
ITT Year 2 
Serious Adverse Events by SOC and PT - On Study (Year 2) 
• New output (formatting appropriate for CSR) 
• Use new ‘ITT Year 2’ Population defined in 
Section 2.2. 
23.55.  
NEW 
ITT 
Serious Adverse Events by SOC and PT - On Study (Year 1&2) 
• New output (formatting appropriate for CSR) 
 
2.1.8. 
Safety Figures 
There are no Safety Figures to produce. 
 
2.1.9. 
Safety Listings 
Safety Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Adverse Events 
23.01.  
23.02 
ITT 
Adverse Events (Year 2) 
 
23.02.  
23.03 
ITT 
Adverse Events Related to Belimumab SC (Year 2) 
 
23.03.  
23.05 
ITT 
Adverse Events Resulting in Belimumab SC Study Treatment 
Discontinuation (Year 2) 
 
23.04.  
23.07 
ITT 
Year 1 Adverse Events reported after LSLV (Year 1) 
 
23.05.  
23.08 
ITT 
Serious Adverse Events (Year 2) 
 


CONFIDENTIAL 
 
 
205646 
20 
 
Safety Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
23.06.  
23.11 
ITT 
Reasons for Considering as a Serious Adverse Event (Year 2) 
 
23.07.  
23.13 
ITT 
MedDRA coding changes (Year 2) 
 
Laboratory Results 
23.08.  
23.14 
ITT 
Laboratory Results: Hematology (Year 2) 
 
23.09.  
23.15 
ITT 
Laboratory Results: Liver Function (Year 2) 
 
23.10.  
23.16 
ITT 
Laboratory Results: Electrolytes (Year 2) 
 
23.11.  
23.17 
ITT 
Laboratory Results: Other Chemistries (Year 2) 
 
23.12.  
23.18 
ITT 
Laboratory Results: Urinalysis (Year 2) 
 
23.13.  
23.19 
ITT 
Laboratory Results: Immunoglobulins (Year 2) 
 
Immunogenicity 
23.14.  
23.26 
ITT 
Immunogenicity Results for Belimumab SC (Year 2) 
 
COVID-19 Pandemic 
23.15.  
23.27 
ITT 
COVID-19 Assessments and Symptom Assessments for Subjects 
with COVID-19 Adverse Events (Year 1&2) 
 


CONFIDENTIAL 
 
 
205646 
21 
 
2.1.10. 
Health Outcomes Tables 
Health Outcomes Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Health Outcome Tables 
24.01.  
24.01 
MITT 
Patient Global Assessment of Disease Activity Change from 
Baseline by Visit (Hypothetical) (Year 1&2) 
 
24.02.  
24.02 
MITT 
Lupus Quality of Life Domain Scores Change from Baseline by Visit 
(Hypothetical) (Year 1&2) 
 
24.03.  
24.03 
MITT 
FACIT-Fatigue Scale Score Change from Baseline by Visit 
(Hypothetical) (Year 1&2) 
 
24.04.  
24.04 
MITT 
Improvement in FACIT-Fatigue Scale Score exceeding the MCID 
(>=4 point increase) by Visit (Hypothetical) (Year 1&2) 
 
24.05.  
24.05 
MITT 
WPAI: Overall Work Productivity Impairment Change from Baseline 
by Visit (Hypothetical) (Year 1&2) 
 
24.06.  
24.06 
MITT 
WPAI: Percent Activity Impairment Score Change from Baseline by 
Visit (Hypothetical) (Year 1&2) 
 
 
2.1.11. 
Health Outcomes Figures 
Health Outcomes Figures 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Health Outcome Figures 
24.01.  
24.02 
MITT 
Lupus Quality of Life Domain Scores Change from Baseline by Visit 
(Observed) (Year 1&2) 
 


CONFIDENTIAL 
 
 
205646 
22 
 
Health Outcomes Figures 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
24.02.  
24.03 
MITT 
FACIT-Fatigue Scale Score Change from Baseline by Visit 
(Observed) (Year 1&2) 
 
24.03.  
24.04 
MITT 
Improvement in FACIT-Fatigue Scale Score Exceeding the MCID 
(>=4 points increase) by Visit (Observed) (Year 1&2) 
 
 
2.1.12. 
Health Outcomes Listings 
Health Outcomes Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Health Outcomes Listings 
24.01.  
24.04 
ITT 
Health Care Resource Utilization (Year 1&2) 
 
 
2.1.13. 
Biomarkers Tables 
Biomarkers Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Immunoglobulins 
25.01.  
25.02 
ITT 
Immunoglobulin Levels Change from Baseline by Visit among 
Subjects who Completed Week 52 On Treatment (Observed) (Year 
1&2) 
 


CONFIDENTIAL 
 
 
205646 
23 
 
Biomarkers Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
25.02.  
25.03 
ITT 
Immunoglobulin Levels Shifts from Baseline by Visit among 
Subjects who Completed Week 52 On Treatment (Observed) (Year 
1&2) 
 
Autoantibodies 
25.03.  
25.06 
ITT 
Autoantibody Levels Change from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
 
25.04.  
25.07 
ITT 
Autoantibody Levels Change from Baseline by Visit among Subjects 
Positive at Baseline who Completed Week 52 On Treatment 
(Observed) (Year 1&2) 
 
25.05.  
25.08 
ITT 
Autoantibody Levels Shifts from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
 
Complement 
25.06.  
25.11 
ITT 
Complement Levels Change from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
 
25.07.  
25.12 
ITT 
Complement Levels Change from Baseline by Visit among Subjects 
with Low Complement at Baseline who Completed Week 52 On 
Treatment (Observed) (Year 1&2) 
 
25.08.  
25.13 
ITT 
Complement Levels Shifts from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
 
B Cells, T Cells and B-Lymphocyte Stimulator 
25.09.  
25.15 
ITT 
B Cells, T Cells and B-Lymphocyte Stimulator Change from 
Baseline by Visit among Subjects who Completed Week 52 On 
Treatment (Observed) (Year 1&2) 
 


CONFIDENTIAL 
 
 
205646 
24 
 
2.1.14. 
Biomarkers Figures 
Biomarkers Figures 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Biomarker Figures 
25.01.  
NEW 
ITT 
Immunoglobulin Levels Change from Baseline by Visit among 
Subjects who Completed Week 52 On Treatment (Observed) (Year 
1&2) 
• New output (omission in original RAP) 
25.02.  
NEW 
ITT 
Autoantibody Levels Change from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
• New output (omission in original RAP) 
25.03.  
NEW 
ITT 
Complement Levels Change from Baseline by Visit among Subjects 
who Completed Week 52 On Treatment (Observed) (Year 1&2) 
• New output (omission in original RAP) 
25.04.  
NEW 
ITT 
B Cells, T Cells and B-Lymphocyte Stimulator Change from 
Baseline by Visit among Subjects who Completed Week 52 On 
Treatment (Observed) (Year 1&2) 
• New output (omission in original RAP) 
 
2.1.15. 
Biomarkers Listings 
Biomarkers Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
Biomarker Listings 
25.01.  
25.01 
ITT 
Biomarker Results (Year 1&2) 
 
25.02.  
25.02 
ITT 
B Cells, T Cells and B-Lymphocyte Stimulator Results (Year 1&2) 
 
 


CONFIDENTIAL 
 
 
205646 
25 
 
2.1.16. 
Pharmacokinetic Tables 
PK Tables 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
 
26.01.  
26.01 
PK 
Belimumab Concentrations (ug/mL) among Subjects who 
Completed Week 52 On Treatment  (Observed) (Year 1&2) 
 
 
2.1.17. 
Pharmacokinetic Figures 
There are no PK Figures to produce. 
 
2.1.18. 
Pharmacokinetic Listings 
PK Listings 
New output 
number 
Old output 
number 
Population 
Title  
Major modifications since original RAP 
 
26.01.  
26.01 
PK 
Serum Belimumab PK Concentrations (Observed) (Year 1&2) 
 
 


CONFIDENTIAL 
 
 
205646 
26 
 
2.2. 
New ‘Intent-to-Treat Year 2’ Population 
An additional population has been defined for use in any Study Population and Adverse 
Event table that presents data only for Year 2. 
The ‘Intent-to-Treat Year 2’ population is defined as “All ITT population participants 
who are ongoing in Year 2.  This includes subjects who confirm that they are continuing 
in the study for Year 2 and/or have an exposure date or early withdrawal visit after the 
Week 52 visit date.”. 
 
2.3. 
Biomarker and Pharmacokinetic (PK) 
2.3.1. 
Specifications in the original RAP 
The original RAP gave minimal information about the data that should be used in the 
Biomarker and PK analyses for the Year 2 reporting.   
For Biomarkers, the original RAP Section 10.1 stated that “The Year 1&2 analyses will 
be performed on the observed data for subjects who completed Week 52 on treatment 
(Ongoing and on treatment at Week 52 analysis as defined in Section 7.1.5).  No 
imputation will be performed for missing data (data post re-start Belimumab will not be 
considered).” 
For PK, the original RAP Section 11 gave no details. 
Section 2.3.2 clarifies the approach that will be used for Year 2 reporting of both 
Biomarker and PK data.  The intended approach for Biomarkers (described above) is 
utilised, explained further and broadened so that the method is also consistent for PK 
analyses. 
 
2.3.2. 
Clarifications for the Year 2 reporting 
The original definition of subjects who completed Week 52 on treatment (referenced in 
the original RAP Section 7.1.5) was based on the MITT population as it was intended to 
be used for Efficacy data.  However, for Biomarker and PK analyses, this needs to be 
modified to be based on all subjects from the ITT population.  Therefore, it has been 
copied directly but with the ITT population as the original population as follows: 
All ITT population Arm A and Arm B participants who are ongoing after 52 weeks of the 
planned double-blind treatment period who received all of both IV doses of rituximab or 
rituximab-placebo, and did not have more than 28 consecutive days from baseline to 
Week 51 without a belimumab dose; includes ITT population Arm C subjects who 
remained on open-label belimumab through Week 52 and did not have more than 28 
consecutive days baseline to Week 51 without a belimumab dose. 
For Arms A&B, the Year 1&2 analyses will be performed on the observed data collected 
in Year 1 and prior to any re-start Belimumab in Year 2, for subjects who completed 
Week 52 on treatment.   


CONFIDENTIAL 
 
 
205646 
27 
 
For Arm C, the Year 1&2 analyses will be performed on the observed data up to IP 
discontinuation, for subjects who completed Week 52 on treatment. 
No imputation will be carried out for missing data. 
Note that the PK outputs will be presented for the PK population. 


Signature Page for  205646 TMF-13873132 v1.0
Signature Page for TMF-13873132 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 22-Jul-2021 12:38:41 GMT+0000
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 22-Jul-2021 14:16:22 GMT+0000
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205646 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan Addendum 
Title 
: Reporting and Analysis Plan Addendum for 205646, 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) 
Compound Number  
: GSK1550188 
Effective Date  
: 08-OCT-2020 
Description: 
• This RAP addendum is supplemental to the RAP (Dated: 05/AUG/2020), and 
based on protocol amendment 04 (Dated: 30/APR/2020) of study 205646. 
• The purpose of this RAP addendum is to document minor additions/clarifications 
made after RAP approval but before Database Release.  
 
Author(s) 
Author  
Date 
Approval 
Method 
Statistics Leader (Rheumatology Biostatistics) 
08-OCT-2020 
eTMF 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited 
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205646 
2 
 
RAP Team Confirmations: 
Reviewer 
Date 
Approval Method 
08-OCT-2020 
Email filed in 
eTMF 
Medical Monitor (Immuno-Inflammation 
Clinical Development) 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval Method 
08-OCT-2020 
eTMF 
(Rheumatology Biostatistics) 
(Rheumatology Programming) 
Delegate for
(Rheumatology Programming) 
08-OCT-2020 
eTMF 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205646 
3 
 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ........................................................................................................... 4 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
CHANGES/CLARIFICATIONS TO THE RAP ........................................................... 5 
2.1. 
Additional Cochran-Mantel-Haenszel (CMH) analysis (RAP Section 
7) .................................................................................................................. 5 
2.2. 
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K 
Missing Item Scores (RAP Section 15.6.3, Section 15.6.4, Section 
15.6.5, Section 15.6.6 and Section 15.6.9) ................................................... 5 
2.3. 
Tipping Point Analysis (RAP Section 7.1.6) .................................................. 6 
2.4. 
Analysis method to Assess the Impact of the Coronavirus Disease 
2019 (COVID-19) Pandemic on the Primary Endpoint (RAP Section 
7.1.7.1) ......................................................................................................... 7 
2.5. 
Clarification on Missing Data for SLEDAI-2K in additional COVID-19 
Analyses (RAP Section 7.1.7.4) .................................................................... 7 
2.6. 
Duration of Disease Control (RAP Section 15.6.4) ........................................ 9 
2.7. 
Lupus Low Disease Activity State (LLDAS) Missing Data (RAP 
Section 7.4 and Section 15.6.9) .................................................................... 9 
2.8. 
LLDAS – clarification of endpoint definition (RAP Section 15.6.9) ................. 9 
 


 
CONFIDENTIAL 
 
 
 
205646 
4 
 
ABBREVIATIONS 
Abbreviation 
Description 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
IBA 
Independent Blinded Assessor 
LLDAS 
Lupus Low Disease Activity State 
MedDRA 
Medical Dictionary for Regulatory Activities 
NR 
Non-Responder 
PI 
Principal Investigator 
R 
Responder 
RAP 
Reporting and Analysis Plan 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
 
Trademarks  
Trademarks owned by 
GlaxoSmithKline group of companies 
 
Trademarks not owned by 
GlaxoSmithKline group of companies 
None 
 
None 
 
 


 
CONFIDENTIAL 
 
 
 
205646 
5 
 
1. 
INTRODUCTION 
This RAP addendum is supplemental to the RAP (Dated: 05/AUG/2020), and based on 
protocol amendment 04 (Dated: 30/APR/2020) of study 205646. 
The purpose of this RAP addendum is to document minor additions/clarifications made 
after RAP approval but prior to Database Release.  
 
2. 
CHANGES/CLARIFICATIONS TO THE RAP 
2.1. 
Additional Cochran-Mantel-Haenszel (CMH) analysis (RAP 
Section 7) 
The RAP specifies that CMH analysis will be conducted for 
• Disease Control at Week 52: RAP Section 7.1.5.1 
• Clinical Remission at Week 64: RAP Section 7.2.5.1 
• Disease Control at Week 104: RAP Section 7.3.5.1 
 
Following re-review of the FDA Request 29 June 2020 – comment 5: 
To facilitate an evaluation of benefit-risk, report point estimates and 95% CI for 
the difference in proportions for these endpoints 
It was decided that most other binary endpoints would also conduct the CMH analysis.  
The exceptions are the following outputs: 
• Disease control at Week 52 by subgroup 
• Sensitivity analyses that were unadjusted for covariates (disease control and clinical remission) 
• COVID-19 additional analyses using multiple imputation methods (disease control and clinical 
remission) 
 
2.2. 
Systemic Lupus Erythematosus Disease Activity Index 
(SLEDAI)-2K Missing Item Scores (RAP Section 15.6.3, 
Section 15.6.4, Section 15.6.5, Section 15.6.6 and Section 
15.6.9) 
The RAP Section 15.6.3 states the following: 
“SLEDAI-2K missing scores for laboratory parameters i.e. 
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.


 
CONFIDENTIAL 
 
 
 
205646 
6 
 
 
Will be imputed from the previous assessment if the previous assessment is no more than 
35 days prior.” 
 
For clarification, the following rules apply for SLEDAI-2K missing item scores: 
• It is only the 8 lab items that can be imputed.  If any of the other 16 items are missing, they will 
be left missing. 
• An imputed assessment cannot be used to impute another assessment. 
• The imputation of these missing lab items is carried out independently for the Principal 
Investigator (PI) and Independent Blinded Assessor (IBA), i.e. the PI assessment of the lab 
items will never be carried forward to a missing IBA assessment and vice versa. 
 
The following sections of the RAP should not re-define what happens with missing 
SLEDAI-2K item scores, they should all use the principles stated above: 
• RAP Section 15.6.4: Disease Control 
• RAP Section 15.6.5: Clinical Remission 
• RAP Section 15.6.6: Complete Remission 
• RAP Section 15.6.9: Lupus Low Disease Activity State (LLDAS) 
 
2.3. 
Tipping Point Analysis (RAP Section 7.1.6) 
The RAP Section 7.1.6 describes the tipping point analyses only in terms of “missing 
data caused by study withdrawal”.  This description is clarified here to also include any 
missing/partial non-informative SLEDAI-2K data, regardless of study withdrawal. 
To explicitly clarify this in terms of the two strategies, the bold text has been added to the 
following existing RAP text: 
“The first tipping point analysis will use the Hybrid strategy (as described in RAP 
Section 7.1.4 as per the primary estimand).  If a subject’s study withdrawal (or missing 
data) is subsequent to treatment failure the subject will still be considered as a non-
responder, i.e. the non-responder assumption will only be varied for withdrawn subjects 
(or subjects with missing/partial non-informative SLEDAI-2K data) that were not 
treatment failures.  
The second tipping point analysis will use the treatment policy strategy (RAP Section 
7.1.4).  In this approach, treatment failure data is ignored, i.e. the non-responder 
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.


 
CONFIDENTIAL 
 
 
 
205646 
7 
 
assumption is varied for all withdrawn subjects (or subjects with missing/partial non-
informative SLEDAI-2K data) regardless of treatment failures.” 
 
2.4. 
Analysis method to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic on the Primary Endpoint 
(RAP Section 7.1.7.1) 
The RAP Section 7.1.7.1 states the following text as the first step in the method for the 
imputation of missing data due to COVID-19: 
• A bayesian repeated measures logistic regression model will be fitted to the observed data, 
using a Markov Chain Monte Carlo (MCMC) approach, adjusting for treatment group, baseline 
SLEDAI-2K score (9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), and 
baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day).  Non-
informative priors will be used. 
 
However, the planned approach is not a repeated measures approach, it is an imputation 
approach that will proceed sequentially through affected visits, so the text ‘repeated 
measures’ should be removed. 
 
2.5. 
Clarification on Missing Data for SLEDAI-2K in additional 
COVID-19 Analyses (RAP Section 7.1.7.4) 
Table 3 in the RAP (Section 7.1.7.4) displays a graphical representation of specific 
scenarios for individual subjects, in terms of their completion status or any Intercurrent 
Events, and the timing of them in relation to the COVID-19 environment onset date.   
In the existing table, there was one row for subjects who complete at Week 52 after the 
COVID environment onset date.  To cover the scenario of missing (or partial non-
informative) SLEDAI-2K data, that row has been split into two rows, as shown in Table 
1 below: 
 


CONFIDENTIAL 
 
 
205646 
8 
 
Table 1 
Graphical Representation of the Additional Analyses 
 
                                         COVID-19 environment  
                                                      Onset date 
 
Description 
Primary 
Analysis 
Hybrid 
 
COVID 
Attributed 
 
COVID 
Environment 
 
Pre-
COVID 
                   X                                              0  Comp. 
Subject Completes Week 52 on or 
after COVID-19 environment onset 
date and has a completed (or partial 
but informative) S2K Score  
R/NR 
R/NR 
Imputed 
Excluded 
                    X                                              0  Comp. 
Subject Completes Week 52 on or 
after COVID-19 environment onset 
date and has a missing or partial 
non-informative S2K Score that 
cannot be determined to definitely be 
either R or NR 
NR 
Imputed 
Imputed 
Excluded 
 
Comp. = Completed; R/NR = Responder/Non-Responder based on SLEDAI-2K criteria; NR = Non-Responder 
 


CONFIDENTIAL 
 
 
205646 
9 
 
2.6. 
Duration of Disease Control (RAP Section 15.6.4) 
The formula for the duration of disease control specified in RAP Section 15.6.4 should be 
as follows: 
Duration of disease control = longest period where  
     Last visit of disease control – First visit of disease control + 1 
 
Also, it is not appropriate to derive disease control at Baseline, therefore the first visit of 
disease control considered in this calculation will always be the first post-baseline visit 
where the subject meets the disease control criteria. 
 
2.7. 
Lupus Low Disease Activity State (LLDAS) Missing Data 
(RAP Section 7.4 and Section 15.6.9) 
The RAP does not explicitly state what happens when the subject has missing data for a 
component of their LLDAS assessment.  Adding these clarifying sentences would be 
clearer: 
“Within each criteria, a subject with an incomplete assessment (due to missing data) will 
be considered as missing, i.e. observed data will be presented for the individual criteria.   
A subject is only considered an overall responder for LLDAS if they are a responder for 
all 6 criteria, i.e. missing data within one or more criteria would make them an overall 
non-responder.” 
 
2.8. 
LLDAS – clarification of endpoint definition (RAP Section 
15.6.9) 
Clarifications have been made to the LLDAS endpoint definition table in RAP Section 
15.6.9. for the criteria of “well tolerated standard maintenance doses of 
immunosuppressive drugs and approved biological agents, excluding investigational 
drugs”. 
Firstly, the RAP Section 15.6.9 and protocol Section 7.7.14 refer to “Cyclosporine”, 
however the MedDRA dictionary name is “Ciclosporin”. 
Secondly the existing text in RAP Section 15.6.9 (shown below) has been clarified to 
include the additional text shown in bold.  This additional text makes it clearer that the 
Anti-TNF therapy and other biologics listed are just examples and it also provides 
additional examples of other biologics based on the Year 1 blinded data: 
“Not to be taken within 28 days prior to the assessment: 
• 
Intravenous Cyclophosphamide 
• 
Other investigation agent 


CONFIDENTIAL 
 
 
205646 
10 
 
• 
Anti-TNF therapy (e.g. adalimumab, etanercept, infliximab) 
• 
Other biologics (e.g. abatacept, anakinra, commercial rituximab, tocilizumab) 
• 
IVIG 
• 
Plasmapheresis” 
 
The following sentence has also been added to clarify the use of commercial Belimumab: 
“Subjects can take commercial Belimumab IV or SC and this doesn’t prevent them from 
being a responder on this criteria for the LLDAS.”. 
 
 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205646 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for 205646, 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) 
Compound Number  : GSK1550188 
Effective Date  
: 5-AUG-2020 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205646. 
• 
This RAP is intended to describe the planned efficacy, safety, pharmacokinetics 
and biomarker analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author: 
Author 
Approval Method 
eTMF 
Statistics Leader (Rheumatology Biostatistics) 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205646 
 
2 
 
RAP Team Confirmationss: 
Reviewer 
Approval Method 
eTMF 
Medical Monitor (Immuno-inflammation Clinical 
Development) 
Statistics Leader (Immuno-inflammation Biostatistics) 
eTMF 
Programming Leader (Rheumatology Biostatistics) 
eTMF 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Approval Method 
eTMF 
(Rheumatology Biostatistics) 
eTMF 
(Rheumatology Programming) 
Delegate for
(Rheumatology Programming) 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
 
205646 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 9 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 9 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.3. 
Study Design .............................................................................................. 13 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 14 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Interim Analyses ......................................................................................... 15 
3.2. 
Final Analyses ............................................................................................ 16 
4. 
ANALYSIS POPULATIONS ................................................................................... 17 
4.1. 
Protocol Deviations ..................................................................................... 20 
4.2. 
Per Protocol Population .............................................................................. 20 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 22 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 22 
5.2. 
Study Day ................................................................................................... 22 
5.3. 
Baseline Definitions .................................................................................... 23 
5.4. 
Multicentre Studies ..................................................................................... 24 
5.5. 
Examination of Covariates, Strata and Subgroups ...................................... 24 
5.5.1. 
Covariates and Strata .................................................................. 24 
5.5.2. 
Examination of Subgroups ........................................................... 24 
5.6. 
Multiple Comparisons and Multiplicity ......................................................... 25 
5.7. 
Cut-off Date for Primary Analyses (Year 1) ................................................. 26 
5.8. 
Database for End of Study Analyses (Year 2 and Years 1&2 
Combined) .................................................................................................. 27 
5.9. 
Study Withdrawal ........................................................................................ 27 
5.10. 
Treatment Failures ...................................................................................... 27 
5.11. 
On Study..................................................................................................... 28 
5.12. 
On Treatment ............................................................................................. 28 
5.13. 
Race Hierarchy (minority rule) .................................................................... 28 
5.14. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 29 
6. 
STUDY POPULATION ANALYSES ....................................................................... 30 
6.1. 
Overview of Planned Study Population Analyses ........................................ 30 
6.2. 
Disposition of Subjects ................................................................................ 30 
6.3. 
Demographic and Baseline Characteristics ................................................. 31 
6.4. 
Concomitant Medications ............................................................................ 36 
6.5. 
Extent of Exposure to Study Treatment ...................................................... 37 
6.6. 
Time to Study Treatment Discontinuation ................................................... 38 
7. 
EFFICACY ANALYSES .......................................................................................... 40 
7.1. 
Primary Efficacy Analyses .......................................................................... 41 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
4 
 
7.1.1. 
Endpoint / Variables ..................................................................... 41 
7.1.2. 
Summary Measure ...................................................................... 42 
7.1.3. 
Population of Interest ................................................................... 42 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 42 
7.1.5. 
Statistical Analyses / Methods ..................................................... 45 
7.1.5.1. 
Statistical Methodology Specification .......................... 45 
7.1.6. 
Tipping Point Analysis.................................................................. 47 
7.1.7. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic on the 
Primary Endpoint ......................................................................... 49 
7.1.7.1. 
COVID Attributed – Observed Data until 
Intercurrent Events That Could be Attributable 
to the COVID-19 Pandemic ........................................ 49 
7.1.7.2. 
COVID Environment – Observed Data Until the 
COVID-19 Pandemic .................................................. 50 
7.1.7.3. 
Pre-COVID – MITT Population Prior to the 
COVID-19 Pandemic .................................................. 51 
7.1.7.4. 
Graphical Representation of the Additional 
Analyses ..................................................................... 52 
7.2. 
First Major Secondary Efficacy Analyses .................................................... 55 
7.2.1. 
Endpoint / Variables ..................................................................... 55 
7.2.2. 
Summary Measure ...................................................................... 56 
7.2.3. 
Population of Interest ................................................................... 56 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 56 
7.2.5. 
Statistical Analyses / Methods ..................................................... 56 
7.2.5.1. 
Statistical Methodology Specification .......................... 56 
7.2.6. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic on the 
First Major Secondary Endpoint ................................................... 58 
7.2.6.1. 
COVID Attributed – Observed data until 
Intercurrent Events that could be attributable to 
the COVID-19 pandemic ............................................ 58 
7.2.6.2. 
COVID Environment – Observed data until the 
COVID-19 pandemic .................................................. 58 
7.2.6.3. 
Pre-COVID – MITT Population prior to the 
COVID-19 pandemic .................................................. 58 
7.3. 
Second Major Secondary Efficacy Analyses ............................................... 58 
7.3.1. 
Endpoint / Variables ..................................................................... 58 
7.3.2. 
Summary Measure ...................................................................... 58 
7.3.3. 
Population of Interest ................................................................... 59 
7.3.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 59 
7.3.5. 
Statistical Analyses / Methods ..................................................... 59 
7.3.5.1. 
Statistical Methodology Specification .......................... 59 
7.3.6. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic on the 
Second Major Secondary Endpoint .............................................. 60 
7.3.6.1. 
COVID Attributed – Observed Data Until 
Intercurrent Events That Could be Attributable 
to the COVID-19 Pandemic ........................................ 60 
7.3.6.2. 
COVID Modified – SLEDAI 2K-Score ≤2 (IBA), 
Without Current Immunosuppressants, Without 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
5 
 
Current Belimumab (arms A&B), and 
prednisone equivalent dose of 5mg/day at 
Week 104 ................................................................... 60 
7.4. 
Lupus Low Disease Activity State (LLDAS) ................................................. 62 
7.4.1. 
Endpoint / Variables ..................................................................... 62 
7.4.2. 
Summary Measure ...................................................................... 62 
7.4.3. 
Population of Interest ................................................................... 62 
7.4.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 62 
7.4.5. 
Subgroup, Supportive and Sensitivity Analyses ........................... 63 
7.4.6. 
Statistical Methodology Specification ........................................... 63 
7.5. 
Other Secondary Efficacy Analyses - Proportion Endpoints (Hybrid) .......... 63 
7.5.1. 
Summary Measure ...................................................................... 63 
7.5.2. 
Population of Interest ................................................................... 63 
7.5.3. 
Strategy for Intercurrent (Post-Randomization) Events ................ 64 
7.5.4. 
Subgroup, Supportive and Sensitivity Analyses ........................... 64 
7.5.5. 
Statistical Methodology Specification ........................................... 64 
7.6. 
Other Secondary Efficacy Analyses - Proportion Endpoints 
(Observed Case) ........................................................................................ 65 
7.6.1. 
Summary Measure ...................................................................... 65 
7.6.2. 
Population of Interest ................................................................... 65 
7.6.3. 
Strategy for Intercurrent (Post-Randomization) Events ................ 65 
7.6.4. 
Subgroup, Supportive and Sensitivity Analyses ........................... 65 
7.6.5. 
Statistical Methodology Specification ........................................... 65 
7.7. 
Other Secondary Efficacy Analyses - Time to Event Endpoints .................. 66 
7.7.1. 
Summary Measures ..................................................................... 66 
7.7.2. 
Population of Interest ................................................................... 66 
7.7.3. 
Strategy for Intercurrent (Post-Randomization) Events ................ 66 
7.7.4. 
Subgroup, Supportive and Sensitivity Analyses ........................... 66 
7.7.5. 
Statistical Methodology Specification for Time to Event 
Endpoints..................................................................................... 66 
7.8. 
Other Secondary Efficacy Analyses - Duration Endpoints ........................... 69 
7.8.1. 
Population of Interest ................................................................... 69 
7.8.2. 
Strategy for Intercurrent (Post-Randomization) Events ................ 69 
7.8.3. 
Endpoint / Variables ..................................................................... 69 
7.8.4. 
Subgroup, Supportive and Sensitivity Analyses ........................... 69 
7.8.5. 
Statistical Methodology Specification for Duration 
Endpoints..................................................................................... 69 
7.9. 
Other Secondary Efficacy Analyses Continuous Endpoints ........................ 70 
7.9.1. 
Endpoint / Variables ..................................................................... 70 
7.9.2. 
Summary Measure ...................................................................... 70 
7.9.3. 
Population of Interest ................................................................... 70 
7.9.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 70 
7.9.5. 
Subgroup, Supportive and Sensitivity Analyses ........................... 70 
7.9.6. 
Statistical Methodology Specification for Continuous 
Endpoints..................................................................................... 71 
7.10. 
Other Secondary Efficacy Analyses: SLEDAI-2K Score ≤2 (IBA), 
Without Current Immunosuppressant and Corticosteroids 
<=5mg/day .................................................................................................. 72 
7.10.1. 
Endpoint / Variables ..................................................................... 72 
7.10.2. 
Summary Measure ...................................................................... 73 
7.10.3. 
Population of Interest ................................................................... 73 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
6 
 
7.10.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 73 
7.10.5. 
Statistical Analyses / Methods ..................................................... 73 
7.10.5.1. Statistical Methodology Specification .......................... 73 
7.11. 
Additional Efficacy Analyses ....................................................................... 74 
7.12. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic on the Secondary Efficacy 
Endpoints.................................................................................................... 76 
8. 
SAFETY ANALYSES ............................................................................................. 77 
8.1. 
Adverse Events........................................................................................... 77 
8.1.1. 
Reporting Phases ........................................................................ 77 
8.1.1.1. 
Pre Treatment ............................................................ 77 
8.1.1.2. 
On Treatment (Year 1 only) ........................................ 77 
8.1.1.3. 
On Study .................................................................... 77 
8.1.1.4. 
Post Withdrawal/Completion ....................................... 77 
8.1.2. 
Adverse Events Analyses ............................................................ 77 
8.1.3. 
Deaths, Serious Adverse Events, and Survival Status ................. 80 
8.1.4. 
Adverse Events of Special Interest Analyses ............................... 82 
8.1.5. 
Post-Injection Systemic Reactions ............................................... 84 
8.1.6. 
Additional Adverse Event Summaries to Assess the 
Impact of the Coronavirus Disease 2019 (COVID-19) 
Pandemic..................................................................................... 85 
8.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................... 86 
8.2.1. 
C-SSRS Suicidal Ideation or Behaviour on Study [T13.52, 
T23.45]. ....................................................................................... 87 
8.2.2. 
C-SSRS Suicidal Ideation or Behavior Relative to Pre-
Treatment [T13.53, T23.46]. ........................................................ 87 
8.2.3. 
C-SSRS Shift Changes in Categories from Pre-Treatment 
to On-Study [T13.54, T23.47]. ...................................................... 88 
8.2.4. 
C-SSRS Shift Changes in Categories from Year 1 to Year 
2 [T23.48]. ................................................................................... 88 
8.3. 
Clinical Laboratory Analyses ....................................................................... 88 
8.3.1. 
Laboratory Descriptive Statistics by Visit ..................................... 89 
8.3.2. 
Laboratory Toxicity ≥ 2 Grade Shift Post-Baseline ....................... 89 
8.3.3. 
Laboratory Reference Range Shifts from Baseline by Visit .......... 89 
8.3.4. 
Immunoglobulin Reference Range Shifts from Baseline by 
Visit .............................................................................................. 90 
8.3.5. 
Worst Laboratory Toxicity Grade Post-Baseline ........................... 90 
8.3.6. 
Immunoglobulin Below LLN by Visit ............................................. 90 
8.3.7. 
Immunoglobulin Relative to LLN by Visit ...................................... 90 
8.3.8. 
Immunogenicity............................................................................ 91 
8.3.9. 
Further Research Samples .......................................................... 91 
8.4. 
Other Safety Analyses ................................................................................ 91 
8.4.1. 
Vital Signs .................................................................................... 92 
8.4.2. 
Neurological Assessment ............................................................ 92 
9. 
HEALTH OUTCOMES ANALYSES ........................................................................ 93 
9.1. 
Statistical Methodology Specification for Continuous Endpoints ................. 93 
9.1.1. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic 
(Continuous Endpoints upto Week 52 and Week 64) ................... 95 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
7 
 
9.2. 
Statistical Methodology Specification for Proportion Endpoints ................... 96 
9.2.1. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic ...................... 97 
9.3. 
Health Care Resource Utilization ................................................................ 97 
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 98 
10.1. 
Biomarker Change and Percent Change from Baseline Analyses ............... 99 
10.2. 
Shifts in Immunoglobulins, Autoantibodies, and Complement by 
Visit ........................................................................................................... 101 
11. PHARMACOKINETIC ANALYSES ....................................................................... 103 
11.1. 
Primary Pharmacokinetic Analyses ........................................................... 103 
11.1.1. 
Endpoint / Variables ................................................................... 103 
11.1.1.1. Drug Concentration Measures .................................. 103 
11.1.2. 
Population of Interest ................................................................. 103 
11.1.3. 
Statistical Analyses / Methods ................................................... 103 
12. POPULATION PHARMACOKINETIC (POPPK) ANALYSES ................................ 104 
12.1. 
Statistical Analyses / Methods .................................................................. 104 
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ............................... 104 
14. REFERENCES ..................................................................................................... 105 
15. APPENDICES ...................................................................................................... 106 
15.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ................................................................................... 106 
15.1.1. 
Exclusions from Per Protocol Population ................................... 106 
15.2. 
Appendix 2: Protocol Defined Schedule of Activities ................................. 108 
15.3. 
Appendix 3: Assessment Windows ........................................................... 123 
15.3.1. 
Definitions of Assessment Windows for Analyses ...................... 123 
15.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ...................................................................................................... 125 
15.4.1. 
Study Phases for Concomitant Medication ................................. 125 
15.4.2. 
Treatment Emergent Flag for Adverse Events ........................... 125 
15.5. 
Appendix 5: Data Display Standards & Handling Conventions .................. 126 
15.5.1. 
Reporting Process ..................................................................... 126 
15.5.2. 
Reporting Standards .................................................................. 126 
15.6. 
Appendix 6: Derived and Transformed Data ............................................. 128 
15.6.1. 
General ...................................................................................... 128 
15.6.2. 
Study Population ........................................................................ 129 
15.6.3. 
SLEDAI-2K Total and Organ System Domain ............................ 130 
15.6.4. 
Disease Control ......................................................................... 132 
15.6.5. 
Clinical Remission ..................................................................... 136 
15.6.6. 
Complete Remission .................................................................. 137 
15.6.7. 
SFI FLARE INDEX ..................................................................... 138 
15.6.8. 
Physicians Global Assessment (PGA) Scoring .......................... 140 
15.6.9. 
Lupus Low Disease Activity State (LLDAS) ................................ 140 
15.6.10. Lupus QOL Scale ...................................................................... 142 
15.6.11. Work Productivity and Activity Impairment (WPAI) ..................... 142 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
8 
 
15.6.12. Functional Assessment of Chronic Illness Therapy 
(FACIT) ...................................................................................... 144 
15.6.13. Disease Control Without Current Immunosuppressant and 
with Current Corticosteroids  5mg/day ..................................... 145 
15.6.14. Prednisone Equivalent Conversion ............................................ 145 
15.6.15. Treatment Failure Rules During Study Conduct ......................... 148 
15.6.15.1. Summary .................................................................. 148 
15.6.15.2. SLE Medication Categories ...................................... 149 
15.6.15.3. General Conventions ................................................ 150 
15.6.15.4. Steroids .................................................................... 151 
15.6.15.5. Anti-malarials ............................................................ 152 
15.6.15.6. Other Immunosuppressant Agents ........................... 153 
15.6.15.7. Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs), Aspirin, and Acetominophen .................... 154 
15.6.15.8. Prohibited Medications ............................................. 155 
15.6.15.9. Belimumab in Year 2 ................................................ 155 
15.6.16. Coronavirus Disease 2019 (COVID-19) Environment 
Onset Date ................................................................................ 156 
15.7. 
Appendix 7: Reporting Standards for Missing Data ................................... 157 
15.7.1. 
Premature Withdrawals .............................................................. 157 
15.7.2. 
Missing Data .............................................................................. 157 
15.7.2.1. Missing and Partial Dates ......................................... 157 
15.8. 
Appendix 8: Laboratory Parameters and Toxicity Grades ......................... 159 
15.8.1. 
Adverse Event and Laboratory Value Severity Grade 
Tables ........................................................................................ 162 
15.9. 
Appendix 9: Biomarkers ............................................................................ 169 
15.10. Appendix 10: Abbreviations & Trade Marks .............................................. 171 
15.10.1. Abbreviations ............................................................................. 171 
15.10.2. Trademarks ............................................................................... 172 
15.11. Appendix 11: List of Data Displays............................................................ 173 
15.11.1. Data Display Numbering ............................................................ 173 
15.11.2. Mock Example Shell Referencing .............................................. 173 
15.11.3. Deliverables ............................................................................... 173 
16. ATTACHMENTS .................................................................................................. 174 
16.1. 
Attachment 1: AESI Preferred Term Definitions ........................................ 174 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
9 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol versions: 
Protocol Revision Chronology: 
Amendment 4 (Global) 
30 APR 2020 
COVID-19 amendments 
Amendment 3 (Global) 
15-AUG-2019 
Treatment for subjects with neutropenia corrected 
Amendment 2 (Global) 
17-NOV-2018 
Sample size increased following potential unblinding issue 
identified.   
Amendment1 / ARG 
02-JUL-2018 
Argentina Specific amendment 
Amendment1 / DEU-2 
27-NOV-2017 
Germany Specific amendment 
Amendment1 / DEU -1 
23-OCT-2017 
Germany Specific amendment 
Amendment1 / KOR- 1 
22-JUN 2017 
Korea Specific amendment 
Amendment 1 (Global) 
17-APR-2017 
Comments and feedback from EMA and FDA  
Original 
16-JAN-2017 
Original 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
This the 2nd version of the Reporting and Analysis Plan, and is in keeping with additional 
detail to that provided in the Protocol (30 APR 2020), and the critical components 
document of 27FEB2018.  Additional clarification has been added to text copied from the 
protocol when referring to the SLEDAI-2K, to clarify when referring to the independent 
blinded assessor assessment (IBA) and when referring to the principal investigator 
assessment (PI).  The derivation of the endpoints (including the primary) has been 
clarified to be in accordance with ICH E9 R1 terminology.  Additional analysis to assess 
the impact of the COVID-19 pandemic has been added. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
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 (IBA) score 2, achieved 
without immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 5 mg/day at Week 52 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
10 
 
Objectives 
Endpoints 
Secondary Objectives: Efficacy (Major) 
Secondary Endpoints: Efficacy (Major) 
• 
Secondary: Efficacy (Major) 
• 
Proportion of participants with a state of clinical remission 
defined as a Clinical SLEDAI-2K score (IBA) =0 (Section 
15.6.3), achieved without immunosuppressants and with 
corticosteroids at a prednisone equivalent dose of 0 
mg/day at Week 64.  
• 
Proportion of participants with a state of disease control 
defined as a SLEDAI-2K score (IBA) 2, achieved without 
immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 5 mg/day at Week 104 
Secondary Objectives: Efficacy (Other)  
Secondary Endpoints: Efficacy (Other) 
• 
Secondary: Efficacy (Other) 
• 
Proportion of participants with a state of disease control, 
defined as a SLEDAI-2K score (IBA) 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 (IBA) 
=0 (Section 15.6.3), achieved without 
immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day, by visit.  
• 
Proportion of participants with a state of complete 
remission, defined as SLEDAI-2K score (PI) =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 (PI) =0 
(Section 15.6.3), 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 complete 
remission, defined as a SLEDAI-2K score (PI) =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 (PI) 2, achieved without 
immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 5 mg/day. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
11 
 
Objectives 
Endpoints 
• 
Time to clinical remission sustained to Week 104 , 
defined as Clinical SLEDAI-2K score (PI) =0 (Section 
15.6.3), achieved without immunosuppressants and with 
corticosteroids at a prednisone equivalent dose of 0 
mg/day.  
• 
Duration of disease control, defined as SLEDAI-2K score 
(PI) 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 (PI) =0 (Section 15.6.3), achieved without 
immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day.  
• 
Change from baseline in SLEDAI-2K score (PI) by visit 
• 
Proportion of participants with SLEDAI-2K (PI) organ 
improvement by visit 
• 
Proportion of participants with SLEDAI-2K (PI) 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 anaemia 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 (PI) 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 (PI) =0 
(Section 15.6.3), achieved without immunosuppressants 
and with corticosteroids at a prednisone equivalent dose 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
12 
 
Objectives 
Endpoints 
of 0 mg/day, by visit; using the principal investigators 
assessment of SLEDAI-2K.  
Secondary (Safety) Objectives 
Secondary (Safety) Endpoints 
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) Objectives 
Secondary: Patient Reported Outcomes (PROs) 
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 participants with improvement in FACIT-
Fatigue score exceeding the Minimal Clinically Important 
Difference (MCID, 4) by visit 
Exploratory: Pharmacokinetics and 
Biomarkers Objectives 
Exploratory: Pharmacokinetics and Biomarkers 
Endpoints 
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 Objectives 
Exploratory: Patient Reported Work Productivity 
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 
 
These are the protocol defined endpoints (Protocol Section 4),  protocol Section 10.4.1 
Efficacy analysis then clarifies further that: 
 
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 . 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
13 
 
Hence when adopting the ICH Estimands and Sensitivity Analysis in Clinical Trials E9 
R1 addendum terminology, an endpoint has been defined which combines this 
information. 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
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 active SLE, 
i.e. SLEDAI-2K score 6. The primary efficacy endpoint will be measured at 
Week 52. 
• 
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 52 weeks. Arm C (reference) is an open-label 
arm with belimumab subcutaneous (SC) 200 mg/week and standard therapy for 
104 weeks. 
• 
Randomization and the first dose of belimumab should be completed within 35 days 
of initiation of screening procedures. 
• 
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). 
• 
Participants randomized to Arms A and B, who enter the study on 
immunosuppressants, will discontinue immunosuppressants at or prior to the Week 
4 infusion visit 
• 
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. 
Dosing 
• 
Arms A and B are double-blind; participants will receive belimumab 200 mg/week 
SC for 52 weeks. Rituximab-placebo or rituximab (1000 mg IV) will be administered 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
14 
 
Overview of Study Design and Key Features 
by intravenous (IV) infusions in a double-blind manner at Weeks 4 and 6 for Arms A 
and B. 
• 
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 oral antihistamine, and an acetaminophen or equivalent. 
• 
Arm C (reference) is an open-label arm with belimumab subcutaneous (SC) 200 
mg/week and standard therapy for 104 weeks. 
Schedule of 
Activities 
• 
See Section 15.2 Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 
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 52 weeks.  
• 
Arm C (reference) is an open-label arm with belimumab subcutaneous (SC) 
200 mg/week and standard therapy for 104 weeks. Currently available 
standard therapy includes continuation of immunosuppressant agents 
throughout the course of the study (See Protocol Section 7.7.1.4 for detailed 
information regarding immunosuppressant medications dosing). 
• 
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) 
Interim 
Analysis 
• 
No formal interim analyses planned for this study 
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
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.  
Analysis of the primary objective will use data from the whole population and therefore 
includes subjects from treatment Arms A, B, and C, even though the primary objective is 
only comparing treatment Arms A and B.  Hence an exploratory assessment of the 
relative performance of Arm A (Control) and Arm B (Combination) vs. standard SLE 
therapy (Arm C: Reference) will also be conducted using the same analysis. 
The primary efficacy endpoint is defined as: the proportion of participants with a state of 
disease control defined as a SLEDAI-2K score (IBA) 2, achieved without 
immunosuppressants and with corticosteroids at a prednisone equivalent dose of 
5mg/day at Week 52. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
15 
 
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 and the two major secondary endpoints will be evaluated for statistical 
significance based on a pre-specified sequence for interpretation (i.e., disease control at 
Week 52, followed by clinical remission at Week 64 and then disease control at Week 
104, see Figure 1). Specifically, endpoints will be tested in the sequence above (2-sided 
alpha=0.05) provided that statistical significance is achieved by all prior tests. If at any 
point in the sequence statistical significance is not met, then subsequent endpoints in the 
sequence cannot be deemed statistically significant. Analyses of other efficacy endpoints 
will not be subject to any multiple comparison procedure. 
3. 
PLANNED ANALYSES 
3.1. 
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 occurred in Sept 2018 (6months 
after the 1st subject was randomised) and continued in approximately 6 monthly intervals.  
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 non-
serious), 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. 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. 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
16 
 
3.2. 
Final Analyses 
There will be two database locks for this study, corresponding to the primary analyses 
and the end of study analyses. The primary analyses will include data up to the 52 week 
visits for the primary endpoint. 
The primary analyses will be performed after the completion of the following sequential 
steps: 
1. All subjects have completed the Week 52 visit (or Early Withdrawal visit for those 
subjects who withdraw from the study during Year 1). 
2. All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management. 
3. All criteria for unblinding the randomisation codes have been met, including: 
• Review of Protocol Deviations through Week 52 
• Adjudication of AESI through Week 52 
• Review of treatment failures through Week 52  
4. Randomisation codes have been distributed according to RandAll NG procedures. 
5. Database freeze (DBF) has been declared by Data Management. 
A final analysis will be conducted following the last subject completion of year 2 
(including all 8 week-follow-up visits) when all required database cleaning activities 
have been completed and final database release and database freeze has been declared by 
Data Management as described in Steps 2, 3 and 5 above 
This RAP details the planned analysis for both database locks, with the expectation of an 
observed treatment benefit at Week 52.  If the Week 52 reporting does not identify a 
treatment benefit, an abridged set of analysis may be conducted at the end of the study, 
which will be detailed in a RAP amendment or RAP addendum. 
 
 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
17 
 
4. 
ANALYSIS POPULATIONS 
During the early conduct of the study some participants in ARM C (n=29) were 
inappropriately identified on a laboratory report which could have unblinded the 
independent blinded assessors.  Blinding of Arms A and B was not compromised.  For 
this reason the sample size was increased, and a Modified Intent To Treat (MITT) 
population has been created to exclude the potentially unblinded (to the independent 
blinded assessor) Arm C subjects.  
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
(Enrolled) 
• All screened candidates who sign the ICF 
• Screen failures and 
Study Population 
Randomized  
 
• All participants who were randomly assigned to 
treatment in the study. 
• Any participant who receives a treatment 
randomization number will be considered to 
have been randomized. 
• This population will be based on the treatment 
the participant was randomized to. 
• Study Population 
Intent-To-Treat 
(ITT) 
• All randomized participants who received at 
least one dose of study treatment (Belimumab 
or Rituximab/placebo) . 
• This population will be based on the treatment 
the subject was randomized to. 
• Study Population 
• Safety 
• Pharmacodynamic 
and Biomarker 
Modified Intent-
To-Treat (MITT) 
• All randomized participants who received at 
least one dose of study treatment (Belimumab 
or Rituximab/placebo) . 
• Arm C subjects randomized prior to 07 
September 2018, whose independent blinded 
assessor had potential to be unblinded, are 
excluded from this population. 
• This population will be based on the treatment 
the subject was randomized to. 
• Efficacy 
• Health Outcomes 
 
Per Protocol  
(PP) 
• All participants in the MITT population who 
comply with the protocol. 
• Protocol deviations that would exclude 
participants from the PP population are defined 
in Section 4.2 (Per Protocol Population) and 
Appendix 1: Protocol Deviation Management 
and Definitions for Per Protocol Population. 
• The PP set will not be analysed if this population 
comprises more than 85% of the MITT 
population. 
• Efficacy 
 
These additional populations will also be considered in order to consider missing data 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
18 
 
Population 
Definition / Criteria 
Analyses Evaluated 
Ongoing on 
study treatment  
at Week 52 
• All MITT population Arm A and Arm B 
participants who are ongoing after 52 weeks of 
the planned double-blind treatment period who 
received all of both IV doses of rituximab or 
rituximab-placebo, and did not have more than 
28 consecutive days  from baseline to Week 51 
without a belimumab dose; includes MITT 
population Arm C subjects who remained on 
open-label belimumab through Week 52 and did 
not have more than 28 consecutive days baseline 
to Week 51 without a belimumab dose. 
• Sensitivity 
analysis of the 
primary efficacy 
endpoint 
Ongoing on 
study treatment  
at Week 64 
• All MITT population Arm A and Arm B 
participants who are ongoing after 64 weeks who 
received all of both IV doses of rituximab or 
rituximab-placebo, and did not have more than 
28 consecutive days  from baseline to Week 51 
without a belimumab dose; includes MITT 
population Arm C subjects who remained on 
open-label belimumab through Week 64 and did 
not have more than 28 consecutive days from 
baseline to Week 63 without a belimumab dose. 
• Sensitivity 
analysis of the 
1st Major 
secondary 
efficacy endpoint 
Completers on 
study treatment  
• All MITT population Arm A and Arm B 
participants who complete Week 104 who 
received all of both IV doses of rituximab or 
rituximab-placebo, and did not have more than 
28 consecutive days from baseline to Week 51 
without a belimumab dose; includes MITT 
population Arm C subjects who remained on 
open-label belimumab through Week 104 and did 
not have more than 28 consecutive days from 
baseline to Week 103 without a belimumab dose. 
• Sensitivity 
analysis of the 
2nd Major 
secondary 
efficacy endpoint 
As Treated 
• All randomized participants who received at least 
one dose of study treatment (Belimumab or 
Rituximab/placebo) . 
• Subjects in Arms A or B who receive one or more 
infusions of rituximab will be included in Arm B 
for the As Treated analysis. Subject in Arm B 
who receive two doses of rituximab-placebo (and 
no rituximab) will be included in Arm A. 
• If more than 5% 
of subjects 
received the 
incorrect RTX 
treatment, then 
the Primary 
efficacy endpoint 
will be repeated 
for this 
population  
• Safety endpoints 
if more than 5% 
received the 
wrong RTX 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
19 
 
treatment,  then 
this population 
will replace the 
ITT for safety 
Pharmacokinetic 
(PK) 
• All participants in the ITT population who had at 
least 1 non-missing PK assessment (Non-
quantifiable [NQ]. values will be considered as 
non-missing values). 
• PK 
 
 
The following additional populations will be defined as pre-COVID-19 populations.  The COVID-19 
environment onset date is defined in Section 15.6.16. 
Population 
Definition / Criteria 
Analyses Evaluated 
MITT Week 52 
prior to COVID-
19 
• All randomized participants who received at 
least one dose of study treatment and had their 
first dose of study medication early enough that 
they should have completed their Week 52 visit 
prior to the COVID-19 environment onset date, 
i.e. their first dose of study treatment was prior 
to the onset date minus 52 weeks 
• Arm C subjects randomized prior to 07 
September 2018, whose independent blinded 
assessor had potential to be unblinded, are 
excluded from this population 
• This population will be based on the treatment 
the subject was randomized to. 
• Efficacy 
 
 
MITT Week 64 
prior to COVID-
19 
• All randomized participants who received at 
least one dose of study treatment and had their 
first dose of study medication early enough that 
they should have completed their Week 64 visit 
prior to the COVID-19 environment onset date, 
i.e. their first dose of study treatment was prior 
to the onset date minus 64 weeks 
• Arm C subjects randomized prior to 07 
September 2018, whose independent blinded 
assessor had potential to be unblinded, are 
excluded from this population 
• This population will be based on the treatment 
the subject was randomized to. 
• Efficacy 
 
 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
20 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed for both the double-blind phase (Year 1) and observational phase 
(Year 2) separately [T11.13, T21.09, L11.07, L21.04]. The tables will display the number 
and percentage of subjects who experience any important protocol deviation and for each 
deviation type. 
All protocol deviations that relate to COVID-19 will be summarized and listed for both 
the double-blind phase (Year 1) and observational phase (Year 2) separately [T11.14, 
T21.10, L11.07, L21.04].  The tables will display the number and percentage of subjects 
who experience any protocol deviation related to COVID-19. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP). [Version 6]. 
o Year 1 data will be reviewed prior to unblinding and freezing the database to 
ensure all important deviations and deviations which may lead to exclusion from 
the analysis are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
o Year 2 data will be reviewed by the blinded study team prior to unblinding and 
freezing the database to ensure all important deviations are captured and 
categorised on the protocol deviations dataset. 
All deviations will be discussed and adjudicated as important or not important according 
to the PDMP.  
This preliminary assessment of the deviation resulting in the subject being excluded from 
the per protocol population, but will be subject to a final review as detailed in Section 
4.2.  
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF [T11.12, L11.06]. 
 
4.2. 
Per Protocol Population 
Periodic review of the per protocol population will be conducted during the course of the 
study, with a final assessment made prior to unblinding the data for the Year 1 reporting.   
The per protocol population will be primarily based on an assessment of the important 
protocol deviations.  However non-important deviations or other study conduct issues 
may be identified during the study that warrant a subject’s exclusion from the per 
protocol population.  This will be documented in the protocol deviation adjudication 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
21 
 
meeting minutes prior to database freeze.  Only protocol deviations or study conduct 
issues that have the potential to impact the efficacy evaluation will lead to exclusion from 
the per protocol population.  
The per protocol population will be derived based on the Year 1 data.  If Year 2 reporting 
(or combined Year 1&2) per protocol analysis is required it will be based on the per 
protocol population defined for Year 1. 
Subjects excluded from the Per Protocol (PP) population will be summarized [T11.15]. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
22 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF 
A 
Belimumab plus Placebo 
BEL SC plus PBO IV 
1 
B 
Belimumab plus Rituximab 
BEL SC plus RTX IV 
2 
C 
Belimumab Open-Label 
BEL SC plus STD Therapy 
3 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. 
BEL SC plus RTX IV vs BEL SC plus PBO IV 
2. BEL SC plus RTX IV vs BEL SC plus STD Therapy  
3. 
BEL SC plus PBO IV vs BEL SC plus STD Therapy 
 
Table 1 
Treatment Descriptors, Colors, Line Style and Symbols for 
Reporting in Double-Blind Phase 
Treatment 
Descriptor 
Color 
SAS Color 
Line Style 
Symbol 
BEL SC plus PBO 
IV 
Blue 
CX0000FF 
Dashed 
Triangle (filled) 
BEL SC plus RTX 
IV 
Green 
CX2A8307 
Long dashes 
Circle (filled) 
BEL SC plus 
Standard Therapy 
Brown 
CXA05000 
Solid 
Square (open) 
 
5.2. 
Study Day 
Study day is the number of days from Belimumab study treatment start date to the study 
day of interest and is calculated as: 
Criteria: 
Study day is: 
Study date < treatment start date 
Study date - treatment start date 
Study date >= treatment start date 
Study date - treatment start date + 1 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
23 
 
Note: Study day cannot be zero. If either date is missing the study day is missing.  
Further detail is provided in Section 15.6.1 
5.3. 
Baseline Definitions 
For all the endpoints for both the Week 52  and Week 104 analysis (except as noted in 
baseline definitions) the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. 
Parameter 
Study Assessments Considered as 
Baseline 
Baseline Used 
in Data Display 
Screening 
 
Day 1 (Pre-Dose) 
Efficacy 
SLEDAI-2K Principal Investigator (PI) 
X 
X 
Day 1 
SLEDAI-2K Independent Blinded 
Assessor (IBA) 
 
X 
Day 1 
SLICC Damage Index 
 
X 
Day 1 
Physician Global Assessment (PGA) 
 
X 
Day 1 
Safety and Biomarker 
Laboratory assessments (including 
liver chemistry, serum 
immunoglobulin, Anti-dsDNA/ANA, 
and complement C3/C4) 
X 
X 
Day 1 
Biomarkers (including 
Antiphospholipid antibodies, PBMC, 
B-Cells, BLys Protein, RNA for 
interferon, and immunogenicity) 
 
X 
Day 1 
C-SSRS 
X 
X 
Day 1 
PROs 
Patient Global Assessment (PtGA) 
 
X 
Day 1 
FACIT-Fatigue score 
 
X 
Day 1 
LupusQoL 
 
X 
Day 1 
WPAI: Lupus 
 
X 
Day 1 
 
Baseline dose of corticosteroids is the 7-day average based on the 7 days prior to, but not 
including, treatment start date.  
Concomitant medications are considered to be present at baseline if the start date is prior 
to Day 1 and the end date is on or after Day 1. Medications or events with a start date on 
Day 1 are considered as being on treatment (Section 15.4.1). 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
24 
 
Adverse events (AEs) are considered pre-treatment if the start date is prior to Day 1. AEs 
with a start date on or after Day 1 are considered as being treatment-emergent. 
Baseline flares are flares that occur on or prior to the treatment start date.  Therefore, 
flares that occur on Day 1 are not counted as post-baseline flares. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.4. 
Multicentre Studies 
In this multicentre global study, enrolment will be presented by country and investigative 
site. Countries will be grouped into geographic regions for summary presentation 
[T11.01] as shown in Section 5.5.2. 
5.5. 
Examination of Covariates, Strata and Subgroups 
5.5.1. 
Covariates and Strata 
The list of strata is based on the randomization stratification and will be used in 
descriptive summaries and statistical analyses, some of which may also be used for 
subgroup analyses. Additional covariates and other strata of clinical interest have not 
been identified for planned analyses, but may be considered for post-hoc analyses. 
Category 
Details 
Strata (As 
Randomized) 
SLEDAI-2K: ≤9 vs. ≥10 
Immunosuppressant: Use vs. Non-use 
Corticosteroid dose: ≤10 mg/day vs. >10 mg/day 
 
The following covariates will be included in the analysis as detailed in Section 7 Efficacy 
Analyses  
Covariate 
Details 
SLEDAI-2K: ≤9 vs. ≥10 
Derived from the principal investigators’ assessment at baseline  
(reference level: ≥10) 
Immunosuppressant: Use 
vs. Non-use 
Derived from reported concomitant medications at baseline 
(reference level: Non-use) 
Corticosteroid dose: ≤10 
mg/day vs. >10 mg/day 
Derived from reported concomitant medications at baseline 
(reference level: >10mg/day) 
Covariates 
No additional covariates 
 
5.5.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered for post-hoc analyses. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
25 
 
• 
If the percentage of subjects responding is small within a subgroup, then the 
subgroup categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the subgroup. 
Subgroup 
Categories  
Age Group 
<65 vs. >=65 
If there are less than 10 subjects >=65, this sub group will be 
summarised but not analysed  
Race  
Black vs. Non-Black 
Gender  
Female vs Male 
Country Region 
USA/Canada: USA and Canada,  
Europe: France, Germany, Netherlands, Spain 
Rest of World: All other countries 
Baseline SLEDAI  
≤9 vs. ≥10 
Baseline Immunosuppressant 
Use 
Use vs. Non-use 
Baseline corticosteroid dose 
≤10 mg/day vs. >10 mg/day (Prednisone equivalent) 
Baseline complement level 
At least one low C3/C4 vs. No low C3/C4 
Baseline anti-dsDNA  
≥30 IU/mL vs. <30 IU/mL 
Baseline C3/C4 levels & anti-
dsDNA  
At least one low C3/C4 & anti-dsDNA ≥30 IU/mL vs. Not (At least 
one low C3/C4 & anti-dsDNA ≥ 30 IU/mL) 
Baseline BLyS (free) Protein  
>= 75th Percentile vs. < 75th Percentile 
Baseline RNA Interferon 
Signature  
Low vs. High 
 
 
5.6. 
Multiple Comparisons and Multiplicity 
The primary comparison of interest is the comparison between Arm B (combination) vs 
Arm A (control) for the primary endpoint (SLEDAI-2K≤2 (IBA)) in the MITT 
population. This analysis will be adjusted for  baseline SLEDAI-2K (≤9 vs. ≥10), 
baseline immunosuppressant (Use vs. Non-use) and baseline corticosteroid dose (≤10 
mg/day vs. >10 mg/day). . 
For the analysis of the primary and the major secondary efficacy endpoints, a step-down 
sequential testing procedure will be used to control the overall type 1 error rate for 
comparing Arm B (combination) vs Arm A (control). With this procedure, the primary 
endpoint aand the two major secondary endpoints will be evaluated for statistical 
significance based on a pre-specified sequence for interpretation (i.e. the endpoints based 
on SLEDAI-2K score (IBA) ≤ 2 at Week 52, followed by Clinical SLEDAI-2K score 
(IBA) =0 at Week 64 and then SLEDAI-2K score (IBA) ≤ 2 at Week 104, see Figure 1). 
Specifically, endpoints will be tested in the sequence above (2-sided alpha=0.05) 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
26 
 
provided that statistical significance is achieved by all prior tests. If at any point in the 
sequence statistical significance is not met, then subsequent endpoints in the sequence 
cannot be deemed statistically significant. The primary endpoint will be tested at the 
primary analysis using the first locked database; the first and second major secondary 
endpoints will be tested using the end of study locked database. 
 
An overview of the multiplicity control is provided in Figure 1. 
Figure 1 
Overview of Multiplicity Control 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analyses of other efficacy endpoints will not be subject to any multiplicity adjustment. 
5.7. 
Cut-off Date for Primary Analyses (Year 1) 
For study participants continuing in the study past the Week 52 visit, the cut-off date in 
the Year 1 analysis dataset will be the date of the Week 52 visit.  
For participants who discontinue from the study prior to the Week 52 visit, the 
exit/withdrawal visit will be assigned to an assessment window as defined in Section 
15.3. Exit/withdrawal visit assigned to week 52 or earlier will be included in the week 52 
report; exit/withdrawal visits assigned to an assessment window from Week 60 or later, 
will be reported in the Week 104 analysis.   
Participants who withdraw at or prior to the Week 52 visit will have their follow-up visit 
included in the Year 1 reporting if the follow-up visit is prior to or on the day of the last 
subject’s Week 52 visit.  Follow-up visits that occur after the last subjects’ Week 52 
Primary endpoint: 
Disease Control at week 52 
First major secondary endpoint: 
Clinical Remission at week 64 
Second major secondary endpoint: 
Disease Control at week 104 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
27 
 
assessment will be reported in the Year 2 reporting.  Hence subjects who withdraw at or 
prior to Week 52 will have a cut-off date that is the earliest of their week follow-up date 
and the last subject’s Week 52 date. 
Displays for the primary analysis reporting effort will include all data collected up to and 
including the Year 1 cut-off date for each participant.  This includes adverse events and 
concomitant medications with a start date less than or equal to the cut-off date.   
5.8. 
Database for End of Study Analyses (Year 2 and Years 1&2 
Combined) 
The final database will be an accumulation of all data from both Year 1 and Year 2 
including the 8-week Follow-up visit.   
5.9. 
Study Withdrawal 
Study withdrawal (referred to in the protocol as dropout), is the combination of subjects 
who withdraw, are lost to follow-up (LTFU), or die during the study 
Study withdrawal is defined as any subject who withdraws from the study prior to the 
analysis visit of interest (e.g. Week 52, Week 64, Week 104) and does not have a  visit 
within ± 28 days of the target analysis visit date (excluding follow up visits). 
This rule is applied consistently across all efficacy endpoints. The assessment of whether 
or not a subject had a visit within the ± 28 day of an analysis visit (e.g. Week 52) is 
performed at the domain level [e.g., a subject who had visit within 28 days for SLEDAI-
2K but not a SLICC ACR assessment would be assessed on their observed data for 
SLEDAI-2K but would be considered withdrawn (non-responder) in SLICC ACR 
assessment]. 
5.10. 
Treatment Failures  
Treatment failures are subjects meeting any of the criteria defined below, from the time 
they 1st met the criteria: 
• Received a protocol prohibited medication 
• Arm A&B: Received immunosuppressants after Week 4 rituximab infusion visit; 
Arm C: Increased immunosuppressants (at a dose higher than at baseline and 
Week 12) after Week 12 
• Arms A&B only: Received PI prescribed re-start belimumab medication after 
Week 52 visit and prior to Week 104 visit 
• Started any new immunosuppressant after Day 1 
• Received a prednisone equivalent corticosteroid 7-day average dose of >5 mg/day 
after Week 26 visit 
• Received a dose above the allowable level or after a protocol specified timepoint 
(Section 7.7.1 of the protocol) prior to Week 52 visit 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
28 
 
Further detail is provided in Section 15.6.15 Treatment Failure Rules During Study 
Conduct 
5.11. 
On Study 
For Year 1, on study is defined as from 1st dose of belimumab to the earliest of: 
• Week 52 visit assessment 
• Study withdrawal (including LTFU and Death)  
 
However, for subjects that withdraw during Year 1, the on treatment period could end 
later than the on study period.  In this situation the on study period will be reset such that 
it ends at the same time as the on treatment period. 
NOTE: Some subjects who are enrolled toward the end of the enrolment period and 
withdraw at or near their Week 52 assessment may have some of their Year 1 on study 
period reported at the end of the study (Section 5.7). 
For Year 2, on study is defined as from the Week 52 visit assessment* until the date of 
study completion or study withdrawal (including LTFU and death).  
*Subjects who did not complete week 52 but had not withdrawn prior to Week 52, and 
have post Week 52 assessments will use scheduled visit date. 
For Year 1&2 on study is defined as from the 1st dose of belimumab until the date of 
study completion or study withdrawal (including LTFU and death).  
5.12. 
On Treatment 
For Year 1 on treatment is defined as from 1st dose of belimumab to the latter of: last 
dose of belimumab + 28 days or last dose of rituximab + 28 days 
For Year 1&2 arm C, on treatment is defined as from 1st dose to last dose of belimumab + 
28 days. 
For Year 2 Arms A&B on treatment is not defined as there is no on treatment reporting 
(as all subjects are off treatment)  
5.13. 
Race Hierarchy (minority rule) 
If multiple race categories are checked on the eCRF, the subject will be assigned to a 
unique race group based on which of the races checked appears first in the list below: 
1. Native Hawaiian or Other Pacific Islander 
2. American Indian or Alaska Native 
3. Asian 
4. African American/African Heritage  
5. White 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
29 
 
For example, if African American/African Heritage and Asian are both checked, then the 
subject will be assigned as Asian since it appears highest in the list. Race assigned based 
on this minority rule will be applied to all analyses related to race (as per PSAP). In the 
race and racial combination details table, subjects with multiple race categories checked 
will be reported in the race per the minority rule as well as in the multiracial category. 
 
5.14. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
15.3 
Appendix 3: Assessment Windows 
15.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
15.5 
Appendix 5: Data Display Standards & Handling Conventions 
15.6 
Appendix 6: Derived and Transformed Data 
15.7 
Appendix 7: Reporting Standards for Missing Data 
15.8 
Appendix 8: Laboratory Parameters and Toxicity Grades 
15.9 
Appendix 9: Biomarkers 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
30 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Intent-to-Treat population, unless 
otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.   See 
Study Population shells for mock displays. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects randomized by country and site will be 
summarized overall and by treatment group using the Randomized population [T11.01]. 
The number of subjects in each population for the primary analyses (Screened, 
Randomized, ITT, MITT, MITT Week 52 prior to COVID-19, MITT Week 64 prior to 
COVID-19, Per Protocol, Ongoing at Week 52, Ongoing on study treatment at Week 52, 
As Treated and PK) and for the end-of-study analysis (Ongoing at Week 64, Ongoing on 
study treatment at Week 64, and Completed) will be summarized overall and by 
treatment group [T11.02, T21.01]. A summary of the reasons for the screen failures will 
be provided along with a listing of the subjects who were screen failures [T11.03, 
L11.01]. If there are any subjects who are randomized but do not receive any study 
treatment, they will be included on the subject disposition listing in the Randomized 
population, but not the ITT population. 
Subject status through Week 52 (Year 1), and over the entire study (Years 1&2 
Combined) will be summarized for the ITT [T11.04, T21.02] and MITT [T11.05, T21.03] 
populations.  
For the ITT population, a summary of treatment status and reasons for discontinuation of 
study treatment will be produced at Week 52 and at end of study. The number and 
percentage of subjects who completed the study treatment as planned as well as subjects 
who stopped study treatment prematurely, including reasons for treatment 
discontinuation, will be displayed by treatment group [T11.08, T11.09, T21.04]. 
The cumulative number and percentage of subjects withdrawing from the study by visit 
will be summarized for the ITT (T11.07) population at Week 52, and at Week 104 
(T21.05) and listed (L11.03, L21.02). 
A Kaplan-Meier (KM) plot of time to study withdrawal will be generated to evaluate the 
pattern of study withdrawals/LTFU/death over time up to Week 52 [F11.01].   
Subjects who withdraw (including LTFU and death) will be considered to have 
experienced an event (cens=0) at: 
   Time to study withdrawal = withdrawal date – 1st Belimumab injection date + 1 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
31 
 
Subjects ongoing at Week 52 will be considered censored (cens=1) at: 
   Time to study withdrawal = Week 52 date – 1st Belimumab injection date + 1 
The figure will be repeated for the Week 104 reporting with all data from Year 1 and 2 
[F21.01]. 
Subjects completing at Week 104 will be considered censored (cens=1) at: 
   Time to study withdrawal = Week 104 date – 1st Belimumab injection date + 1 
For the ITT population, the subject’s study completion status will be assessed to evaluate 
percentages of study withdrawals by treatment group as well as the reasons for study 
withdrawal.  The number and percentage of subjects who completed through Week 52 
(Week 64 and 104) and who withdrew from the study, including reasons for withdrawal, 
will be displayed by treatment group and overall for Year 1 and Year 1&2 separately 
[T11.06, T21.06].  A listing of subjects who withdrew from the study, including reason 
for and time to study withdrawal will also be provided.  [L11.03, L21.02]. 
Additionally, the cumulative number and percentage of subjects who prematurely 
discontinued from the planned study treatment by visit will be displayed by treatment 
group and overall for Year 1 and 2 separately for the ITT and MITT populations [T11.10, 
T11.11, T21.07, T21.08].  
A listing of subject disposition will be provided showing their completion status and 
whether they are included in each population [L11.02, L21.01].   
A shift table that summarizes the differences between the levels of each stratification 
factor at screening compared to values used in randomization will be provided [T11.16]. 
The COVID-19 environment onset and end dates will be listed (L11.15, L21.09).  
Current COVID-19 environment onset dates are shown in Section 15.6.16 
6.3. 
Demographic and Baseline Characteristics 
Continuous parameters will be summarized using descriptive statistics (mean, standard 
deviation, median, 25th percentile, 75th percentile, minimum, and maximum).  Categorical 
parameters will be summarized using counts and percentages. 
Demographic and baseline characteristics, as well as stratification factors, will be listed 
for all patients [L11.08, L11.09]. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
32 
 
The following Demographic and baseline disease activity indicators will be summarized: 
PARAMETER 
SUMMARY TYPE 
Medical History 
Past Medical Conditions [T11.22]. and Current 
Medical Conditions [T11.23]. 
Categorical: presented if past [current]. 
medical history is present 
Family History of Cardiovascular Risk Factors 
[T11.24]. 
Categorical: Yes, No 
Stratification Factors at Randomization [T11.25] 
SLEDAI-2K (PI) 
Categorical: <=9, >=10 
Baseline immunosuppressant use  
Categorical:  
- 
Use  
- 
Non-use 
Corticosteroid dose 
(prednisone equivalent) 
Categorical:  
- 
10 mg/day 
- 
>10 mg/day 
Demographic [T11.17, T11.18 (MITT population), T11.19] 
Age (years) 
Continuous 
Categorical: 
- 
<=45 years,  
- 
>45 – <65 years 
- 
>=65 years 
o >=65 – <75 years  
o >=75 years   
Country Region 
USA/Canada, 
Europe, 
Rest Of World (Section 5.5.2) 
Country  
As observed 
Corticosteroid dose 
(prednisone equivalent) 
Categorical:  
- 
5 mg/day 
       >5 mg/day 
Corticosteroid dose 
(prednisone equivalent) 
Categorical:  
- 
 0 mg/day 
       >0 mg/day 
Height (cm) 
Continuous 
Weight (kg) 
Continuous 
Body Mass Index (BMI) (kg/m2)  
Continuous 
Blood Pressure [T11.21]. 
Continuous 
Heart Rate (beats/min) [T11.21]. 
Continuous 
Sex 
Categorical: Female, Male 
Ethnicity: Hispanic or Latino origin  
Categorical: Hispanic or Latino origin, Not 
Hispanic or Latino origin 
Race and Racial Combination Details [T11.20]. 
Categorical: White/Caucasian, Asian, African 
American/African Heritage, Alaskan Native 
or American Indian, Native Hawaiian or 
Other Pacific Islander, and Multiracial  


 
CONFIDENTIAL 
 
 
 
 
205646 
 
33 
 
PARAMETER 
SUMMARY TYPE 
Baseline Disease Activity 
SLEDAI-2K score (IBA) [T11.26, T11.27 (MITT)]. Continuous 
Categorical: <=9, 10-11, >=12 
SLEDAI-2K score (PI) [T11.26, T11.27 (MITT)]. 
Continuous 
Categorical: <=9, 10-11, >=12 
 
PGA score [T11.26, T11.27 (MITT)]. 
Continuous 
Categorical: 0-1, >1 – 2.5, >2.5 
SLICC/ACR Damage Index score [T11.26, 
T11.27 (MITT)]. 
Continuous 
Categorical: 0, 1, >1 
SLE disease duration (years) [T11.26, T11.27 
(MITT)]. 
Continuous 
SLEDAI-2K (PI) by organ domain and item at 
baseline [T11.29]. 
Categorical: presented if Yes 
Baseline immunoglobulin levels (g/L):  
IgA, IgG, and IgM [T11.30]. 
 
Continuous value 
Categorical: 
- IgA: <LLN (0.81 g/L), >ULN (4.63 g/L) 
- IgG: <LLN (6.94 g/L), >ULN (16.18 g/L) 
- IgM: <LLN (0.48 g/L), >ULN (2.71 g/L) 
Baseline levels of complement:  
C3 [mg/dL] [T11.26, T11.27 (MITT)]. 
Continuous 
Categorical: high (>180 mg/dL), normal (90 -
180 mg/dL), low (<90 mg/dL)  
Baseline levels of complement:  
C4 [mg/dL] [T11.26, T11.27 (MITT)]. 
Continuous 
Categorical: high (>40 mg/dL), normal (10 -
40 mg/dL), low (<10 mg/dL)  
Complement Level [T11.26, T11.27 (MITT)] 
Categorical: At least one low C3/C4, No low 
C3/C4 
Anti-dsDNA [IU/mL] [T11.26, T11.27 (MITT)]. 
Continuous 
Categorical: 
-positive ( 30 IU/mL) 
-negative (< 30 IU/mL) 
Complement Level and anti-dsDNA Level 
[T11.26, T11.27 (MITT)].  
Categorical: At least one low C3/C4 and anti-
dsDNA ≥30 IU/mL; Not (At least one low 
C3/C4 and anti-dsDNA ≥30 IU/mL) 
Proteinuria (g/24h) [T11.26, T11.27 (MITT)] 
Continuous value 
Categorical: 
<=0.5 
>0.5-<1 
1-<2 
>=2 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
34 
 
PARAMETER 
SUMMARY TYPE 
Baseline autoantibody levels [T11.31]. 
ANA [Titer]. 
Continuous 
Categorical: 
-positive ( 80 Titer) 
-negative (< 80 Titer) 
 
anti-cardiolipin (aCL) 
Continuous for each of aCL-IgA, aCL-IgG, 
aCL-IgM 
Categorical (Positive is >=15) : 
-positive (if any of the three isotypes aCL-
IgG, aCL-IgA or aCL-IgM are above the 
upper limit of normal) 
-negative (if at least one is non-missing and 
none of the isotypes above the limit of 
quantification) 
-missing (all three isotypes are missing) 
 
anti-dsDNA and/or ANA positive  
Categorical: Yes, No 
Beta-2-glycoprotein [U/mL]. for each of the  
isotypes IgG, IgA, and IgM 
Continuous 
Categorical: Positive (>=21 U/mL), Negative 
Lupus anticoagulant  
Continuous 
RNA Interferon Signature  [T21.16] 
Continuous 
Categorical: Low, High 
B cells and T-cells at Baseline [T11.32] 
CD19+ Total B cells (cells/mL) 
B cells CD20+ (cells/mL) 
B cells CD20+ (%) 
Naive B cells IgD+ (cells/mL) 
Naive B cells IgD+ (%) 
Naive CD20+ CD27- (cells/mL) 
Naive CD20+ CD27- (%) 
Activated Total B cells CD95+ (cells/mL) 
Activated Total B cells CD95+ (%) 
Memory CD20+ CD27+ (cells/mL) 
Memory CD20+ CD27+ (%) 
Non-switched memory CD27+ IgD+ (cells/mL) 
Non-switched memory CD27+ IgD+ (%) 
Switched memory CD27+ IgD- (cells/mL) 
Switched memory CD27+ IgD- (%) 
Plasmablasts CD27b CD38b (cells/mL) 
Plasmablasts CD27b CD38b (%) 
Plasmablasts CD20+ CD27b CD38b  (cells/mL) 
Plasmablasts CD20+ CD27b CD38b  (%) 
Plasmablasts CD20- CD27b CD38b  (cells/mL) 
Plasmablasts CD20- CD27b CD38b  (%) 
Continuous 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
35 
 
PARAMETER 
SUMMARY TYPE 
Transitional CD10+ CD24b CD27- CD38b  
(cells/mL) 
Transitional CD10+ CD24b CD27- CD38b  (%) 
Transitional CD24b CD27- CD38b  (cells/mL) 
Transitional CD24b CD27- CD38b  (%) 
CD3+ Total T cells (/uL) 
CD8+ T cells (/uL) 
CD4+ T cells (/uL) 
 
BLyS (free) [ng/mL] . 
 
Continuous 
Categorical: below limit of quantification 
[LOQ]. (<0.05 ng/mL), above LOQ; <75th 
percentile, >=75th percentile 
 
Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline [T11.33]. 
C-SSRS responses by behavior and ideation 
components for lifetime and over the last six 
months 
Categorical: 
-Ideation: categories 1-5 with corresponding 
text 
-Behavior: categories 6-10 with 
corresponding text 
-Self-injurious behavior, no suicidal attempt 
 
Patient Reported Outcomes (PROs) [T11.28] 
Patient Global Assessment (PtGA) 
Continuous 
Baseline FACIT-Fatigue scale score 
 
Continuous 
Categorical: (<20; 20-<35; ≥35) 
LupusQoL 
Continuous 
WPAI: Lupus 
Continuous 
Allowable SLE Medication Usage at Baseline [T11.34] 
Allowable SLE medications by class and drug 
Categorical: 
Steroids, Anti-malarials, 
Immunosuppressants, Aspirin, NSAIDs 
Average daily prednisone dose (mg/day) at 
baseline 
 
Continuous 
Categorical: (0, >0 - ≤5, >5) 
 
Steroid, Anti-malarial and Immunosuppressant 
Use at Baseline 
 
Categorical: 
-Steroid Only 
-Immunosuppressant Only 
-Anti-malarial Only 
-Steroid and Immunosuppressant Only 
-Steroid and Anti-malarial Only 
-Immunosuppressant and Anti-malarial Only 
-Steroid and Immunosuppressant and Anti-
malarial 
Listings will be provided for current and past medical conditions [L11.10, L21.05]. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
36 
 
The summary of demographic and baseline characteristics, baseline disease activity and 
allowable SLE medication will be repeated for the following subgroups: 
• Age (<65 years, 65 years) [T11.40, T11.41, T11.42] 
• Race (Black vs. Non-Black) [T11.43, T11.44, T11.45] 
• Baseline SLEDAI-2K score (≤ 9 vs. ≥ 10) [T11.46, T11.47, T11.48] 
• Baseline Immunosuppressant use (use vs. non-use) [T11.49, T11.50, T11.51] 
• Baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day) 
[T11.52, T11.53, T11.54] 
• Gender (Male vs Female) [T11.55, T11.56, T11.57] 
• Country Region (USA/Canada, Europe, Rest of World) [T11.58, T11.59, T11.60] 
• Baseline complement level (At least one low C3/C4 vs. No low C3/C4) [T11.61, 
T11.62, T11.63] 
• Anti-dsDNA (≥ 30 IU/mL vs < 30 IU/mL) [T11.64, T11.65, T11.66] 
• Baseline C3/C4 levels & anti-dsDNA (At least one low C3/C4 & anti-dsDNA ≥30 
IU/mL vs. Not (At least one low C3/C4 & anti-dsDNA ≥ 30 IU/mL)) [T11.67, 
T11.68, T11.69] 
• Baseline BLyS Protein (>=75th Percentile vs <75th Percentile) [T11.70, T11.71, 
T11.72] 
• RNA Interferon Signature (Low vs. High) [T21.17, T21.18, TT21.19] 
 
 
6.4. 
Concomitant Medications 
Concomitant medications will be coded according to drug name as defined in the GSK 
Drug Dictionary, and classified according to the GSK-Drug ATC classification level 1 
and ATC level 4.  Concomitant medications are defined as medications that start on or 
before the first dose date of study treatment and end on or after the first dose date of study 
treatment, or medications that start after the first dose date of study treatment (see Section 
15.4.1 for further details).  Note that medications with partial or missing start and/or stop 
dates will be assumed to be concomitant unless there is evidence through comparison of 
partial dates to suggest otherwise, for example if the day is missing, then the month and 
year will be compared to the month and year of the first dose date of study treatment and 
if the month and year are the same or later, then the medication will be considered 
concomitant (see Section 15.7.2.1 for further details). 
A summary of the number and percentage of subjects with concomitant medications by 
ATC level 1 term and ATC level 4 term will be displayed for both Year 1 and Year 2 
separately [T11.35, T21.11]. A further summary of concomitant medications by ATC 
level 4 term and preferred term will be provided for both Year 1  and Year 2  [T11.36, 
T21.12].  A listing of all concomitant medication data will be displayed by treatment and 
subject [L11.11, L21.06].  
Protocol-prohibited medication and allowable medication that results in treatment failure 
designation (see Section 7.7 of the protocol) will be summarized by treatment group.  
[T11.37, T21.13]. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
37 
 
A listing of protocol-prohibited medication and allowable medication that result in 
treatment failure designation will be displayed by treatment and subject [L11.12, 
L21.07]. 
6.5. 
Extent of Exposure to Study Treatment 
Exposure listings detail the amount of planned study medication that was taken, and re-
start medication (belimumab taken in Year 2 for Arms A and B).  However they do not 
include concomitant medication  of  non-study belimumab or rituximab. 
Exposure data for both belimumab and rituximab will be listed for: 
• Year1: Arm A, B, and C for belimumab; and Arms A and B for rituximab/placebo in 
Year 1 [L11.13]. 
• Year 2: Arm A&B: Includes late Year 1 doses (taken in year 2) for Belimumab and 
re-start Belimumab;  Arm C belimumab in Year 2 [L21.08]. 
See Section 15.6.2 for further details. 
Belimumab 
The extent of exposure to belimumab through Week 52 for Arm A and Arm B and 
through Week 104 for Arm C will be assessed by examining the duration of exposure to 
belimumab in days and the total number of injections a subject receives.  Duration of 
exposure in days will be calculated as: 
Duration of exposure (days) = (Last injection date – First injection date + 7).   
Only complete dates will be used when calculating duration of exposure.  First and last 
injection dates will be used, regardless of any missed doses. 
Percent compliance will be calculated as: 
100* (Number of injections prescribed – Number of injections missed)/Number of 
injections prescribed. 
The duration of exposure, the total number of injections, and the percent compliance will 
be summarized using descriptive statistics for the treatment phase.  The total number of 
injections will also be summarized using counts and percentages using the following 
categories: 1 – 12 doses, 13 – 24 doses, 25 – 36 doses, 37 - 52 and > 52 doses (if 
applicable).  [T11.38].  Similarly, exposure to belimumab in Arm C from Baseline to 
Week 104 will also be summarized using the following categories: 1 – 12 doses, 13 – 24 
doses, 25 – 36 doses, 37 - 52 doses, 53 - 64 doses, 65 - 76 doses, 77 – 88 doses, 89 - 104 
doses, and >104 doses (if applicable) [T21.14]. 
Exposure to belimumab will also be summarized for subjects during Year 2 only.  For 
subjects in Arms A and B this will include incorrectly taken Year 1 medication after 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
38 
 
Week 52 and re-start medication [T21.15].  The first dose in Year 2 will be the 1st  dose 
the subject took on the day of or after the Week 52 visit date. 
Duration of exposure (days) = (Last injection date – First injection date + 7).   
 
Rituximab 
For subjects randomized to Arms A and B, the extent of exposure to rituximab/rituximab-
placebo will be assessed by examining the dose intensity and the total number of 
infusions, i.e. 0, 1 or 2. Dose intensity in mg will be calculated as the cumulative actual 
dose divided by 2. If the total volume of an infusion is not administered, the actual dose 
infused for that visit will be calculated as: 
Actual Dose infused (mg) = Planned Dose (mg) * Percentage of volume infused 
Dose intensity and total number of infusions will be summarized using descriptive 
statistics [T11.39].  
Data Listings 
Subjects for whom the treatment blind was broken [L11.14], or potentially the treatment 
blind broken (29 subjects inappropriately identified on a lab report) will be provided 
[L11.02]. 
6.6. 
Time to Study Treatment Discontinuation 
This only includes the belimumab study medication as prescribed in Year 1 (and Year 2 
for Arms C) i.e. this does not include re-start belimumab for subjects in Arms A&B in 
Year 2. 
Year 1 (all arms) and Year 1&2 for Arms A&B only 
• If the last dose of belimumab+10 days is prior to the Week 52 visit date (where 
Week 52 visit date is as observed, or predicted as day1+364 for subjects who do 
not have a Week 52 visit) then the subject has discontinued treatment (had the 
event / CENSOR=NO=0) at the earliest non-missing date of (last dose date +7, 
date of death, withdrawal date, LTFU date) 
• If the last dose of belimumab + 10 days is on or post the Week 52 visit date 
(where Week 52 visit date is as observed, or predicted as day1+364 for subjects 
who do not have a Week 52 visit) then the subject has a censored time to 
discontinued treatment (does not have the event / CENSOR=Yes=1) at the earliest 
non-missing date of (observed or predicted Week 52 visit date, death date, 
withdrawal date, LTFU date) 
 
Year 1&2 for arm C only 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
39 
 
• If the last dose of belimumab + 10 days is prior to the Week 104 visit date (where 
Week 104 visit date is as observed, or predicted as day1+728 for subjects who do 
not have a Week 104 visit) then the subject has discontinued treatment (had the 
event / CENSOR=NO=0) at the earliest non-missing date of ( last dose date +7, 
date of death, withdrawal date, LTFU date) 
• If the last dose of belimumab + 10 days is on or post the Week 104 visit date 
(where Week 104 visit date is as observed, or predicted as day1+728 for subjects 
who do not have a Week 104 visit) then the subject has a censored time to 
discontinued treatment (does not have the event / CENSOR=Yes=1) at the earliest 
non-missing date of (observed or predicted Week 104 visit date, death date, 
withdrawal date, LTFU date) 
A KM plot of time to belimumab treatment discontinuation will also be generated 
[F11.02].  The figures will be repeated for the Week 104 reporting with all data from 
Year 1 and 2 combined [F21.02].  Due to the design of the study Arms A & B will be 
truncated at the end of Year 1.  A listing of subjects who discontinued belimumab or 
Rituximab treatment, including reason will be produced [L11.04, L11.05 , L21.03]. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
40 
 
7. 
EFFICACY ANALYSES 
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 summary of Arm B (Combination) vs Arm C (Reference) will also be 
shown. 
SLEDAI-2K score has been measured by both the principal investigator (PI) and the 
independent blinded assessor (IBA).  The key differences between these assessments is 
the frequency of assessment and awareness of the treatment allocation for Arm C: 
• The principal investigator conducts a SLEDAI-2K assessment every 4 weeks in Year 
1 (at least every 8 weeks in Year 2), whereas the independent blinded assessor 
conducts a SLEDAI-2K assessment at a reduced set of key time points (weeks 
baseline, 12, 26, 40, 52, 64, 80, and 104). 
• The principal investigator knows which of their subjects are randomised to treatment 
arm C, but does not know if their remaining subjects are randomised to arm A or arm 
B.  The independent blinded assessor however is not aware of any MITT population 
subject’s treatment randomisation (Section 4). 
Due to the level of blinding the primary and major secondary efficacy endpoints will be 
conducted using the independent blinded assessors’ SLEDAI-2K assessment.   Note 
however the PI assessment of SLEDAI-2K at baseline, is used as the baseline covariate in 
all adjusted analysis  (the baseline SLEDAI-2K assessment is conducted prior to 
randomisation). 
 
The other secondary endpoints analysis utilises the greater visit frequency of the principal 
investigator assessment.  This is particularly pertinent for differentiating between 
treatments when considering time to response or duration of response.  In by visit 
summaries, it also allows for the assessment of fluctuating response. 
 
The primary and major secondary efficacy endpoints are repeated using the principal 
investigator assessment. 
 
Details of the planned displays are provided in Section 15.11 and are based on GSK data 
standards and statistical principles.  Listings of all key efficacy endpoints will be 
provided [L12.01 – L12.02, and L22.01-L22.02]. 
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
41 
 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
The protocol defined primary endpoint is the proportion of participants with a state of 
disease control defined as a SLEDAI-2K score ≤2 (IBA), achieved without 
immunosuppressants and with corticosteroids at a prednisone equivalent dose of 
5mg/day at Week 52 (Protocol Section 4).    
 
The protocol Section 10.4.1 Efficacy analysis then clarifies that: 
 
For participants who withdraw prematurely from study treatment and for who 
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 . 
 
Hence when adopting the ICH Estimands and Sensitivity Analysis in Clinical Trials E9 
R1 addendum terminology, this endpoint is defined as: 
 
Disease Control 
Responder: 
• SLEDAI-2K score ≤2 (IBA); and 
• Not a TF at the current or any prior visit (TF includes consideration of corticosteroids 
and immunosuppressants); and 
• Did not withdraw  from the study prior to the visit 
Non-Responder: 
• SLEDAI-2K score >2 (IBA); or 
• TF at the current or any prior visit (TF includes consideration of corticosteroids and 
immunosuppressants); or 
• Withdrew from the study prior to visit (which includes study withdrawal, lost to 
follow-up and death) 
The derivation of SLEDAI-2K score is provided in Section 15.6.3, treatment failures are 
defined in Section 15.6.15. and withdrawal from the study prior to Week 52 in Section 5.9. 
Note: Discontinuation of study investigational product (belimumab or rituximab) is NOT a 
component of this endpoint, subjects who discontinue investigational product will only be 
non-responders if they also meet one of the criteria above. 
Note this clarification of notation does not change the protocol-specified primary 
analysis.  
 
The analysis of the primary endpoint of Arm A vs Arm B will use data from treatment 
Arms A, and B only.   
An exploratory analysis of the relative performance of Arm B  vs. Arm C will also be 
conducted, using data from Arms B and C only. 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
42 
 
7.1.2. 
Summary Measure 
The odds ratio at Week 52 between Arm B (Combination) vs Arm A (Control). 
7.1.3. 
Population of Interest  
The primary efficacy analyses will be based on the Modified Intent-To-Treat population, 
unless otherwise specified. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
There are 5 potential types of intercurrent events considered for this study: 
• Treatment Failure 
• Study Withdrawal 
• Lost to Follow-up 
• Death 
• Investigational Product (IP) Discontinuation . 
 
Whilst study withdrawal and lost to follow-up (LTFU) are not true intercurrent events per 
ICH Estimands and Sensitivity Analysis in Clinical Trials E9 R1 addendum terminology; 
they are included in the reporting here to allow for backward compatibility to the study 
Protocol (see Section 7.1.1). 
 
Four intercurrent event strategies are employed: 
• Hybrid strategy considers all data while the subject is continuing in the study 
irrespective of IP discontinuation.  Treatment failure and study withdrawal (including 
LTFU and death) are components of the endpoint definition.  Subjects who 
discontinue investigational product (belimumab) are encouraged to continue in the 
study.  
• Composite strategy considers data collected only while the subject is continuing to 
receive study treatment.  Treatment failure and study withdrawal (including LTFU 
and death), and IP discontinuation are components of the endpoint definition. 
• Hybrid on treatment strategy considers data collected only while the subject is 
receiving study treatment.  Treatment failure and study withdrawal (including LTFU 
and death), are components of the endpoint definition. IP discontinuation are 
excluded (unless already experienced treatment failure). 
• Treatment Policy strategy considers all data while the subject is continuing in the 
study irrespective of IP discontinuation or Treatment Failure.  Study withdrawal 
(including LTFU and death), are components of the endpoint definition 
The main estimand of this endpoint, is a Hybrid strategy, subjects who discontinue 
investigational product will continue in the study, assessments after treatment 
discontinuation will be included in the main estimand.  Subjects who are a treatment 
failure or withdraw from the study will be a non-responder for this estimand.   
 


 
CONFIDENTIAL 
 
 
 
 
205646 
 
43 
 
An analysis of 3 supportive estimands will also be conducted using the alternative 
intercurrent event strategies, namely: 
• Composite,  
This will include IP discontinuation as an intercurrent event resulting in the 
subject being a non-responder. 
• Hybrid On treatment,  
This will only include subjects whilst they are on treatment, or if they have 
met the definition of a non-responder prior to discontinuing treatment. 
• Treatment Policy,  
Assessments after IP discontinuation and assessments after Treatment Failure 
will be included.  Subjects who withdraw from the study will be non-
responders. 
 
 
The impact of the different IP discontinuation components of the endpoint for the Hybrid  
and composite estimands is summarised by considering 6 hypothetical scenarios: 
 


 
CONFIDENTIAL 
 
205646 
 
44 
 
Table 2 
Scenarios for the components of the Hybrid and composite endpoint 
Example 
Subject 
SLEDAI-2K score at Week 52 
Study 
Withdrawal(including 
Lost to Follow-up, or 
Death) prior to Week 52 
Treatment 
Failure 
prior to 
Week 52 
IP 
Discontinuation 
prior to Week 
52 
 
Main Estimand 
Hybrid  
 
Supplemental 
Estimand 
Composite 
 
 
 
 
 
 
 
 
1 
>2 
N 
N or Y 
N or Y 
 
NR 
NR 
2 
<=2 
N 
N 
N 
 
R 
R 
3 
<=2 
N 
N 
Y 
 
R 
NR 
4 
<=2 
N 
Y 
N or Y 
 
NR 
NR 
5 
Incomplete* or entirely missing  N 
N or Y 
N or Y 
 
NR 
NR 
6 
Missing - does not exist due to 
study withdrawal   
Y  
N or Y 
Y 
 
NR 
NR 
 
R = Responder; NR = Non-Responder 
*Incomplete: does not include partial scores where it is possible to determine that the total score must be >2, or that the maximum 
possible score (assuming worst case for missing data) is <=2 (see Section 15.6.4 Partial but informative SLEDAI-2K score ). 
 
A full breakdown of scenarios ‘by subject type’ and including Hybrid On Treatment and Treatment Policy is provided in Section 15.6.4 
 


 
CONFIDENTIAL 
 
205646 
 
45 
 
7.1.5. 
Statistical Analyses / Methods 
7.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• The proportion of participants with a state of disease control defined as a SLEDAI-2K score ≤2 
(IBA), achieved without treatment failure or study withdrawal 
 Derivation  
• Derivation of the endpoint for Arms A, B and C is provided in Section 15 
Model Specification 
• Logistic regression model. 
• Terms in the model: 
• Dependent: response (yes/no) 
• Categorical: treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose (prednisone 
equivalent 10 mg/day vs. >10 mg/day). 
Model Checking & Diagnostics 
• 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. 
• If the model diagnostics raise questions about the validity of the analysis additional non-
parametric analysis will also be conducted.    
Model Results Presentation 
• The table [T12.01] will display: 
• the number, percentage, SE of percentage, and the 95% CI for the percentage of 
subjects achieving a response by treatment group,  
• the observed difference in percentage of responders for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C, 
• the stratified (baseline SLEDAI-2K score, baseline immunosuppressant use, 
baseline corticosteroid dose) Cochran-Mantel-Haenszel treatment difference and 
95% confidence interval (CI) for the comparison of Arm B vs Arm A; and Arm B vs 
Arm C. 
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs Arm 
A; and Arm B vs Arm C. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A.  
• A table [T12.02]. showing the details from the logistic regression will also be presented; 
including:  
• the parameter estimate and standard error for each of the terms in the model  
• the odds ratio and 95% CI and p-value for each covariate in the model 
• the parameter estimate, standard error, odds ratio, 95% CI and p-value for the 
comparison of Arm B vs Arm A 


 
CONFIDENTIAL 
 
205646 
 
46 
 
• the parameter estimate, standard error, odds ratio, and 95% CI for the comparison 
of Arm B vs Arm C 
• the odds ratio and 95% CI for the comparison of Arm A vs Arm C 
• The proportion of participants with a state of disease control at Week 52 will be displayed in a 
point estimate +/- SE figure, by treatment group [F12.01]. 
Subgroup Analyses 
The comparison of the primary efficacy endpoint between Arm B vs. Arm A will be performed by the 
following subgroups [F12.02]: 
• Age (<65 years vs. 65 years) [T12.16]. 
• Race (Black vs. Non-Black) [T12.17]. 
• Gender (Male vs. Female) [T12.18] 
• Baseline SLEDAI-2K score (≤ 9 vs. ≥ 10) [T12.19]. 
• Baseline immunosuppressant use (use vs. non-use) [T12.20]. 
• Baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day) [T12.21]. 
• Baseline C3/C4 levels & anti-dsDNA (At least one C3/C4 low & anti-dsDNA >= 30 IU/mL vs. 
NOT (At least one C3/C4 low & anti-dsDNA >= 30 IU/mL)) [T12.24]. 
• BLyS Protein at baseline (>= 75th Percentile vs. < 75th Percentile) [T12.25]. 
• Country Region (USA/Canada vs. Europe vs. Rest of World) [T12.26]. 
• Baseline complement level (At least one low C3/C4 vs. No low C3/C4) [T12.22]. 
• Anti-dsDNA (<30 IU/mL vs. >=30 IU/mL) [T12.23] 
• RNA Interferon Signature at baseline (Low vs. High) [T22.34] (note this assessment of 
subgroups for the primary endpoint will be reported at the end of the study). 
Each of the subgroups will be analysed separately using a logistic regression model with adjustment 
for the stratification factors, using the Intercurrent event strategy: Hybrid .  If the model fails to 
converge the relevant stratification factor(s) will be removed from the model. 
To further assess each subgroup, the interaction between treatment and the subgroup will be tested 
by fitting a logistic regression model to the data (all subgroups combined).  The model, will include 
the stratification factors, the variable for the subgroup, and the interaction term between treatment 
group and the subgroup.  The summary table will include the p-value for  the interaction that tests the 
of stability of Arm B vs Arm A over the 2 (or more) levels of the subgroup.  If the logistic model fails to 
converge then the interaction p-value will not be presented. 
Supportive Analyses 
• The disposition of the primary endpoint, detailing the reasons why a subject was a non-
responder will be summarized (n,%) [T12.03, T12.04]. 
• The components of the primary endpoint will be summarized [T12.05].  i.e. proportion of 
participants with: 
o SLEDAI 2K-score ≤2 (IBA) 
o Treatment failure due to corticosteroid use 
o Treatment failure due to immunosuppressant use 
o Treatment failure due to anti-malarial, NSAID, Aspirin or other prohibited medication 
use  
o Study withdrawal 
• The table will include 


 
CONFIDENTIAL 
 
205646 
 
47 
 
• the number, percentage, SE of percentage, and the 95% CI for the percentage of 
subjects achieving a response by treatment group 
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs Arm 
A; and Arm B vs Arm C. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A 
• The primary efficacy analysis at Week 52 will be repeated to assess the robustness of the 
primary efficacy results: 
• ITT population –Including subjects where the independent blinded assessor was potentially 
unblinded at Week 52 .  Intercurrent event strategy: Hybrid [T12.06]. 
• Unadjusted for covariates. the only independent variable in the model will be treatment 
group.  Intercurrent event strategy: Hybrid  [T12.07]. 
• Composite. Intercurrent event strategy: Composite [T12.08]. 
• Hybrid On treatment.  Intercurrent event strategy: Hybrid On Treatment [T12.10]. 
• Treatment Policy.  Intercurrent event strategy: Treatment Policy [12.11]. 
• Per Protocol population.  Intercurrent event strategy: Hybrid[T12.09]. 
• Ongoing on study treatment at Week 52 population.  Intercurrent event strategy: Hybrid on 
Treatment [T12.12]. 
• A supportive analysis that considers all the data from Arms A, B, and C in the same model will 
also be conducted.  Estimates of the treatment effect will be made for comparison of Arms A vs 
B and Arms B vs C. Intercurrent event strategy: Hybrid (T12.13) 
• Two tipping point analyses may be performed if there is a significant treatment difference, 
including all recorded data up to the time of study withdrawal, and using differing assumptions 
regarding data missing following study withdrawal (Section 7.1.6).  Intercurrent event strategy: 
Hybrid [T12.14, F12.03]. Intercurrent event strategy: Treatment Policy [T12.15, F12.04]. 
 
7.1.6. 
Tipping Point Analysis 
Tipping point analyses will be performed for the primary endpoint if the endpoint is 
statistically significant and it is plausible that missing data caused by study withdrawal could 
alter the conclusions of the analysis (treatment p-value is ≤ 0.05 and > 0.001). If the tipping 
point analyses are needed, they will be performed shortly after the Statistical Analysis 
Complete milestone has been met and will be presented in the clinical study report. 
The tipping point analyses will be based on the Intent-to-Treat population.  Only the subjects 
in the belimumab plus placebo, and belimumab plus rituximab arms will be considered. 
For the primary analysis, subjects for whom the Week 52 disease control status cannot be 
determined due to study withdrawal (including lost to follow-up, and death) are imputed as 
non-responders.  In contrast, the missing data due to study withdrawal in the tipping point 
analysis is evaluated using multiple imputation methods, by simulating all combinations of 
response probability in the treatment arms independently.   
The first tipping point analysis will use the Hybrid strategy (as described in Section 7.1.4 as 
per the primary estimand).  If a subject’s study withdrawal is subsequent to treatment failure 
the subject will still be considered as a non-responder, i.e. the non-responder assumption will 
only be varied for withdrawn subjects that were not treatment failures.  


 
CONFIDENTIAL 
 
205646 
 
48 
 
The second tipping point analysis will use the treatment policy strategy (Section 7.1.4).  In 
this approach, treatment failure data is ignored, i.e. the non-responder assumption is varied 
for all withdrawn subjects regardless of treatment failures. 
The tipping point analyses will not consider covariates.  However, if the conclusions of the 
primary analysis adjusting for covariates differ from the conclusions of the unadjusted 
analysis, a post hoc analysis assessing the impact of covariate adjustment in the tipping point 
analyses may be performed.  
The following multiple imputation method will be implemented: 
1. For subjects in Arm A (belimumab plus placebo) and Arm B (belimumab plus 
rituximab) with missing Bernoulli outcomes, a grid of the probability of response 
varying from 0.025 to 0.975 by 0.025 will be created.  This will create all 
combinations, from low to high response probability, for subjects with a missing 
response.   
2. For a given of probability (e.g., 0.025 for Arm A, 0.500 for Arm B) 
a. An incidence of the number of additional responders for Arm A (Arm B) 
given the number of Arm A (Arm B) subjects with missing outcome and the 
probability assumed (e.g., 0.025 (e.g., 0.500)) will be simulated using the 
binomial distribution.  
b. The statistics (sample mean and standard error) will be calculated and used to 
construct the Mantel-Haenszel Chi-Square test. 
Steps 2a and 2b will be repeated 1000 times, and Rubin’s rules applied to combine them, in 
order to obtain a single p-value for each given probability combination. 
Heat maps will be produced (Figure 2) to show the results of the multiple imputation tipping 
point analyses for disease control at Week 52.  The black lines on each heat map will 
represent a plausible scenario whereby the probability of response for the missing data in 
Arms A and B will be equal to the observed case response rate on the control arm (Arm A: 
belimumab plus placebo). 


 
CONFIDENTIAL 
 
205646 
 
49 
 
Figure 2 
Tipping Point for Disease Control at Week 52 
 
A tipping point analysis will also be performed for the key secondary endpoints if there is 
hierarchical significance for the endpoint, and it is plausible that the imputation strategy for 
missing data could alter the conclusions of the analysis (treatment p-value is ≤ 0.05 and > 
0.001). 
7.1.7. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic on the Primary Endpoint 
Additional analyses will be carried out to assess the impact of the COVID-19 pandemic on the primary 
endpoint.  The additional analyses will utilise the COVID-19 environment onset date (Section 15.6.16) 
to establish which data might be affected by COVID-19.   
7.1.7.1. 
COVID Attributed – Observed Data until Intercurrent Events That Could be 
Attributable to the COVID-19 Pandemic 
The first additional analysis (T12.40) uses the observed SLEDAI-2K data, as long the subject has not 
experienced a treatment failure or study withdrawal that could have been attributable to COVID-19 (i.e. 
after the COVID-19 environment onset date). 
A Hypothetical estimand will be used to estimate the treatment effect had the COVID-19 pandemic not 
occurred.  The difference in response rates between Arm A and Arm B at Week 52 will be assessed for 
subjects who: 
• achieve a SLEDAI 2K-score ≤2 (IBA),  
• without immunosuppressants that could be attributable to the COVID-19 pandemic and  
• with corticosteroids at a prednisone equivalent dose of 5mg/day, in the absence of higher 
doses that could be attributable to the COVID-19 pandemic 
The full MITT population will be used, with the following attributes: 


 
CONFIDENTIAL 
 
205646 
 
50 
 
• A strategy that matches the primary analysis (Hybrid) will be used for the following Intercurrent 
Events to classify the subject as a Non-Responder:  
o Study Withdrawal (includes  Lost to Follow Up) that occurs prior to the COVID-19 
environment onset date 
o Treatment Failure (includes consideration of corticosteroids and immunosuppressants) 
that occurs prior to the COVID-19 environment onset date 
o Death that occurs at any time 
• A hypothetical strategy will be used for any subject who has their  Week 52 assessment 
scheduled to be on or after the COVID-19 environment onset date, who has not been classified 
as a Non-Responder using the strategy above, and has any of the following Intercurrent Events 
on or after the COVID-19 onset date: 
o Study Withdrawal (includes Lost to Follow Up) 
o Treatment Failure (includes consideration of corticosteroids and immunosuppressants) 
o Missing SLEDAI-2K score (IBA) 
The response status for these subjects will be treated as a missing value and will be assumed 
to be Missing At Random (MAR).  It will be imputed using Multiple Imputation methods, which 
take into account the subjects baseline characteristics and their existing pre-COVID-19 data. 
• Discontinuation of study investigational product (belimumab or rituximab) is NOT a component 
of this endpoint.  
Imputation of Missing Data 
• A bayesian repeated measures logistic regression model will be fitted to the observed data, 
using a Markov Chain Monte Carlo (MCMC) approach, adjusting for treatment group, baseline 
SLEDAI-2K score (9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), and 
baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day).  Non-
informative priors will be used. 
• Samples will be drawn from the posterior distribution of the model parameters of the Bernoulli 
distribution for each treatment group and each missingness pattern. 
• Each sample leads to a separate imputed dataset, in which the missing values are replaced by 
values drawn randomly from their conditional distribution. This distribution is based on the 
observed data and the covariates for that subject using the imputation model and the sampled 
parameter values. 
• These steps will be repeated at least 1000 times. 
Model Specification 
• Each imputed dataset will be analyzed using logistic regression to evaluate the treatment effect 
controlling for treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose (prednisone 
equivalent 10 mg/day vs. >10 mg/day).   
• The resulting Odds Ratios and their Standard Errors will be combined across imputations using 
Rubin’s rules. 
 
7.1.7.2. 
COVID Environment – Observed Data Until the COVID-19 Pandemic 
The second additional analysis assumes that all data after the COVID-19 environment onset date may 
either be missing due to the pandemic or affected by the pandemic.  There may be intangible ways that 


 
CONFIDENTIAL 
 
205646 
 
51 
 
the data may have been affected even if it has been collected, therefore this analysis accepts that we 
cannot distinguish between affected and unaffected data after the COVID-19 environment onset date. 
A Hypothetical estimand will be used to estimate the treatment effect had the COVID-19 pandemic not 
occurred.  The difference in response rates between Arm A and Arm B at Week 52 will be assessed for 
subjects who: 
• achieve a SLEDAI 2K-score ≤2 (IBA),  
• without immunosuppressants and  
• with corticosteroids at a prednisone equivalent dose of 5mg/day and 
• in the absence of any Intercurrent Events that could be attributable to the COVID-19 pandemic, 
based on the COVID-19 environment onset date. 
The full MITT population will be used, with the following attributes: 
• A strategy that matches the primary analysis (Hybrid) will be used for the following Intercurrent 
Events to classify the subject as a Non-Responder:  
o Study Withdrawal (includes Lost to Follow Up and death) that occurs prior to the onset 
date 
o Treatment Failure (includes consideration of corticosteroids and immunosuppressants) 
that occurs prior to the onset date 
o  
• A hypothetical strategy using the COVID-19 environment onset date as the Intercurrent Event 
will be used for any subject who has their Week 52 assessment scheduled to be on or after the 
COVID-19 environment onset date, who has not already been classified as a Non-Responder 
using the strategy above.  The response status for these subjects will be treated as a missing 
value and will be assumed to be Missing At Random (MAR).  It will be imputed using Multiple 
Imputation methods, which take into account the subjects baseline characteristics and their 
existing pre-COVID data. 
• Discontinuation of study investigational product (belimumab or rituximab) is NOT a component 
of this endpoint. 
The statistical methods will match the first additional analysis (Section 7.1.7.1) [T12.41]. 
7.1.7.3. 
Pre-COVID – MITT Population Prior to the COVID-19 Pandemic 
The third additional analysis will use the “MITT Week 52 prior to COVID-19” analysis population.  This 
will assess the treatment difference on the subset of subjects who completed Week 52 before the 
COVID-19 environment onset date and hence have  no possible COVID-19 impact on any of their 
assessments.   
A Hybrid estimand will be used to estimate the treatment effect in the population of subjects for which 
the COVID-19 pandemic not occurred.  The difference in response rates between Arm A and Arm B at 
Week 52 will be assessed for subjects who complete Week 52 prior to the COVID-19 environment 
onset date and who: 
• achieve a SLEDAI 2K-score ≤2 (IBA),  
• without immunosuppressants and  
• with corticosteroids at a prednisone equivalent dose of 5mg/day. 


 
CONFIDENTIAL 
 
205646 
 
52 
 
The “MITT Week 52 prior to COVID-19” population will be used, with the following attributes: 
• A strategy that matches the primary analysis (Hybrid) will be used for the following Intercurrent 
Events to classify the subject as a Non-Responder:  
o Study Withdrawal (includes Lost to Follow Up and Death) 
o Treatment Failure (includes consideration of corticosteroids and immunosuppressants) 
• Discontinuation of study investigational product (belimumab or rituximab) is NOT a component 
of this endpoint. 
The statistical methods will match the primary analysis (Section 7.1.5) for the endpoint definition, 
derivation, model specification, model checking and diagnostics and the model results presentation 
[T12.42]. 
7.1.7.4. 
Graphical Representation of the Additional Analyses 
Table 3 shows a graphical representation of specific scenarios for individual subjects, in terms of their 
completion status or any Intercurrent Events, and the timing of them in relation to the COVID-19 
environment onset date (Section 15.6.16).  The way in which the data for subjects in each scenario will 
be used is presented for the primary analysis, plus each of the three pre-specified additional analyses 
to investigate the COVID-19 pandemic. 
 


 
CONFIDENTIAL 
 
205646 
 
53 
 
Table 3 
Graphical Representation of the Additional Analyses 
                                                    COVID-19 environment  
                                                                Onset date 
 
Description 
Primary 
Analysis 
Hybrid 
 
COVID 
Attributed 
 
COVID 
Environment 
 
Pre-
COVID 
X                                                  0   Comp. 
 
Subject Completes Week 52 prior to 
onset date 
R/NR 
R/NR 
R/NR 
R/NR 
X                    0   WD/Death 
 
Subject had scheduled Week 52 
prior to COVID-19 environment 
onset date, but Withdraws / LTFU / 
Dies prior to COVID-19 environment 
onset date 
NR 
NR 
NR 
NR 
X                          0   TF 
 
Subject had scheduled Week 52 
prior to onset date, but has 
Treatment Failure prior to onset date 
NR 
NR 
NR 
NR 
                                  X                                           0   Comp. Subject Completes on or after 
COVID-19 environment onset date  
R/NR 
R/NR 
Imputed 
Excluded 
                                  X             0   
WD/Death 
 
Subject had scheduled Week 52 on 
or after onset date, but 
Withdraws/Dies prior to onset date 
NR 
NR 
NR 
Excluded 
                                  X                        0   
TF 
 
Subject had scheduled Week 52 on 
or after onset date, but has 
Treatment Failure prior to onset date 
NR 
NR 
NR 
Excluded 


 
CONFIDENTIAL 
 
205646 
 
54 
 
                                  X                                       0   WD 
Subject Withdraws on or after onset 
date 
NR 
Imputed 
Imputed 
Excluded 
                                  X                     
    0   Death 
Subject Dies on or after onset date 
NR 
NR 
Imputed  
Excluded 
                                  X                           
     0   TF 
Subject has Treatment Failure on or 
after onset date 
NR 
Imputed 
Imputed 
Excluded 
Comp. = Completed; WD = Study Withdrawal (includes Lost to Follow Up); TF = Treatment Failure (includes consideration of corticosteroids and 
immunosuppressants); R/NR = Responder/Non-Responder based on SLEDAI-2K criteria; NR = Non-Responder 
 


 
CONFIDENTIAL 
 
205646 
 
55 
 
7.2. 
First Major Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
The proportion of participants with a state of clinical remission defined as a Clinical 
SLEDAI-2K score =0 (IBA) (Section 15.6.3), achieved without immunosuppressants and 
corticosteroids at a prednisone equivalent dose of 0 mg/day at Week 64.  
The protocol Section 10.4.1 Efficacy analysis then clarifies that: 
 
For participants who discontinue prematurely from study treatment and for who 
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 . 
 
Hence when adopting the ICH Estimands and Sensitivity Analysis in Clinical Trials E9 
R1 addendum terminology, this endpoint is defined as: 
 
Clinical Remission 
Responder: 
• Clinical SLEDAI-2K score =0 (IBA); and 
• 7-day average prednisone equivalent dose of 0mg/kg at the visit; and 
• Not a TF at the current or any prior visit (TF includes consideration of corticosteroids 
and immunosuppressants); and 
• Did not Withdraw from the study prior to the visit 
Non-Responder: 
• Clinical SLEDAI-2K score >0 (IBA); or 
• 7-day average prednisone equivalent dose > 0mg/kg at the visit; or 
• TF at the current or any prior visit (TF includes consideration of corticosteroids and 
immunosuppressants); or 
• Withdrew from the study prior to the visit (includes lost to follow-up and death) 
The derivation of Clinical SLEDAI-2K score is provided in Section 15.6.3.   
Treatment failures are defined in Section 15.6.15. and includes the use of re–start 
belimumab for Arms A&B.  Re-start belimumab is principal investigator prescribed 
belimumab, it does not include late dosing of Year 1 (prescribed pre Week 52) belimumab 
injections that were taken incorrectly after Week 52. 
Withdrawal from the study prior to Week 64 is defined in Section 5.9. 
Note: Discontinuation of study investigational product (belimumab or rituximab) is NOT a 
component of this endpoint, subjects who discontinue investigational product will only be 
non-responders if they also meet 1 of the criteria above. 
Note this clarification of notation does not change the protocol-specified analysis. 
 


 
CONFIDENTIAL 
 
205646 
 
56 
 
The analysis of Arm A vs Arm B will use data from treatment Arms A, and B only.  An 
exploratory analysis of the relative performance of Arm B vs. Arm C will also be 
conducted, using data from Arms B and C only. 
 
Note: A subject can be a responder for this key secondary endpoint without being a 
responder for the primary endpoint. 
7.2.2. 
Summary Measure 
The odds ratio at Week 64 between Arm B (Combination) vs Arm A (Control). 
7.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the Modified Intent-To-Treat 
population, unless otherwise specified. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The intercurrent event strategies used for the primary endpoint (as defined in Section 
7.1.4) will be used for this major secondary endpoint.  
Subjects in Arms A and B will not receive investigational product post Week 52, these 
subjects will be considered as on treatment if they completed treatment through Week 52.  
 
The main estimand of this endpoint, is a Hybrid strategy, subjects who discontinue 
investigational product will continue in the study, assessments after treatment 
discontinuation will be included in the main estimand.  
 
 
7.2.5. 
Statistical Analyses / Methods 
7.2.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• The proportion of participants with a state of clinical remission defined as a Clinical SLEDAI-
2K  score = 0 (IBA), achieved without immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day at Week 64, and without treatment failure or study 
withdrawal 
Model Specification 
• The proposed statistical analyses planned for the primary endpoint will be repeated for this 
major secondary endpoint. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
this major secondary endpoint. 


 
CONFIDENTIAL 
 
205646 
 
57 
 
Model Results Presentation 
• The proposed tables and figure for the primary endpoint will be repeated for this major 
secondary endpoint [T22.01, T22.02, F22.01]. . 
Subgroup Analyses 
• Subgroup analyses will not be conducted for major secondary endpoints.  
Supportive Analyses 
• The disposition of the endpoint, detailing the reasons why a subject was a non-responder 
will be summarized (n,%) [T22.03]. 
• The components of the endpoint will be summarized [T22.04].  i.e. proportion of participants 
with 
o Clinical SLEDAI-2K score =0 (IBA) 
o Treatment failure due to corticosteroid use 
o Corticosteroids at a prednisone equivalent dose of >0mg/day and <=5mg/day 
o Treatment failure due to immunosuppressant use 
o Treatment failure due to anti-malarial, NSAID, Aspirin or other prohibited 
medication use 
o Study withdrawal 
• The table will include: 
• the number, percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group,  
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C. 
• the stratified (baseline SLEDAI-2K score, baseline immunosuppressant use, 
baseline corticosteroid dose) Cochran-Mantel-Haenszel treatment difference 
and 95% confidence interval (CI) for the comparison of Arm B vs Arm A; and 
Arm B vs Arm C. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A 
• This key Secondary efficacy analysis at Week 64 will be repeated to assess the robustness 
of the results: 
• Including subjects where the independent blinded assessor was potentially 
unblinded, at Week 64 (i.e. ITT population).  Intercurrent event strategy: Hybrid 
[T22.05]. 
• Unadjusted for covariates. The only independent variable in the model will be 
treatment group.  Intercurrent event strategy: Hybrid [T22.06]. 
Tipping point analyses may be performed, including all recorded data up to the time of study 
withdrawal, and using differing assumptions regarding data missing following withdrawal from 
the study as detailed in Section 7.1.6.  Intercurrent event strategy: Hybrid [T22.07, F22.12].   
 


 
CONFIDENTIAL 
 
205646 
 
58 
 
7.2.6. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic on the First Major Secondary 
Endpoint 
Additional analyses will be carried out to assess the impact of the COVID-19 pandemic on the first 
major secondary endpoint.   
7.2.6.1. 
COVID Attributed – Observed data until Intercurrent Events that could 
be attributable to the COVID-19 pandemic 
The first additional analysis specified for the primary endpoint (Section 7.1.7.1) will be repeated for 
the first major secondary endpoint [T22.35]. 
7.2.6.2. 
COVID Environment – Observed data until the COVID-19 pandemic 
The second additional analysis specified for the primary endpoint (Section 7.1.7.2) will be repeated 
for the first major secondary endpoint [T22.36]. 
7.2.6.3. 
Pre-COVID – MITT Population prior to the COVID-19 pandemic 
The third additional analysis specified for the primary endpoint (Section 7.1.7.3) will be repeated for 
the first major secondary endpoint [T22.37] using the “MITT Week 64 prior to COVID-19” 
population. 
 
7.3. 
Second Major Secondary Efficacy Analyses 
7.3.1. 
Endpoint / Variables 
The proportion of participants with a state of disease control defined as a SLEDAI-2K 
score 2 (IBA), achieved without immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 5mg/day at Week 104. 
This endpoint is as defined for the primary endpoint (Section 7.1) but at Week 104. 
The primary comparison is Arm B (Combination) vs Arm A (Control), and an 
exploratory summary of Arm B (Combination) vs Arm C (Reference) will also be shown. 
Note: A subject can be a responder for this key secondary endpoint without being a 
responder for the primary endpoint or the first major secondary endpoint. 
7.3.2. 
Summary Measure 
The odds ratio at Week 104 between Arm B (combination) vs Arm A (control). 


 
CONFIDENTIAL 
 
205646 
 
59 
 
7.3.3. 
Population of Interest  
The secondary efficacy analyses will be based on the Modified Intent-To-Treat 
population, unless otherwise specified. 
7.3.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The intercurrent event strategies used for the primary endpoint (see as defined in Section 
7.1.4) will be used for this major secondary endpoint.  
Subjects in Arms A and B will not receive investigational product post Week 51, these 
subjects will be considered as on treatment if they completed treatment through Week 52.  
 
The main estimand of this endpoint, is a Hybrid strategy, subjects who discontinue 
investigational product will continue in the study, assessments after treatment 
discontinuation will be included in the main estimand.  
 
7.3.5. 
Statistical Analyses / Methods 
7.3.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• The proportion of participants with a state of disease control defined as a SLEDAI-2K score 
2 (IBA), without treatment failure or study withdrawal 
Model Specification 
• The proposed statistical analyses planned for the primary endpoint will be repeated for this 
major secondary endpoint. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
this major secondary endpoint. 
Model Results Presentation 
• The proposed tables and figure for the primary endpoint will be repeated for this major 
secondary endpoint [T22.10, T22.11, F22.04]. 
Subgroup Analyses 
• Subgroup analyses will not be conducted for major secondary endpoints. 
Supportive Analyses 
• The disposition of the endpoint, detailing the reasons why a subject was a non-responder 
will be summarized (n,%) [T22.12]. 
The components of the endpoint will be summarized [T22.13].  i.e. proportion of participants 
with: 
o SLEDAI-2K score <=2 (IBA) 
o Treatment failure due to corticosteroid use 
o Treatment failure due to immunosuppressant use 


 
CONFIDENTIAL 
 
205646 
 
60 
 
o Treatment failure due to anti-malarial, NSAID, Aspirin or other prohibited 
medication use  
o Study withdrawal 
• The table will include: 
• the number, percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group,  
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C. 
• the stratified (baseline SLEDAI-2K score, baseline immunosuppressant use, 
baseline corticosteroid dose) Cochran-Mantel-Haenszel treatment difference 
and 95% confidence interval (CI) for the comparison of Arm B vs Arm A; and 
Arm B vs Arm C. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A 
• This key Secondary efficacy analysis at Week 104 will be repeated to assess the robustness 
of the results: 
• Including subjects where the independent blinded assessor was potentially unblinded, at 
Week 104 (i.e. ITT population).  Intercurrent event strategy: Hybrid [T22.14]. 
• Unadjusted for covariates. The only independent variable in the model will be treatment 
group.  Intercurrent event strategy: Hybrid [T22.15]. 
Tipping point analyses may be performed, including all recorded data up to the time of study 
withdrawal, and using differing assumptions regarding data missing following withdrawal from 
the study, as detailed in Section 7.1.6.  Intercurrent event strategy: Hybrid [T22.16, F22.13].   
 
 
7.3.6. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic on the Second Major 
Secondary Endpoint 
Additional analyses will be carried out to assess the impact of the COVID-19 pandemic on the 
second major secondary endpoint.  It may not be possible to conduct all the proposed analysis, the 
feasibility of the analysis is dependent on the number of observed intercurrent events after the 
COVID-19 environment onset date or quantity of missed assessments.  
7.3.6.1. 
COVID Attributed – Observed Data Until Intercurrent Events That Could 
be Attributable to the COVID-19 Pandemic 
The first additional analysis specified for the primary endpoint (Section 7.1.7.1) will be repeated for 
the second major secondary endpoint [T22.38]. 
7.3.6.2. 
COVID Modified – SLEDAI 2K-Score ≤2 (IBA), Without Current 
Immunosuppressants, Without Current Belimumab (arms A&B), and 
prednisone equivalent dose of 5mg/day at Week 104 
This is an additional endpoint to that specified in the protocol, using a modified definition of disease 
control.  It will be defined as a SLEDAI-2K score 2 (IBA), without Current Immunosuppressants 


 
CONFIDENTIAL 
 
205646 
 
61 
 
or Current Belimumab dosing (Arms A and B) and corticosteroids at a prednisone equivalent dose 
of 5mg/day at Week 104. 
It is possible that subjects may take extra immunosuppressants/corticosteroids/Belimumab during 
the COVID-19 environment, which would class them as a Treatment Failure and therefore a Non-
Responder for the main analysis.  This additional analysis will allow the subjects to take these 
concomitant medications / re-start Belimumab during the study, as long as their dose is back to the 
pre-defined levels for an adequate period prior to  Week 104.  Therefore, these subjects will not 
automatically be classed as a Treatment Failure (Non-Responder) for this additional analysis. 
 
Disease Control without Treatment Failure 
Responder: 
• SLEDAI 2K-score ≤2 (IBA); and 
• Did not withdraw from the study prior to the visit; and 
• Did not receive a protocol non-allowed immunosuppressant or change in 
immunosuppressant on the day of the visit or the 55 days prior; and 
• Did not receive corticosteroids at a prednisone equivalent dose of >5mg/day (7day 
average) on the day of the visit or the 6 days prior; and 
• Did not have a Belimumab dose on the day of the visit or the 112 days (16 weeks) 
prior (Arms A and B). 
Non-Responder: 
• SLEDAI 2K-score >2 (IBA); or 
• Withdrew from the study prior to Week 104 (which includes study withdrawal, lost to 
follow-up and death); or 
• Received a protocol non-allowed immunosuppressant or change in 
immunosuppressant on the day of the visit or the 55 days prior; or 
• Received corticosteroids at a prednisone equivalent dose of >5mg/day (7day 
average) on the day of the visit or the 6 days prior; or 
• Had a Belimumab dose on the day of the visit or the 112 days (16 weeks) prior 
(Arms A and B). 
The derivation of SLEDAI-2K score is provided in Section 15.6.3 and withdrew from the 
study prior to Week 104 in Section 5.9. 
Note: Discontinuation of study investigational product (belimumab or rituximab) is NOT a 
component of this endpoint, subjects who discontinue investigational product will only be 
non-responders if they also meet one of the criteria above. 
 
The statistical methods will match the primary analysis (Section 7.1.5 Hybrid strategy) for the 
model specification, model checking and diagnostics and the model results presentation at Week 
104 [T22.39]. 
 


 
CONFIDENTIAL 
 
205646 
 
62 
 
7.4. 
Lupus Low Disease Activity State (LLDAS) 
7.4.1. 
Endpoint / Variables 
The LLDAS endpoint is derived based on [Franklyn, 2016] and [Oon, 2019] given the 
available data in this study, namely:  
o SLEDAI-2K 4, with no activity in major organ systems (renal, CNS, 
cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal 
activity;  
o no new features of lupus disease activity compared with the previous assessment; 
o PGA (scale 0-3) 1; 
o current prednisolone (or equivalent) dose 7.5 mg daily; and 
o well tolerated standard maintenance doses of immunosuppressive drugs and 
approved biological agents, excluding investigational drugs. 
o Not study withdrawal (including death and lost to follow-up) 
Further details of the derivation that is applied to this study is provided in Section 15.6.9 
Lupus Low Disease Activity State (LLDAS).  The principal investigators assessment of 
the SLEDAI-2K is used in the derivation of LLDAS. Treatment Failures (TF) is not a 
component of the endpoint. 
7.4.2. 
Summary Measure 
The odds ratio between Arm B (Combination) vs Arm A (Control). 
7.4.3. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 
7.4.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The definition of the endpoint includes consideration for the intercurrent events of study 
withdrawal (including LTFU and death)(as defined in Section 7.1.4).  Treatment failure is 
not a component of the endpoint and is not considered as an intercurrent event.  Data 
from subjects who discontinue IP is included  in this secondary endpoint.  
Subjects in Arms A and B will not receive investigational product post Week 52, these 
subjects will be considered as on treatment if they completed treatment through Week 52.  
 


 
CONFIDENTIAL 
 
205646 
 
63 
 
Subjects who discontinue investigational product will continue in the study, assessments 
after treatment discontinuation will be included in the estimand.  
 
7.4.5. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 
7.4.6. 
Statistical Methodology Specification  
Endpoint / Variables 
• Proportion of participants that meet the Lupus Low Disease Activity State (LLDAS) response 
criteria by Visit [T12.37, T22.31] 
• Proportion of participants for each component of the Lupus Low Disease Activity State 
(LLDAS) response criteria at Weeks 52, 64, and 104 [T12.38,T22.32] 
Model Specification 
• The proposed statistical analyses planned for the primary endpoint will be repeated for 
LLDAS. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
the LLDAS endpoints. 
Model Results Presentation 
• The table will display: 
• the number, percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group  
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A at 
Weeks 52, 64 and 104.  
 
7.5. 
Other Secondary Efficacy Analyses - Proportion Endpoints 
(Hybrid) 
7.5.1. 
Summary Measure 
The odds ratio between Arm B (combination) vs Arm A (control). 
7.5.2. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 


 
CONFIDENTIAL 
 
205646 
 
64 
 
7.5.3. 
Strategy for Intercurrent (Post-Randomization) Events 
The same intercurrent event strategy as used for the primary endpoint (Section 7.1.4) will 
also be used for other secondary endpoints.  
7.5.4. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 
7.5.5. 
Statistical Methodology Specification  
Endpoint / Variables 
• The proportion of participants with a state of disease control defined as a SLEDAI-2K score 
2 (IBA), achieved without treatment failure or study withdrawal by visit (T12.27, T22.17, 
F12.05, F22.05). 
• Proportion of participants with a state of clinical remission, defined as a Clinical SLEDAI-2K 
score = 0 (IBA) (Section 15.6.3), achieved without treatment failure or study withdrawal and 
with corticosteroids at a prednisone equivalent dose of 0 mg/day, by visit. (T22.08, F22.02) 
• Proportion of participants with a state of complete remission, defined as SLEDAI-2K score = 
0 (PI), achieved without treatment failure or study withdrawal, and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day, sustained for at least 24 weeks.(T22.19) 
• Proportion of participants with a state of clinical remission, defined as Clinical SLEDAI-2K 
score =0 (PI) (Section 15.6.3), achieved without treatment failure or study withdrawal and 
with corticosteroids at a prednisone equivalent dose of 0 mg/day, sustained for at least 24 
weeks. (T22.20) 
• Proportion of participants with a state of complete remission, defined as a SLEDAI-2K score 
=0 (PI), achieved without treatment failure or study withdrawal and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day, by visit (T22.21,F22.08) 
• The proportion of participants with a state of disease control defined as a SLEDAI-2K score 
≤2 (PI), achieved without treatment failure or study  and with corticosteroids at a prednisone 
equivalent dose of 5mg/day by visit (T12.28, T22.18, F12.06). 
• The proportion of participants with a state of clinical remission defined as a Clinical SLEDAI-
2K score =0 (PI) (Section 15.6.3), achieved without treatment failure or study withdrawal and 
with corticosteroids at a prednisone equivalent dose of 0 mg/day, by visit (T22.18,F22.03). 
Model Specification 
• The proposed statistical analyses planned for the primary endpoint (Hybrid) will be repeated 
for the other binary secondary endpoints. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
the other binary secondary endpoints. 
Model Results Presentation 
• For each endpoint a table will display: 


 
CONFIDENTIAL 
 
205646 
 
65 
 
• the number, percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group  
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A at 
Weeks 52, 64 and 104.  
 
7.6. 
Other Secondary Efficacy Analyses - Proportion Endpoints 
(Observed Case) 
7.6.1. 
Summary Measure 
The odds ratio between Arm B (combination) vs Arm A (control). 
7.6.2. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 
7.6.3. 
Strategy for Intercurrent (Post-Randomization) Events 
Treatment failure and study withdrawal will not be considered as components of the 
endpoint and an observed case analysis will be conducted.  
7.6.4. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 
 
7.6.5. 
Statistical Methodology Specification 
Endpoint / Variables 
• Proportion of participants with SLEDAI-2K (PI) organ improvement by visit (T12.31, T22.27) 
• Proportion of participants with SLEDAI-2K (PI) organ worsening by visit (T12.32,T22.28) 
• Proportion of participants with any SLICC Damage Index worsening (change >0) compared 
with baseline at Week 52 and Week 104 (Worst Observation Carried Forward for observed 
visits) (T12.36, T22.30). Note: The scoring of the SLICC Damage Index is such that it should 
not be possible for a subject to improve.  Hence the WOCF is used to ensure the correct 
scoring has been applied the highest score for an individual item is carried forward to 
subsequent observed visits, it does not impute missing visits.  Only observed (but potentially 
corrected by WOCF) data will be analysed, irrespective of treatment failure or IP 
discontinuation (all data reported will be included).   


 
CONFIDENTIAL 
 
205646 
 
66 
 
Model Specification 
• The proposed statistical analyses planned for the primary endpoint will be repeated for the 
other binary secondary endpoints.  The SLICC Damage Index worsening will also include 
SLICC DAMAGE index score at baseline as a covariate. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
the other binary secondary endpoints. 
Model Results Presentation 
• For each endpoint a table will display: 
• the number, percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group  
• For the SLICC analysis (T12.36, T22.30) the table will also display: 
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A at 
weeks 52, 64 and 104.  
 
7.7. 
Other Secondary Efficacy Analyses - Time to Event 
Endpoints 
7.7.1. 
Summary Measures 
The hazard ratio of Arm B (combination) and Arm A (control). 
7.7.2. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 
7.7.3. 
Strategy for Intercurrent (Post-Randomization) Events 
Subjects without an event will be considered censored at the last observed timepoint.  
7.7.4. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 
7.7.5. 
Statistical Methodology Specification for Time to Event 
Endpoints
 Endpoints  
• Time to first severe flare (as measured by the modified SLE Flare Index) [T12.33, T22.22, 
F12.12,F22.06] 


 
CONFIDENTIAL 
 
205646 
 
67 
 
• Time to first flare (as measured by the modified SLE Flare Index) [T12.34, 
T22.23,F12.09,F22.07] 
• Time to disease control sustained to Week 104, defined as SLEDAI-2K score 2 (PI), 
achieved without immunosuppressants and with corticosteroids at a prednisone equivalent 
dose of 5 mg/day.[T22.24,F22.09]. 
• Time to clinical remission sustained to Week 104, defined as Clinical SLEDAI-2K score=0 
(PI) (Section 15.6.3), achieved without immunosuppressants and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day [T22.33].   
Derivation  
Flare Endpoints 
Subject  
Time to defined as: 
Censored 
Flare 
Date of 1st flare – trt start date +1 
No = 0  
TF before or without flare 
Date of 1st TF – trt start date +1 
No = 0  
Subjects without a Flare or TF who have an intercurrent event: 
Withdraw 
Date of last Flare assessment prior to 
intercurrent event – trt start date +1 
Yes =1  
Lost to Follow-up 
Die 
Date of Death – trt start date +1 
Yes =1 
For Year 1 reporting: 
 
 
Subject completes Week 52 
Date of Week 52 visit – trt start date +1 
Yes =1 
For Year 2 reporting: 
 
 
Subject completes Week 
104 
Date of Week 104 visit – trt start date +1 
Yes =1 
• The flare criteria will be programmed from the SLEDAI-2K irrespective of data recorded 
on the SFI form 
• Flares recorded as severe on the SFI form will be downgraded to not severe in the 
programmed endpoint if the only cause of the severe flare was SLEDAI-2K>12 
• Only post baseline flares will be included in the analysis (Flares on Day 1 will not be 
considered) 
• Treatment failure is considered as a severe flare. 
• Subjects who do not have a flare assessment post baseline will be censored at Day 1 
and hence reported as ‘time to’ defined as 1 and censor =Yes = 1 
 
Time to Response Endpoints 
Subject  
Time to defined as: 
Censored 
Sustained response 
Date of 1st sustained response – trt start date 
+1 
No = 0  
 
 
 
Subjects without a sustained response 


 
CONFIDENTIAL 
 
205646 
 
68 
 
Withdraw 
Date of last visit prior to intercurrent event – trt 
start date +1 
Yes =1  
Lost to Follow-up 
Treatment Failure 
Die 
Date of Death – trt start date +1 
Yes =1 
For Year 1 reporting: 
 
 
Subject completes Week 52 
without treatment failure 
Date of Week 52 visit – trt start date +1 
Yes =1 
For Year 2 reporting: 
 
 
Subject completes Week 
104 without treatment failure 
Date of Week 104 visit – trt start date +1 
Yes =1 
Further detail is provided in Section 15.6.7. 
Model Specification 
A Cox proportional hazards model  controlling for treatment group, baseline SLEDAI-2K score 
(9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), and baseline corticosteroid 
dose (prednisone equivalent 10 mg/day vs. >10 mg/day) will be used to evaluate time to event 
endpoints. 
Ties will be managed using Efron’s approximation. 
Model Checking & Diagnostics 
Overall model Goodness of fit tests using the -2 Log Likelihood, Akaike’s Information Criterion 
(AIC), and Schwarz Bayesian criterion (SBC) tests will be performed.  The AIC and SBC 
statistics offer two different ways of adjusting the -2 log likelihood statistic for the number of 
terms in the model and the number of observations used.  Lower values in these statistics 
represent a more desirable model. These tests will aid in the assessment of model fit but the 
final decision regarding goodness of fit will be based on statistician review.  If the model fit is 
considered inadequate additional analysis will be conducted. 
Model Results Presentation 
A table for each endpoint [as above] will present: 
• The number and percentage of subjects with an event and the median, 25th 
percentile, and 75th percentile of days to event by treatment group,  
• the hazard ratio and 95% confidence interval (CI) for the comparison of Arm B 
vs Arm A; and Arm B vs Arm C. 
• the p-value for the hazard ratio for Arm B vs Arm A.  
• the median, 25th percentile, and 75th percentile of days, min and max for the 
study day of 1st event  
A Kaplan-Meier plot of time to event for each endpoint will be displayed by treatment group.  
Subgroup Analyses 
Subgroup analyses will not be conducted for secondary endpoints. 
 


 
CONFIDENTIAL 
 
205646 
 
69 
 
7.8. 
Other Secondary Efficacy Analyses - Duration Endpoints 
7.8.1. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 
7.8.2. 
Strategy for Intercurrent (Post-Randomization) Events 
A Hybrid strategy will be adopted  
7.8.3. 
Endpoint / Variables 
The endpoint points are defined as per the primary (Section 7.1) and secondary (Section 
7.2) endpoints. The duration is defined as the longest period between any 2 assessments 
that the subject remains a responder throughout (missing assessments are not considered).   
7.8.4. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 
 
7.8.5. 
Statistical Methodology Specification for Duration Endpoints
 Endpoints 
• 
Duration of disease control, defined as SLEDAI-2K score ≤2 (PI), achieved without 
treatment failure or study withdrawal [T12.29]. 
• 
Duration of clinical remission, defined as Clinical SLEDAI-2K score =0 (PI) (Section 15.6.3), 
achieved without treatment failure or study withdrawal and with corticosteroids at a 
prednisone equivalent dose of 0 mg/day. [T22.25]. 
Imputation of Missing Data  
Duration endpoints: 
There will be no imputation of missing data, only observed data will be considered.  Duration will 
be derived based on the date of the assessment as: 
   Date of last visit meeting criteria - Date of first visit meeting criteria +1 
Model Specification 
• Duration endpoints will be analyzed using ANCOVA to evaluate the treatment effect 
controlling for treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose (prednisone 
equivalent 10 mg/day vs. >10 mg/day). 
Model Checking & Diagnostics 
• The Kolmogorov-Smirnov D statistic will be used to test the assumption of normality. 
Residuals will be reviewed to assess the homogeneity of variance assumption.  If the model 
fit is inadequate additional analysis will be conducted.  


 
CONFIDENTIAL 
 
205646 
 
70 
 
Model Results Presentation 
The tables  will display: 
• Baseline: the number of subjects, mean, standard error, standard deviation, median, 
25th percentile, 75th percentile, minimum, maximum for each arm 
• At each visit: 
o the number subjects, mean, standard error, standard deviation, median, 25th 
percentile, 75th percentile, minimum, and maximum,  
o LS Mean, and standard error of the LS Mean for each arm at Weeks 52, 64 and 
104. 
o the treatment difference and 95% confidence interval (CI) for the comparison of 
Arm B vs Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
o the p-value for treatment difference for Arm B vs Arm A at Weeks 52, 64 and 
104.  
 
 
7.9. 
Other Secondary Efficacy Analyses Continuous Endpoints 
7.9.1. 
Endpoint / Variables 
Change from baseline in SLEDAI-2K (PI) score and change from baseline in Physician 
Global Assessment (PGA) by visit. 
 
7.9.2. 
Summary Measure 
The difference in mean change from baseline between Arm B (Combination) vs Arm A 
(Control). 
7.9.3. 
Population of Interest  
The secondary efficacy analyses will be based on the modified Intent-To-Treat 
population, unless otherwise specified. 
7.9.4. 
Strategy for Intercurrent (Post-Randomization) Events 
A hypothetical strategy will be used to estimate what the treatment effect would have 
been had the subjects not withdrawn from the study . Data collected after TF will be used 
in the analysis.   
7.9.5. 
Subgroup, Supportive and Sensitivity Analyses 
There are no planned subgroup, supportive or sensitivity analyses for other secondary 
endpoints. 


 
CONFIDENTIAL 
 
205646 
 
71 
 
7.9.6. 
Statistical Methodology Specification for Continuous Endpoints
 Endpoints 
• 
Change from baseline in SLEDAI-2K (PI) score by visit.[T12.30, T22.26,F12.07, F22.10]. 
• 
Change from baseline in Physician Global Assessment (PGA) by visit [T12.35,T22.29, 
F12.08, F22.11]. 
Imputation of Data for Missed Visits and Following Study Withdrawal 
• A bayesian repeated measures normal model will be fitted to the data collected prior to 
study withdrawal, using a Markov Chain Monte Carlo approach, adjusting for treatment 
group, baseline SLEDAI-2K score (9 vs. 10 ), baseline immunosuppressant use (use vs. 
non-use), and baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 
mg/day).  Non-informative priors will be used. 
• Quasi-independent samples will be drawn from the posterior distributions for the parameters 
of the multivariate normal distribution for each treatment group and each missingness 
pattern. 
• Each sample leads to a separate imputed dataset, in which the missing values are replaced 
by values drawn randomly from their conditional distribution. This distribution is based on the 
observed data and the covariates for that subject using the imputation model and the 
sampled parameter values. 
• These steps will be repeated at least 1000 times. 
Imputation of Data Following Partially Missing SLEDAI-2K 
The same imputation approach will be used for subjects with partially completed SLEDAI-2K 
scores (i.e. some missing items) however imputed values that are below the minimum possible 
score (determined from the completed items) will be replaced with the known minimum score.    
Similarly, imputed values that are above the maximum possible score will be replaced with the 
known maximum score 
Minimum and maximum possible SLEDAI-2K scores are detailed in Section 15.6.3. 
Model Specification 
• Each imputed dataset will be analyzed using ANCOVA to evaluate the treatment effect 
controlling for treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose (prednisone 
equivalent 10 mg/day vs. >10 mg/day).   
• The resulting treatment differences and their SEs will be combined across imputations using 
Rubin’s rules. 
• The models for the SLEDAI-2K endpoints will include the baseline (PI) SLEDAI-2K score 
(continuous) rather that the stratification factor (9 vs. 10). 
• The model for PGA endpoints will also include the baseline PGA score (continuous). 
Model Checking & Diagnostics 
The Kolmogorov-Smirnov D statistic will be used to test the assumption of normality. Residuals 
will be reviewed to assess the homogeneity of variance assumption.  If the model fit is 
inadequate additional analysis will be conducted 
Model Results Presentation 
The tables  will display: 


 
CONFIDENTIAL 
 
205646 
 
72 
 
• Baseline: the number of subjects, mean, standard error, standard deviation, median, 
25th percentile, 75th percentile, minimum, maximum for each arm 
• At each visit: 
o the number subjects, mean, standard error, standard deviation, median, 25th 
percentile, 75th percentile, minimum, and maximum 
o LS Mean, and standard error of the LS Mean for each arm at Weeks 52, 64 and 
104. 
o the treatment difference and 95% confidence interval (CI) for the comparison of 
Arm B vs Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
o the p-value for treatment difference for Arm B vs Arm A at Weeks 52, 64 and 
104.  
For change from baseline endpoints, a plot of LS means +/- SE by visit and treatment group will 
be provided. 
 
7.10. 
Other Secondary Efficacy Analyses: SLEDAI-2K Score ≤2 
(IBA), Without Current Immunosuppressant and 
Corticosteroids <=5mg/day  
7.10.1. 
Endpoint / Variables 
This is an additional endpoint to that specified in the protocol.  The proportion of 
participants with a state of disease control defined as a SLEDAI-2K score ≤2 (IBA), 
achieved without current immunosuppressants and with current corticosteroids at a 
prednisone equivalent dose of 5mg/day at Week 52.  Immunosuppressant use and 
corticosteroid reduction are key components of the endpoint in the protocol and are 
included in the synopsis definition without referring to treatment failure.  Hence a 
supportive analysis that considers immunosuppressant use and corticosteroids without 
other treatment failure criteria will be conducted. 
 
Disease Control without Treatment Failure 
Responder: 
• SLEDAI-2K score ≤2 (IBA); and 
• Did not withdraw (including LTFU and death) from the study prior to the visit; and 
• Did not receive a protocol non-allowed immunosuppressant or change in 
immunosuppressant on the day of the visit or the 55 days prior; and 
• Did not receive corticosteroids at a prednisone equivalent dose of >5mg/day (7day 
average) on the day of the visit or the 6 days prior. 
Non-Responder: 
• SLEDAI-2K score >2 (IBA); or 
• withdrew from the study prior to Week 52 (including, LTFU and death); or 
• Received a protocol non-allowed immunosuppressant or change in 
immunosuppressant on the day of the visit or the 55 days prior; or 


 
CONFIDENTIAL 
 
205646 
 
73 
 
• Received corticosteroids at a prednisone equivalent dose of >5mg/day (7day 
average) on the day of the visit or the 6 days prior. 
The derivation of SLEDAI-2K score is provided in Section 15.6.3 and withdrawal from the 
study prior to Week 52 in Section 5.9. 
Note: Discontinuation of study investigational product (belimumab or rituximab) is NOT a 
component of this endpoint, subject who discontinue investigational product will only be non-
responders if they also meet 1 of the criteria above. 
 
7.10.2. 
Summary Measure 
The odds ratio at Week 52 between Arm B (Combination) vs Arm A (Control). 
7.10.3. 
Population of Interest  
The efficacy analyses will be based on the Modified Intent-To-Treat population, unless 
otherwise specified. 
7.10.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The definition of the endpoint includes consideration for the intercurrent events of study withdrawal 
(including LTFU and death)(as defined in Section 7.1.4).  Treatment failure is not a component of 
the endpoint and is not considered as an intercurrent event.  Data from subjects who discontinue 
IP is included  in this secondary endpoint.  
 
7.10.5. 
Statistical Analyses / Methods 
7.10.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• The proportion of participants with a state of disease control defined as a SLEDAI-2K score 
≤2 (IBA), achieved without study withdrawal, without current immunosuppressants, and with 
current corticosteroids at a prednisone equivalent dose of 5mg/day 
 Derivation  
• Derivation of the endpoint for Arms A, B and C is provided in Section 15.6.4 
Model Specification 
• Logistic regression model. 
• Terms in the model: 
• Dependent: response (yes/no) 
• Categorical: treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose 
(prednisone equivalent 10 mg/day vs. >10 mg/day). 


 
CONFIDENTIAL 
 
205646 
 
74 
 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
the other binary secondary endpoints. 
Model Results Presentation (T12.39) 
• the number, percentage, SE of percentage, and the 95% CI for the percentage of 
subjects achieving a response by treatment group  
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs Arm A; 
and Arm B vs Arm C at Week 52. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A at Week 52. 
 
7.11. 
Additional Efficacy Analyses  
A scatter plot will be produced to assess the degree to which the Principal Investigators 
assessment of SLEDAI-2K differs from that of the Independent Blinded Assessor at 
Week 52 [F12.10].   
 
This will only include subjects who have both a PI and IBA SLEDAI-2K total score at 
Week 52.  The scatter plot will show the PI SLEDAI-2K total score on the x-axis and 
IBA SLEDAI-2K total score on the y-axis.  No formal statistical testing will be 
conducted.  Different colours (and symbols) will be used for the following groups of 
subjects: 
• Arm A  
• Arm B 
• Arm C included in MITT population 
• Arm C excluded from MITT population 
 
A Bland-Altman plot of the differences between the IBA and PI scores against the mean 
of the IBA and PI scores will also be produced at Week 52 [F12.11]. 
 
If the conclusions of the analysis of the comparison between Arm A and Arm B for 
disease control differ between SLEDAI-2K score based on the IBA assessment and the PI 
assessment at Week 52, then additional analysis may be performed.  Additional analysis 
of endpoints at Week 52 will be performed after the Week 52 Statistical Analysis 
Complete milestone has been met and will be presented in the Week 52 clinical study 
report.  Analysis of endpoints post Week 52 will be performed as part of the Week 104 
reporting. 
 
A difference in conclusion will be determined by the study team after reviewing the 
complete Week 52 SAC outputs.  Consideration will be given to the comparison of the 
magnitude of the odds ratio in the analysis of: 
- 
The proportion of participants with a state of disease control (IBA) 
- 
The proportion of participants with a state of disease control (PI) 
with consideration to the related C.I.s and p-values for the comparison between Arms A 
and B.  


 
CONFIDENTIAL 
 
205646 
 
75 
 
 
The additional analyses will consider some or all of the following endpoints depending 
on the results by endpoint for the Week 52 reporting: 
• Proportion of participants with a state of clinical remission, defined as a Clinical 
SLEDAI-2K score =0 (IBA) (Section 15.6.3), achieved without treatment failure or 
study withdrawal and with corticosteroids at a prednisone equivalent dose of 0 
mg/day, by visit.  
• Proportion of participants with a state of complete remission, defined as SLEDAI-2K 
score=0 (IBA), achieved without treatment failure or study withdrawal 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 (IBA) (Section 15.6.3), achieved without treatment failure or 
study withdrawal 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 complete remission, defined as a SLEDAI-
2K score =0 (IBA), achieved without treatment failure or study withdrawal and with 
corticosteroids at a prednisone equivalent dose of 0 mg/day, by visit 
• Proportion of participants with SLEDAI-2K (IBA) organ improvement by visit (TP, 
Observed) 
• Proportion of participants with SLEDAI-2K (IBA) organ worsening by visit (TP, 
Observed) 
• Time to disease control sustained to Week 104, defined as SLEDAI-2K score 2 
(IBA), achieved without treatment failure or study withdrawal. 
• Time to clinical remission sustained to Week 104, defined as Clinical SLEDAI-2K 
score=0 (IBA) (Section 15.6.3), achieved without treatment failure or study 
withdrawal and with corticosteroids at a prednisone equivalent dose of 0 mg/day.  
• Duration of disease control, defined as SLEDAI-2K score ≤2 (IBA), achieved without 
treatment failure or study withdrawal.. 
• Duration of clinical remission, defined as Clinical SLEDAI-2K score =0 (IBA) 
(Section 15.6.3), achieved without treatment failure or study withdrawal and with 
corticosteroids at a prednisone equivalent dose of 0 mg/day.  
• Change from baseline in SLEDAI-2K (IBA) score by visit. 
• Duration of disease control, defined as SLEDAI-2K score ≤2 (IBA), achieved without 
treatment failure or study withdrawal. 
• Duration of clinical remission, defined as Clinical SLEDAI-2K score =0 (IBA) 
(Section 15.6.3), achieved without treatment failure or study withdrawal and with 
corticosteroids at a prednisone equivalent dose of 0 mg/day.  
• Change from baseline in SLEDAI-2K (IBA) score by visit. 
• Proportion of participants that meet the Lupus Low Disease Activity State (LLDAS) 
response criteria by Visit based on the IBA assessment. 


 
CONFIDENTIAL 
 
205646 
 
76 
 
 
The analysis will be based on the modified Intent-To-Treat population and use the same 
intercurrent event strategy (Hybrid as used for the primary endpoint (Section 7.1.4).  The 
analysis will be conducted as specified in Section 7.4.4, Section 7.4.5, Section 7.4.6) 
 
Similarly if there is a difference in the conclusions of the analysis of clinical remission 
based on the IBA and PI assessment at Week 64, or analysis of disease control based on 
the IBA and PI assessment at Week 104; then additional analyses will be performed 
shortly after the Week 104 Statistical Analysis Complete milestone has been met and will 
be presented in the Week 104 clinical study report.  The additional post Week 104 SAC 
analysis will repeat the analysis of the other secondary endpoints but utilising the IBA 
assessment instead of the PI assessment.  The endpoints to be assessed will potentially 
include all those previously listed in the Section 7.11. 
 
Note that in the event that the Week 52 reporting does not identify a treatment benefit an 
abridged set of analysis may be conducted at the end of the study (Week 104).   
 
7.12. 
Additional Analyses to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic on the 
Secondary Efficacy Endpoints 
There will not be any prospective additional analyses carried out to assess the impact of 
the COVID-19 pandemic on the secondary (non-major) endpoints.  However, if the 
additional analysis of the primary endpoint indicates a major impact of the COVID-19 
pandemic, then additional post-SAC analyses will be performed on the secondary 
endpoints after the Week 52 Statistical Analysis Complete milestone has been met and 
will be presented in the Week 52 clinical study report. 
Similarly, if the additional analysis of the key secondary endpoints indicates a major 
impact of the COVID-19 pandemic, then additional post-SAC analyses will be performed 
on the other secondary endpoints after the Week 104 Statistical Analysis Complete 
milestone has been met and will be presented in the Week 104 clinical study report. 


 
CONFIDENTIAL 
 
205646 
 
77 
 
8. 
SAFETY ANALYSES 
The safety analyses will be based on the ITT population.  However, if there are more than 
5% of subjects who receive a rituximab/placebo infusion that is different from the 
randomized treatment for one or both doses, safety analysis will be performed on the As 
Treated population. 
8.1. 
Adverse Events 
8.1.1. 
Reporting Phases 
Adverse events will be reported for Year 1 and Year 2 study period: 
8.1.1.1. 
Pre Treatment 
Adverse events starting prior to the 1st dose of belimumab.  
8.1.1.2. 
On Treatment (Year 1 only) 
As defined in Section 5.12 
8.1.1.3. 
On Study 
As defined in Section 5.11 
Year 2 reporting will include all events starting on or after Week 52 visit + 1 day and at 
or prior to the Week 104 visit. 
Year 1&2 reporting will include all events starting on or after the 1st dose of belimumab 
and at or prior to the Week 104 visit.   
The tabular summary for each category of AE listed below will include the number of 
events, number of subjects who reported at least one event, and percentage of subjects 
who reported at least one AE (incidence) by treatment group for each SOC (where 
applicable), each PT, and overall. 
8.1.1.4. 
Post Withdrawal/Completion 
Adverse events starting after the on study period (Section 5.11 / Section 8.1.1.3) will be 
reported separately. 
8.1.2. 
Adverse Events Analyses 
• Adverse events analyses including the analysis of adverse events (AEs), Serious 
Adverse Events (SAEs) and AEs of special interest (AESIs) will be based on GSK 
Core Data Standards. 
• All subjects will be followed for safety through at least 8 weeks post-treatment.  


 
CONFIDENTIAL 
 
205646 
 
78 
 
• A table summarizing AEs that occurred prior to treatment start date will be presented, 
for each system organ class (SOC) and preferred term (PT) by treatment group 
[T13.01]. 
• All AEs will be classified using the current standard GSK Medical Dictionary for 
Regulatory Activities (i.e. MedDRA version in use at the time of reporting), and 
grouped by SOC and PT, unless otherwise stated.  MedDRA version is detailed on 
every table that uses MedDRA . The Year 1 report will be based on MedDRA 
dictionary version 23.  The Year 2 report will use the MedDRA dictionary current at 
the time of reporting the Year 2 data (anticipated to be version 25) and hence will be 
different to Year 1.  Dictionary coding changes between Year 1 and Year 2 will be 
listed (L23.13) and any impact on the interpretation will be detailed in the Year 2 
clinical study report (CSR).  The investigator will evaluate all AEs with respect to 
seriousness, severity, and causality. The severity of an AE is to be determined using 
the Assessment of Intensity provided in Appendix 7 of the protocol, if a grade is 
provided for the AE of interest. 
• AEs during Year 1 that are not reported until Year 2; and AEs that have their 
reporting details (e.g. onset date, severity etc) changed after Year 1, will be reported 
in Year 2 with the latest details.  Changes will be listed and summarised as 
appropriate. 
• All treatment-emergent AEs will be summarized for both the double-blind phase 
(Year 1) and the observational phase (Year 2) separately. Selected tables will also be 
produced for Years 1 and 2 combined.  See Section 8.1.1 for definitions of phases. 
• An overall summary of AEs will be presented showing the number and percent of 
subjects with at least one: AE, related AE, serious AE (SAE), severe AE, AE 
resulting in study treatment discontinuation, and deaths [On Treatment:T13.02, and 
On Study: T13.03, T23.01,T23.02, L13.05, L13.06, L23.12]. 
• Common AEs will be defined as ≥ 5% incidence in any treatment group. 
• The number and percentage of subjects experiencing an AE and the total number of 
AEs will be summarized for each of the following AE categories: 
• 
All AEs (by SOC and PT) [On Treatment: T13.04; On Study: T13.05, T23.03, 
T23.04]. 
• 
AEs (by PT) [On Treatment:T13.06; On Study: T23.05]. (ordered on total 
incidence – Arms A+B+C)  
• 
Study treatment Related AEs (by SOC and PT) – belimumab only [on 
Treatment:T13.07; on Study: T23.06]. 
• 
Study treatment Related AEs (by SOC and PT) – rituximab only [on 
Treatment:T13.08; on Study: T23.07]. 
• 
Study treatment Related AEs (by SOC and PT) – Both belimumab and rituximab 
[on Treatment:T13.09; on Study: T23.08]. 
• 
Severe AEs (by SOC and PT) [On Treatment:T13.11, on Study T23.27]. 
• 
Serious AEs (by SOC and PT) [On Treatment:T13.21, and on Study:T13.22, 
T23.19, T23.20] 


 
CONFIDENTIAL 
 
205646 
 
79 
 
• 
AEs leading to permanent discontinuation of study treatment (by SOC and PT) 
[on Study:T13.26, T13.27; on Study: T23.21, T23.22]. 
• 
Deaths (by Category and PT) [on Study: T13.20, T23.18]. 
• 
Common Non-Serious AEs (by SOC and PT) [on Study: T13.28; T23.23]. 
• 
Study treatment Related Serious AEs (by SOC and PT) [On Treatment:T13.23, 
T13.24, T13.25; on Study: T23.24, T23.25, T23.26]. 
• 
Fatal Serious AEs (by SOC and PT) and Study treatment Related Fatal Serious 
AEs (by SOC and PT)  [On Treatment:T13.29; on Study:T23.28]. 
• By default, adverse events will be sorted by MedDRA SOCs, in descending order 
from the SOC with the highest total incidence (i.e., summed across all treatment 
groups) for any adverse event within the class, to the SOC with the lowest total 
incidence. If the total incidence for any two or more adverse events is equal, the 
events will be presented in alphabetical order. Only SOCs with observed AE PTs will 
be presented.  Repeat sort order for MedDRA PTs within each SOC. 
• The table for all AEs by SOC and PT will be repeated for the following subgroups: 
• Age group (<65, >=65), [On Treatment: T13.12; On Study: T23.10]. 
• Race (Black, non-Black), [On Treatment: T13.13; On Study: T23.11]. 
• Country region, [On Treatment: T13.14; On Study: T23.12].  
• Baseline C3/C4 levels & anti-dsDNA subgroup [On Treatment: T13.15; On 
Study: T23.13].  
• Baseline SLEDAI-2K (<=9, >=10) [On Treatment: T13.16; On Study: T23.14].  
• Baseline Immunosuppressant use (Y,N) )[ On Treatment: T13.17; On Study: 
T23.15]. 
• Baseline Corticosteroid dose (<=10 mg/day, >10 mg/day) )[ On Treatment: 
T13.18; On Study: T23.16]. 
• Gender, [On Treatment: T13.19; On Study: T23.17]. 
• For Year 1 reporting, the table of deaths by category and PT will include deaths that 
occurred during Year 1 and fatal SAEs that started during Year 1 and resulted in 
death during Year 2 by the time of the data cut [On Treatment:T13.20].  For Year 2 
reporting, the table of deaths by category and PT will include deaths that occurred 
during Year 2 (and 8-week Follow-up) that have not been previously reported in Year 
1 as a result of a fatal SAE [On Study: T23.22]. 
• A summary of AEs by SOC, PT and severity will also be provided by treatment 
group.  The number and percentage of subjects will be summarized as mild, moderate 
or severe based on the maximum severity observed within each PT, and within each 
SOC [On Treatment: T13.10; On Study: T23.09]. 
• The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text will be 
displayed in a listing for all AEs [L13.01, L23.01]. 
• A listing of all AEs [On Study: L13.02, L23.02], study treatment related AEs [On 
Study: L13.03, L13.04, L23.03, L23.04], and AEs resulting in study treatment 


 
CONFIDENTIAL 
 
205646 
 
80 
 
discontinuation [On Study: L13.05, L13.06, L23.05] and post withdrawal 
[L13.07,23.06] will be presented, including duration, study day of onset/resolution 
and days since 1st / last belimumab dose. 
• If a Year 1 adverse events is reported after year 1 database lock it will be reported in 
year 2 (L23.07]. 
• 
A summary of Adverse Events including Exposure-Adjusted Incidence Rates will be 
produced for Year 1 On Treatment (Section 5.12) [T13.44] and Years 1&2 combined 
On Study (Section 5.11) [T23.37].  These will present Adverse Events Overall and 
by System Organ Class and Preferred Term and will display:  
• the number of subjects experiencing the event (n);  
• For Year 1: the sum of the total time to the first event or total on treatment time* 
if no event (years) across all subjects (e), * defined in Section 15.6.2: On 
Treatment Exposure (Year 1); 
• For Years 1&2 combined: the sum of the total time to the first event or total on-
study time* if no event (years) across all subjects (e), * defined in Section 15.6.2: 
On-Study Exposure (Years 1&2 Combined); 
• the exposure adjusted subject rate per 100 subject years (r = (n/e)*100).  
• 
A summary of Adverse Events leading to Permanent Discontinuation of Belimumab 
Study Drug including Exposure-Adjusted Incidence Rates will be produced for Year 
1 On Treatment (Section 5.12) [T13.45] and Years 1&2 combined On Study (Section 
5.11) [T23.39].  These will present Adverse Events Overall and by System Organ 
Class and Preferred Term and will display:  
• the number of subjects experiencing the event (n);  
• For Year 1: the sum of the total time to the first event or total on treatment time* 
if no event (years) across all subjects (e), * defined in Section 15.6.2: On 
Treatment Exposure (Year 1); 
• For Years 1&2 combined: the sum of the total time to the first event or total on-
study time* if no event (years) across all subjects (e), * defined in Section 15.6.2: 
On-Study Exposure (Years 1&2 Combined); 
• the exposure adjusted subject rate per 100 subject years (r = (n/e)*100).  
 
8.1.3. 
Deaths, Serious Adverse Events, and Survival Status 
In addition to the tabular summaries of AEs described in Section 8.1.2, listings for all 
SAEs [L13.08, L23.08], all deaths [L13.09, L23.09] and all non-fatal SAEs [L13.10, 
L23.10] will be produced (which will also identify on study events).  The categorization 
of the cause of death will be adjudicated by GSK.  
A listing of reasons for considering an AE as serious will be provided [L13.11, L23.11]. 
A summary of Serious Adverse Events including Exposure-Adjusted Incidence Rates will 
be produced for Year 1 On Treatment (Section 5.12) [T13.46] and Years 1&2 combined 


 
CONFIDENTIAL 
 
205646 
 
81 
 
On Study (Section 5.11) [T23.38].  These will present Serious Adverse Events Overall 
and by System Organ Class and Preferred Term and will display:  
• the number of subjects experiencing the event (n);  
• For Year 1: the sum of the total time to the first event or total on treatment time* 
if no event (years) across all subjects (e), * defined in Section 15.6.2: On 
Treatment Exposure (Year 1); 
• For Years 1&2 combined: the sum of the total time to the first event or total on-
study time* if no event (years) across all subjects (e), * defined in Section 15.6.2: 
On-Study Exposure (Years 1&2 Combined); 
• the exposure adjusted subject rate per 100 subject years (r = (n/e)*100).  
A summary of Deaths including Exposure-Adjusted Incidence Rates will be produced for 
Year 1 On Treatment (Section 5.12) [T13.47] and Years 1&2 combined On Study 
(Section 5.11) [T23.40].  These will present Deaths Overall and by Category and 
Preferred Term and will display:  
• the number of subjects experiencing the event (n);  
• For Year 1: the sum of the total time to the first event or total on treatment time* 
if no event (years) across all subjects (e), * defined in Section 15.6.2: On 
Treatment Exposure (Year 1); 
• For Years 1&2 combined: the sum of the total time to the first event or total on-
study time* if no event (years) across all subjects (e), * defined in Section 15.6.2: 
On-Study Exposure (Years 1&2 Combined); 
• the exposure adjusted subject rate per 100 subject years (r = (n/e)*100) 
 
Survival status will also be summarized at Weeks 52 and 104.  The number and 
percentage of subjects will be summarized for each of the following categories for Year 1 
and Year 1&2 [T13.30, T23.29]. 
• Alive 
• Consent Withdrawn 
• Lost to Follow-up 
• All Deaths based on the date of death relative to the planned or actual Week 52 visit. 
• For Year 1 reporting, include deaths that occur at or prior to the observed Week 
52 visit. 
• For Year 2 reporting (after the actual Week 52 visit): 
• Include all deaths  
 


 
CONFIDENTIAL 
 
205646 
 
82 
 
8.1.4. 
Adverse Events of Special Interest Analyses 
To ensure consistency across belimumab studies, AESI will be defined per the version of 
the PSAP and MedDRA in effect at the time of DBR.  
The Benlysta Program Safety Analysis Plan (PSAP) has been developed to include an 
adverse event of special interest (AESI) analysis for consistent reporting across 
belimumab studies.  Categorizations for the AESIs are defined in the PSAP.  
The milestone defined in the PSAP (i.e. before database release) for adjudications will be 
“primary analysis database release” (Year 1) and “end of study database release” (Year 
2). 
Events with a start date on or prior to the week 52 visit date will be attributed to Year 1; 
otherwise events will be attributed to Year 2.  Events will only be reported once even if 
the event does not resolve by the Week 52 visit. 
An overall summary of AESIs will be presented and each specific category of AESI will 
be presented separately by PT.  The number and percentage of subjects with at least one 
occurrence and the number of events of the following AESIs will be provided [On 
Treatment: T13.31; On Study: T23.30].  
A summary of AESI including Exposure-Adjusted Incidence Rates will be produced for 
Year 1 On Treatment (Section 5.12) [T13.48] and Years 1&2 combined On Study 
(Section 5.11) [T23.xxx].  These will present AESI Overall and by each specific category 
and Preferred Term and will display:  
• the number of subjects experiencing the event (n);  
• For Year 1: the sum of the total time to the first event or total on treatment time* 
if no event (years) across all subjects (e), * defined in Section 15.6.2: On 
Treatment Exposure (Year 1); 
• For Years 1&2 combined: the sum of the total time to the first event or total on-
study time* if no event (years) across all subjects (e), * defined in Section 15.6.2: 
On-Study Exposure (Years 1&2 Combined); 
• the exposure adjusted subject rate per 100 subject years (r = (n/e)*100).  
The following AESI will be identified and adjudicated as detailed in the PSAP. 
 
Adverse Events 
Adverse Events of Special Interest (AESI) 
AESI will be defined per the version of the PSAP/MedDRA in effect at the time of DBR. 
Malignant Neoplasms 
• 
Malignancies Excluding non-melanoma skin cancer (NMSC) 
• 
Malignancies Including NMSC 
• Solid Tumour 
• Hematologic 


 
CONFIDENTIAL 
 
205646 
 
83 
 
Adverse Events 
Adverse Events of Special Interest (AESI) 
• Skin (All) 
• 
NMSC 
• 
Excluding NMSC 
• 
Tumours of unspecified malignancy adjudicated as malignant per GSK 
Post-Injection Systemic Reactions (PISR) 
• PISR per Anaphylactic Reaction Customized MedDRA Query (CMQ) narrow search 
• PISR per Anaphylactic Reaction CMQ broad search 
• PISR per Anaphylactic Reaction CMQ algorithmic search 
• Serious Anaphylaxis per Sampson Criteria per GSK adjudication 
• Serious Acute PISR/Hypersensitivity Per GSK adjudication 
– Serious Acute PISR Excluding Hypersensitivity per GSK adjudication 
– Serious Acute Hypersensitivity Reactions per GSK adjudication 
• Serious Delayed Acute Hypersensitivity Reactions per GSK adjudication 
• Serious Delayed Non-Acute Hypersensitivity Reactions per GSK adjudication 
All Infections of Special Interest (Opportunistic Infections (OI), Herpes Zoster (HZ), Tuberculosis 
(TB), And Sepsis; All and Serious, separately) 
• All opportunistic infections (OI) per GSK adjudication 
• OI per GSK adjudication excluding Tuberculosis and Herpes Zoster 
• Active Tuberculosis 
– Non-Opportunistic  
– Opportunistic 
• Herpes Zoster 
– Non-Opportunistic  
– Opportunistic 
▪ Recurrent  
▪ Disseminated 
• Sepsis 
Depression (including mood disorders and anxiety)/suicide/self-injury (All and Serious, 
separately)  
• Depression (including mood disorders and anxiety) (excluding suicide and self-injury)  
• Suicide/self-injury 
• Serous suicide/self-injury per GSK adjudication  
– Suicidal Behavior  
▪ Completed Suicide  
– Suicidal Ideation  
– Self-injurious Behavior without Suicidal Intent   
• 
Deaths 
Malignant neoplasm events identified as “tumours of unspecified malignancy” will be 
reviewed for classification as malignant per GSK adjudication and will be presented by 
category and PT [On Treatment: T13.32; On Study: T23.31]. 


 
CONFIDENTIAL 
 
205646 
 
84 
 
Post-injection systemic reactions and serious post- injection systemic reactions will be 
presented using nine different definitions as indicated above. These will be presented by 
category and PT [On Treatment: T13.33, T13.34; On Study: T23.32, T23.33]. 
Infection AESIs will be presented by Category and PT for all infections and for infections 
leading to study treatment discontinuation [On Treatment: T13.41, T13.42; On Study: 
T23.34, T23.35]. 
Depression, suicide and self-injury as defined in the PSAP will be presented by Category 
and PT [On Treatment: T13.43; On Study: T23.36]. 
All AESI will be presented in a listing [L13.12, L23.12]. Post-Treatment AESIs will be 
summarized and presented by Category. 
8.1.5. 
Post-Injection Systemic Reactions 
Summaries of post-injection systemic reactions that occur on the day of an injection or 
within 3 days after an injection will be presented by treatment group, by the first six 
injections and over all injections, and PT for the following:   
• 
Post-Injection Systemic Reactions Adverse Events of Special Interest by 
Category and PT [T13.33, T23.32]. 
• 
Serious Post-Injection Systemic Reactions Adverse Events of Special Interest by 
Category and PT [T13.34, T23.33]. 
• 
Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ broad 
search (on the day of the injection or within 3 days after the Belimumab 
injection) by PT in the first six injections [On treatment:T13.35]. 
• 
Serious Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ 
broad search (on the day of the injection or within 3 days after the Belimumab 
injection) by PT in the first six injections [on Treatment: T13.36]. 
• 
Serious Acute Post-Injection Systemic Reactions/Hypersensitivity per GSK 
Adjudication by PT in the First Six Injections  [On Treatment: T13.37]. 
• 
Serious Delayed Acute Hypersensitivity Reactions per GSK Adjudication by PT 
in First Six Injections [On Treatment:T13.38]. 
• 
Serious Delayed Non-Acute Hypersensitivity Reactions per GSK Adjudication 
by PT in First Six Injections [On Treatment: T13.39]. 
• 
Post-Injection Systemic Reactions per Anaphylactic Reaction CMQ broad 
search (on the day of the injection or within 3 days after the Rituximab infusion) 
by PT [On treatment:T13.40]. 
 


 
CONFIDENTIAL 
 
205646 
 
85 
 
8.1.6. 
Additional Adverse Event Summaries to Assess the Impact of the 
Coronavirus Disease 2019 (COVID-19) Pandemic 
Additional adverse event summaries will be produced to further understand the safety profile 
and/or impact of the COVID-19 pandemic on safety. 
Two listings will be produced to show the number of subjects with a suspected, probable or 
confirmed COVID-19 infection.  The first listing will present data for Year 1 On Treatment (Section 
5.12) [L13.26]; the second listing will present data for Years 1 and 2 combined On-Study (Section 
5.11) [L23.27].  Both listings will also show the number of subjects who had a COVID-19 diagnosis 
test performed and the number of subjects with positive, negative, or indeterminate results.  The 
listings will be based on information collected on the COVID-19 Coronavirus Infection Assessment 
CRF page. 
Extra tables will be produced to display the incidence of Adverse Events over the time course of 
the trial.  Event rates will be reported by calendar time defined as either pre or during the COVID-
19 pandemic (or post the pandemic if applicable by the Year 2 reporting).  The COVID-19 
environment onset date will be used to define pre and during the COVID-19 pandemic (Section 
15.6.16). 
The following Tables will summarise the Year 1 On Treatment (Section 5.12) events for pre or 
during the COVID-19 pandemic.  Event rates will be adjusted for on treatment exposure  (Section 
15.6.2, On -Treatment exposure in the relevant pandemic phase (Year 1)). 
• The overall rates of AEs, SAEs and severe AEs [T13.49] 
• The overall rates of AEs, SAEs and severe AEs, presented by Country Region 
(USA/Canada vs. Europe vs. Rest of World) (Section 5.5.2.) [T13.50] 
• The most frequent Adverse Events (≥ 5% incidence in any treatment group) by Preferred 
Term [T13.51] 
The following Tables will summarise the Year 1 and 2 combined On-Study (Section 5.11) events 
for pre or during the COVID-19 pandemic.  Note that if a date is defined prior to the Year 2 
reporting for the ‘end of the pandemic’ then this output will split events into pre, during or post the 
COVID-19 pandemic.  Event rates will be adjusted for on-study exposure in the relevant pandemic 
phase (Section 15.6.2, On-Study exposure (Years 1&2 combined)). 
• The overall rates of AEs, SAEs and severe AEs [T23.42] 
• The overall rates of AEs, SAEs and severe AEs, presented by Country Region 
(USA/Canada vs. Europe vs. Rest of World) (Section 5.5.2.) [T23.43] 
• The most frequent Adverse Events (≥ 5% incidence in any treatment group) by Preferred 
Term [T23.44] 
 


 
CONFIDENTIAL 
 
205646 
 
86 
 
8.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
For suicidal ideation, the pre-treatment reference period is the lifetime history, current 
history and baseline (for further detail refer to the IDSL documentation). For suicidal 
behavior, the pre-treatment reference period is the lifetime history and baseline (note: 
suicidal behavior is not re-assessed for the current history time period). 
Suicidal ideation and suicidal behavior will be considered as distinct categories and 
assessed independently of each other. Treatment emergence will be assessed for the on 
treatment period and the on-study period. 
Suicidal ideation will be assessed using responses to C-SSRS ideation questions 
(categories 1 to 5) only. Suicidal behavior will be assessed using responses to C-SSRS 
behavior questions (categories 6 to 10) only. 
• 
Treatment emergent suicidal ideation will be assessed using the maximum 
ideation score pre-treatment, compared to the maximum ideation score post-
treatment (Year 1 or Year 2 as appropriate). If the maximum ideation score worsens 
relative to the pre-treatment reference period then this will be considered a treatment 
emergent suicidal ideation. This is derived from responses to suicidal ideation 
questions (categories 1 to 5).   
• 
Treatment emergent suicidal behavior will be assessed using the maximum 
behavior score pre-treatment, compared to the maximum behavior score post-
treatment (Year 1 or Year 2 as appropriate). If the maximum behavior score worsens 
relative to the pre-treatment reference period then this will be considered a treatment 
emergent suicidal behavior. This is derived from responses to suicidal behavior 
questions (categories 6 to 10). 
• 
Treatment emergent suicidal ideation or behavior will be defined as a subject 
having a treatment emergent suicidal ideation (as defined above) and/or a treatment 
emergent suicidal behavior (as defined above).  
Suicidal Ideation (categories): 
 
Suicidal Behavior (categories): 
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.


 
CONFIDENTIAL 
 
205646 
 
87 
 
A subject must have at least one pre-treatment C-SSRS assessment (screening and/or 
baseline) and at least one on treatment C-SSRS assessment (post-baseline) to be included 
in any assessment of treatment emergent. 
If a “yes” response is given to any suicidal behavior or a “yes” response is given to 
suicidal ideation questions 3, 4 or 5 on the C-SSRS, the investigator will be prompted to 
complete the Possible Suicidality Related Questionnaire (PSRQ).   
All C-SSRS tables will be presented for subjects whilst on study.  
8.2.1. 
C-SSRS Suicidal Ideation or Behaviour on Study [T13.52, T23.45]. 
The number and percentage of subjects with each category of suicidal ideation or 
behavior during treatment (starting after Day 1 assessment) will be presented for Year 1, 
and Year 2.  For suicidal ideation, the maximum ideation score (1-5) at any time during 
the relevant period will be presented. For suicidal behavior, all behaviors (6-10) present 
at any time during the relevant period will be presented. This will be regardless of 
whether the subject had pre-treatment history (up to and including baseline). The 
categories of suicidal ideation and behavior are presented in increasing order of severity 
from 1 to 5, and 6-10 respectively.  
8.2.2. 
C-SSRS Suicidal Ideation or Behavior Relative to Pre-Treatment 
[T13.53, T23.46]. 
The number and percentage of subjects with treatment-emergent suicidal ideation or 
behavior -post-baseline will be presented for Year 1 and Year 2. 
A subject must have at least one pre-treatment C-SSRS assessment (screening and/or 
baseline) and at least one Year 1 or Year 2 (respectively) C-SSRS assessment to be 
included in this display.  
A subject may have treatment emergent suicidal ideation and/or behavior. 
The following categories will be presented: 
• 
The number (%) of subjects with any treatment emergent suicidal ideation (1-5) 
• 
The number (%) of subjects with any treatment emergent more severe suicidal 
ideation (4-5) 
• 
The number (%) of subjects with any treatment emergent suicidal behavior (6-10) 
• 
The number (%) of subjects with any treatment emergent suicidal ideation (1-5) or 
suicidal behavior (6-10) 
Note: treatment emergent suicidality can only be assessed in subjects with a pre-treatment 
maximum ideation score of 4 or lower (as subjects with a pre-treatment ideation score of 
5 have no potential to worsen on the 1-5 ideation scale) 


 
CONFIDENTIAL 
 
205646 
 
88 
 
8.2.3. 
C-SSRS Shift Changes in Categories from Pre-Treatment to On-
Study [T13.54, T23.47]. 
A summary of the shift from maximum pre-treatment C-SSRS category to maximum 
category during Year 1 and Year 2 separately will be produced by treatment group.   
The pre-treatment period for ideation is based on the lifetime, current and baseline 
history. For behavior, it is based on the lifetime and baseline history.  A subject must 
have at least one pre-treatment assessment and at least one assessment during Year 1 or 
Year 2 (respectively) in order to be included in these displays.  
The table will display the number and percentage of subjects within the specific shift 
categories: No suicidal ideation or behavior, suicidal ideation, and suicidal behavior.   
Each subject will appear in the table only once. For the purposes of this table only, a 
subject with both suicidal ideation and suicidal behavior in any period (pre-treatment/on 
treatment/on-study) will appear in the category of suicidal behavior only. 
8.2.4. 
C-SSRS Shift Changes in Categories from Year 1 to Year 2 
[T23.48]. 
A summary of the shift from last Year 1 C-SSRS assessment to maximum Year 2 C-
SSRS assessment will be produced by treatment group.   
The last Year 1 is based on the current assessment.  A subject must have at least one Year 
1 assessment, and at least one assessment during Year 2 in order to be included in these 
displays.  
The table will display the number and percentage of subjects within the specific shift 
categories: No suicidal ideation or behavior, suicidal ideation, and suicidal behavior.   
Each subject will appear in the table only once. For the purposes of this table only, a 
subject with both suicidal ideation and suicidal behavior in any period (pre-treatment/on 
treatment/on-study) will appear in the category of suicidal behavior only. 
 
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards.  
For laboratory analyses analytes will be analyzed and summaries and analyses will be 
performed based on the observed data.  No imputation will be done for missing data.  
Baseline is defined as described in Section 5.3.  See Protocol Appendix 9 for a list of 
laboratory parameters.  Laboratory toxicity grades will be assigned based on DMID (see 
Section 15.8 Appendix 8: Laboratory Parameters and Toxicity Grades) by the laboratory, 


 
CONFIDENTIAL 
 
205646 
 
89 
 
with the exception of Lymphopenia (as there is no DMID grade).  Lymphopenia will be 
graded as per CTCAE v4.03. 
Calcium, will be presented as hypercalcaemia and hypocalcaemia separately (with each 
subject appearing in both categories) and similarly for sodium (hypernatremia, 
hyponatremia), potassium (hyperkalemia, hypokalemia), and glucose (hyperglycemia, 
hypoglycemia). 
 
Listings will be generated for all laboratory results and for Grade 3 or Grade 4 laboratory 
toxicity results [L13.13 – L13.24, L23.14 - L23.26]. 
If a numeric laboratory value, has a non-detectable level reported in the database, then 
typically the numeric value is missing, and a character value starting with ‘<x’ or ‘>x’ is 
present. A numeric value will be derived using the number of decimal places in the 
observed character values i.e.  
• 
2 Decimal Places = ‘< x ‘ becomes x – 0.01 
• 
1 Decimal Place = ‘> x’ becomes x + 0.1 
• 
0 Decimal Places = ‘< x’ becomes x – 1 
8.3.1. 
Laboratory Descriptive Statistics by Visit 
Descriptive statistics for each analyte will be displayed for each visit for both the Year 1 
and Year 1&2 reporting separately. The tables will display the mean value, standard 
deviation, median, 25th and 75th percentiles, minimum and maximum. No statistical tests 
will be performed [T13.55, T13.59, T13.63, T13.67, T13.74, T23.49, T23.53, T23.57, 
T23.61, T23.68].  
A line graph will be produced for each analyte which displays the mean value (±SE) by 
visit and treatment group for both Year 1 and Year 1&2 separately [F13.01-F13.05, 
F23.01-F23.05]. 
8.3.2. 
Laboratory Toxicity ≥ 2 Grade Shift Post-Baseline 
Toxicity grade shifts from baseline of ≥ 2 grades will be summarized during treatment for 
each laboratory parameter within each laboratory category (hematology, liver function, 
electrolytes, other chemistries, urinalysis and immunoglobulins) for Year 1 and Year 1&2 
separately.  The table will display the number and percentage of subjects with at least one 
≥ 2 grade shift as well as the specific shift categories: Grade 0 to 2, Grade 0 to 3, Grade 0 
to 4, Grade 1 to 3, Grade 1 to 4 and Grade 2 to 4  [T13.57, T13.61, T13.65, T13.69, 
T13.72, T13.76, T23.51, T23.55, T23.59, T23.63, T23.66, T23.70]. 
8.3.3. 
Laboratory Reference Range Shifts from Baseline by Visit 
For laboratory tests without toxicity grades, shifts relative to the normal range will be 
summarized for each analyte as shifts ‘to low’ and shifts ‘to normal/high.’  For the ‘to 
low’ category the percentage of subjects with at least one low post-baseline value relative 


 
CONFIDENTIAL 
 
205646 
 
90 
 
to the baseline will be displayed using the categories:   remained low and normal/high to 
low. For the ‘to normal/high’ category the percentage of subjects with at least one 
normal/high post-baseline value relative to baseline will be displayed using the 
categories:   remained normal/high and low to normal/high.  No statistical tests will be 
performed.  This analysis will be performed for Year 1 and Year 1&2 separately [T13.58, 
T13.62, T13.66, T13.70, T13.73, T23.52, T23.56, T23.60, T23.64, T23.67]. 
A laboratory value that is above the testing laboratory’s normal range will be considered 
a high abnormal laboratory value. A laboratory value that is below the testing 
laboratory’s normal range will be considered a low abnormal value. 
8.3.4. 
Immunoglobulin Reference Range Shifts from Baseline by Visit 
For immunoglobulins (IgA, and IgM) reference range shifts will be summarized across 
all visits based on the baseline normal range category.  For subjects with immunoglobulin 
values below the LLN, the number and percentage of subjects who ‘remained low’ or 
went ‘to normal/high’ post-baseline will be summarized.  Similarly, for subjects with 
immunoglobulin values within the normal range or above the ULN, the number and 
percentage of subjects who ‘remained normal/high’ or went ‘to low’ post-baseline will be 
summarized.  This analysis will be performed for Year 1 and Year 1&2  separately 
[T13.77, T23.71]. 
8.3.5. 
Worst Laboratory Toxicity Grade Post-Baseline 
Laboratory toxicity will be graded using grades corresponding to mild, moderate, severe, 
and life-threatening when possible. The worst laboratory toxicity grade for each 
laboratory parameter within each laboratory category (hematology, liver function, 
electrolytes, other chemistries, urinalysis and immunoglobulins) during Year 1 and Year 
1&2 separately will be presented. Data for both scheduled and unscheduled visits will be 
included.  For calcium, sodium, potassium and glucose, grades associated with hypo- and 
hyper- conditions will be included [T13.56, T13.60, T13.64, T13.68, T13.71, T13.75, 
T23.50, T23.54, T23.58, T23.62, T23.65, T23.69]. 
8.3.6. 
Immunoglobulin Below LLN by Visit 
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) 
below the LLN at each visit will also be presented for all subjects and then repeated for 
subjects ≥ LLN at baseline for Year 1 and Year 1&2 separately. No statistical test will be 
performed [T13.78, T13.79, T23.72, T23.73]. 
8.3.7. 
Immunoglobulin Relative to LLN by Visit 
The number and percentage of subjects with immunoglobulin values (IgG, IgA, and IgM) 
greater than or equal to the LLN at each visit will also be presented for all subjects and 
then repeated for subjects < LLN at baseline for Year 1 and Year 2  separately. No 
statistical test will be performed [T13.80, T13.81, T23.74, T23.75]. 


 
CONFIDENTIAL 
 
205646 
 
91 
 
8.3.8. 
Immunogenicity 
For the immunogenicity assessment for belimumab, two types of antibody assays will be 
performed, i.e. a binding assay and neutralizing assay.  For the immunogenicity 
assessment for rituximab only a binding assay will be performed . For the binding assay, 
there will be 3-testing steps.  A screening assessment is performed which produces a 
result of positive or negative. Confirmed positive samples will be further characterised 
for a relative level of binding (titre value).  Subjects will be viewed as positive for anti-
drug antibody (ADA) if the confirmation assay is positive. Subjects, who confirm 
positive in the anti-belimumab ADA assay, will be evaluated for the presence of 
neutralising antibody (Nab) response with the NAb assay, which again produces a result 
of positive or negative.    
For incidence of subjects with positive binding antibody during the study period, a table 
will be produced summarizing results for the binding antibody assay by treatment group 
and visit. The table will include the number and proportion of subjects in each results 
category for each visit in the study period (including early withdrawal visit). Binding 
confirmatory assay results will be categorized as negative, persistent positive (defined as 
a positive immunogenic response at least two consecutive assessments during the study 
period or a single result at the final assessment in the study period) or transient positive 
(defined as a single positive immunogenic response that does not occur at the final 
assessment in the study period). 
Results will be summarized by visit and by treatment group for belimumab (Year 1 and 
Year 2, separately) and for Arms A and B only for rituximab (Year 1) [T13.82 T13.83, 
T23.76].  A listing of immunogenicity results will also be presented [L13.33, L23.33]. 
 
8.3.9. 
Further Research Samples 
Blood leukocyte analysis and B cell receptor samples collected at selected sites in the 
USA will be reported separately and are not considered in this RAP. 
B Cell subsets collected at selected sites in the European Union (EU) will be reported 
separately and are not considered in this RAP. 
 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including vital signs will be based on 
GSK Core Data Standards, unless otherwise specified.  


 
CONFIDENTIAL 
 
205646 
 
92 
 
8.4.1. 
Vital Signs 
A summary of vital signs and change from baseline in vital signs will be presented by 
visit for Year 1 and Year 2 separately. Weight will be included in these summaries 
[T13.84, T13.85, T23.77, T23.780]. 
8.4.2. 
Neurological Assessment 
Findings consistent with the diagnosis of Progressive Multifocal Leukoencephalopathy 
(PML) will be recorded as adverse events.  


 
CONFIDENTIAL 
 
205646 
 
93 
 
9. 
HEALTH OUTCOMES ANALYSES  
Health outcomes reporting will be conducted on the MITT population, following the 
principles of the Efficacy analysis.  
Additional details for the Health Outcome scales are provided in the appendix: Lupus Qol 
(Section 15.6.10); WPAI (Section 15.6.11); FACIT-Fatigue Scale (Section 15.6.12)..  A 
listing of all health outcomes endpoints will be presented [L24.01-L24.03]. 
Exit interviews assessing patients experience of the clinical trial will be databased and 
reported separately.  
The Health Outcome scales are completed by the subject and are very subjective, 
therefore, all data after the COVID-19 environment onset date (Section 15.6.16) is very 
likely to be either missing due to the pandemic or affected by the pandemic.  It is also 
expected that the Health Outcomes data collected at different stages of the COVID-19 
pandemic may be affected in different ways.  As per the second additional analysis for 
the primary Efficacy endpoint, there may be intangible ways that the data may have been 
affected even if it has been collected, therefore we cannot distinguish between affected 
and unaffected data after the COVID-19 environment onset date.  
For these reasons, additional analyses defined below have been added for Week 52 and 
Week 64.  A hypothetical strategy was already proposed to deal with missing data due to 
study withdrawal and this has been expanded to also define the COVID-19 environment 
onset date as an Intercurrent Event for any subject who has their (scheduled) Week 52 (or 
Week 64) assessment on or after the onset date.  The data for these subjects will be 
treated as missing values and will be assumed to be Missing At Random (MAR).  It will 
be imputed using Multiple Imputation methods, which take into account the subjects 
baseline characteristics and their existing pre-COVID data. 
The analysis for Week 104 has not been modified as all observed Week 104 data will be 
collected after the COVID-19 environment onset date, so the Multiple Imputation 
approach will not be possible.  This means that the results should be interpreted with 
caution. 
Additional post-SAC analyses may be carried out to assess the impact of the COVID-19 
pandemic on the Health Outcomes data. 
9.1. 
Statistical Methodology Specification for Continuous 
Endpoints 
Endpoints 
For all reported timepoints upto Week 52 (Year 1 reporting) and upto week 104 (Year 2 
reporting): 
 
Patient Global Assessment (PtGA) of Disease Activity 
• 
Change from baseline in PtGA by visit [T14.01, T24.01]. 


 
CONFIDENTIAL 
 
205646 
 
94 
 
 
LupusQoL Domain Scores 
• 
Change from baseline in each of the 8 LupusQoL Domain scores by visit [T14.02, T24.02]. 
 
FACIT-Fatigue Scale Score 
• 
Change from baseline in FACIT-Fatigue Scale score by visit  [T14.03, T24.03]. 
 
Work Productivity and Activity Impairment (WPAI) 
• 
Change from baseline in WPAI percent overall work productivity impairment by visit  
[T14.05, T24.05]. 
• 
Change from baseline in WPAI percent activity impairment score by visit [T14.06, T24.06]. 
Derivation 
Derivation of the endpoints is provided in Section 15: Lupus Qol (Section 15.6.10); 
WPAI (Section 15.6.11); FACIT-Fatigue Scale (Section 15.6.12). 
Strategy for Intercurrent (Post-Randomization) Events 
A hypothetical strategy will be used to estimate what the treatment effect would have 
been had the subjects not had missing data. 
Imputation of Data  for Missed Visits, and Following  Study Withdrawal 
• A bayesian repeated measures normal model will be fitted to the observed data, using a 
Markov Chain Monte Carlo approach, adjusting for treatment group, baseline SLEDAI-2K 
score (9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), and baseline 
corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day).  Non-informative 
priors will be used 
• Quasi-independent samples will be drawn from the posterior distributions for the parameters 
of the multivariate normal distribution for each treatment group and each missingness 
pattern. 
• Each sample leads to a separate imputed dataset, in which the missing values are replaced 
by values drawn randomly from their conditional distribution. This distribution is based on the 
observed data and the covariates for that subject using the imputation model and the 
sampled parameter values. 
•  
These steps will be repeated at least 1000 times. 
Model Specification 
• Each imputed dataset will be analyzed using ANCOVA to evaluate the treatment effect 
controlling for treatment group, baseline SLEDAI-2K score (9 vs. 10 ), baseline 
immunosuppressant use (use vs. non-use), and baseline corticosteroid dose (prednisone 
equivalent 10 mg/day vs. >10 mg/day) and baseline value.   
• The resulting treatment differences and their SEs will be combined across imputations using 
Rubin’s rules. 


 
CONFIDENTIAL 
 
205646 
 
95 
 
Model Checking & Diagnostics 
The Kolmogorov-Smirnov D statistic will be used to test the assumption of normality. Residuals 
will be reviewed to assess the homogeneity of variance assumption. 
Model Results Presentation 
The tables  will display: 
• Baseline: the number subjects, mean, standard error, standard deviation, median, 25th 
percentile, 75th percentile, minimum, maximum for each arm 
• At each visit: 
o the number subjects, mean, standard error, standard deviation, median, 25th 
percentile, 75th percentile, minimum, and maximum  
o LS Mean, and standard error of the LS Mean for each arm at Weeks 52, 64 and 
104. 
o the treatment difference and 95% confidence interval (CI) for the comparison of 
Arm B vs Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
o the p-value for treatment difference for Arm B vs Arm A at Weeks 52, 64 and 
104.  
 
9.1.1. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic (Continuous Endpoints upto 
Week 52 and Week 64) 
The analysis will be repeated, but visits that were conducted on or after the COVID-19 
environment onset date (Section 15.6.16) will be considered as impacted and hence 
removed from the analysis, as if the subjects had withdrawn. 
A hypothetical strategy will be used to estimate what the treatment effect would have 
been had the subjects not had missing data (including the missing data from the  removal 
of impacted COVID-19 visits). Weeks 72 and 104  are anticipated to have too much data 
post the COVID-19 environment onset date and hence will not be included. 
Patient Global Assessment (PtGA) of Disease Activity 
• 
Change from baseline in PtGA by visit [T14.08,T24.08]. 
 
LupusQoL Domain Scores 
• 
Change from baseline in each of the 8 LupusQoL Domain scores by visit [T14.09,T24.09]. 
 
FACIT-Fatigue Scale Score 
• 
Change from baseline in FACIT-Fatigue Scale score by visit  [T14.10,24.09] 
 
Work Productivity and Activity Impairment (WPAI) 
• 
Change from baseline in WPAI percent overall work productivity impairment by visit  [T14.12, 
24.12]. 
• 
Change from baseline in WPAI percent activity impairment score by visit [T14.13, 24.13]. 
 


 
CONFIDENTIAL 
 
205646 
 
96 
 
For change from baseline endpoints, a plot of LS means +/- SE by visit and treatment group will be 
provided.[Year 1: F14.01, Year 1 and 2 combined, but only up to Week 64: F24.01-24.06]. 
 
9.2. 
Statistical Methodology Specification for Proportion 
Endpoints 
Endpoint / Variables 
• The proportion of participants with an improvement in FACIT-fatigue score exceeding the 
minimal clinically important difference (MCID is >=4) by visit. 
Derivation 
Derivation of the FACIT endpoint is provided in Section 15.6.12.  A subject is considered to have 
an improvement exceeding the minimal clinically important difference if they have  4 points 
improvement in their FACIT-Fatigue Scale score from baseline. 
Imputation of Data for missed visits, and following study withdrawal.. 
Missing Data will be imputed as detailed in Section 9.1.1, then categorized as Responder/Non-
Responder using the derivation above.  For consistency of results, the same seed will be used 
for the imputation of missing data on the continuous FACIT scale and the imputation on the 
continuous scale that is then dichotomized into the binary response. 
Model Specification 
• Each imputed dataset will analyzed using the proposed statistical analyses planned for the 
primary endpoint.  The FACIT-fatigue score at baseline will also be included as a covariate. 
• The resulting Odds Ratios and their SEs will be combined across imputations using Rubin’s 
rules. 
Model Checking & Diagnostics 
• The model and diagnostics checks proposed for the primary endpoint will be repeated for 
this endpoint. 
Model Results Presentation 
• For each endpoint a table [T14.04, T24.04]. will display: 
• the number,  percentage, SE of percentage, and the 95% CI for the percentage 
of subjects achieving a response by treatment group,  
• the observed difference in percentage of responders for the comparison of Arm 
B vs Arm A; and Arm B vs Arm C, 
• the odds ratio and 95% confidence interval (CI) for the comparison of Arm B vs 
Arm A; and Arm B vs Arm C at Weeks 52, 64 and 104. 
• the p-value for the odds ratio the treatment difference for Arm B vs Arm A at 
Weeks 52, 64 and 104.  
 


 
CONFIDENTIAL 
 
205646 
 
97 
 
9.2.1. 
Additional Analyses to Assess the Impact of the Coronavirus 
Disease 2019 (COVID-19) Pandemic  
The analysis will be repeated however visits that were conducted on or after the COVID-
19 environment onset date (Section 15.6.16) will be considered as impacted and hence 
removed from the analysis, as if the subjects had withdrawn. 
A hypothetical strategy will be used to estimate what the treatment effect would have 
been had the subjects not had missing data (including the missing data from the  removal 
of impacted COVID-19 visits).  Weeks 72 and 104  are anticipated to have too much data 
post the COVID-19 environment onset date and hence will not be included. 
The proportion of participants with an improvement in FACIT-fatigue score exceeding 
the minimal clinically important difference (MCID is >=4) by visit [T14.11, T24.11 ]. 
9.3. 
Health Care Resource Utilization 
The health care resource utilization (HCRU) data will be used to conduct exploratory 
economic analyses of:  
• 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. 
These data will be provided by CRF Health, and planned analyses will be described in a 
separate document 
A listing of data will be provided at Year 2 [L24.04].  Health care resource utilization 
will be summarised at Week 52 for Year 1 (T14.07), and at Week 104 for Year 1&2 
(T24.07). 
Duration of hospitalization will be summed for subjects with more than 1 hospitalisation.  
Subjects with ongoing hospitalization at Week 52 will be truncated for the Week 52 
(Year 1) summary.  Subjects with ongoing hospitalization at Week 104 will be truncated 
for the Week 104 (Year 2) summary at the last known date of hospitalization (i.e. 
including  post study hospitalization if the hospitalization is ongoing at Week 104). 
If subjects are withdrawing due to hospitalization then an additional exploratory analysis 
will be performed shortly after the Statistical Analysis Complete milestone. 
 


 
CONFIDENTIAL 
 
205646 
 
98 
 
10. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES  
Biomarker Endpoints, Autoantibodies, complement, and peripheral B lymphocytes 
(referred to as B cells) will be collected per the study calendar (Section 15.2 Appendix 2: 
Schedule of Activities).   The peripheral B lymphocytes will be measured (using FACS 
analysis). The specific biomarkers collected and analyzed are listed in Table 4: 
Table 4 
Biomarkers for Analysis 
Autoantibodies  
Immunoglobulin 
aCL (IgA, IgG, IgM) 
IgG, IgM, and IgA 
ANA 
B cells (present in tables in this order) 
Beta-2-glycoprotein 
(IgA, IgG, IgM) 
CD19+ Total B cells (cells/mL) 
Lupus anticoagulant 
B cells CD20+ (cells/mL and % of CD19+ Total B cells) 
Anti-dsDNA 
Naive B cells IgD+ (cells/mL and % of CD19+ Total B cells) 
Naive CD20+ CD27- (cells/mL and % of CD19+ Total B cells) 
Extractable nuclear 
antigens (ENAs) 
Activated Total B cells CD95+ (cells/mL and % of CD19+ Total B 
cells) 
Anti-Ribosomal-P ;  
Memory CD20+ CD27+ (cells/mL and % of CD19+ Total B cells) 
Anti-RNP-70;  
Non-switched memory CD27+ IgD+ (cells/mL and % of CD19+ 
Total B cells) 
Anti-SS-A;  
Switched memory CD27+ IgD- (cells/mL and % of CD19+ Total B 
cells) 
Anti-SS-B  
Plasmablasts CD27b CD38b (cells/mL and % of CD19+ Total B 
cells) 
Anti-Smith 
Plasmablasts CD20+ CD27b CD38b  (cells/mL and % of CD19+ 
Total B cells) 
Complement 
Plasmablasts CD20- CD27b CD38b  (cells/mL and % of CD19+ 
Total B cells) 
C3 
Transitional CD10+ CD24b CD27- CD38b  (cells/mL and % of 
CD19+ Total B cells) 
C4 
Transitional CD24b CD27- CD38b  (cells/mL and % of CD19+ Total 
B cells) 
T cells 
Cytokines 
CD3+ Total T cells 
(/uL) 
BLyS (Total and Free) 
CD8+ T cells (/uL) 
 
CD4+ T cells (/uL) 
 
 
For the duration of the study, biomarker data (serum immunoglobulin isotypes IgA and 
IgM and B cell results) that have the potential to unblind the study team will not be 
transferred to the blinded study team.  Instead, blinded datasets will only contain data 
from the baseline visit (hence not impacted by treatment group). These datasets will 


 
CONFIDENTIAL 
 
205646 
 
99 
 
display the format for the real datasets which will be received following unblinding. This 
will ensure that programs written using blinded data will still run on the real treatment 
codes and real unblinded data following the first database lock. 
 
10.1. 
Biomarker Change and Percent Change from Baseline 
Analyses 
Endpoints  
The change from baseline and percent change (not for % endpoints) from baseline will be 
evaluated by visit for each of the biomarkers listed in Table 4 [T15.01-15.02, T15.04-T15.07, 
T15.09-T15.12, T15.14-T15.15, T25.01-25.02, T25.04-T25.07, T25.09-T25.12, T25.14-T25.15,]. 
Tables of descriptive statistics for changes in Year 2 relative to at the end of Year 1 will be 
summarised for immunoglobulins, auto-antibodies and B-Cells [T25.21, T25.22,T25.23]. 
Population of Interest 
The Intent-to-Treat population will be used for the analysis. 
Intercurrent Event Strategy 
The Year 1 analyses will be performed on the observed data up to IP discontinuation.  No 
imputation will be done for missing data. 
The Year 1&2 analyses will be performed on the observed data for subjects who completed 
Week 52 on treatment (Ongoing and on treatment at Week 52 analysis as defined in Section 
7.1.5 ).  No imputation will be performed for missing data (data post re-start Belimumab will not 
be considered. 
Model Specification 
Immunoglobulins and Complement 
An ANCOVA will be used to evaluate the treatment effect controlling for treatment group, 
baseline SLEDAI-2K score (9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), 
baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day), and baseline 
value (continuous). 
If the distribution of the observed data is not consistent with conducting ANCOVA then a non-
parametric rank ANCOVA will also be conducted. 
 
Auto-Antibody, B-Cells, T-Cells, and BLyS (Total and Free): 
A Rank ANCOVA will be used to evaluate the treatment effect controlling for treatment group, 
baseline SLEDAI-2K score (9 vs. 10 ), baseline immunosuppressant use (use vs. non-use), 
baseline corticosteroid dose (prednisone equivalent 10 mg/day vs. >10 mg/day), and rank 
baseline value (continuous). 
Model Checking & Diagnostics 
For the ANCOVA analysis the Kolmogorov-Smirnov D statistic will be used to test the 
assumption of normality. Residuals will be reviewed to assess the homogeneity of variance 
assumption. 


 
CONFIDENTIAL 
 
205646 
 
100 
 
Model Results Presentation 
The tables  will display: 
• Baseline: the number subjects, number of subjects, mean, standard error, standard 
deviation, median, 25th percentile, 75th percentile, minimum, maximum for each arm 
• the number of subjects, mean, standard error, standard deviation, median, 25th 
percentile, 75th percentile, minimum, and maximum, for each arm at each visit 
• For ANCOVA analysed endpoints the LS Mean, standard error of the LS Mean, 
treatment difference for each arm, and 95% confidence interval (CI) for the comparison 
of Arm B vs Arm A; and Arm B vs Arm C will be presented at Weeks 52, 64, and 104 
• For all endpoints the p-value for treatment difference for Arm B vs Arm A will be 
presented at Weeks 52, 64, and 104.  
For change from baseline endpoints, a plot of LS means +/- SE or Median +/- Quartiles 
(dependent on observed data distribution) by visit and treatment group will be provided. 
 
There will also be additional reporting of lab parameters (Haematology, chemistry, 
urinalysis and other chemistries) to explore the changes in Year 2 relative to at the end of 
Year 1. Descriptive statistic tables considering the change from Week 52 by visit for 
Year 2 will be produced [T25.16-25.19]. 
 
 


 
CONFIDENTIAL 
 
205646 
 
101 
 
10.2. 
Shifts in Immunoglobulins, Autoantibodies, and 
Complement by Visit 
Endpoints [T15.03, T15.08, T15.13, T25.03, T25.08, T25.13]. 
Shift tables will be used to summarize the changes in immunoglobulins, autoantibodies, and 
complement by treatment group and visit.  Autoantibodies will be evaluated for shifts from 
positive to negative.  Immunoglobulins and complement will be evaluated for shifts from Low to 
Normal/High.  
 
Autoantibody 
Positive 
Negative 
Anti-dsDNA 
>=30 IU/mL 
<30 IU/mL 
ANA 
>=80 Titer 
<80 Titer 
aCL 
If any of the three aCL 
parameters, IgG (>=14 
U/mL), IgA (>=11 U/mL) or 
IgM (>=12 U/mL), is positive. 
If at least 1 is non-missing 
then aCL is negative; 
otherwise aCL is missing. 
Beta-2-glycoprotein isotypes: 
IgA, IgG, IgM 
≥21 U/mL 
<21 U/mL 
Lupus anticoagulant 
N/A 
 
ENAs 
> Upper limit of normal range 
≤ Upper limit of normal range 
Cytokines 
 
 
BlyS (Total and Free) 
<75th percentile 
>=75th percentile 
Ig and Complement 
Low 
Normal/High 
IgG 
<6.94 g/L 
≥6.94 g/L 
IgA 
<0.81 g/L 
≥0.81 g/L 
IgM 
<0.48 g/L 
≥0.48 g/L 
C3 
<90 mg/dL 
≥90 mg/dL 
C4 
<10 mg/dL 
≥10 mg/dL 
Statistical Analysis 
Fisher’s exact test will be performed within each baseline category to evaluate the treatment 
effect at Week 52 only. 
Summary Measure 
The difference in proportions Arm B (Combination)– Arm A (Control) will be used to measure the 
treatment effect.  
Population of Interest 
The Intent-to-Treat population will be used for the analysis. 
 
Intercurrent Event Strategy 
These analyses will be performed on the observed data up to IP discontinuation.  No imputation 
will be done for missing data. 
Variables 
• Immunoglobulins, autoantibodies, and complement endpoints evaluated one at a time. 


 
CONFIDENTIAL 
 
205646 
 
102 
 
• Treatment (belimumab plus rituximab=1, belimumab plus placebo=0) 
Results Presentation 
For IgG, IgA, IgM, C3,C4, and C3 and C4 combined baseline data will be summarized as the 
number and percent of subjects who are low or normal/high at baseline.  For post-baseline visits 
the data will be summarized by baseline status defined as low or normal/high.  Among subjects 
low at baseline the shifts presented will be low to normal/high and low to low. Among subjects 
normal/high at baseline, the shifts presented will be normal/high to normal/high and normal/high 
to low.   
For anti-dsDNA, ANA, aCL, Beta-2-glycoprotein, Lupus anticoagulant,ENAs and BlyS, baseline 
data will be summarized as the number and percent of subjects who are positive and negative at 
baseline.  For post-baseline visits the data will be summarized by baseline status defined as 
positive or negative.  Among subjects positive at baseline, the shifts presented will be positive to 
negative and positive to positive (no change).  Among subjects negative at baseline, the shifts 
presented will be negative to negative (no change) and negative to positive.   
Subgroup Analyses 
Subgroup analyses will not be conducted  
 


 
CONFIDENTIAL 
 
205646 
 
103 
 
11. 
PHARMACOKINETIC ANALYSES 
11.1. 
Primary Pharmacokinetic Analyses 
Descriptive statistics for serum belimumab (from all three treatment arms combined) and 
rituximab concentrations will be displayed for each visit for Year 1 and for Years 1&2 
Combined. The tables will display the mean value, standard deviation, 95% confidence 
interval, geometric mean, geometric standard deviation, geometric 95% confidence 
interval, coefficient of variation (%), median, 25th and 75th percentiles, minimum, and 
maximum. No statistical tests will be performed [T16.01, T16.02, T26.01]. 
A line graph will be produced which displays the median belimumab or rituximab 
concentration values along with 25th and 75th percentiles by visit Year 1 and for Years 
1&2 Combined [F16.01, F16.02, F26.01].  
A listing of serum belimumab and rituximab PK concentration-time data will be 
presented [L16.01, L16.02, LL26.01]. 
11.1.1. 
Endpoint / Variables 
11.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Reporting 
Standards for Pharmacokinetic). 
11.1.2. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic PK 
population, unless otherwise specified. 
11.1.3. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical Principals. 
Unless otherwise specified, endpoints / variables defined in Section 11.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 


 
CONFIDENTIAL 
 
205646 
 
104 
 
12. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
12.1. 
Statistical Analyses / Methods 
There will not be a formal requirement to carry out a population pharmacokinetic 
(PopPK) analysis for this study. However, depending on the study results a PopPK 
analysis may be performed on a post-hoc basis to quantity the combined effects of 
belimumab and rituximab in an adult SLE population with respect to belimumab PK, the 
pharmacological response, and efficacy and safety end-points.  
• 
To develop a PopPK model that characterizes the PK disposition of belimumab 
following sub-cutaneous administration in adult subjects with SLE. 
• 
Evaluate the potential effect of rituximab administration on belimumab PK 
parameters. 
• 
Estimate the individual PK parameters for each subject in the study receiving 
belimumab and summarise across the study. 
• 
Evaluate the effect of belimumab exposure on the response of selected 
biomarkers, efficacy and safety end-points when dosed alone and in 
combination with rituximab. 
 
Belimumab serum concentration-time data will be analyzed using a non-linear mixed-
effects modelling approach.  Pharmacokinetic data will be presented in graphical and/or 
tabular form and will be summarized descriptively. All pharmacokinetic data will be 
stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.  
 
13. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Pharmacokinetic/Pharmacodynamic (PD) analyses are not prospectively planned for this 
study.  Based on the results obtained, exploratory analyses may be performed on an ad 
hoc basis. 


 
CONFIDENTIAL 
 
205646 
 
105 
 
14. 
REFERENCES 
Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone 
hormone replacement therapy on disease activity in systemic lupus erythematosus: A 
randomized trial. Ann Intern Med 2005;142(12 Pt 1):953-62. 
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables, May 
2001.http://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Document
s/dmidadulttox.doc  
Franklyn K, Chak Sing Lau, Sandra V Navarra, Worawit Louthrenoo, Aisha Lateef, 
Laniyati Hamijoyo, C Singgih Wahono, Shun Le Chen, Ou Jin, Susan Morton, Alberta 
Hoi, Molla Huq, Mandana Nikpour, Eric F Morand, for the Asia-Paciﬁc Lupus 
Collaboration. Deﬁnition and initial validation of a Lupus Low Disease Activity State 
(LLDAS). Ann Rheum Dis 2016;75:1615–1621  
Gladman DD, Ibanez D, Urowitz MB. Systemic lupus Erythematosus disease activity 
index 2000. J Rheumatol 2002;29(2):288-91. 
Mehrotra D V, Fang Liu, Thomas Permutt. Missing data in clinical trials: control-based 
mean imputation and sensitivity analysis. Pharmaceutical Statistics 2017; 16: 378-392 
Neergard. Reducing the risk of blood thinners. Associated press, September 2006. 
Oon S, Molla Huq, Vera Golder, Pei Xuan Ong, Eric F Morand, Mandana Nikpour.  
Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 
and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus. Ann 
Rheum Dis 2019; 78: 629-633 
Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical 
trials. Lupus. 1999;8:685-91. 
Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with 
systemic lupus erythematosus. N Engl J Med 2005;353(24):2550-8. 
 


 
CONFIDENTIAL 
 
205646 
 
106 
 
15. 
APPENDICES 
15.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
15.1.1. 
Exclusions from Per Protocol Population 
The per protocol population will be based on the review of the important protocol 
deviations as detailed in PDMP review document 
 
Important protocol deviations in these categories of the PDMP will be assessed as 
detailed for exclusion from the per protocol population 
ELIGIBILITY CRITERIA NOT MET  
Subjects who do not meet the following criteria  
Did not have a clinical diagnosis of SLE according to the ACR criteria (Inclusion 
Criterion 2). 
Did not have clinically active SLE disease defined as a SLEDAI-2K score ≥ 6 at 
screening (Inclusion Criterion 3) 
Did not have unequivocally positive ANA test results from 2 independent time 
points (Inclusion Criterion 4) 
Was not on a stable SLE treatment regimen at baseline as defined in the protocol 
(Inclusion Criteria 5) 
Received an excluded medication prior to Day 0 (Exclusion Criteria 23-26) and 
adjudicated to have had a reasonable probability of impacting on the assessment of 
efficacy post Day 1. 
 
ASSESSMENT OR TIME POINT COMPLETION and VISIT COMPLETION 
Missed assessment  
Missed SLEDAI-2K assessment at Week 52 will be excuded 
Out Of Window Assessment  
More than 28 days late for Week 52 visit or Week 52 SLEDAI-2K assessment 
 
WRONG STUDY TREATMENT/ADMINISTRATION/DOSE Study treatment not 
administered per protocol  


 
CONFIDENTIAL 
 
205646 
 
107 
 
Subjects randomised to Arms A or B who did not receive all of both scheduled rituximab 
/ rituximab-placebo infusions 
Subjects with 4 or more missed consecutive Belimumab doses. 
Subjects with 4 or more missed consecutive Belimumab doses irrespective of subject re-
initiating Belimuab injections in the presence of the investigator 
 
Wrong study treatment or assignment administered  
Subjects who did not receive their assigned treatment will be assessed on a case by case 
basis.  
 
STUDY PROCEDURES 
Study blinding/unblinding procedures  
Subjects from whom their Investigator/site staff/GSK Clinical team did not remain 
blinded to treatment assignment through Week 52/Exit visit efficacy evaluation 
 
OTHER REASONS 
As determined during  
protocol population review meeting prior to unblinding that are determined to have the 
potential to impact the efficacy evaluation.   
 


 
CONFIDENTIAL 
 
205646 
 
108 
 
15.2. 
Appendix 2: Protocol Defined Schedule of Activities 
Table 5 
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 


 
CONFIDENTIAL 
 
205646 
 
109 
 
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 
 


 
CONFIDENTIAL 
 
205646 
 
110 
 
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 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Further Research 
Blood Leukocyte Analysis 
(PBMC) (p) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
RNA for Interferon Signature 
 
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) 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
205646 
 
111 
 
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 Protocol Section 9 for pregnancy test requirements a. 
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. 


 
CONFIDENTIAL 
 
205646 
 
112 
 
l. 
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Guidance is 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 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 selected European sites   
 


 
CONFIDENTIAL 
 
205646 
 
113 
 
Table 6 
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 
 


 
CONFIDENTIAL 
 
205646 
 
114 
 
 
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 
Exploratory Research 
Blood Leukocyte Analysis (PBMC) (k) 
 
 
 
X 
 
X 
 
X 
 
B cell receptor (l) 
 
 
 
 
 
X 
X 
X 
 
B cell subsets (n) 
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 Protocol 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.) 


 
CONFIDENTIAL 
 
205646 
 
115 
 
e. 
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. 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 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 re-start therapy.  
j. 
Follow up visit is required only for subjects who receive belimumab re-start 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 experience a 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.  


 
CONFIDENTIAL 
 
205646 
 
116 
 
Table 7 
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 
 


 
CONFIDENTIAL 
 
205646 
 
117 
 
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 


 
CONFIDENTIAL 
 
205646 
 
118 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Research 
B cells subsets (o) 
 
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 
 
 


 
CONFIDENTIAL 
 
205646 
 
119 
 
a. 
Starting at Week 4and 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 study 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 WCBP 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 Protocol 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. Guidance is 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 SLE Flare (refer to footnote l). 
k. 
To be conducted at US sites only.  
l. 
To be conducted only at US study sites. B-cell receptor samples are also collected when subjects experience a 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.   
 


 
CONFIDENTIAL 
 
205646 
 
120 
 
Table 8 
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 
Extractable nuclear antigens (ENAs) 
X 
 
 
X 
 
X 
 
X 
 


 
CONFIDENTIAL 
 
205646 
 
121 
 
 
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) 
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 
Exploratory 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 
 


 
CONFIDENTIAL 
 
205646 
 
122 
 
 
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) 
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.  
e. 
Procedures to be performed at Unscheduled Visits are based on reason for Unscheduled Visit, including adverse event or discontinuation of study agent. Guidance is provided 
in the Study Reference Manual. 
f. 
Blood samples for a B cell receptor analysis should be obtained in the event of a 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 when subjects experience a 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. 
j. 
 
 
 


 
CONFIDENTIAL 
 
 
 
205646 
 
123 
 
15.3. 
Appendix 3: Assessment Windows 
15.3.1. 
Definitions of Assessment Windows for Analyses 
The data is analyzed as per the planned visit assignment.   
Exit/withdrawal and unscheduled visits will be slotted to the appropriate planned visit.  
The assigned visit is based on the interval in which the Study Day for the exit/withdrawal 
or unscheduled visit falls according to intervals (inclusive) provided below.  For 
completeness, the table also includes visits which are not slotted; these visits will have 
‘na’ for ‘not available’ listed for the Interval Start and End Day. 
Analysis Set / 
Domain 
Parameter      
(if applicable) 
Target1  
Analysis Window 
Analysis 
Timepoint 
Number4 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
All 
All 
NA 
NA 
NA 
10 
Screening 
Year 1 Treatment Phase visits: 
All 
All 
1 
NA 
NA 
20 
Baseline 
29 
2 
35 
30 
Week 4 
43 
36 
49 
40 
Week 6 
57 
50 
70 
50 
Week 8 
85 
71 
98 
60 
Week 12 
113 
99 
126 
70 
Week 16 
141 
127 
154 
80 
Week 20 
169 
155 
175 
90 
Week 24 
183 
176 
189 
100 
Week 26 
197 
190 
210 
110 
Week 28 
225 
211 
238 
120 
Week 32 
253 
239 
266 
130 
Week 36 
281 
267 
294 
140 
Week 40 
309 
295 
322 
150 
Week 44 
337 
323 
350 
160 
Week 48 
365 
351 
392 
170 
Week 52 
365 
na 
Na 
175 
Survival-
W522 
Year 2 Phase Visits: 
All 
All 
421 
393 
434 
180 
Week 60 
449 
435 
476 
190 
Week 64 
505 
477 
532 
200 
Week 72 
561 
533 
588 
210 
Week 80 
617 
589 
644 
220 
Week 88 
673 
645 
700 
230 
Week 96 
729 
701 
742 
240 
Week 104 


 
CONFIDENTIAL 
 
 
 
205646 
 
124 
 
Analysis Set / 
Domain 
Parameter      
(if applicable) 
Target1  
Analysis Window 
Analysis 
Timepoint 
Number4 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
729 
na 
na 
245 
Survival-
W1042 
Na 
na 
na 
250 
Follow-Up3 
NOTES: 
1 Study Day with Baseline/Treatment Start Date as Day 1. Baseline record will be derived in each 
analysis dataset, analysis visit number will be 15. 
2 Survival visit for subjects who withdraw from the double-blind treatment phase but consent to the Week 52 
and Week 104 survival assessments. 
3 The follow-up visit occurs 8 weeks after last dose of belimumab for subjects who discontinue study 
treatment and withdraw from the study up to (i) Week 52 in Arms A and B or (ii) Week 104 in Arm C.  
4 If there are multiple visits within a visit window, the visit closest to the target date will be used. If there are 
two visits equidistant from the target date, then the scheduled visit will be given preference, if both are 
unscheduled then the first assessment will be used. 


 
CONFIDENTIAL 
 
 
 
205646 
 
125 
 
15.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
15.4.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before the first exposure date to study 
treatment 
Concomitant 
Any medication that is not a prior.  Note that medications with partial or missing start 
and/or stop dates will be assumed to be concomitant unless there is evidence 
through comparison of partial dates to suggest otherwise 
15.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date, having been absent pre-
treatment, or that worsens relative to the pre-treatment state. 


 
CONFIDENTIAL 
 
 
 
205646 
 
126 
 
15.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
15.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: us1salx00259 
HARP Compound 
: gsk1550188 
Study location 
: gsk1550188\mid205646 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0).  
Generation of RTF Files 
• 
RTF files will be generated for all reporting efforts. 
15.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for reporting 
of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DPs.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study treatment dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
• 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings but omitted from figures, summaries and statistical analyses. 


 
CONFIDENTIAL 
 
 
 
205646 
 
127 
 
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables with the exception of certain 
summaries by year interval in which unscheduled visits may appear in the “anytime post 
baseline” category where specified e.g. worst laboratory toxicity grades. 
• 
Unscheduled visits will not be included in figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
 


 
CONFIDENTIAL 
 
 
 
205646 
 
128 
 
15.6. 
Appendix 6: Derived and Transformed Data 
15.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
For continuous data, the mean of the measurements will be calculated and used in any derivation of 
summary statistics but if listed, all data will be presented. 
• 
For continuous data, if there are two values within a time window (as per Section 15.3.1) the value 
closest to the target day for that window will be used. If values are the same distance from the target, 
then the scheduled assessment will be used, if both assessments are also unscheduled then the 1st 
assessment will be taken. 
• 
For categorical data, if there are two values within a time window (as per Section 15.3.1) the value 
closest to the target day for that window will be used. If values are the same distance from the target, 
then the value prior to the target day will be taken. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables.  
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
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 Schedule of Activities(SoA) (see 
Section 2 of the protocol) 
• A participant is considered to have completed the double-blind treatment phase (Year 1) of 
the study if he/she has completed all 52 weeks of the double-blind treatment phase, 
including the Week 52 Visit, as defined in the SoA (see Section 2 of the protocol) 
• 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 
Visit assessments completed late 
In the event that a PGA, or SLE flare assessment, which may be only completed once labs have 
been returned to the site, is recorded later than the visit date, then an imputed date will be used.  
The imputed PGA / SLE flare assessment date will be the earliest date for a completed SLEDAI-
2K (IBA or PI) assessment. This may be different than the earliest visit within that window.  If 
there are no SLEDAI-2K assessment dates available then the visit date is used. 
 


 
CONFIDENTIAL 
 
 
 
205646 
 
129 
 
15.6.2. 
Study Population 
Age Derivation 
Age on any specified day (e.g. screening, 1st dose etc.) will be derived as: 
If the specified day is on or after the 30th June then: 
• Year of specific timepoint – DOB year 
If the specified day is before the 30th June then: 
• (Year of specific timepoint – DOB year) -1 
(Note this assumes day and month of birth is 30 June - as this information is not collected) 
Age at baseline will be defined as the latest of randomization date and baseline visit date, and 
derived as above. 
 
Treatment Compliance – Belimumab 
• 
Percent compliance will be calculated based on the formula:   
Percent Compliance = 100* (Number of injections prescribed - Number of injections missed) / Number of 
injections prescribed 
 
Extent of Exposure – Belimumab 
• 
Number of days of exposure to belimumab will be calculated based on the formula:   
Duration of Exposure in Days = Last injection date – First injection date + 7 
• 
Only complete dates will be used when calculating duration of exposure.  First and last 
injection dates will be used, regardless of any missed doses. 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
 
Extent of Exposure – Rituximab 
• 
Dose intensity in mg will be calculated as the cumulative actual dose divided by 2. 
• 
If the total volume of an infusion is not administered, the actual dose infused for that visit will be 
calculated as: 
Actual Dose infused (mg) = Planned Dose (mg) * Percentage of volume infused 
 
On Treatment Exposure (Year 1) 
• 
Number of days of On-Treatment exposure will be calculated based on the formula:   
   Duration of On-Treatment Exposure in Days  
          = Year 1 on-treatment end date (see Section 5.12)  – First Belimumab injection date + 1 
• 
Only complete dates will be used when calculating duration of study exposure. 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
 
On-Study Exposure (Years 1&2 Combined) 
• 
Number of days of On-Study exposure will be calculated based on the formula:   


 
CONFIDENTIAL 
 
 
 
205646 
 
130 
 
On-Study Exposure (Years 1&2 Combined) 
Duration of On-Study Exposure in Days = Date of study completion or withdrawal – First 
Belimumab injection date + 1 
• 
Only complete dates will be used when calculating duration of study exposure. 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
 
Disease Duration  
When the start day is missing, impute with 01.  When the start day and month is 
missing, impute with 01 January. This will impute the longest possible duration. 
 
 
15.6.3. 
SLEDAI-2K Total and Organ System Domain
 SLEDAI-2K Total and Organ System Domain Scores 
SLEDAI-2K assessments consist of 24 individual items in which signs and symptoms, laboratory tests, 
and physician’s assessment for each of 9 organ systems are given a weighted score and summed if 
present (marked ‘Yes’) at the time of the visit or in the preceding 10 days. The maximum theoretical score 
is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease (marked ‘No’). 
 
Organ system domain scores are the sum of the weights of items within the organ domain as defined in 
Table 9. 
In this study, proteinuria is evaluated using spot-urine protein [represented as protein-creatinine ratio or 
PC Ratio in the laboratory dataset]. in lieu of the 24-hour urine collection, as evaluated by the 
investigator. 
 
Table 9 
SLEDAI-2K 
Organ System 
Descriptor 
Weight 
Definition 
CNSa 
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.


 
CONFIDENTIAL 
 
 
 
205646 
 
131 
 
Vasculara 
Musculoskeletal 
Renal 
Mucocutaneous 
Cardiovascular &  
Respiratory 
Immunologic 
Constitutionala 
Hematologica 
a. In the summaries and analyses of SLEDAI-2K organ systems, CVA will be moved from the CNS to the 
Vascular organ system and the Constitutional organ system will be eliminated and its one component, fever, 
will be moved to the hematologic organ system. 
 
Adapted from the original source: [Gladman, 2002]. Used with permission from author (Murray Urowitz).  
• 
Blinded independent assessors will conduct the SLEDAI-2K at key time points. The primary and 
major secondary efficacy endpoints will be conducted using the blinded independent assessors’ 
SLEDAI-2K data 
• 
For SLEDAI-2K after the Day 1 visit, the window is -10 days to + 7 days from the date of assessment 
post Day 1 visit, excluding the sample that was used in the previous visit assessment. 
 
The SLEDAI-2K score is the sum of all 24 individual items from the SLEDAI-2K. 
 
 SLEDAI-2K missing values 
SLEDAI-2K missing scores for laboratory parameters i.e. 
Renal 
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.


 
CONFIDENTIAL 
 
 
 
205646 
 
132 
 
Immunologic 
Hematologic 
 
Will be imputed from the previous assessment if the previous assessment is no more than 35days prior.   
 
When it is not possible to calculate SLEDAI-2K score but it is still possible to ascertain that the SLEDAI-
2K score is >0, >2, or >4, then this information will be used in the derivation of disease control, clinical 
remission, complete remission, and LLDAS. 
Similarly, when it is possible to determine that the maximum possible value for the SLEDAI-2K,  
assuming the highest score for missing values is <=2 or <=4 then this will be used in the derivation of 
disease control nd LLDAS. 
SLEDAI-2K Organ System Improvement and Worsening 
In the analysis of SLEDAI-2K organ system improvements and worsening, CVA will be moved from the 
CNS to the Vascular organ system and the Constitutional organ system will be eliminated and its one 
component, fever, will be moved to the hematologic organ system 
Clinical SLEDAI-2K Score (Excluding Serological Activity) 
 
The clinical SLEDAI-2K score (Excluding Serological Activity assessments) is the sum of 22 of the 24 
individual items from the SLEDAI-2K, excluding the following 2 items:   
Immunologic 
 
The scoring of the 22 questions is weighted in the same manner as the SLEDAI-2K, however the 
maximum theoretical score is now 101. 
 
Note that the wording in the Protocol was “Serological activity score, i.e., anti-dsDNA positivity and/or 
hypocomplementemia, is excluded from the Clinical SLEDAI-2K endpoint”.  The endpoint has been 
clarified here by using the names of the two SLEDAI-2K item scores, however, this does not represent a 
change to the planned endpoint, just a clarification. 
 
Partial but informative SLEDAI-2K score  
If after imputation for missing questions the SLEDAI-2K total score is still not derivable due to 
missing individual questions, then the minimum possible score will be considered (sum of the 
answered questions). 
Similarly a maximum possible score (observed questions + maximum response for missing 
questions) will be considered. 
 
15.6.4. 
Disease Control 
Endpoint Definition 
The disease control endpoint is defined as: 
• SLEDAI-2K score ≤2 (IBA*),  
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.


 
CONFIDENTIAL 
 
 
 
205646 
 
133 
 
• Not a Treatment failure  
• Not a Study withdrawal 
The same derivation will be applied to the secondary endpoint “Disease control (PI)” using the 
principal investigators assessment of the SLEDAI-2K. 
Imputation of Missing values – IBA assessment 
Missing IBA assessments based on laboratory assessments  i.e.: 
Urinary Casts, Hematuria, Proteinuria, Pyuria, Low Complement, Increased DNA Binding, 
Thrombocytopenia, and Leukopenia  
will be imputed from the PI assessment if the laboratory sample (for the PI assessment) was 
drawn no more than 35 days prior.  An imputed assessment can not be used to impute another 
assessment. 
There will be no imputation of missing IBA assessments based on physical examination 
Imputation of Missing values – PI assessment 
If an individual question of the SLEDAI-2K  assessment or the full assessment is missed the 
previous assessment may be used as a substitute if it was no more than 35 days prior.  An 
imputed assessment cannot be used to impute another assessment. 
Partial but informative SLEDAI-2K score  
If after imputation for missing questions the SLEDAI-2K total score is still not derivable due to 
missing individual questions, then the minimum possible score will be considered. If the 
minimum possible score is >2 then the subject will be considered as a non-responder. 
Similarly a maximum possible score  will be considered to determine if the maximum possible 
score is ≤2. 
Time to Disease Control Sustained to Week 104 
A subject has a sustained disease control at a visit if all of the following criteria are 
met: 
1 In disease control at the visit 
2 In disease control at the first visit that is at least 24 study weeks prior, or if 
disease control cannot be assessed at that visit, then in disease control at the 
visit prior. 
3 In disease control for all assessed visits between (1) and (2).  Note assessments 
can be missing. 
Note: 24 weeks refers to the difference in visit ‘labels’ not calendar weeks between 
visits. 
The first visit of sustained disease control is defined as the 1st visit that the subject is a disease 
control responder and all subsequent visits up to and including Week 104 the subjects is also a 
disease control responder.  Missing assessments are not considered. 
Time to disease control sustained to Week 104 =  
     1st visit of sustained disease control - treatment start date (Day 1) +1 
Duration of  Disease Control  
The duration of disease control is defined as the longest period between 2 visits that the subject 
is a disease control responder at all visits.  Missing assessments are not considered. 
Duration of disease control = longest period where  
     1st visit of disease control – last visit of disease control + 1 
 
 


 
CONFIDENTIAL 
 
205646 
134 
 
Example 
Subject 
SLEDAI-2K score at Week 
52 
Study Withdrawal 
(including Lost to 
Follow-up, or Death) 
prior to Week 52 
Treatment 
Failure prior to 
Week 52 
IP Discontinuation 
prior to Week 52  
 
Main Estimand 
(Hybrid) 
Supportive 
Estimand 
(Composite) 
 
(Hybrid On 
Treatment) 
 
Treatment 
Policy 
 
 
1 
>2 
N 
N 
N 
NR 
NR 
NR 
NR 
2 
>2 
N 
N 
Y 
NR 
NR 
Excluded 
NR 
3 
>2 
N 
Y 
N 
NR 
NR 
NR 
NR 
4 
>2 
N 
Y and prior to IP 
discontinuation 
Y 
NR 
NR 
NR 
NR 
5 
>2 
N 
Y but post IP 
discontinuation 
Y 
NR 
NR 
Excluded 
NR 
6 
<=2 
N 
N 
N 
R 
R 
R 
R 
7 
<=2 
N 
N 
Y 
R 
NR 
Excluded 
R 
8 
<=2 
N 
Y 
N 
NR 
NR 
NR 
R 
9 
<=2 
N 
Y and prior to IP 
discontinuation 
Y 
NR 
NR 
NR 
R 
10 
<=2 
N 
Y but post IP 
discontinuation 
Y 
NR 
NR 
Excluded 
R 
11 
Incomplete* or entirely 
missing  
N 
N 
N 
NR 
NR 
NR 
NR 
12 
Incomplete* or entirely 
missing but not due to 
study withdrawal 
N 
N 
Y 
NR 
NR 
Excluded 
NR 
13 
Incomplete* or entirely 
missing but not due to 
study withdrawal 
N 
Y 
N 
NR 
NR 
NR 
NR 
14 
Incomplete* or entirely 
missing but not 
meaningful 
N 
Y and prior to IP 
discontinuation 
Y 
NR 
NR 
NR 
NR 
15 
Incomplete* or entirely 
missing but not due to 
study withdrawal 
N 
Y but post IP 
discontinuation 
Y 
NR 
NR 
Excluded 
NR 
16 
Missing - does not exist 
due to study withdrawal 
Y and at the same time 
as IP discontinuation 
N 
Y 
NR 
NR 
NR 
NR 


 
CONFIDENTIAL 
 
205646 
135 
 
Example 
Subject 
SLEDAI-2K score at Week 
52 
Study Withdrawal 
(including Lost to 
Follow-up, or Death) 
prior to Week 52 
Treatment 
Failure prior to 
Week 52 
IP Discontinuation 
prior to Week 52  
 
Main Estimand 
(Hybrid) 
Supportive 
Estimand 
(Composite) 
 
(Hybrid On 
Treatment) 
 
Treatment 
Policy 
17 
Missing - does not exist 
due to study withdrawal 
Y but post IP 
discontinuation 
N 
Y 
NR 
NR 
Excluded 
NR 
18 
Missing - does not exist 
due to study withdrawal 
Y and at the same time 
as IP discontinuation 
Y and prior to IP 
discontinuation 
Y 
NR 
NR 
NR 
NR 
19 
Missing - does not exist 
due to study withdrawal  
Y but post IP 
discontinuation 
Y and prior to IP 
discontinuation 
Y 
NR 
NR 
NR 
NR 
20 
Missing - does not exist 
due to study withdrawal 
Y but post IP 
discontinuation 
Y but post IP 
discontinuation 
Y 
NR 
NR 
Excluded 
NR 
 
R = Responder; NR = Non-Responder 
*Incomplete: does not include partial scores where it is possible to determine that the total score must be >2, or that the maximum 
possible score (assuming worst case for missing data) is <=2 
 
 


 
CONFIDENTIAL 
 
205646 
136 
 
15.6.5. 
Clinical Remission 
Endpoint Definition 
Clinical remission for Arms A & B (secondary endpoint) is defined as: 
• Clinical SLEDAI-2K score# = 0 (IBA*),  
• Not a Treatment Failure  
• Did not withdraw from the study  
• 7-day average corticosteroids at a prednisone equivalent dose of 0mg/day for 
the assessment (7 day average is the average of current and 6 previous days) 
#See Section 15.6.3 
*at baseline the principal investigators assessment will be used 
 
The same derivation will be applied to the secondary endpoint “clinical remission (PI)” 
using the principal investigators assessment of the SLEDAI-2K. 
Imputation of Missing values – IBA assessment 
Missing IBA assessments based on laboratory assessments  i.e.: 
Urinary Casts, Hematuria, Proteinuria, Pyuria, Thrombocytopenia, and Leukopenia  
will be imputed from the PI assessment if the laboratory sample (for the PI assessment) was 
drawn no more than 35 days prior.  An imputed assessment can not be used to impute another 
assessment. 
There will be no imputation of missing IBA assessments based on physical examination 
Imputation of Missing values – PI assessment 
If an individual question of the SLEDAI-2K  assessment or the full assessment is 
missed the previous assessment may be used as a substitute if it was no more than 35 
days prior.  An imputed assessment cannot be used to impute another assessment. 
Partial but informative Clinical SLEDAI-2K score  
If after imputation for missing questions the Clinical SLEDAI-2K score is still not derivable due to 
missing individual questions, then the minimum possible score will be considered (sum of the 
answered questions). If the minimum possible score is >0 then the subject will be considered as 
an observed non-responder (rather than non-responder due to missing data). 
Clinical Remission Sustained For At Least 24 Weeks 
Sustained response will be reported for all weeks post Week 52 (Year 2), and at any 
timepoint (i.e. any subjects who had a sustained response at any time during Year 2).  
Statistical analysis will only be conducted at Week 104 and at ‘any timepoint’. 
A subject has a sustained remission at a visit if all of the following criteria are met: 
1 In clinical remission at the visit 
2 In clinical remission at the first visit at least 24 study weeks prior, or if clinical 
remission cannot be assessed at that visit , then in clinical remission at the visit 
prior. 
3 In clinical remission for all assessed visits between (1) and (2). – Note 
assessments can be missing. 
Note: 24 weeks refers to the difference in visit ‘labels’ not calendar weeks between 
visits.   


 
CONFIDENTIAL 
 
205646 
137 
 
Time to Clinical Remission Sustained to Week 104 
The first visit of sustained clinical remission is defined as the 1st visit that the subject is a clinical 
remission responder and all subsequent visits up to and including Week 104 the subjects is also 
a clinical remission responder.  Missing assessments are not considered (the rules for sustained 
response for at least 24 weeks as defined above are also applied here). 
 
Time to clinical remission sustained to Week 104 =  
     1st visit of sustained clinical remission - treatment start date (Day 1) +1 
Duration of Clinical Remission  
The duration of clinical remission is defined as the longest period between 2 visits that the 
subject is a clinical remission responder at all visits.  Missing assessments are not considered  
Duration of clinical remission  = longest period where  
     1st visit of clinical remission – last visit of clinical remission + 1 
 
 
15.6.6. 
Complete Remission 
Endpoint Definition 
Complete remission for Arms A & B (secondary endpoint) is defined as: 
• SLEDAI-2K score = 0 (IBA*),  
• Not a Treatment Failure (specific to Arms A&B) 
• Did not withdraw from the study 
• 7-day average corticosteroids at a prednisone equivalent dose of 0mg/day for 
the assessment (7 day average is the average of current and 6 previous days) 
Complete remission for Arm C (the exploratory endpoint) is defined as: 
• SLEDAI-2K score = 0  (IBA*),  
• Not a Treatment Failure (specific to Arm C) 
• Did not withdraw from the study 
• 7-day average corticosteroids at a prednisone equivalent dose of 0mg/day for 
the assessment (7 day average is the average of current and 6 previous days) 
*at baseline the principal investigators assessment will be used 
 
Note some tables will contain the endpoint using these 2 different definitions in the 
same table. 
Imputation of Missing values – IBA assessment 
Missing IBA assessments based on laboratory assessments  i.e.: 
Urinary Casts, Hematuria, Proteinuria, Pyuria, Low Complement, Increased DNA Binding, 
Thrombocytopenia, and Leukopenia  
will be imputed from the PI assessment if the laboratory sample (for the PI assessment) was 
drawn no more than 35 days prior.  An imputed assessment can not be used to impute another 
assessment. 
There will be no imputation of missing IBA assessments based on physical examination 


 
CONFIDENTIAL 
 
205646 
138 
 
Imputation of Missing values – PI assessment 
If an individual question of the SLEDAI-2K  assessment or the full assessment is 
missed the previous assessment may be used as a substitute if it was no more that 35 
days prior.  An imputed assessment cannot be used to impute another assessment. 
Partial but informative SLEDAI-2K score  
If after imputation for missing questions the SLEDAI-2K total score is still not derivable due to 
missing individual questions, then the minimum possible score will be considered (sum of the 
answered questions). If the minimum possible score is >0 then the subject will be considered as 
an observed non-responder (rather than non-responder due to missing data). 
Complete Remission Sustained For At Least 24 Weeks 
Sustained response will be reported for all weeks post Week 52 (Year 2), and at any 
timepoint (i.e. any subjects who had a sustained response at any time during Year 2).  
Statistical analysis will only be conducted at Week 104 and at ‘any timepoint’. 
A subject has a sustained remission at a visit if all of the following criteria are met: 
1 In complete remission at the visit 
2 In complete remission at the first visit at least 24 study weeks prior, or if 
complete remission cannot be assessed at that visit , then in clinical remission 
the visit prior. 
3 In complete remission for all assessed visits between (1) and (2). – Note 
assessment can be missing. 
Note: 24 weeks refers to the difference in visit ‘labels’ not calendar weeks between 
visits.   
 
 
15.6.7. 
SFI FLARE INDEX 
SLEDAI-2K Flare Index 
(Adapted from Buyon, 2005; Petri, 2005; Neergard, 2006. Petri, 1999) 
Mild-moderate flare 
Severe flare 
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.


 
CONFIDENTIAL 
 
205646 
139 
 
a. 
The modified SLE Flare index excludes severe flares that are triggered only by an increase is SLEDAI-2K 
Score to greater than 12. 
 
The following scoring rules are based on the SLEDAI-2K flare index: 
• 
SFI reports the first mild /moderate or severe flare occurrence since the last non-
missing assessment.   
• 
The SLEDAI-2K criteria will be assessed programmatically (based on the PI 
assessment at the visit that the flare was reported) to determine if the SLEDAI-2K 
criteria for a flare has been met and used for the assessment of flare, irrespective of 
what was recorded on the SFI form. 
• 
Although there are boxes on the form for the investigator to classify the most recent 
flare to mild/moderate or severe, the classification will be re-derived from the 
subcategory scores. Flares originally marked severe will be downgraded to “Not 
Severe” if the only reason marked is a change in SLEDAI-2K score to >12.   
• 
In this case, if any of the mild/moderate reasons are checked or if the 
SLEDAI-2K score has a change from the last non-missing assessment of at 
least 3, then the flare will be considered mild/moderate.  Otherwise this not a 
flare 
The last non-missing assessment is the last previous visit were SLE flare was 
assessed (and is not entirely missing). 
Partial but informative SLEDAI-2K score  
If after imputation for missing questions the SLEDAI-2K total score is still not 
derivable due to missing individual questions, then the minimum possible score will be 
considered (sum of the answered questions). Similarly a maximum possible score (sum 
of observed questions + maximum response for missing questions) will be considered.  
If from these scores it is possible to determine that there has be an increase in score 
from the previous visit of at least 3 then this will be used as indication of a 
mild/moderate flare.  However if it is not possible to determine whether there has been 
a change of at least 3 from the previous assessment then no assumption will be made 
about the presence of a mild/moderate flare. 
 
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.


 
CONFIDENTIAL 
 
205646 
140 
 
15.6.8. 
Physicians Global Assessment (PGA) Scoring 
Physicians Global Assessment (PGA) Scoring 
PGA is collected on a 10cm visual analogue scale (VAS).  However, the standard 
scoring range for the PGA is 0 to 3, therefore the score will be rescaled for reporting by 
multiplying the collected score by 3/10.  
 
15.6.9. 
Lupus Low Disease Activity State (LLDAS) 
Endpoint Definition 
Criteria 
Source data and derivation 
Rationale 
SLEDAI-2K 4, with 
no activity in major 
organ systems (renal, 
CNS, 
cardiopulmonary, 
vasculitis, fever) and 
no hemolytic anemia 
or gastrointestinal 
activity;  
SLEDAI – 2K score as assessed by the 
principal investigator 
Individual stated organ systems must 
have a score of 0, Note: 
Cardiopulmonary = Cardiovascular & 
respiratory organ system 
Vasculitis = Vascular organ system 
Fever = Constitutional organ system 
Data on hemolytic anemia and 
gastrointestinal activity are not 
available and is not considered in 
evaluating this criterion but assumed 
to be captured in the PGA item.  
 
no new features of 
lupus disease activity 
compared with the 
previous assessment; 
No worsening of any of the item 
scores of the SLEDAI–2K (principal 
investigator assessment) score 
compared to the previous assessment  
Compared to 
previous visit to 
reflect a stable 
disease state.  
PGA (scale 0-3) 1; 
PGA as reported (closest assessment to 
the target date that is within the visit 
window) 
 
current prednisolone 
(or equivalent) dose 
7.5 mg daily;  
7 day average prednisone dose (day of 
visit and 6 prior days) assessed on the 
day of the SLEDAI-2k assessment  
7 Day average due 
to the planned 
tapering, as subjects 
may be on a dosing 
regimen that varies 
by day (e.g. 1mg 
every other day)  
well tolerated standard 
maintenance doses of 
The dose on the day of the SLEDAI-
2K assessment must not exceed: 
The protocol stated 
‘equivalent’ 


 
CONFIDENTIAL 
 
205646 
141 
 
Endpoint Definition 
immunosuppressive 
drugs and approved 
biological agents, 
excluding 
investigational drugs 
• 
azathioprine: 300mg/day 
• 
methotrexate 25mg/week 
• 
leflunomide 40mg/day 
• 
Mycophenolate 
sodium≤2.88g/day 
• 
Mycophenolate mofetil≤4g/day 
• 
Oral 
cyclophosphamide≤2.5mg/kg/day 
• 
6-mercaptopurine <= 300mg/day 
• 
Cyclosporine<=4mg/kg/day 
• 
Tacrolimus<=0.2mg/kg/day 
• 
Sirolimus<=2mg/day 
• 
Thalidomide<=200mg/day 
• 
mizoribine<=150mg/day 
Not to be taken within 28 days prior to 
the assessment: 
• 
Intravenous Cyclophosphamide 
• 
Other investigation agent 
• 
Anti-TNF therapy (adalimumab, 
etanercept, infliximab) 
• 
Other biologics (abatacept, 
anakinra) 
• 
IVIG 
• 
Plasmapheresis 
 
Topical treatments will not be 
considered 
medications to those 
stated in . [Oon, 
2019] supplement 
On the day of 
assessment as 
identified in the 
publications 
 
Not Study withdrawal 
(including death and 
lost to follow-up 
 
Did not withdraw or 
discontinue for any 
reason 
SLEDAI-2K Component: Imputation of Missing values – PI assessment 
If an individual question of the SLEDAI-2K assessment or the full assessment is missed the 
previous assessment may be used as a substitute if it was no more than 35 days prior.  An 
imputed assessment can not be used to impute another assessment. 
SLEDAI-2K Component: Partial but informative SLEDAI-2K score  
If after imputation for missing questions the SLEDAI-2K total score is still not derivable due to 
missing individual questions, then the minimum possible score will be considered (sum of the 
answered questions). If the minimum possible score is >4 then the subject will be considered as 
a non-responder. 


 
CONFIDENTIAL 
 
205646 
142 
 
SLEDAI-2K Component: Imputation of Missing values – PI assessment 
Similarly a maximum possible score (observed questions + maximum response for missing 
questions) will be considered to determine if the maximum possible score is ≤4. 
 
15.6.10. 
Lupus QOL Scale 
The LupusQoL consists of 34 items in eight domains. The number of items in each 
domain and the item numbers that refer to that domain are tabulated below: 
 
The LupusQoL has a five-point Likert response scale for each item and are scored as: 
Each domain of the LupusQoL is scored separately as : 
Calculate the mean raw domain score by adding up the item response scores for the 
domain and then divide by the number of items answered in that domain.  Mean raw 
domain scores can only be obtained when at least 50% of the items for the domain are 
answered. A non-applicable response is treated as unanswered. 
Transform the mean raw domain score by dividing by four (the number of Likert 
responses [five] minus one) and then multiplying by 100, as below: 
Mean raw domain score x 25 = Transformed score for domain 
Transformed scores range from 0 
) to 100 (
 
15.6.11. 
Work Productivity and Activity Impairment (WPAI) 
The WPAI consists of 6 questions  
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.
CCI
CCI


 
CONFIDENTIAL 
 
205646 
143 
 
 
The following summary measures will be derived: 
 
If a question is missing all summary measures that use that question will not be derived. 
Only the ‘Percent overall work impairment due to Lupus’ and ‘Percent activity impairment 
due to Lupus’ are summarised in the tables. 
 
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.


 
CONFIDENTIAL 
 
205646 
144 
 
15.6.12. 
Functional Assessment of Chronic Illness Therapy (FACIT) 
The FACIT – Fatigue scale consists of 13 questions: 
 
Each Question is answered on a Likert response scale and scored as numbered: 
 
The total score is the sum of the responses (inverted for reversed items) multiplied by 13, 
then divided by the number of questions answered i.e. 
{(4 −HI7) + (4 −HI12) + (4 −An1) + (4 −An2) + (4 −An3) + (4 −An4) + An5 +  An7
+(4 −An8) + (4 −An12) + (4 −An14) + (4 −An15) + (4 −An16)} ∗13
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑞𝑢𝑒𝑠𝑡𝑖𝑜𝑛𝑠 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑
 
The total score will only be derived if at least 11 questions (80%) of the scale is 
completed. 
 
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.


 
CONFIDENTIAL 
 
205646 
145 
 
15.6.13. 
Disease Control Without Current Immunosuppressant and with 
Current Corticosteroids  5mg/day  
 Disease Control 
Disease control for Arms A & B (the primary endpoint) is defined as: 
• SLEDAI-2K score ≤2 (IBA*),  
• Without immunosuppressants on the day of the assessment and 55 days prior to 
the assessment, 
• 7-day average corticosteroids at a prednisone equivalent dose of 5mg/day for 
the assessment (7 day average is the average of current and 6 previous days) 
• Without study withdrawal 
Disease control for Arms C (the exploratory endpoint) is defined as: 
• SLEDAI-2K score ≤2 (IBA*),  
• Without any new immunosuppressants, and not greater than the maximum of 
baseline (Day 1) day and Week 12 visit dose on the day of the assessment and 
55 days prior to the assessment, 
• 7-day average corticosteroids at a prednisone equivalent dose of 5mg/day for 
the assessment (7 day average is the average of current and 6 previous days) 
• Without study withdrawal 
*at baseline the principal investigators assessment will be used 
 
Note some tables will contain the endpoint using these 2 different definitions in the 
same table. 
The same derivation will be applied to the secondary endpoint “disease control (PI)” 
using the principal investigators assessment of the SLEDAI-2K.  
 
15.6.14. 
Prednisone Equivalent Conversion 
• A concomitant medication is identified as a steroid if at least one associated ATC 
code (ATCCD1 – ATCCD6) begins with ‘H02.’ Mineralocorticords are included in 
the group of ATC codes beginning with ‘H02’ but do not have sufficient anti-
inflammatory properties to be considered as a prednisone equivalent.  For this reason, 
the conversion factor has been set to 0. 
• 
The following routes are considered to provide systemic exposure: oral, buccal, 
parenteral  subcutaneous, intramuscular, intradermal, and intravenous.  Although not 
systemic, intra-articular steroids are also identified for treatment failure rules.  
Topical routes of administration are excluded (e.g., topical, conjunctival, intranasal).   
• 
At data base release, all preferred terms identified with an ATC code beginning with 
‘H02’ will be reviewed to ensure a conversion factor exists for all terms with a 
systemic route of administration.  
• 
Similarly, all routes of administration for preferred terms with an ATC code 
beginning with ‘H02’will be reviewed to ensure all systemic routes have been 
identified in the list below.   


 
CONFIDENTIAL 
 
205646 
146 
 
• In order to be converted the frequency and dose of the steroid must be present with 
the unit dose in milligrams (mg) or grams (g).  Doses recorded in grams will be 
converted to milligrams by multiplying the dose in grams by 1000 prior to applying 
the conversion factor. 
• 
Reported dose for systemic steroid is converted to prednisone equivalent dose using 
conversion factor for each particular medication (refer to online calculator 
http://www.globalrph.com/corticocalc.htm). 
Prednisone Equivalent 
Daily Dose (mg) 
= Collected 
Dose (mg) 
X Conversion 
Factor 
x Frequency 
Factor 
 
Prednisone Conversion Factors (mg)  
Preferred term 
Conversion factor for converting to a 
prednisone-equivalent dose 
BETAMETHASONE 
8.3333` 
BETAMETHASONE DIPROPIONATE 
8.3333` 
BETAMETHASONE SODIUM PHOSPHATE 
8.3333` 
BETROSPAM 
8.3333` 
BUDESONIDE 
0.3333` 
CORTISONE 
0.2 
CORTISONE ACETATE 
0.2 
CRONOLEVEL 
8.3333` 
DEFLAZACORT 
0.8333` 
DEXAMETHASONE 
6.6666` 
DEXAMETHASONE ACETATE 
6.6666` 
DEXAMETHASONE SODIUM PHOSPHATE 
6.6666` 
FLUDROCORTISONE 
0 
FLUOCORTOLONE 
3 
HYDROCORTISONE 
0.25 
HYDROCORTISONE ACETATE 
0.25 
HYDROCORTISONE SODIUM SUCCINATE 
0.25 
MEPREDNISONE 
1.25 
METHYLPREDNISOLONE 
1.25 
METHYLPREDNISOLONE ACETATE 
1.25 
METHYLPREDNISOLONE SODIUM SUCCINATE 
1.25 
PARAMETHASONE 
2.5 
PREDNISOLONE 
1 
PREDNISOLONE ACETATE 
1 
PREDNISOLONE SODIUM PHOSPHATE 
1 
PREDNISOLONE SODIUM SUCCINATE 
1 
PREDNISONE 
1 
PREDNISONE ACETATE 
1 
TRIAMCINOLONE 
1.25 
TRIAMCINOLONE ACETATE 
1.25 


 
CONFIDENTIAL 
 
205646 
147 
 
Prednisone Conversion Factors (mg)  
Preferred term 
Conversion factor for converting to a 
prednisone-equivalent dose 
TRIAMCINOLONE ACETONIDE 
1.25 
 
 
 
Frequency Factors 
Frequency 
Factor 
BID 
2 
BIW 
2/7 
HS 
1 
OAM 
1/30 
Once 
1 
PRN 
Null 
Q2H 
12 
Q2W 
1/14 
Q3H 
8 
Q3MO 
1/84 
Q3w 
1/21 
Q4H 
6 
Q4W 
1/28 
Q6H 
4 
Q8H 
3 
QAM 
1 
QD 
1 
QH 
24 
QHS 
1 
QID 
4 
QOD 
½ 
QPM 
1 
Combination Products:  Prednisone Conversion Factors (mg)  
Preferred term 
Ingredients 
Conversion factor for 
converting to a 
prednisone-equivalent 
dose 
CELESTONA BIFAS  
Betamethasone acetate + 
Betamethasone sodium phosphate 
8.3333` 
DEPO-MEDROL MED 
LIDOKAIN 
Methylprednisolone + Lidocaine 
1.25 
CELESTAMINE 
Betamethasone + 
Dexchlorpheniramine maleate 
8.3333` 
SYNBETAMINE 
Betamethasone + 
Dexchlorpheniramine maleate 
8.3333` 


 
CONFIDENTIAL 
 
205646 
148 
 
 
Frequency Factors 
Frequency 
Factor 
QW 
1/7 
QWK 
1/7 
TID 
3 
TIW 
3/7 
UNK 
Null 
2 TIMES PER WEEK 
2/7 
3 TIMES PER WEEK 
3/7 
EVERY 2 WEEKS 
1/14 
EVERY 3 WEEKS 
1/21 
EVERY 4 Weeks  
1/28 
EVERY WEEK 
1/7 
 
15.6.15. 
Treatment Failure Rules During Study Conduct 
A treatment failure is defined as any subject who receives a protocol-prohibited 
medication or a dose of allowable (but protocol restricted) medication that results in 
treatment failure designation prior to the analysis visit of interest (e.g. Week 52, Week 
64, Week 104). 
The treatment failure rules are detailed in the protocol Section 7.7. 
15.6.15.1. Summary 
Occurrence 
Post Study Start Treatments 
TX 
Failure: 
Arms A/B 
TX 
Failure: 
Arm C 
After Day 1 
• NEW anti-malarial medication for 
SLE (other than for anti-malarial 
prophylaxis) 
• NEW immunosuppressant 
medication 
• Prohibited Medications and Non-
Drug therapies   
Yes 
Yes 
After Week 4  
• Immunosuppressant medication 
Yes 
No 
After Week 12 
• Immunosuppressant medication dose 
increased over baseline (Day 1) or 
Week 12 visit dose, whichever is 
higher 
Not 
Applicable 
Yes 
Week 27 
onwards 
• Corticosteroid (Prednisone 
equivalent) dose >5mg/day (Average 
day of assessment and 6 prior days) 
Yes 
Yes 


 
CONFIDENTIAL 
 
205646 
149 
 
Occurrence 
Post Study Start Treatments 
TX 
Failure: 
Arms A/B 
TX 
Failure: 
Arm C 
After Week 26 
 
• High Dose CS for Non-SLE use 
(Maximum use 7 days, taper [≤5 
mg/day]. 21 days) 
Yes 
Yes 
After Week 44 
• Aspirin doses >1000 mg days if 
never received such doses between 
Day 1 and Week 44  
(Note: It does Not apply if given <7 
days) 
Yes 
Yes 
Weeks 44 to 
52* 
• NSAIDs (dose above Day 1 or the 
visit day starting the 8 weeks interval 
for ≥7 days) 
• Intraarticular CS injections 
• High Dose CS for Non-SLE use 
Yes 
Yes 
After Week 52 
• IP – Belimumab SC 
Yes 
No 
Weeks 56 to 
64* 
• NSAIDs (dose above Day 1 or the 
visit day starting the 8 weeks interval 
for ≥7 days)  
• Intraarticular CS injection 
• High Dose CS for Non-SLE use 
Yes 
Yes 
Weeks 96 to 
104* 
• NSAIDs (dose above Day 1 or the 
visit day starting the 8 weeks interval 
for ≥7 days) 
• Intraarticular CS injections 
• High Dose CS for Non-SLE use 
Yes 
Yes 
*8 weeks prior to major efficacy assessments (Primary endpoint [Week 52] and major secondary endpoints [Weeks 64, 
104]). 
15.6.15.2. SLE Medication Categories 
Medication Category 
Rule 
Anti-malarials 
Set to "ANTIMALARIALS" if the preferred term begins with "QUINACRINE", 
"QUININE", "HYDROXYCHLOROQUINE", 
"MEPACRINE", or "CHLOROQUINE"  
AND  
the route of administration is not 'TOPICAL', 'VAGINAL', 'CONJUNCTIVAL', 
'INTRANASAL', 'INHALATION', 'INTRA-OCULAR', 'INTRATRACHEAL', 
'EPIDURAL', 'INTRA-ARTICULAR', or 'OTHER'. 
Steroids 
Set to ‘STEROIDS’ if at least one associated ATC code (ATCCD1 – 
ATCCD6) begins with ‘H02’  
AND  
Route of administration is  
"INTRADERMAL", "INTRAMUSCULAR", “BUCCAL”, “PARENTERAL” 
"INTRAVENOUS", "ORAL", "SUBCUTANEOUS", or "INTRA-ARTICULAR". 


 
CONFIDENTIAL 
 
205646 
150 
 
Medication Category 
Rule 
Immunosuppressants 
Set to ‘IMMUNOSUPPRESSANTS’ if at least one associated ATC code 
(ATCCD1 – ATCCD6) begins with ‘L04A’ or the preferred term begins with 
“CYCLOPHOSPHAMIDE” (oral and parenteral routes) or 
“MERCAPTOPURINE” (oral route) AND route of administration is not 
“TOPICAL” or “OPHTHAMLIC”AND not classified above as 
"ANTIMALARIALS".   
NSAIDs 
Set to NSAIDs if at least one associated ATC code (ATCCD1 – ATCCD6) 
begins with ‘M01A’.Glucosamine and Chondroitin not considered 
NSAIDs 
 
Aspirin 
Set to "ASPIRIN" if CMDECOD contains "ACETYLSALICYLIC ACID" or 
"ACETYLSALICYLATE LYSINE". 
Prohibited 
Set to "PROHIBITED"   
if at least one associated ATC code (ATCCD1 – ATCCD6) begins with 
‘L04AB’ or ‘V98’ 
or if any of the following conditions are met, if CMDECOD equals ,” 
BELIMUMAB”, "ADALIMUMAB", "ETANERCEPT", "INFLIXIMAB", 
"CERTOLIZUMAB”, “TOCILIZUMAB”, "GOLIMUMAB", "RITUXIMAB", 
"ABATACEPT", "ANAKINRA", “CANAKINUMAB”, “USTEKINUMAB”, 
“BRODALUMAB”, “SECUKINUMAB”, “IXEKIZUMAB”, 
“EPRATUZUMAB”, “TABALUMAB”, “ATACICEPT”, 
"IMMUNOGLOBULIN" (IV route), “CYCLOPHOSPHAMIDE” (IV route), or 
"PLASMAPHERESIS"  
 
 
15.6.15.3. General Conventions 
• 
Assessment of dose is based on analysis dose. Analysis dose is daily dose adjusted 
for dosing frequency, and in the case of steroid is converted to prednisone 
equivalents. Exception is intra-articular dose where analysis dose is not populated. 
• 
In the event there are multiple visit dates within a visit window, the date for 
determining treatment failure, will be the earliest date at which efficacy data (from 
SLEDAI-2K (IBA), SLEDAI-2K (PI), PGA, and SLE Flare) is recorded. This may 
be different than the earliest visit within that window.  
• 
If a critical visit (Week 52, 64 , and 104], is missing from efficacy data (from 
SLEDAI-2K (IBA and PI), PGA, SLE Flare, LLDAS) then the date is imputed as the 
target day for that visit. 
• 
Actual visit date, not target visit date, is used to assess treatment failures.  
• 
If the subject’s Day 169 (Week 24) study visit occurs on Day 171, the date for 
Day 171 is used when applying the treatment failure rules.  
• 
Prohibited medications/dosages started on the date of early withdrawal are 
considered a TF (see clarification below for steroids).  If the prohibited 
medication/dose starts after the date of withdrawal it will not be part of the TF 
assessment. 


 
CONFIDENTIAL 
 
205646 
151 
 
• 
All potential TF rule violation are output programmatically and all adjudicated. 
• 
Clinical may amend the date of TF during adjudication if, for instance, a subject did 
not meet the criterion on the date identified by the program but did meet it later.  
 
15.6.15.4. Steroids 
• 
SLE-related steroids are steroids where medication type is marked as ‘Systemic 
Lupus Erythematosus (SLE)’ (CMTYPCD=156), regardless of reason for medication 
(CMREAS). 
• 
Total steroids include steroids for SLE and non-SLE reasons. 
• 
Baseline dose is the 7-day average based on the 7 days prior to, but not including, 
treatment start date. 
• 
The average steroid dose on any post baseline day is the sum of the steroids on that 
day and the prior 6 days divided by 7, so long as all days are post the baseline visit. 
• 
The first day that the TF rule  
• 
Received a prednisone equivalent corticosteroid 7-day average dose of >5 
mg/day after Week 26 visit  
is applied will be when all values used in the average steroid dose are after Week 26 
visit  (not including the week 26 visit day) i.e. 7 days after Week 26 visit 
• 
The final week interval for subjects who complete Week 104 will be 7 days prior to 
the exit visit date; [exit visit -7 days]. to [exit visit -1 day]. The day of Week 104 
visit will not be included. 
• 
The final interval for subjects who withdraw early will be the 7 days up to and 
including the exit visit date; [exit visit/early withdrawal date -6]. to [exit visit/ early 
withdrawal date]. The day of withdrawal will be included.  
• 
The above rules may miss a subject who starts/increases a steroid close to the day of 
withdrawal. In this situation it is possible that the subject may have withdrawn prior 
to the end of the interval for computing their 7-day average exceeding the TF 
threshold. Hence all subjects whose dose of steroid increased within 7 days 
(including day of withdrawal) of withdrawal, and have not already crossed the dose 
threshold for TF based on the 7-day average rule, will be output for clinical 
adjudication. If clinical adjudication determines these to be treatment failures the 
date of treatment failure will be set to the date of withdrawal. 
• 
A subject who is receiving 0mg of steroid at baseline will be allowed to take 5mg 
of steroid post baseline without being considered a treatment failure. 
• 
Intra-articular steroids are not included in average steroid dose calculations. 
• 
Subjects with more than one dosing regimen that involves alternate day dosing will 
be reviewed to ensure the daily dose is calculated correctly.  
• 
The 7 day average steroid >5mg/day rule will include SLE and non-SLE steroids in 
the identification of potential treatment failures.  Treatment failure review will 


 
CONFIDENTIAL 
 
205646 
152 
 
exclude cases where the 7 day average steroids is >5mg/day due non-SLE steroids on 
a by subject review basis.  
 
Intra-articular (IA) injections 
• 
Participants may receive intraarticular injections during the study with the exception 
of within 8 weeks prior to the key efficacy endpoints (i.e. Week 52, 64, and 104). A 
participant who receives any intraarticular injection(s) within 8 weeks before to the 
Weeks 52, 64, and/or  104 visits will be defined as a treatment failure. 
 
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 (imputed visit date will be used for Week 56). 
 
NOTE: Inhaled and topical corticosteroids are allowed throughout the course of the 
study 
 
15.6.15.5. Anti-malarials 
Dose of anti-malarial at baseline is the dose the subject received on the treatment start 
date (Day 1).  If a patient is receiving an anti-malarial at baseline it will be assumed that 
the dose is stable and not a loading dose. 
 
Anti-malarial therapies may be continued, or dose adjusted during the study. 
 
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 


 
CONFIDENTIAL 
 
205646 
153 
 
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. 
 
Clinical loading dose is permitted for initiation or replacement. Whether or not the dose 
was a loading dose will be assessed by clinical adjudication. 
 
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. 
NOTE: The use of anti-malarials for anti-malarial prophylaxis is permitted. 
 
15.6.15.6. Other Immunosuppressant Agents 
Arms A, B, and C 
• 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.  Replacement to be 
determined by clinical review 
• New topical immunosuppressive agents (e.g., eye drops, topical creams) are 
allowed after Day 1. 
 
Arms A and B 
• Participants can maintain their baseline stable immunosuppressant regimen or 
adjust their dose as clinically required, up to the Week 4.    
• At or prior to the Week 4 visit, immunosuppressants will be discontinued. 
• All immunosuppressant medications post Week 4 (day after the visit 4 visit date) 
will be clinically reviewed to determine if they are a treatment failure.   
 
Arms C 
• Participants may continue their baseline immunosuppressant agents throughout 
the study. 
• Dosage of existing immunosuppressant agents may be increased as clinically 
necessary until Week 12. From the day 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. 


 
CONFIDENTIAL 
 
205646 
154 
 
 
The common allowable maximum doses for immunosuppressant agents at baseline (Day 
1) and during the study (pre Week 4 for Arms  and B) are listed below: 
• Azathioprine – 300 mg/day 
• 6-mercaptopurine – 300 mg/day 
• Mycophenolate mofetil (PO)/ mycophenolate mofetil hydrochloride (IV) – 4 
g/day 
• Mycophenolate sodium (PO) – 2.88 g/day 
• Methotrexate – 25 mg/week 
• Oral cyclophosphamide – 2.5 mg/kg/day 
• Cyclosporine – 4 mg/kg/day* 
• Tacrolimus – 0.2 mg/kg/day* 
• Sirolimus – 2 mg/day* 
• Thalidomide – 200 mg/day 
• Leflunomide – 40 mg/day* 
• Mizoribine – 150 mg/day 
• Other immunosuppressant agents not listed above, the investigator must contact 
the Medical Monitor for approval 
*Clinical loading dose is permitted when replacing immunosuppressant agents. 
 
15.6.15.7. Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Aspirin, and 
Acetominophen 
NSAIDs and aspirin should be initiated and stabilized prior to entry into the trial. 
 
Baseline is defined as the NSAID/Aspirin received on the treatment start date (Day 1) 
 
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.  
 
An NSAID may be replaced with another NSAID due to documented toxicity or lack of 
availability.  Replacement due to toxicity/ lack of availability will be assessed during 
clinical adjudication.  
 
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. 
 
NSAIDS with an administration route of ‘TOPICAL’ or ‘CONJUNCTIVAL’’ will not be 
considered as TF’s. 
 
Aspirin will not be considered in the NSAID TF rules. 


 
CONFIDENTIAL 
 
205646 
155 
 
 
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. 
 
Daily doses of aspirin above 1000 mg/day may not be initiated in the 8 weeks before 
Week 64 and 104.  The same rules as at Week 44 will be applied at Weeks 56 and 96  
 
ACETYLSALICYLATE LYSINE (in mg) will be converted to standardised dose by 
multiplying by 0.556. 
 
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. 
 
PRN use of NSAIDs or Aspirin will be identified as a potential TF and reviewed on a by 
subject review basis. 
 
15.6.15.8. Prohibited Medications 
Medications prohibited by the protocol specified rule of: 
• 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. 
cannot be assessed by the data recorded on the CRF, but would be identified through 
CRA monitoring.  Should such events occur they will be addressed through the TF 
review process. 
 
Receiving a live vaccine is prohibited due to safety reasons but is not a treatment failure 
criterion. 
 
15.6.15.9. Belimumab in Year 2 
This use of PI prescribed belimumab in Year 2 is a treatment failure for subjects in Arms 
A and B.  Incorrectly taking Year 1 belimumab in Year 2  is not a treatment failure.  For 
subjects in Arms A and B all belimumab taken in Year 2 will be adjudicated to determine 
if it is an incorrect late dose or a prescribed re-start medication.   
 
Receiving belimumab is not a treatment failure for Arm C subjects. 
 


 
CONFIDENTIAL 
 
205646 
156 
 
15.6.16. 
Coronavirus Disease 2019 (COVID-19) Environment Onset Date 
A COVID-19 environment onset date has been defined by GlaxoSmithKline for each Country as: 
Country 
COVID-19) Environment Onset Date 
Argentina 
10/FEB/2020 
Brazil 
10/FEB/2020 
Canada 
10/MAR/2020 
France 
25/FEB/2020 
Germany 
10 FEB/2020 
Korea, Repubic of 
10/FEB/2020 
Mexico 
10/FEB/2020 
Netherlands 
10/FEB/2020 
Russia Federation 
13/MAR/2020 
Spain 
10/FEB/2020 
United States 
10/FEB/2020 
This represents the best estimate of the outbreak of COVID-19 within each Country at this time. 
 


 
CONFIDENTIAL 
 
205646 
157 
 
15.7. 
Appendix 7: Reporting Standards for Missing Data 
15.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Subject study completion (i.e. as specified in the protocol) is defined as completing all 
phases of the study, including the Week 104 visit.  
• 
Withdrawn subjects will not be replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be slotted as per Appendix 3 or will be summarized as withdrawal 
visits. 
15.7.2. 
Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should not be displayed as missing. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
15.7.2.1. 
Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
• 
 Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
Missing concomitant medication start date (CMSTDT) is imputed as treatment start date 
(TRTSDT) unless:  
o concomitant medication end date (CMENDT) is prior to treatment start date 
(TRTSDT), whether CMENDT is complete (DD/MM/YY) or partial (some 
combination of CMENDT day, month or year imputed) OR 
o The month or month and year of the partial CMSTDT are different from the 
month and/or year of TRTSDT OR  


 
CONFIDENTIAL 
 
205646 
158 
 
Element 
Reporting Detail 
o “Taken prior to study?” is checked. 
If any of the above conditions are met then CMSTDT is imputed with JAN for missing month 
and 01 for missing day, whatever is applicable. 
The recorded partial date will be displayed in listings. 
 


 
CONFIDENTIAL 
 
205646 
159 
 
15.8. 
Appendix 8: Laboratory Parameters and Toxicity Grades 
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 
Activated partial 
thromoplastin time 
Prothrombin Time 
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, 
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) 


 
CONFIDENTIAL 
 
205646 
160 
 
Laboratory 
Assessments 
Parameters 
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) 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) 
•  
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are stated in the protocol.  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). 
 
Laboratory parameters may need to have units converted for reporting.  Equivalent units 
are: 


 
CONFIDENTIAL 
 
205646 
161 
 
1x109/L = 1,000,000,000cells/L = 1,000cells/µL = 1,000cells/mm3  
1g/L = 100mg/dL = 100mg/100mL = 1mg/mL 
 
 
 


 
CONFIDENTIAL 
 
205646 
162 
 
15.8.1. 
Adverse Event and Laboratory Value Severity Grade Tables 
 
HEMATOLOGY 
 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Hemoglobin 
> 9.5 - 11.0 g/dL > 8.0 – 9.5 g/dL 
6.5 - 8.0 g/dL 
< 6.5 g/dL 
Leukocytes 
3000-3999/mm3 2000-2999/mm3 1000-1999/mm3 
< 1000/mm3 
Absolute Neutrophil Count 
1500-1999/mm3 1000-1499/mm3 500-999/mm3 
< 500/mm3 
Platelets 
75,000 - 
99,999/mm3 
50,000 – 
74,999/mm3 
25,000 - 
49,999/mm3 
< 25,000/mm3 
Prothrombin Time (PT) 
> 1.0-1.25 x 
ULN* 
> 1.25-1.5 x ULN > 1.5-3.0 x ULN 
> 3.0 x ULN 
Partial Thromboplastin 
Time (PTT) 
> 1.0-1.66 x 
ULN 
> 1.66-2.33 x 
ULN 
> 2.33-3.0 x ULN > 3.0 x ULN 
Methemoglobin 
5.0-10.0 % 
10.1-15.0 % 
15.1-20.0 % 
> 20% 
 
 
 
 
 
(continued) 
 
*ULN = Upper Limit of Normal.  
Modified from DMID Adult Toxicity Tables, 2001 
 
 


 
CONFIDENTIAL 
 
 
205646 
163 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
 
CARDIOVASCULAR 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
 
MODERATE 
 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Cardiac Arrhythmia 
- 
Asymptomatic/transient; 
dysrhythmia; no 
treatment req 
Recurrent/persistent 
dysrhythmia. 
Symptomatic; 
treatment req 
 
Unstable dysrhythmia 
hospitalization 
and treatment required 
Hypotension 
Transient 
orthostatic 
hypotension, no 
treatment 
Symptoms correctable  
with oral fluid treatment 
IV fluid req, 
no hospitalization 
req 
 
Hospitalization req 
Hypertension 
Transient, 
increase 
> 20 mm/Hg; no 
treatment 
Recurrent; chronic 
increase 
> 20 mm/Hg, treatment 
req 
Acute treatment 
req; out patient 
hospitalization 
possible 
 
Hospitalization req 
Pericarditis 
Minimal effusion Mild/moderate 
asymptomatic effusion, 
no treatment 
Symptomatic 
effusion, 
pain, ECG changes 
 
Tamponade OR 
pericardiocentesis  
OR surgery req 
Hemorrhage, Blood 
Loss 
- 
Mildly symptomatic;  
no treatment required 
Gross blood loss 
OR 
1-2 units transfused 
Massive blood loss OR 
> 2 units transfused 
 
 
 
 
 
(continued) 
1. Modified from (DMID) Adult Toxicity Tables, 2001 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
164 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
 
CHEMISTRIES 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Sodium 
   Hyponatremia 
130-135 meq/L 
123-129 meq/L 
116-122 meq/L 
< 116 meq/L 
   Hypernatremia 
146-150 meq/L 
151-157 meq/L 
158-165 meq/L 
> 165 meq/L 
Potassium 
   Hypokalemia 
3.0-3.4 meq/L 
2.5-2.9 meq/L 
2.0-2.4 meq/L 
< 2.0 meq/L 
   Hyperkalemia 
5.6-6.0 meq/L 
6.1-6.5 meq/L 
6.6-7.0 meq/L 
> 7.0 meq/L 
Phosphate 
   Hypophosphatemia 
2.0-2.4 mg/dL 
1.5-1.9 mg/dL 
1.0-1.4 mg/dL 
< 1.0 mg/dL 
Calcium- (Corrected For Albumin) 
   Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.1-6.9 mg/dL 
< 6.1 mg/dL 
   Hypercalcemia 
10.6-11.5 mg/dL 
11.6-12.5 mg/dL 
12.6-13.5 mg/dL 
>13.5 mg/dL 
Magnesium 
   Hypomagnesemia 
1.2-1.4 meq/L 
0.9-1.1 meq/L 
0.6-0.8 meq/L 
< 0.6 meq/L 
Albumin 
   Hypoalbuminemia 
3.00-3.49 g/dL 
2.50-2.99 g/dL 
2.00-2.49 g/dL 
< 2.00 g/dL 
Bilirubin (Total) 
   Hyperbilirubinemia (Total) 
> 1.0-1.5 x ULN 
> 1.5-2.5 x ULN 
> 2.5-5 x ULN 
> 5 x ULN 
Glucose 
   Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
< 30 mg/dL 
   Hyperglycemia  
116-160 mg/dL 
161-250 mg/dL 
251-500 mg/dL 
> 500 mg/dL 
   (nonfasting & no prior 
diabetes) 
 
 
 
 
   Triglycerides 
151-399 mg/dL 
400-750 mg/dL 
751-1200 mg/dL 
> 1200 mg/dL 
Creatinine 
> 1.0-1.5 x ULN 
> 1.5-3.0 x ULN 
> 3.0-6.0 x ULN 
> 6.0 x ULN 
Uric Acid 
   Hyperuricemia 
7.5-10.0 mg/dL 
10.1-12.0 mg/dL 
12.1-15.0 mg/dL 
> 15.0 mg/dL 
Liver Transferases  (AST, 
ALT, and GGT) 
1.25-2.5 x ULN 
> 2.5-5.0 x ULN 
> 5.0-10.0 x ULN 
> 10.0 x ULN 
Alkaline Phosphatase 
1.25-2.5 x ULN 
> 2.5-5.0 x ULN 
> 5.0-10.0 x ULN 
> 10.0 x ULN 
Pancreatic Enzymes 
Amylase 
> 1.0-1.5 x ULN 
> 1.5-2.0 x ULN 
> 2.0-5.0 x ULN 
> 5.0 x ULN 
Pancreatic amylase 
> 1.0-1.5 x ULN 
> 1.5-2.0 x ULN 
> 2.0-5.0 x ULN 
> 5.0 x ULN 
Lipase 
> 1.0-1.5 x ULN 
> 1.5-2.0 x ULN 
> 2.0-5.0 x ULN 
> 5.0 x ULN 
Hypoglobulinemia (IgG)* 
550-700 mg/dL 
400-549 mg/dL 
250-399 mg/dL 
< 250 mg/dL 
 
 
 
 
 
(continued) 
 
Modified from (DMID) Adult Toxicity Tables, 2001 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
165 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
 
GASTROINTESTINAL 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
 
Nausea 
Mild OR 
transient; 
reasonable intake 
maintained 
Mod discomfort  
OR intake 
decreased  
for < 3 days 
Severe discomfort 
OR  
minimal intake  
for  3 days 
Hospitalization required 
Vomiting 
Mild OR 
transient;  
2-3 episodes/day 
OR  
mild vomiting 
lasting  
< 1 week 
Mod OR 
persistent;  
4-5 episodes per 
day;  
OR vomiting 
lasting  
 1 week 
Severe vomiting of 
all foods/fluids in 24 
hours  
OR orthostatic 
hypotension 
 OR IV treatment 
req 
Hypotensive shock OR 
hospitalization  
required for IV treatment req 
Diarrhea 
Mild or transient;  
3-4 loose stools 
per day  
OR mild diarrhea 
lasting  
< 1 week 
Mod OR 
persistent;  
5-7 loose stools 
per day  
or diarrhea lasting  
 1 week 
Bloody diarrhea;  
OR orthostatic 
hypotension  
OR > 7 loose 
stools/day  
OR IV treatment req 
Hypotensive shock  
OR hospitalization req 
Oral 
Discomfort/Dysphagia 
Mild discomfort, 
no difficulty 
swallowing 
Difficulty 
swallowing but 
able to eat and 
drink 
Unable to swallow 
solids 
Unable to drink fluids;  
IV fluids req 
Constipation 
Mild 
Moderate 
Severe 
Distention with vomiting 
 
 
Modified from (DMID) Adult Toxicity Tables, 2001 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
166 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
RESPIRATORY 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Cough  
(for aerosol 
studies)  
Transient; no 
treatment 
Treatment associated  
cough; inhaled 
bronchodilator 
Uncontrolled cough;  
systemic treatment 
req 
 
Bronchospasm 
Acute 
Transient; no 
treatment;  
FEV1 70% to  
< 80%  
(or peak flow) 
treatment req; 
normalizes with 
bronchodilator;  
FEV1 50% to < 70%  
(or peak flow) 
 
No Normalization  
with bronchodilator;  
FEV 25% to < 50%  
(or peak flow), 
retractions 
Cyanosis; FEV1 < 25%  
(or peak flow) OR intubated 
Dyspnea 
Dyspnea on 
exertion 
Dyspnea with  
normal activity 
Dyspnea at rest 
Dyspnea requiring O2 therapy 
 
 
 
URINALYSIS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Proteinuria 
 
Dispstick 
 
 
 
 
Protein 
 
1 + 
2-3 + 
4 + 
Nephrotic syndrome 
Spot Urine:    
Protein:Creatinine  
Ratio mg/mg 
0.2-1.0 
> 1.0-2.0 
> 2.0-3.5 
> 3.5 
24 Hour Urine: 
Protein 
200 mg - 1g 
loss/day 
 
> 1-2 g loss/day 
 
> 2-3.5 g loss/day 
 
Nephrotic syndrome 
OR > 3.5 g loss/day 
 
Hematuria 
Microscopic only 
> 3 to < 10 
RBC/hpf 
Gross, No clots 
 10 RBC/hpf 
Gross plus clots OR  
RBC casts 
Obstructive OR transfusion 
required 
 
RBC = red blood cell; hpf = high power field. 
Modified from (DMID) Adult Toxicity Tables, 2001 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
167 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
 
MISCELLANEOUS 
 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Fever (oral > 12 
hours) 
37.7-38.5C or 
100.0-101.5F 
 
38.6-39.5C OR 
101.6-102.9F 
39.6-40.5C OR 
103-105F 
> 40.5C OR > 105F 
Headache 
Mild; No 
treatment req 
Mod; or non-
narcotic analgesia 
treatment 
Severe; OR 
responds to initial 
narcotic treatment 
Intractable; OR requiring  
repeated narcotic treatment 
 
Allergic Reaction 
Pruritus without 
rash 
Localized urticaria 
Generalized 
urticaria 
angioedema 
 
Anaphylaxis 
Cutaneous/Rash/ 
Dermatitis 
Erythema, 
pruritus rash  
OR dry 
desquamation 
Diffuse 
maculopapular  
OR dry 
desquamation 
Vesiculation OR 
moist 
desquamation 
ulceration 
ANY ONE: mucous 
membrane involvement, 
suspected  
Stevens-Johnson (TEN), 
erythema multiforme, necrosis 
req surgery, exfoliative 
dermatitis 
 
Local Reaction 
(secondary  
to parenteral 
treatment- not 
vaccination or skin 
test) 
 
Erythema 
Induration < 10 mm  
OR inflammation  
OR phlebitis 
Induration > 10 mm  
OR ulceration 
Necrosis of skin 
Fatigue 
Normal activity  
Reduced < 25% 
Normal activity  
Reduced 25-50% 
Normal activity  
reduced > 50%;  
cannot work 
Unable to care for self 
 
Modified from (DMID) Adult Toxicity Tables, 2001 
 
Adverse Event and Laboratory Value Severity Grade Tables (continued) 
 
 
NEUROLOGIC 
 
GRADE 1 
 
GRADE 2 
 
GRADE 3 
 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Neuro-
cerebellar 
Slight 
incoordination OR 
dysdiadochokinesia 
Intention tremor OR  
dysmetria OR slurred 
speech  
OR nystagmus 
Ataxia requiring 
assistance to walk or 
arm incoordination 
interfering with ADLs 
 
Unable to stand 
Neuro-psych/ 
mood 
 
None 
Severe mood 
changes requires 
medical intervention 
 
Acute psychosis requiring  
Hospitalization 
Paresthesia  
(burning, 
tingling, etc) 
Mild discomfort;  
no treatment 
needed 
Mod discomfort  
non-narcotic analgesia 
req 
Severe discomfort; 
OR narcotic 
analgesia req with 
symptomatic 
improvement 
Incapacitating; OR not 
responsive  
to narcotic analgesia 


 
CONFIDENTIAL 
 
 
205646 
168 
 
 
Neuro-motor 
Mild weakness in 
muscle of feet but  
able to walk and/or 
mild increase or 
decrease in 
reflexes 
Mod weakness in feet 
(unable to walk on heels 
and/or toes), mild 
weakness in hands, still 
able to do most hand 
tasks and/or loss of 
previously present reflex 
or development of 
hyperreflexia  
and/or unable to do 
deep knee  
bends due to weakness 
 
Marked distal 
weakness (unable to 
dorsiflex toes or foot 
drop), and mod 
proximal weakness 
ie, in hands 
interfering with ADLs 
and/or requiring 
assistance to walk 
and/or unable to rise 
from chair 
unassisted 
Confined to bed or 
wheelchair  
because of muscle weakness 
Neuro-sensory Mild impairment 
sensations,  
(ie, vibratory, 
pinprick, hot/cold in 
great toes) in focal 
area or 
symmetrical 
distribution 
Mod impairment mod 
de-sensation,  
(ie, of vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position or 
mild impairment that is 
not symmetrical. 
Severe impairment 
(dec or loss of 
sensation to knees 
or wrists) or loss of 
sensation of at least 
mod degree in 
multiple different 
body areas (ie, 
upper and lower 
extremities) 
Sensory loss involves limbs  
and trunk 
 
 
 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY LIFE-
THREATENING 
Lymphopenia 
>0.8 (GI/L) 
<=0.8 - >.5(GI/L) 
<=0.5->0.2(GI/L) 
<=0.2(GI/L) 
Source: CTCAE 4.03  
 


 
CONFIDENTIAL 
 
 
205646 
169 
 
15.9. 
Appendix 9: Biomarkers 
 
SI BIOMARKER DATASET 
SDTM LB DATASET 
Name 
BICATCD 
BICAT 
BITESTCD 
BIORRESU 
LBTESTCD 
LBSTRESU 
 
GSK_TestCode 
GSK_TestName 
  
GSK_Unit 
SDTM 
TESTCD 
SDTM UNIT 
Anti-dsDNA 
ANDSAB 
Anti-dsDNA 
antibody 
CONC 
IU/ML 
ADSDNAAB 
IU/mL 
C3 
C3 
Complement 
component 3 
CONC 
G/L 
C3 
g/L 
C4 
C4 
Complement 
component 4 
CONC 
G/L 
C4 
g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD19+ Total B 
cells 
CD19 
CD19+ 
CONC 
CELLS/ML 
CD19 
10^3/L 
 
 
 
 
 
 
 
B cells CD20+ 
CDX111 
CD19+ CD20+ 
CONC 
CELLS/ML 
CDX111_C 
10^3/L 
B cells CD20+ 
CDX111 
CD19+ CD20+ 
PCTBCELL 
% 
CDX111_P 
% 
Naive B cells 
IgD+ 
CDX203 
CD19+ CD27- 
IgD+ 
CONC 
CELLS/ML 
CDX203 
10^3/L 
Naive B cells 
IgD+ 
CDX203 
CD19+ CD27- 
IgD+ 
PCTBCELL 
% 
CDX203 
% 
Naive CD20+ 
CD27- 
CDX731 
CD19+CD20+C
D27- 
CONC 
CELLS/ML 
CDX731_C 
10^3/L 
Naive CD20+ 
CD27- 
CDX731 
CD19+CD20+C
D27- 
PCTBCELL 
% 
CDX731_P 
% 
Activated 
Total B cells 
CD95+ 
CDX742 
CD19+CD95b+ 
CONC 
CELLS/ML 
CDX742_C 
10^3/L 
Activated 
Total B cells 
CD95+ 
CDX742 
CD19+CD95b+ 
PCTBCELL 
% 
CDX742_P 
% 
Memory 
CD20+ CD27+ 
CDX732 
CD19+CD20+C
D27+ 
CONC 
CELLS/ML 
CDX732_C 
10^3/L 
Memory 
CD20+ CD27+ 
CDX732 
CD19+CD20+C
D27+ 
PCTBCELL 
% 
CDX732_P 
% 
Non-switched 
memory 
CD27+ IgD+ 
CDX84 
CD19+ CD27+ 
IgD+ 
CONC 
CELLS/ML 
CDX84 
10^3/L 


 
CONFIDENTIAL 
 
 
205646 
170 
 
 
SI BIOMARKER DATASET 
SDTM LB DATASET 
Name 
BICATCD 
BICAT 
BITESTCD 
BIORRESU 
LBTESTCD 
LBSTRESU 
 
GSK_TestCode 
GSK_TestName 
  
GSK_Unit 
SDTM 
TESTCD 
SDTM UNIT 
Non-switched 
memory 
CD27+ IgD+ 
CDX84 
CD19+ CD27+ 
IgD+ 
PCTBCELL 
% 
CDX84_PC 
% 
Switched 
memory 
CD27+ IgD- 
CDX86 
CD19+ CD27+ 
IgD- 
CONC 
CELLS/ML 
CDX86 
10^3/L 
Switched 
memory 
CD27+ IgD- 
CDX86 
CD19+ CD27+ 
IgD- 
PCTBCELL 
% 
CDX86_PC 
% 
Plasmablasts 
CD27b CD38b 
CDX734 
CD19+CD27b+
CD38b+ 
CONC 
CELLS/ML 
CDX734_C 
10^3/L 
Plasmablasts 
CD27b CD38b 
CDX734 
CD19+CD27b+
CD38b+ 
PCTBCELL 
% 
CDX734_P 
% 
Plasmablasts 
CD20+ CD27b 
CD38b  
CDX735 
CD19+CD20+C
D27b+CD38b+ 
CONC 
CELLS/ML 
CDX735_C 
10^3/L 
Plasmablasts 
CD20+ CD27b 
CD38b  
CDX735 
CD19+CD20+C
D27b+CD38b+ 
PCTBCELL 
% 
CDX735_P 
% 
Plasmablasts 
CD20- CD27b 
CD38b  
CDX736 
CD19+CD20-
CD27b+CD38b+ 
CONC 
CELLS/ML 
CDX736_C 
10^3/L 
Plasmablasts 
CD20- CD27b 
CD38b  
CDX736 
CD19+CD20-
CD27b+CD38b+ 
PCTBCELL 
% 
CDX736_P 
% 
Transitional 
CD24b CD27- 
CD38b  
CDX199 
CD19+ CD24b+ 
CD38b+ CD27- 
CONC 
CELLS/ML 
CDX199 
10^3/L 
Transitional 
CD24b CD27- 
CD38b  
CDX199 
CD19+ CD24b+ 
CD38b+ CD27- 
PCTBCELL 
% 
CDX199_P 
% 
Transitional 
CD10+ CD24b 
CD27- CD38b  
CDX738 
CD19+CD10+C
D24b+CD27-
CD38b+ 
CONC 
CELLS/ML 
CDX738_C 
10^3/L 
Transitional 
CD10+ CD24b 
CD27- CD38b  
CDX738 
CD19+CD10+C
D24b+CD27-
CD38b+ 
PCTBCELL 
% 
CDX738_P 
% 
CD3+ Total T 
cells 
CD3 
CD3+ 
CONC 
GI/L 
CD3 
10^9/L 
CD4+ T cells 
CDX03 
CD3+ CD4+ 
CONC 
GI/L 
CDX03 
10^9/L 
CD8+ T cells 
CDX02 
CD3+ CD8+ 
CONC 
GI/L 
CDX02 
10^9/L 


 
CONFIDENTIAL 
 
 
205646 
171 
 
15.10. 
Appendix 10: Abbreviations & Trade Marks 
15.10.1. 
Abbreviations 
Abbreviation 
Description 
aCL 
Anti-cardiolipin 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibody 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANA 
Anti-nuclear Antibody 
ANCOVA 
Analysis of Covariance 
anti-dsDNA 
Anti-double-stranded DNA 
BLyS 
B-Lymphocyte Stimulator 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CMQ 
Customized MedDRA Query 
CNS 
Central Nervous System 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBF 
Database Freeze 
DBR 
Database Release 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
EU 
European Union 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue Scale 
FACS 
Florescence Activated Cell Sorting 
FDA 
Food and Drug Administration 
GSK 
GlaxoSmithKline 
HZ 
Herpes Zoster 
IBA 
Independent Blinded Assessor 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
Ig 
Immunoglobulin 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
IV 
Intravenous 
LLDAS 
Lupus Low Disease Activity State 
LLN 
Lower Limit of Normal 
LOQ 
Limit of Quantification 
MAR 
Missing At Random 
MCID 
Minimal Clinically Important Difference 


 
CONFIDENTIAL 
 
 
205646 
172 
 
Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-To-Treat 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OI 
Opportunistic Infections 
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PISR 
Post-Injection Systemic Reactions 
PK 
Pharmacokinetic 
PopPK 
Population Pharmacokinetic 
PP 
Per Protocol 
PROs 
Patient Reported Outcomes 
PSAP 
Program Safety Analysis Plan 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SDTM 
Study Data Tabulation Model 
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 
SOC 
System Organ Class 
TB 
Tuberculosis 
ULN 
Upper Limit of Normal 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 
15.10.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
BENLYSTA (belimumab) 
 
Rituxan 
 
 
SAS 
 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
173 
 
15.11. 
Appendix 11: List of Data Displays 
15.11.1. 
Data Display Numbering 
RAP generated displays follow the Format A XY.ZZ, where:  
A refers to the reporting effort i.e. 
• T = Table 
• L = Listing 
• F = Figure 
X refers to the reporting effort i.e.  
• 1 = After all subjects have completed Week 52 i.e. Year 1 data 
• 2 = After all subjects have completed Week 104 i.e.Year 2 & Year 1&2 
Y refers to the Section i.e. 
• 1 = Study population 
• 2 = Efficacy 
• 3 = Safety 
• 4 = Health outcomes 
• 5 = Biomarkers 
• 6 = Pharmacokinetic 
ZZ is an incremental count with a new number for every output.  
15.11.2. 
Mock Example Shell Referencing 
Example mock-up displays are provided in documents 
205646 Study Pop Shells 
205646 Efficacy Shells 
205646 Safety Shells 
205646 Health Outcomes Shells 
205646 Biomarker Shells 
205646 PK Shells 
15.11.3. 
Deliverables 
Delivery  
Description 
DB SAC 
Double Blind Statistical Analysis Complete – Primary SAC for Year 1 
EOS SAC 
End of Study Statistical Analysis Complete – EoS SAC for Year 2 and Years 
1&2 Combined 
 
 
 


 
CONFIDENTIAL 
 
 
205646 
174 
 
16. 
ATTACHMENTS 
16.1. 
Attachment 1: AESI Preferred Term Definitions 
The AESI definitions under the current version of MedDRA at the time of reporting will 
be found via the following IMMS pathname: 
/Study File/GSK1550188/_Project/Meta Analysis/PSAP/