A Phase 3/4, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Adult Subjects of Black Race With Systemic Lupus Erythematosus (SLE)
Phase: PHASE4
Conditions: Systemic Lupus Erythematosus
Sponsor: Human Genome Sciences Inc., a GSK Company

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recipient that no unpublished information contained herein will be published or 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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1.
BACKGROUND
1.1.
Disease Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by 
autoantibody production and abnormal B lymphocyte function (Pisetsky, 2001). The 
etiology of SLE is unknown, although genetics, sex hormones, and environmental 
conditions are thought to play a role (Kotzin, 1996; Pisetsky, 1998; Sobel et al, 1999). 
This disease is more common in women (~90% of patients) than men (NWHIC, 2003) 
and more prevalent in African-Americans than Caucasians (OMHRC, 2001; NWHIC, 
2003). In the United States (US) the reported prevalence is 100,000 to 500,000 patients 
with some estimates of 1 million as the incidence increased 2-3 fold between 1950 and 
1979. In the European Union (EU), prevalence rates have been reported ranging from 25 
to 39 cases per 100,000 persons (Jiménez et al, 2003). The disease onset is generally 
between the ages of 20 and 40 years. Patients with SLE have about a 3-fold greater risk 
of mortality than the general population. Approximately 70% of SLE patients survive 20 
years from time of diagnosis (Houssiau et al, 2004).
SLE can lead to arthritis, kidney failure, heart and lung inflammation, central nervous 
system (CNS) changes, vasculitis, severe skin rash, and blood dyscrasias such as anemia, 
leukopenia, and thrombocytopenia. The manifestations of SLE vary from patient to 
patient and it may take many years to render the proper diagnosis. The American College 
of Rheumatology (ACR) criteria that define a diagnosis of this heterogeneous disease 
require 4 of 11 criteria that include SLE-associated signs or symptoms, lab abnormalities, 
and the presence of specific anti-nuclear autoantibodies (Tan et al, 1982).
The current paradigm of the pathogenesis of SLE begins with a genetic predisposition 
(multi-factorial as > 10 chromosomal regions have been identified) that leads to the 
production of pathogenic autoantibodies, cytokine abnormalities, and autoreactive 
effector B and T lymphocytes (Harley et al, 1998; Lipsky, 2001; Schur, 1995). B 
lymphocyte abnormalities include an altered state of B lymphocyte differentiation, 
indicated by increased numbers of plasma cells secreting immunoglobulin (Ig), especially 
during times of increased clinical activity (Grammer and Lipsky, 2003). B lymphocytes 
isolated from SLE patients often have dysregulated expression of cell surface molecules, 
such as B7 and CD40, suggesting an enhanced state of B lymphocyte activation 
(Yazdany and Davis, 2004). 
The behavior of laboratory biomarkers in SLE is under active investigation (Illei et al, 
2004a; Illei, 2004b; Schiffenbauer et al, 2004). As yet, no clear surrogate endpoints have 
been widely accepted that clearly define clinical outcomes for the multi-organ system 
manifestations of SLE. As such, it is important to evaluate multiple markers of disease 
activity which may be clinically meaningful. Autoantibodies have been shown to be 
important early markers of specific disease processes or severity in SLE (Hahn, 1998; 
Leslie
et al, 2001; Ravirajan
et al, 2001) and are associated with disease 
activity (Villarreal et al, 1997). Autoantibodies can be directly involved in the disease 
process by binding to their target antigen and initiating immune injury by triggering a 
cascade of cellular and cytokine responses or indirectly, through immune complex 

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

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

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

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

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

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

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Table 1-2
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Post-injection 
systemic reactions 
and 
Hypersensitivity 
Administration of belimumab may result in 
infusion and hypersensitivity reactions, 
which can be severe and can be fatal.  
Non-serious infusion reactions and 
hypersensitivity reactions are common in 
SLE clinical trials with IV belimumab.  
Serious infusion and hypersensitivity 
reactions affected less than 1% of patients 
and included anaphylactic reaction, 
bradycardia, hypotension, angioedema, 
and dyspnea. Delays in the onset of 
hypersensitivity reactions have been 
observed. Infusion reactions following 
administration of belimumab occurred 
more frequently on the first 2 infusion days 
and tended to decrease with subsequent 
administrations. Delayed-type, non-acute 
hypersensitivity reactions have also been 
observed and included symptoms such as
rash, nausea, fatigue, myalgia, headache, 
and facial oedema.
Exclusion of subjects with a 
history of an anaphylactic reaction 
to parenteral administration of 
contrast agents, human or murine 
proteins or monoclonal antibodies.
Subjects should remain under clinical 
supervision for 3 hours after completion of the 
first 2 infusions. Should symptoms of acute 
hypersensitivity occur, an extended period of 
monitoring may be appropriate, based on 
clinical judgment. Otherwise, subjects will be 
monitored during and after each infusion 
according to study sites’ guidelines or 
standard operating procedure for IV infusions. 
This may include, but is not limited to, 
monitoring vital signs and observing for any 
untoward reactions.  Subjects should be 
made aware of the potential risk, the signs 
and symptoms of such reactions, and the 
importance of immediately seeking medical 
attention.  Belimumab should be administered 
by a healthcare professional prepared to treat 
hypersensitivity reactions including 
anaphylaxis.
Infections
Infections occurred in a slightly greater 
proportion of subjects treated with 
belimumab compared with placebo. 
Infections occurring in at least 3% of 
patients receiving belimumab and at least 
1% more frequently than patients receiving 
Exclude patients with any of the 
following: currently on any 
suppressive therapy for a chronic 
infection; hospitalization for 
treatment of an infection within 60 
days of Day 0; use of IV or IM 
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately.

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
placebo were nasopharyngitis, bronchitis, 
pharyngitis, cystitis, and gastroenteritis 
viral.  Serious infections occurred in 5% of 
patients receiving either belimumab or 
placebo.
antibiotics within 60 days of Day 
0; a history of or positive test at 
screening for HIV, hepatatis B or 
hepatitis C; have Grade 3 or 4 
lymphopenia; or have Grade 3 or 
4 IgG or IgA deficiency
Progressive 
multifocal 
leukoencephalopa
thy (PML)
No association between belimumab and 
the risk of opportunistic infections, 
including PML, has been indentified to 
date, but data are limited. PML resulting in 
neurological deficits, including fatal cases, 
has been reported in SLE patients 
receiving immunosuppressant 
pharmacotherapy, including belimumab.
A diagnosis of PML should be considered in 
any subject presenting with new-onset or 
deteriorating neurological signs and 
symptoms. The subject should be referred to 
a neurologist or other appropriate specialist 
for evaluation. If PML is confirmed, study 
agent should be discontinued and 
consideration should be given to stopping
immunosuppressant therapy. If PML is 
suspected, this should be immediately 
reported to the Medical Monitor. The 
appropriateness of continuing study agent, 
while the case is being assessed, should be 
discussed.
Malignancies
As with other immunomodulating agents, 
the mechanism of action of belimumab 
may increase the potential risk for the 
development of malignancies.
Exclude patients with a history of 
malignant neoplasm within the 
last 5 years, except for adequately 
treated basal or squamous cell 
cancers of the skin, or carcinoma 
in situ of the uterine cervix.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, 
request that patients report signs and 
symptoms.  Treat appropriately.
Immunogenecity
As with other monoclonal antibodies, 
treatment with belimumab could lead to the 
development of anti-drug antibodies 
Monitor anti-drug antibody laboratory values.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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6.8.1.2.
Scoring for Proteinuria at Day 0 and Subsequent Study Visits
According to the SELENA SLEDAI scoring rules, unless the proteinuria continues to rise 
such that it has increased by > 0.5 g/24 hour equivalent at Day 0 (ie, baseline), the 
subject, by default, will have an improving SELENA SLEDAI score prior to treatment. 
Two assessments of 24-hour proteinuria (by spot urinary protein to urinary creatinine 
ratio) obtained in a 2 to 3 week period are unlikely to show a > 0.5 g/24 hour equivalent 
increase except in acute renal flare. This is problematic for data analysis since the percent 
change in the disease activity scales are calculated from the baseline (not screening) 
SELENA SLEDAI score. As such, the following scoring rules will be applied:
6.8.1.2.1.
Scoring for a Subject with Proteinuria and 4 Points Assigned in 
SELENA SLEDAI 
If there is an increase from the last visit of > 0.5 g/24 hour equivalent, only 4 points for 
proteinuria will continue to be applied (so no subject can get more than 4 points for 
proteinuria at any 1 time point).
If the proteinuria has not improved (ie, there has not been a decrease in proteinuria of 
> 0.5 g/24 hour equivalent) since the previous assessment, then 4 points will continue to 
be assigned on the SELENA SLEDAI index at the current visit. 
If proteinuria has improved (decrease of > 0.5 g/24 hour equivalent or a decrease to ≤0.5 
g/24 hour equivalent) from the previous visit to the current visit, then 0 points will be 
assigned on the SELENA SLEDAI index at the current visit.
6.8.1.2.2.
Scoring for a Subject with 0 Points for Proteinuria in SELENA SLEDAI
If the proteinuria score for SELENA SLEDAI is 0 and at the subsequent visit the 
assessment of 24-hour proteinuria (by spot urinary protein to urinary creatinine ratio) 
shows > 0.5 g/24 hour equivalent increase above the previous value or the subject 
develops new onset of proteinuria > 0.5 g/24 hour equivalent, 4 points will be assigned at 
this current visit. 
6.8.2.
Pharmacokinetics
All randomized subjects will be sampled for serum belimumab levels during the double-
blind treatment period. A blood sample for pharmacokinetic analysis will be drawn
according to the time schedule below.

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Table 6-3
PK visit days and sample times
Day (Week)
Time (Related to Dosing of Study Agent)
0
Before the start of infusion
14 (Week 2)
0 - 4 hours after the end of infusion
56 (Week 8)
Before the start of infusion
168 (Week 24)
0 - 4 hours after the end of infusion
364/Exit (Week 52) 
Any time during visit (or prior to dosing if going into 
the open-label extension)
8-week follow-up 
(8 weeks after last dose)
Any time during visit
(if not going into the 6-month open-label extension)
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.  
6.8.3.
Liver Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 13.

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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 13.
6.8.3.1.
Study Agent Restart
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
Refer to Appendix 14 for full guidance
6.8.4.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent on Days 0, 56 (Week 8), 
168 (Week 24), 364 (Week 52), and at the 8-week follow-up visit (if applicable). 

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

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information is important for the safety of other subjects currently in the study. Any 
broken blind will be clearly justified and explained by a comment in the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
7.
ADVERSE EVENT REPORTING
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.
Definitions
ADVERSE EVENT - Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (ie, lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

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
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
SERIOUS ADVERSE EVENT – A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalisation or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity, or
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 

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emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver 
injury.
7.2.
Reporting Adverse Events to the Sponsor
All adverse events (AEs) that are identified from the start of study agent administration 
(Day 0) through 8 weeks following administration of the last dose of study agent will be 
recorded on the Adverse Event Case Report Form (AE eCRF). All data fields on the AE 
eCRF must be completed. 
Serious Adverse Events (SAEs) must be recorded on the SAE eCRF within 24 hours of 
site personnel becoming aware of a SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
SAE eCRF within 24 hours of site personnel becoming aware of the follow-up 
information as described in the Study Procedure Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an 
SAE from the time a subject consents to participate in the study.
SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study 
agent) that are assessed by the investigator as possibly related to study agent must be 
reported to the Sponsor as outlined in the Study Procedures Manual.
7.3.
Laboratory Abnormalities as Adverse Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.

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

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

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SEVERITY
Mild
An event that is easily tolerated by the subject, causing 
minimal discomfort and not interfering with everyday 
activities (Grade 1 DMID).
Moderate
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 
or 4 DMID).
Not applicable
Those event(s) where intensity is meaningless or 
impossible to determine (ie, blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the pre-
defined outcomes as described in the definition of an SAE.
CAUSALITY
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out. The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated. The investigator will also consult the 
IB and/or Product Information, for marketed products, in the determination of his/her 
assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.  The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
7.8.
Follow-Up of Adverse Events
Serious and nonserious adverse events that occur from the start of study agent 
administration through 8 weeks after the date of last administration of study agent are 
reported.

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After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up. This applies to 
all subjects, including those withdrawn prematurely.
7.9.
Disease Related Events
Disease related events (DREs) can occur in the study population regardless of belimumab 
exposure and are not reported as AEs or SAEs, unless judged by the investigator to be 
more severe than expected for the subject’s condition.
The following DREs (preferred terms; MedDRA v. 14.0) are common in subjects with 
SLE and can be serious/life-threatening:
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis
Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
When these conditions are considered SAEs, they must be reported to the Sponsor within 
24 hours of site personnel becoming aware as described in Section 7.2. The Sponsor will 
not submit these events as expedited reports to regulatory authorities, investigators, or 
IRBs/IECs (unless considered by the Sponsor to be related to study agent).
7.10. Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  The 
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and the Sponsor’s policy and are 
forwarded to investigators as necessary.

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

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

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

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

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

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

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

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

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will not occur for any of these baseline randomization factors that has < 10 events (ie, 
having a prednisone reduction by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 
through 52) or < 10 non-events in a stratification level. The analysis will be performed on
subjects who used prednisone > 7.5 mg/day at baseline. Any subject who withdraws from 
the study prior to the Day 364 (Week 52) visit, misses the Day 364 (Week 52) visit, 
and/or receives a dose of protocol prohibited/restricted medication that results in 
treatment failure designation prior to the Day 364 (Week 52) visit will be considered as 
without any prednisone reduction for the analysis.
8.5.6.
Other Efficacy Analyses
The analysis of all other efficacy endpoints will be described in the statistical analysis 
plan.
8.6.
Safety
8.6.1.
Definition of Safety Variables
Safety will be evaluated by adverse events, changes in laboratory parameters, and 
immunogenicity.
8.6.2.
Analysis of Safety Variables
AEs will graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 12) or the grades in Section 7.7, as appropriate. The frequency of AEs 
will be tabulated by MedDRA system organ class (SOC) and preferred term. Additional 
analysis may be performed based on event rates adjusting for subject-years on study 
agent if the dropout rates are unbalanced across treatment groups. AEs will also be 
summarized by MedDRA SOC and preferred terms for those that are considered to be 
severe (Grade 3 and Grade 4) and those that are considered serious. Discontinuations due 
to AEs will be summarized. 
The frequency of laboratory abnormalities will be tabulated by treatment group. 
Laboratory values will be assessed for significant changes from baseline. Laboratory 
toxicity will be graded using Adverse Event Severity Grading Tables when possible. 
Shift tables will be used to determine if subjects move from normal to abnormal during 
the course of the study. Shifts of ≥ 2 grades and Grade 3 or 4 laboratory abnormalities 
will be summarized.
Safety Endpoints of Special Interest
•
All cause mortality 
•
Serious and/or severe infections 
•
Opportunistic infections 
•
Malignant neoplasms
•
Selected serious psychiatric events 
•
Suicidality assessment (see Appendix 3 and Appendix 4)

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

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

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

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

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

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

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

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

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Appendix 2
Concurrent Medications
Figure 2-1
Concurrent Medications

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

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

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

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

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

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

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

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

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

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

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

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

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Appendix 10
Laboratory Tests
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)*
Partial thromboplastin time 
(PTT)*
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Dysmorphic RBC
Casts (specified by 
type eg, RBC, WBC)
Spot Urine (protein : 
creatinine ratio)
Urine Pregnancy
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutanyl transpeptidase 
(GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
Estimated Creatinine Clearance/ GFR 
(Cockcroft-Gault)
Other Screening Labs
HIV-1/2 antibody
Hepatitis C antibody
HBsAg and HB Core antibody
Serum pregnancy
Alcohol and Drug screen
PT / PTT
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen 
IgM antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal 
antibodies
Biological Markers
FACS of peripheral lymphocytes: B lymphocytes (CD20+, 
CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, 
CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH /CD38HIGH regulatory B cell, and CD20-/138+ 
plasma cells)  
BLyS protein 
Serum complement (C3, C4) 
Immunoglobulins
Serum immunoglobulin isotypes:  IgG, IgM, IgA
PK and Immunogenicity
Belimumab pharmacokinetic assessment
Belimumab immunogenicity assessment
Autoantibodies
ANA titer and OD
Anti-dsDNA
aCL
Lupus anticoagulant
±beta-2-glycoprotein-1**
ENAs**
*Refer to Table 6-1 and Table 6-2 for assessment time points
**May be collected in selected sites/regions

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Appendix 11
Pharmacogenetic Research
Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in different populations. There is increasing evidence that an individual's genetic 
composition 
(ie, genotype) 
may 
impact 
pharmacokinetics, 
pharmacodynamics 
(relationship between concentrations and pharmacologic effects or the time course of 
pharmacologic effects), and/or clinical outcome (in terms of efficacy and/or safety and 
tolerability).
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies. 
Research Rationale
Blood samples for pharmacogenetics will be drawn as described in Section 9. Collection 
of whole blood samples, even when no a priori hypothesis has been identified, may 
enable PGx analyses to be conducted if there is unexplained or unexpected variation in 
response to belimumab. 
If at any time it appears there is potential variability in response in this clinical study or in 
a series of clinical studies with belimumab that may be attributable to genetic variations 
of subjects, the following objectives may be investigated: 
•
Relationship between genetic variants and the pharmacokinetics of belimumab.
•
Relationship between genetic variants and safety and/or tolerability of belimumab.
•
Relationship between genetic variants and efficacy of belimumab.
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives belimumab may take part in the 
PGx research. 
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood being taken for 
PGx research.

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Study Assessments and Procedures
In addition to any blood samples drawn for the clinical study, a whole blood sample (~6 
to 8 mL) will be collected for the PGx research at baseline. The PGx sample is labeled (or 
coded) with a study specific number that can be traced or linked back to the subject by 
the investigator or site staff. Coded samples do not carry personal identifiers (such as 
name or social security number). The blood sample will be taken on a single occasion 
unless a duplicate sample is required due to inability to utilize the original sample. The 
blood samples should be drawn on Day 0 (baseline), provided informed consent for PGx 
research has been obtained from the subject, but the sample may be taken at any time 
while the subject is participating in the clinical study. 
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA will be 
subjected to sample quality control analysis. This analysis will involve the genotyping of 
several genetic markers to confirm the integrity of individual samples. If inconsistencies 
are noted in the analysis, then those samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
belimumab has been completed and the study data reviewed. In some cases, the samples 
may not be studied. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or the sponsor may destroy the samples sooner. The sponsor or those 
working with the sponsor (for example, other researchers or a contract lab) will use 
samples collected from the study for the purpose stated in this protocol and in the subject 
informed consent form.
Subjects may request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:
1. The sample is retained for PGx research.
2. The sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by the sponsor and maintain the 
documentation in the site study records. In either case, the sponsor will only use study 
information collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 

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

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

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Appendix 12
Adverse Event Severity Grading Tables
HEMATOLOGY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Hemoglobin
> 9.5 - 11.0 g/dL
> 8.0 – 9.5 g/dL
6.5 - 8.0 g/dL
< 6.5 g/dL
Leukocytes
3000-3999/mm3
2000-2999/mm3
1000-1999/mm3
< 1000/mm3
Absolute Neutrophil Count
1500-1999/mm3
1000-1499/mm3
500-999/mm3
< 500/mm3
Platelets
75,000 - 99,999/mm3
50,000 – 74,999/mm3
25,000 - 49,999/mm3
< 25,000/mm3
Prothrombin Time (PT)
> 1.0-1.25 x ULN*
> 1.25-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0 x ULN
Partial Thromboplastin Time (PTT)
> 1.0-1.66 x ULN
> 1.66-2.33 x ULN
> 2.33-3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0-10.0 %
10.1-15.0 %
15.1-20.0 %
> 20%
(continued)
*ULN = Upper Limit of Normal.                                                                                                                                                              Modified from DMID Adult Toxicity Tables, 2001

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

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CHEMISTRIES
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Sodium
   Hyponatremia
130-135 meq/L
123-129 meq/L
116-122 meq/L
< 116 meq/L
   Hypernatremia
146-150 meq/L
151-157 meq/L
158-165 meq/L
> 165 meq/L
Potassium
   Hypokalemia
3.0-3.4 meq/L
2.5-2.9 meq/L
2.0-2.4 meq/L
< 2.0 meq/L
   Hyperkalemia
5.6-6.0 meq/L
6.1-6.5 meq/L
6.6-7.0 meq/L
> 7.0 meq/L
Phosphate
   Hypophosphatemia
2.0-2.4 mg/dL
1.5-1.9 mg/dL
1.0-1.4 mg/dL
< 1.0 mg/dL
Calcium- (Corrected For Albumin)
   Hypocalcemia
7.8-8.4 mg/dL
7.0-7.7 mg/dL
6.1-6.9 mg/dL
< 6.1 mg/dL
   Hypercalcemia
10.6-11.5 mg/dL
11.6-12.5 mg/dL
12.6-13.5 mg/dL
>13.5 mg/dL
Magnesium
   Hypomagnesemia
1.2-1.4 meq/L
0.9-1.1 meq/L
0.6-0.8 meq/L
< 0.6 meq/L
Albumin
   Hypoalbuminemia
3.00-3.49 g/dL
2.50-2.99 g/dL
2.00-2.49 g/dL
< 2.00 g/dL
Bilirubin (Total)
   Hyperbilirubinemia (Total)
> 1.0-1.5 x ULN
> 1.5-2.5 x ULN
> 2.5-5 x ULN
> 5 x ULN
Glucose
   Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
< 30 mg/dL
   Hyperglycemia 
116-160 mg/dL
161-250 mg/dL
251-500 mg/dL
> 500 mg/dL
   (nonfasting & no prior diabetes)
   Triglycerides
151-399 mg/dL
400-750 mg/dL
751-1200 mg/dL
> 1200 mg/dL
Creatinine
> 1.0-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0-6.0 x ULN
> 6.0 x ULN
(continued)
Modified from DMID Adult Toxicity Tables, 2001

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CHEMISTRIES
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Uric Acid
   Hyperuricemia
7.5-10.0 mg/dL
10.1-12.0 mg/dL
12.1-15.0 mg/dL
> 15.0 mg/dL
Liver Transferases  (AST, ALT, and 
GGT)
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Alkaline Phosphatase
1.25-2.5 x ULN
> 2.5-5.0 x ULN
> 5.0-10.0 x ULN
> 10.0 x ULN
Pancreatic Enzymes
Amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Pancreatic amylase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Lipase
> 1.0-1.5 x ULN
> 1.5-2.0 x ULN
> 2.0-5.0 x ULN
> 5.0 x ULN
Hypoglobulinemia (IgG)*
550-700 mg/dL
400-549 mg/dL
250-399 mg/dL
< 250 mg/dL
(continued)
*(Goldfarb et al, 2001; Yamani et al, 2001; Eibl and Rosen, 1995).                                                                 Modified from DMID Adult Toxicity Tables, 2001

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

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RESPIRATORY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Cough 
(for aerosol studies) 
Transient; no treatment
Treatment associated 
cough; inhaled bronchodilator
Uncontrolled cough; 
systemic treatment req
Bronchospasm Acute
Transient; no 
treatment; 
FEV1 70% to 
< 80% 
(or peak flow)
treatment req; normalizes with 
bronchodilator; 
FEV1 50% to < 70% 
(or peak flow)
No Normalization 
with bronchodilator; 
FEV 25% to < 50% 
(or peak flow), retractions
Cyanosis; FEV1 < 25% 
(or peak flow) OR intubated
Dyspnea
Dyspnea on exertion
Dyspnea with 
normal activity
Dyspnea at rest
Dyspnea requiring O2 therapy
(continued)

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URINALYSIS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Proteinuria:
Dipstick: Protein
1 +
2-3 +
4 +
Nephrotic syndrome
Spot Urine:  
Protein:Creatinine 
Ratio mg/mg
0.2-1.0
> 1.0-2.0
> 2.0-3.5
> 3.5
24 hour Urine: Protein
200 mg - 1g loss/day
> 1-2 g loss/day
> 2-3.5 g loss/day
Nephrotic syndrome
OR > 3.5 g loss/day
Hematuria
Microscopic only
< 10 RBC/hpf
Gross, No clots
≥ 10 RBC/hpf
Gross plus clots OR 
RBC casts
Obstructive OR transfusion required
(continued)
RBC = red blood cell; hpf = high power field.
Modified from DMID Adult Toxicity Tables, 2001

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MISCELLANEOUS
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Fever (oral > 12 hours)
37.7-38.5C or
100.0-101.5F
38.6-39.5C OR
101.6-102.9F
39.6-40.5C OR
103-105F
> 40.5C OR > 105F
Headache
Mild; No treatment req
Mod; or non-narcotic 
analgesia treatment
Severe; OR responds to 
initial narcotic treatment
Intractable; OR requiring 
repeated narcotic treatment
Allergic Reaction
Pruritus without rash
Localized urticaria
Generalized urticaria 
angioedema
Anaphylaxis
Cutaneous/Rash/ Dermatitis
Erythema, pruritus rash 
OR dry desquamation
Diffuse maculopapular 
OR dry desquamation
Vesiculation OR moist 
desquamation ulceration
ANY ONE: mucous membrane 
involvement, suspected 
Stevens-Johnson (TEN), erythema 
multiforme, necrosis req surgery, 
exfoliative dermatitis
Local Reaction (secondary 
to parenteral treatment- not 
vaccination or skin test)
Erythema
Induration < 10 mm 
OR inflammation 
OR phlebitis
Induration > 10 mm 
OR ulceration
Necrosis of skin
Fatigue
Normal activity 
Reduced < 25%
Normal activity 
Reduced 25-50%
Normal activity 
reduced > 50%; 
cannot work
Unable to care for self
(continued)
Modified from DMID Adult Toxicity Tables, 2001

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NEUROLOGIC
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Neuro-cerebellar
Slight incoordination 
OR 
dysdiadochokinesia
Intention tremor OR 
dysmetria OR slurred speech 
OR nystagmus
Ataxia requiring assistance to 
walk or arm incoordination 
interfering with ADLs
Unable to stand
Neuro-psych/ mood
none
Severe mood changes requires 
medical intervention
Acute psychosis requiring 
hospitalization
Paresthesia 
(burning, tingling, etc)
Mild discomfort; 
no treatment needed
Mod discomfort 
non-narcotic analgesia req
Severe discomfort; OR 
narcotic analgesia req with 
symptomatic improvement
Incapacitating; OR not responsive 
to narcotic analgesia
Neuro-motor
Mild weakness in 
muscle of feet but 
able to walk and/or 
mild increase or 
decrease in reflexes
Mod weakness in feet (unable to 
walk on heels and/or toes), mild 
weakness in hands, still able to do 
most hand tasks and/or loss of 
previously present reflex or 
development of hyperreflexia 
and/or unable to do deep knee 
bends due to weakness
Marked distal weakness 
(unable to dorsiflex toes or 
foot drop), and mod proximal 
weakness ie, in hands 
interfering with ADLs and/or 
requiring assistance to walk 
and/or unable to rise from 
chair unassisted
Confined to bed or wheelchair 
because of muscle weakness
Neuro-sensory
Mild impairment 
sensations, 
(ie, vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical 
distribution
Mod impairment mod de-sensation, 
(ie, of vibratory, pinprick, hot/cold 
to ankles) and/or joint position or 
mild impairment that is not 
symmetrical.
Severe impairment (dec or loss 
of sensation to knees or wrists) 
or loss of sensation of at least 
mod degree in multiple 
different body areas (ie, upper 
and lower extremities)
Sensory loss involves limbs 
and trunk
(concluded)
Modified from DMID Adult Toxicity Tables, 2001

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

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

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4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the study reference manual.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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

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
If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 7.2.

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

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

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

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

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
One positive historical test result and 1 positive test result during the screening 
period.

Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer ) or 
anti-dsDNA (eg, anti-dsDNA by Farr assay) must include the date and type of the 
test, the name of the testing laboratory, numerical reference range, and a key that 
explains values provided as positive vs negative OR negative, 
equivocal/borderline positive). Only unequivocally positive values as defined in 
the laboratory’s reference range are acceptable; borderline values will not be 
accepted.
7. A female subject is eligible to enter the study if she is:  

Not pregnant or nursing; 

Of non-childbearing potential (ie, women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed, or have current documented tubal ligation or any other 
permanent female sterilization procedure); or

Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This 
category includes women with oligomenorrhoea [even severe], women who are 
perimenopausal, or have just begun to menstruate. These women must have a 
negative serum pregnancy test at screening, and agree to 1 of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or

Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 16 
weeks after the last dose of study agent:  

Implants of levonorgestrel or etonogestrel;

Ethinyl estradiol/Etonogestrel vaginal ring; 

Injectable progesterone; 

Any intrauterine device (IUD) with a documented failure rate of less than 
1% per year;

Oral contraceptives (either combined or progesterone only); 

Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; 

Transdermal contraceptive patch; 

Male partner who is sterile prior to the female subject’s entry into the 
study and is the sole sexual partner for the female subject.
NOTE: MMF and other forms of mycophenolate affect the metabolism of oral 
contraceptives and may reduce their effectiveness. As such, women receiving 
mycophenolate who are using oral contraceptives for birth control should 
employ an additional method (eg, barrier method).

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

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

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

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

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

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

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

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

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

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Table 1-2 Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Post-injection 
systemic reactions 
and 
Hypersensitivity 
Administration of belimumab may result in 
infusion and hypersensitivity reactions, 
which can be severe and can be fatal.  
Non-serious infusion reactions and 
hypersensitivity reactions are common in 
SLE clinical trials with IV belimumab.  
Serious infusion and hypersensitivity 
reactions affected less than 1% of patients 
and included anaphylactic reaction, 
bradycardia, hypotension, angioedema, 
and dyspnea. Delays in the onset of 
hypersensitivity reactions have been 
observed. Infusion reactions following 
administration of belimumab occurred 
more frequently on the first 2 infusion days 
and tended to decrease with subsequent 
administrations. Delayed-type, non-acute 
hypersensitivity reactions have also been 
observed and included symptoms such as
rash, nausea, fatigue, myalgia, headache, 
and facial oedema.
Exclusion of subjects with a 
history of an anaphylactic reaction 
to parenteral administration of 
contrast agents, human or murine 
proteins or monoclonal antibodies.
Subjects should remain under clinical 
supervision for 3 hours after completion of the 
first 2 infusions. Should symptoms of acute 
hypersensitivity occur, an extended period of 
monitoring may be appropriate, based on 
clinical judgment. Otherwise, subjects will be 
monitored during and after each infusion 
according to study sites’ guidelines or 
standard operating procedure for IV infusions. 
This may include, but is not limited to, 
monitoring vital signs and observing for any 
untoward reactions.  Subjects should be 
made aware of the potential risk, the signs 
and symptoms of such reactions, and the 
importance of immediately seeking medical 
attention.  Belimumab should be administered 
by a healthcare professional prepared to treat 
hypersensitivity reactions including 
anaphylaxis.
Infections
Infections occurred in a slightly greater 
proportion of subjects treated with 
belimumab compared with placebo. 
Infections occurring in at least 3% of 
patients receiving belimumab and at least 
1% more frequently than patients receiving 
Exclude patients with any of the 
following: currently on any 
suppressive therapy for a chronic 
infection; hospitalization for 
treatment of an infection within 60 
days of Day 0; use of IV or IM 
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately.

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
placebo were nasopharyngitis, bronchitis, 
pharyngitis, cystitis, and gastroenteritis 
viral.  Serious infections occurred in 5% of 
patients receiving either belimumab or 
placebo.
antibiotics within 60 days of Day 
0; a history of or positive test at 
screening for HIV, hepatatis B or 
hepatitis C; have Grade 3 or 4 
lymphopenia; or have Grade 3 or 
4 IgG or IgA deficiency
Progressive 
multifocal 
leukoencephalopa
thy (PML)
No association between belimumab and 
the risk of opportunistic infections, 
including PML, has been indentified to 
date, but data are limited. PML resulting in 
neurological deficits, including fatal cases, 
has been reported in SLE patients 
receiving immunosuppressant 
pharmacotherapy, including belimumab.
A diagnosis of PML should be considered in 
any subject presenting with new-onset or 
deteriorating neurological signs and 
symptoms. The subject should be referred to 
a neurologist or other appropriate specialist 
for evaluation. If PML is confirmed, study 
agent should be discontinued and 
consideration should be given to stopping 
immunosuppressant therapy. If PML is 
suspected, this should be immediately 
reported to the Medical Monitor.  The 
appropriateness of continuing study agent, 
while the case is being assessed, should be 
discussed.
Malignancies
As with other immunomodulating agents, 
the mechanism of action of belimumab 
may increase the potential risk for the 
development of malignancies.
Exclude patients with a history of 
malignant neoplasm within the 
last 5 years, except for adequately 
treated basal or squamous cell 
cancers of the skin, or carcinoma 
in situ of the uterine cervix.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, 
request that patients report signs and 
symptoms.  Treat appropriately.
Immunogenecity
As with other monoclonal antibodies, 
treatment with belimumab could lead to the 
development of anti-drug antibodies 
Monitor anti-drug antibody laboratory values.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 13.
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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

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

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

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does not mean that the event is expected with the underlying disease(s) or concomitant 
medications.
Modified to:
ADVERSE EVENT - Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, 
this also includes failure to produce expected benefits (ie, lack of efficacy), abuse or 
misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as 
an AE/SAE) unless this is an intentional overdose taken with possible 
suicidal/self-harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition of 
an AE or SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (eg, endoscopy, appendectomy); the condition 
that leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition

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SERIOUS ADVERSE EVENT: A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer 
to an event, which hypothetically might have caused death, if it were more 
severe.
c.
Requires hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d. Results in disability/incapacity, or
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg,
sprained ankle) which may interfere or prevent everyday life functions but do 
not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  These should 
also be considered serious.  Examples of such events are invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.
g. All events of possible drug-induced liver injury with hyperbilirubinaemia 
defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 
3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR 

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measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then 
the event is still reported as an SAE. If INR is obtained, include values on the 
SAE form. INR elevations >1.5 suggest severe liver injury.   
Section 7.2 Reporting Adverse Events to the Sponsor, paragraphs 2, 3, and 4
Formerly:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent 
to the Drug Safety designee within 24 hours of site personnel becoming aware of the 
SAE, regardless of expectedness. All pages of the SAE Worksheet should be completed, 
but the SAE Worksheet should not be held until all information is available. Additional
information and corrections should be provided on subsequent SAE Worksheets as 
described in the Study Procedure Manual. SAE Worksheets should be sent by the EDC 
system (if EDC functionality is available) or by facsimile to the HGS Drug Safety 
designee using the toll free fax number listed on the SAE Worksheet.
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be recorded on the 
SAE worksheet and reported as described  above from the time a subject consents to 
participate in the study. Pre-treatment SAEs will not be documented on the AE eCRF.
SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study 
agent) that are assessed by the investigator as definitely, possibly, or probably related to 
study agent must be reported to the Drug Safety designee on the SAE worksheet. Post 
study SAEs will not be documented on the AE eCRF.
Modified to:
Serious Adverse Events (SAEs) must be recorded on the SAE eCRF within 24 hours of 
site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until 
all information is available. Follow-up information and corrections should be added to 
the SAE eCRF within 24 hours of site personnel becoming aware of the follow-up 
information as described in the Study Procedures Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an 
SAE from the time a subject consents to participate in the study.

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

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SLE itself, as well as the concurrent use of immunosuppressive drugs. The most common 
signs and symptoms of PML include visual disturbances, ocular movements, ataxia, and 
mental status changes such as disorientation or confusion. Clinical signs and symptoms 
of PML and SLE can be similar. The investigator must exercise best judgment in further 
workup and clinical intervention as appropriate. If PML is suspected this should be 
promptly reported to the HGS.
Modified to:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological 
deficits, including fatal cases, has been reported in SLE patients receiving 
immunosuppressant pharmacotherapy, including belimumab. A diagnosis of PML 
should be considered in any subject presenting with new-onset or deteriorating 
neurological signs and symptoms. The subject should be referred to a neurologist or 
other appropriate specialist for evaluation. If PML is confirmed, study agent should 
be discontinued and consideration should be given to stopping immunosuppressant 
therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor. 
The appropriateness of continuing study agent, while the case is being assessed, 
should be discussed.
Section 7.6 Reporting a Pregnancy
Formerly:
Pregnancies must be reported to the HGS Drug Safety within 24 hours of the site 
becoming aware of a pregnancy in a study subject. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. All pregnancies are tracked up to term or delivery following the last 
study agent treatment. When pregnancy is reported, HGS Drug Safety sends an 
acknowledgement memorandum to the principal investigator along with a Pregnancy 
Assessment Form. A Pregnancy Assessment Form must be completed every 3 months 
until live birth, elective termination of the pregnancy, or miscarriage. The site is 
responsible for following the subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems 
associated with a pregnancy are considered AEs and may be SAEs. Complications or 
medical problems are reported as AEs/SAEs according to the procedure described in 
Sections7.1and 7.2.
Modified to:
Any pregnancy that occurs during study participation and up to 16 weeks post dose 
must be reported using a clinical trial pregnancy form. To ensure subject safety, 
each pregnancy must be reported to the Sponsor within 2 weeks of learning of its 
occurrence. The pregnancy must be followed to delivery to determine outcome 

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

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Probably Not Related - does not have a reasonable temporal relationship OR
- good evidence for a more likely alternative etiology   
Not Related
- does not have a temporal relationship OR
- definitely due to alternative etiology 
The causality assessment must be made by the investigator based on information 
available at the time that the SAE worksheet is completed. The initial causality 
assessment may be revised as new information becomes available.
Modified to:
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to 
study agent). The investigator will make an assessment of intensity based on the 
Division of Microbiology and Infectious Diseases (DMID) Adverse Event Severity 
Grading Tables (see Appendix 12) where possible:
SEVERITY:
Mild
An event that is easily tolerated by the subject, causing 
minimal discomfort and not interfering with everyday 
activities (Grade 1 DMID).
Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 
or 4 DMID).
Not applicable
Those event(s) where intensity is meaningless or impossible 
to determine (ie, blindness and coma).
An AE that is assessed as severe will not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the 
pre-defined outcomes as described in the definition of an SAE.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that 
there are facts/evidence or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.  The investigator will use clinical judgment to 
determine the relationship.  Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the study treatment will be considered and investigated.  
The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.

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

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All SAEs that are considered by the sponsor to be unexpected and related to belimumab 
will be reported by the sponsor or designee as expedited (eg, 7/15-Day) reports to the 
appropriate regulatory authorities AND to all participating investigators (exceptions 
discussed below). In addition, the sponsor or designee follows all applicable local and 
national regulatory requirements regarding safety reporting.  Each investigator must also 
comply with the applicable regulatory requirements related to the reporting of SAEs to 
the IRBs/IECs responsible for reviewing the study at their site, as well as the regulatory 
authority(ies) (if applicable). 
All serious adverse events, including serious disease-related events (discussed below),
will be monitored by treatment group by an independent DMC (Section 8.3). 
Investigators and IRBs/IECs, as appropriate, will be notified of the outcome of each 
DMC meeting, and any recommendations made.
The following conditions (preferred terms; MedDRA v. 14.0) are disease related events 
that can occur in the study population regardless of belimumab exposure. When these 
conditions are considered SAEs, they must be reported to the sponsor within 24 hours of 
site personnel becoming aware as described in Section 7.2. The sponsor will not submit 
these events as expedited reports to regulatory authorities, participating investigators, or 
IRBs/IECs (unless considered by the sponsor to be related to study agent).
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis
Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
Modified to:
7.9 Disease Related Events
Disease related events (DREs) can occur in the study population regardless of 
belimumab exposure and are not reported as AEs or SAEs, unless judged by the 
investigator to be more severe than expected for the subject’s condition.
The following DREs (preferred terms; MedDRA v. 14.0) are common in subjects with 
SLE and can be serious/life-threatening:
Butterfly rash
Lupus pneumonitis
Cutaneous lupus erythematosus
Lupus vasculitis

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Glomerulonephritis membranoproliferative
Nephritic syndrome
Glomerulonephritis membranous
Nephritis
Glomerulonephritis proliferative
Neuropsychiatric lupus
Lupus encephalitis
Pericarditis lupus
Lupus endocarditis
Peritonitis lupus
Lupus enteritis
SLE arthritis
Lupus hepatitis
Systemic lupus erythematosus
Lupus myocarditis
Systemic lupus erythematosus rash
Lupus nephritis
Lupus pancreatitis
When these conditions are considered SAEs, they must be reported to the sponsor 
within 24 hours of site personnel becoming aware as described in Section 7.2. The 
sponsor will not submit these events as expedited reports to regulatory authorities, 
participating investigators, or IRBs/IECs (unless considered by the sponsor to be 
related to study agent).
Section 7.10
The following section has been added:
Section 7.10 Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  The 
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and the Sponsor’s policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Section 8.3 Data Monitoring Committee (DMC)
Formerly:
Data Monitoring Committee (DMC)

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

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

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

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

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

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9. Hematologic disorder 
a.
Hemolytic anemia (with reticulocytosis)
OR
b.
Leukopenia (< 4000/mm3 total on 2 or more occasions), OR
c.
Lymphopenia (< 1500/mm3 on 2 or more occasions), OR
d.
Thrombocytopenia (< 100,000/mm3 in the absence of offending 
drugs).
Appendix 10
Added:
Other Screening Labs
HBsAg and HB Core antibody
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal antibodies
Appendix 11, Pharmacogenetic Research. Study Assessments and Procedures
Formerly:
In addition to any blood samples drawn for the clinical study, a whole blood sample 
(~10 mL) will be collected for the PGx research at baseline.
Modified to:
In addition to any blood samples drawn for the clinical study, a whole blood sample 
(~6 to 8 mL) will be collected for the PGx research at baseline.

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

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

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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the study reference manual.
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.

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

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