A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Belimumab Plus Standard of Care Versus Placebo Plus Standard of Care in Adult Subjects With Active Lupus Nephritis
Phase: PHASE3
Conditions: Lupus Nephritis
Sponsor: Human Genome Sciences Inc., a GSK Company

CLINICAL PROTOCOL HGS1006-C1121
Protocol Amendment: 07
EudraCT Number: 2011-004570-28
Date: 24 January 2019
TITLE OF STUDY: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus 
Standard of Care in Adult Subjects with Active Lupus Nephritis
STUDY SPONSOR:
Human Genome Sciences, Inc.
9910 Belward Campus Drive
Rockville, Maryland 20850
U.S.A.
Confidential and Proprietary
This document contains proprietary and confidential information of Human 
Genome Sciences, Inc. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or 
disclosed without prior written approval from Human Genome Sciences, Inc., 
except that this document may be disclosed to study personnel under your 
supervision who need to know the contents for conducting the study and 
appropriate Institutional Review Boards under the condition that they are 
requested to keep it confidential. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, Human Genome 
Sciences, Inc. must be promptly informed of any such disclosure.

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Revision Chronology for HGS1006-C1121 (BEL114054)
Date
Document*
Global
19 October 2011
Original
Global
27 January 2012
Amendment No 01
Global
08 March 2012
Amendment No 02
Local
16 August 2012
Amendment 02 for Thailand
Global
2013N179093_00
11 February 2014
Amendment No 03
Local
2014N205397_00
29 August 2014
Amendment 04 for China
Global
2013N179093_01
16 March 2015
Amendment No 05
Local
2013N179093_02
17 March 2015
Amendment No 05 for France
Local
2013N179093_03
13 July 2016
Amendment No 05/France-2
Global
2013N179093_04
25 April 2017
Amendment No 06
Local
2013N179093_05
26 April 2017
Amendment No 06/France-2
Global
2013N179093_06
24 January 2019
Amendment No 07
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.

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

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STUDY SYNOPSIS
Study Number: HGS1006-C1121
Title of the Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo 
plus Standard of Care in Adult Subjects with Active Lupus Nephritis
Clinical Development Phase: 3
Objectives:
•
To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV, or V using the 2003 International Society 
for Nephrology (ISN)/Renal Pathology Society (RPS) criteria.
•
To assess the safety and tolerability of belimumab plus standard of care versus 
placebo plus standard of care in adult subjects with lupus nephritis Class III, IV, or V 
using the 2003 ISN/RPS criteria.
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria:
1. Males or females at least 18 years of age.
2. Have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology (ACR) criteria (Appendix 1).
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding 
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or
pure Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy 
must be performed in the 6 months prior to the screening visit or during the screening 
period. The local biopsy report will be used to confirm subject eligibility. A tissue 
sample from the renal biopsy used to qualify the subject for randomization needs to
be sent to a central reading center after Day 0 (baseline). 
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an 
ANA titer ≥ 1:80 (based on Hep-2 immunofluorescence assay or equivalence by 
enzyme immunoassay assay), and/or a positive anti-dsDNA (≥30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results.
5. Have documentation of active renal disease at screening requiring induction therapy 
with high dose corticosteroids (HDCS) with either intravenous (IV)
cyclophosphamide (CYC) or mycophenolate mofetil (MMF) or other oral forms of 
mycophenolate. The following factors will be used to define active renal disease at 
screening:

Urinary protein:creatinine ratio of ≥ 1.0 AND 

Active urinary sediment as defined by at least 1 of the following (in absence 
of menses and genitourinary tract infection).  

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

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surgically removed, or have current documented tubal ligation or any other 
permanent female sterilization procedure); or

Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This 
category includes women with oligomenorrhoea [even severe], women who are 
perimenopausal, or have just begun to menstruate. These women must have a 
negative serum pregnancy test at screening, and agree to 1 of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of 
the 1st dose of study agent until 16 weeks after the last dose of study agent; or

Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during study, and for 
16 weeks after the last dose of study agent: 
◦
Implants of levonorgestrel or etonogestrel; 
◦
Ethinyl estradiol/Etonogestrel vaginal ring;
◦
Injectable progesterone; 
◦
Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
◦
Oral contraceptives (either combined or progesterone only); 
◦
Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; 
◦
Transdermal contraceptive patch; 
◦
Male partner sterilisation with documentation of azoospermia prior to the 
female subject’s entry into the study, and this male is the sole partner for 
that subject. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination 
and/or semen analysis, or medical history interview provided by her or her 
partner.
Note: If stricter female or male contraception requirements are specified in the 
country-specific label for induction and/or maintenance standard of care 
medications, they must be followed.
8. Have the ability to understand the requirements of the study, provide written 
informed consent (including consent for the use and disclosure of research-related 
health information), and comply with the study protocol procedures (including 
required study visits). 

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Exclusion Criteria: Subjects will be excluded from participating in the study if they 
meet any of the following exclusion criteria:
1. Subjects who have previously failed both CYC and MMF (or other forms of 
mycophenolate) induction therapies based on the investigator’s opinion. If a subject 
has failed only 1 of the 2 therapies for induction, they may be eligible for study 
inclusion if the other induction therapy is initiated within 60 days prior to or on Day 0 
(ie, a subject who failed MMF is eligible if newly initiating induction therapy with 
CYC or a subject who failed CYC is eligible if newly initiating induction therapy 
with MMF).
2.
Subjects who received an induction therapy with CYC within 3 months prior to the
planned initiation of the current induction for the study.
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4
based on the Adverse Event Severity Grading Tables (Appendix 7).
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, azathioprine (AZA), 
corticosteroids).
5. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins or monoclonal antibodies.
6. Have received treatment with belimumab within 364 days of baseline (Day 0).
7. Received any of the following within 364 days of baseline (Day 0):  

Nitrogen mustard

Chlorambucil

Vincristine

Procarbazine

Etoposide

Abatacept

Treatment with any B cell targeted therapy (eg, rituximab, other anti-CD20 
agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor 
fusion protein [BR3], TACI-Fc, or LY2127399 [anti-BAFF])

A biologic investigational agent (eg, abetimus sodium, anti-CD40L antibody 
[BG9588/ IDEC-131]). Investigational agent applies to any drug not approved 
for sale in the country in which it is being used.

Treatment with interleukin-6 targeted therapy (e.g., tocilizumab, sirukumab).
8. Received any of the following within 90 days of baseline (Day 0):  

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab, certolizumab, 
golimumab pegol)

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

Plasmapheresis.
9. Received a non-biological investigational agent within 60 days of baseline (Day 0).

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10. Received a live vaccine within 30 days of baseline (Day 0).
11. Have severe active central nervous system (CNS) lupus (including seizures, 
psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis, or
CNS vasculitis) requiring therapeutic intervention within 60 days of baseline (Day 0).
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant or are due to receive transplantation.
13. Subjects who have been on dialysis within 364 days of baseline (Day 0).
14. An estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit
(using the simplified Modification of Diet in Renal Disease [MDRD] equation).
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, 
hepatic, renal, neurological, malignancy, or infectious diseases) which, in the opinion 
of the principal investigator, could confound the results of the study or put the subject 
at undue risk.
16. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
17. Have a history of malignant neoplasm within the last 5 years, except for adequately 
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine 
cervix.  
18. Have acute or chronic infection requiring management, as follows:

Currently on any suppressive therapy for a chronic infection (such as 
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes 
zoster, or atypical mycobacteria).

Hospitalization for treatment of infection within 60 days of baseline (Day 0).

Have had infection requiring treatment with parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days 
of baseline (Day 0).
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to baseline (Day 0). 
20. Have a historically positive test or test positive at screening for HIV antibody.  
21. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:

Patients positive for HBsAg are excluded.

Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-
HBs antibody status, will require clarification of their status by testing for 
HBV DNA

o
if HBV DNA positive, patients will be excluded from participation

o
if HBV DNA negative, patients will be eligible to enrol.

NOTE: For those subjects randomised, additional ongoing assessment during
the study is required (see Section 6.7.5).

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22. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate. Subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing.
23. Have an IgA deficiency (IgA level < 10 mg/dL).
24. Have a Grade 3 or greater laboratory abnormality (including serum IgG level) based 
on the Adverse Event Severity Grading Tables (Appendix 7) except for the following 
that are allowed:

Urinalysis (eg, proteinuria)

Hematuria

Pyuria

Casts

Hypoalbuminemia due to lupus nephritis

Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.

Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant 
and not related to liver disease or anti-coagulant therapy.

Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes or 
viral hepatitis. If present, any abnormalities in the ALT and/or AST must be ≤ 
Grade 2.

Stable Grade 3 reduction in hemoglobin levels due to SLE

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count [with the 
exception of subjects receiving CYC who will be excluded if WBC is Grade 3 
or 4 per Exclusion Criterion 3]. Note that WBC count should be obtained 
immediately prior to starting induction therapy. If immediate pre-induction 
WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used. 

Hyperuricemia or blood urea nitrogen (BUN) elevation due to lupus nephritis 
or SLE.
25. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the 
Columbia- Suicide Severity Rating Scale (C-SSRS) (Appendix 8) in the last 2 months 
or who, in the investigator's opinion, pose a significant suicide risk.
Study Design and Schedule:
This is a Phase 3, multi-centre, multi-national, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of IV belimumab 10 mg/kg plus 

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

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

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

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

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Other efficacy endpoints are described in Section 8.5.4.
Safety Endpoints and Analysis:
Descriptive statistics will be used to summarize adverse events (AEs), changes in 
laboratory parameters, and immunogenicity. The frequency and incidence of laboratory 
abnormalities will be tabulated by treatment group. The frequency and incidence of AEs 
will be tabulated by MedDRA system organ class (SOC) and preferred term and 
compared between placebo and the belimumab treatment group.
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
on an ongoing basis until data through Week 104 of the double-blind treatment period are 
locked and analyzed (after which time monitoring may be assumed by an internal 
GSK/HGS committee). The IDMC will include physicians with expertise in infectious 
disease, rheumatology or nephrology and a statistician, none of whom are affiliated with 
the sponsor. The first review will occur 6 months after the first subject is randomized or 
after the first 20 subjects are randomized and have completed a Week 8 visit, whichever 
is sooner.  Thereafter, the IDMC will review the data approximately every 6 months. At 
all times the sites and sponsor will remain blinded to treatment allocation. Events to be
monitored during the safety review will include at a minimum all serious adverse events
(including deaths, serious psychiatric events, and serious infections), Grade 3 and Grade 
4
laboratory abnormalities, opportunistic infections (serious and nonserious), 
malignancies, and hypersensitivity/anaphylactic reactions during the double-blind Week 
104 and open-label extension portions of the study. Investigators (and IRBs/IECs, as 
appropriate,) will be notified of the outcome of each IDMC meeting.
Pharmacokinetics Endpoints and Analysis:
Blood samples will be collected during the study and analyzed to determine serum 
belimumab concentrations. Serum belimumab concentration data will be used in a 
population PK analysis, which will be reported separately.
Immunogenicity:
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at the baseline visit (Day 0), 
Week 8, Week 24, Week 52, Week 76 and Week 104. During the 6 month open-label 
extension, samples will be obtained at Week 24. Additionally, a sample will be collected 
at the 8-week follow-up visit. 
Biological Markers and Autoantibodies: 
The following biomarkers will be measured at baseline (Day 0) and at selected timepoints 
thereafter:
•
Autoantibodies: ANA, anti-dsDNA, aCL (IgG, IgM, IgA isotypes), anti-Sm, and anti-
C1q
•
Serum immunoglobulin isotypes: IgA, IgG, IgM
•
Serum complement (C3,C4)
•
BLyS protein (baseline only)

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In geographies where feasible, the following biological markers will be measured (using 
FACS analysis) at baseline (Day 0) and at multiple time points thereafter:
•
Peripheral B lymphocytes: 

CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, 
CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH/CD38HIGH regulatory B cells, and CD20-/138+ plasma cells.
An exploratory analysis of urinary biomarkers related to lupus nephritis may be 
performed at baseline (pre-dose) and at selected timepoints thereafter. Data collection and 
analysis will be performed independently of the main study and will form the basis of a 
separate report. The biomarkers include, but are not limited to, MCP-1, hepcidin, NGAL, 
LFABP, Angiogenin, Angiopoietin 2, Angiostatin, IL-6r, Osteopontin, PAI-1, PF4, 
RAGE, RANK, Sgp130, Siglec 5, Siglec 9, Tgf-beta1, TIM1, TIMP-2, TLSP, TNFR-II, 
Trem1, VCAM-1, Vegf-C, and VEGF-R3.
Study Calendar:
See Table 6-1, Table 6-2, and Table 6-3 for a calendar of study visits and assessments.
Study Schematic:  See Figure 1-1.

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Figure 1-1
Study schematic

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

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

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

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

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

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LIST OF ABBREVIATIONS
aCL
anticardiolipin
ACE
angiotensin converting enzyme
ACR
American College of Rheumatology
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody 
ANCOVA
analysis of covariance
ARB
angiotensin receptor antagonists/blockers
anti-dsDNA
anti-double-stranded DNA
anti-HBc
hepatitis B core antibody 
anti-HBs
hepatitis B surface antigen antibody
anti-Sm
anti-Smith antibody 
anti-TNF
anti-tumor necrosis factor
AST
aspartate aminotransferase
AUC
area under the serum drug concentration-time curve
AUCi
area under the curve for an individual subject
AZA
azathioprine
bid
twice a day
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BLyS
B lymphocyte Stimulator
BR3
BLyS-receptor fusion protein
BUN
blood urea nitrogen
ºC
degrees Celsius
CD
compact disc
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CRR
complete renal response
C-SSRS
Columbia-Suicide Severity Rating Scale
CYC
cyclophosphamide
CVA
cerebrovascular accident
dL
deciliter
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
dsDNA
double-stranded DNA
eCRF
electronic case report form
ECL
electrochemiluminescence
EDC
electronic data capture
eGFR 
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorobent assay
ESRD
end stage renal disease
EU
European Union
FACS
florescence activated cell sorting
FDA
United States Food and Drug Administration

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

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

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1.
BACKGROUND
1.1.
Disease Background Relevant to Clinical Study
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by 
autoantibody production and abnormal B lymphocyte function (Pisetsky, 2001). The 
etiology of SLE is unknown, although genetics, sex hormones, and environmental 
conditions are thought to play a role (Kotzin, 1996; Pisetsky, 1998; Sobel et al, 1999). 
This disease is more common in women (~90% of patients) than men (NWHIC, 2003) 
and more prevalent in African-Americans than Caucasians (OMHRC, 2001; NWHIC, 
2003). In the United States (US) the reported prevalence is 100,000 to 500,000 patients 
with some estimates of 1 million as the incidence increased 2-3 fold between 1950 and 
1979. In the European Union (EU), prevalence rates have been reported ranging from 25
to 39 cases per 100,000 persons (Jiménez et al, 2003). In community-based studies 
among Asians, the prevalence (per 100,000) of SLE ranged from 3.2 to 70.4 (Thumboo
and Wee, 2006). The disease onset is generally between the ages of 20 and 40. Patients 
with SLE have about a 3-fold greater risk of mortality than the general population. 
Approximately 70% of SLE patients survive 20 years from time of diagnosis (Houssiau
et al, 2004).
SLE can lead to arthritis, kidney failure, heart and lung inflammation, central nervous 
system (CNS) changes, vasculitis, severe skin rash, and blood dyscrasias such as anemia, 
leukopenia, and thrombocytopenia. The manifestations of SLE vary from patient to 
patient and it may take many years to render the proper diagnosis. The American College 
of Rheumatology (ACR) criteria that define a diagnosis of this heterogeneous disease 
require 4 of 11 criteria that include SLE-associated signs or symptoms, lab abnormalities, 
and the presence of specific anti-nuclear autoantibodies (Tan et al, 1982).
Approximately 35% of all adult patients with SLE develop clinically significant lupus 
nephritis and despite improvements in both diagnosis and treatment over the last few 
decades it remains an indicator of poor prognosis (Gordon et al, 2009; Waldman and 
Appel, 2006). Manifestations of lupus nephritis include proteinuria, elevations in serum 
creatinine, and the presence of urinary sediment. Alongside these clinical manifestations, 
morphological changes can be observed in renal biopsy specimens. In 1975 the World 
Health Organization (WHO) proposed a classification system for renal biopsies in SLE 
which was continually revised by them up until 1995. In 2004 updated criteria jointly 
developed by the International Society of Nephrology (ISN) and the Renal Pathology 
Society (RPS) were published (Weening et al, 2004). Within the 5 overall classes, 
Classes I and II reflect disease restricted to mesangial abnormalities. Classes III and IV 
represent either focal (< 50% glomeruli involved - Class III) or diffuse (≥50% glomeruli 
involved - Class IV) segmental or global glomerulonephritis. Class V represents 
membranous disease with Class VI representing advanced sclerosis. Classes I and II are 
rarely accompanied by clinical manifestations and there is no activity in Class VI only 
damage, so therapy has traditionally focused on Classes III-V.
Belimumab (BENLYSTA™) administered intravenously (IV) is approved in the US, 
Canada, and EU for the treatment of adult patients with active autoantibody-positive SLE 

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who are receiving standard therapy; patients with severe active lupus nephritis and severe 
active CNS lupus were excluded, as were patients receiving other biologics and IV 
cyclophosphamide (refer to specific country labeling for additional information regarding 
the approved indication). Approval of IV belimumab for SLE is being sought in other 
regions of the world.
1.2.
Belimumab
1.2.1.
Mechanism of Action
Belimumab (also known as LymphoStat-B™; BENLYSTA™) is a B lymphocyte 
stimulator (BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B cell 
survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but 
by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B 
cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma 
cells.
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology data generated with
belimumab are provided in the Investigator’s Brochure (IB).
1.2.2.
Clinical Experience with Belimumab
Belimumab administered as an IV infusion has been studied in SLE patients in 1 Phase 1 
trial (LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial (LBSL02),
and 2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 (HGS1006-
C1057) and BLISS 76 (HGS1006-C1056)], and in rheumatoid arthritis (RA) patients in a 
Phase 2 double-blind, placebo-controlled trial (LBRA01).
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the 
basis of the approval of IV belimumab in the US, Canada, and EU. The Phase 3 trials 
included 1,684 subjects where belimumab 10 mg/kg plus standard therapy demonstrated 
superiority over placebo plus standard therapy in reduction in disease activity as 
measured by the SLE responder index (SRI) with an acceptable safety profile. The 
primary safety population supporting approval also included data from a Phase 2 study in 
449 subjects with SLE. Evidence of benefit in other clinical measures such as reductions 
in disease activity as measured by SELENA SLEDAI, severe flare, and reduced steroid 
use was also observed. Treatment with belimumab plus standard of care was generally 
well tolerated, with rates of adverse events (AEs), severe AEs, serious AEs, AEs leading 
to discontinuation, and serious/severe infections generally comparable to the rates 
observed in the placebo plus standard of care group. Mortality rates in the controlled 
clinical trials were low, although numerically higher in the belimumab groups: 0.4% and 
0.8% in the placebo and belimumab groups, respectively. Causes of death were as 
expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as steroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide. Serious infections were observed in 5.2% and 6.0% 
of subjects receiving placebo and belimumab, respectively. The rate of malignancy 
(excluding non-melanoma skin cancer) was the same between the placebo and 
belimumab groups at 0.4%; however, as with other immunomodulating agents, the 

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mechanism of action of belimumab could increase the risk for the development of 
malignancies. Hypersensitivity and infusion reactions were observed. Anaphylaxis was 
also observed, though rare (< 1%). Depression-related events, common in patients with 
SLE, were observed more frequently with belimumab than with placebo; it is unknown if 
belimumab treatment is associated with an increased risk for these events. The most 
commonly-reported adverse reactions, occurring in ≥ 5% of patients in clinical trials,
were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, 
depression, migraine, and pharyngitis.
Experience from open-label, long-term continuation trials of belimumab in SLE subjects
suggests that prolonged treatment with belimumab remains generally well tolerated, with 
no apparent increase in the incidence rate of AEs or serious adverse events (SAEs) over 
time, including important events such as infections and malignancies. The prevalence rate 
of AEs and SAEs has also remained relatively stable over time. Long term belimumab 
treatment through 6 years appears to provide sustained improvement in SLE disease 
activity.
Results of the clinical trials of belimumab administered IV are described in further detail 
in the Investigator’s Brochure.
1.3.
Rationale for the Study
Current standard of care treatment for lupus nephritis consists of corticosteroids and 
immunosuppressants. Several studies have now been conducted in lupus nephritis; 
however at this time no therapies have been approved for lupus nephritis. In the Euro-
lupus trial, a low dose IV cyclophosphamide (CYC) regimen achieved similar clinical 
results with respect to treatment failures, renal remission and renal flares when compared 
to a high dose IV CYC regimen (Houssiau et al, 2002). A recent systematic review of 
recent trials in lupus nephritis concluded that mycophenolate mofetil (MMF) is as 
effective as CYC in inducing disease remission (Touma et al, 2011).
Belimumab treatment at a dose of 10 mg/kg in combination with standard SLE therapy 
demonstrated a statistically significant and clinically meaningful reduction in SLE 
disease activity vs placebo plus standard SLE therapy at week 52 in 2 Phase 3 clinical 
studies (HGS1006-C1056/BLISS 76 and HGS1006-C1057/BLISS 52) in subjects with 
active, autoantibody-positive SLE. While the 2 Phase 3 studies did explore the effect of 
belimumab on individual organ systems, these findings were limited for the renal organ
domain as subjects were excluded if they had severe active lupus nephritis. However, 267 
subjects (16%) included in the Phase 3 trials had renal involvement by SELENA 
SLEDAI (comprising hematuria, proteinuria, pyruia and/or urinary casts). In a post-hoc 
analysis of the pooled data (Table 1-1), there were trends towards SELENA SLEDAI 
renal organ domain improvement, especially in the subgroup of subjects who were anti-
dsDNA positive and had low C3 and/or low C4 at baseline. There were favorable trends 
of greater reduction in proteinuria, hematuria, pyuria, and lower renal flare rate in the 
belimumab treatment groups versus placebo. Understanding whether belimumab plus 
standard of care can reduce the disease activity in subjects with active lupus nephritis 
subjects is of interest to prescribing physicians and health authorities. 

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

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1.4.
Benefit-Risk Assessment
1.4.1.
Risk Assessment
Belimumab administered by IV infusion is indicated for reducing disease activity in adult 
patients with active autoantibody positive SLE who are receiving standard therapy. The 
benefit/risk profile of belimumab for SLE remains favorable. Identified risks include 
hypersensitivity/infusion reactions and infections. Potential risks (i.e., based on 
pharmacology but no association identified to date) include progressive multifocal 
leukoencephalopathy (PML), malignancies, immunogenicity, effects on immunizations 
(including interactions with live vaccine), and psychiatric events including depression 
and suicidality. The most common AEs reported in the primary safety population of 
adults with SLE were associated with hypersensitivity/infusion related reactions, non 
opportunistic infections, and symptoms consistent with SLE.  The majority of reports of 
infusion-related and hypersensitivity reactions were non-serious and include symptoms 
such as nausea, vomiting, diarrhea, chills, fever, rash, urticaria, pruritus, headache, 
dizziness, and dyspnea. However, infusion and hypersensitivity reactions can be severe 
and fatal. Infections were commonly reported events with belimumab and are expected 
due to the mechanism of action of belimumab and the SLE patient population.  
In the post-marketing setting with IV belimumab, delayed onset of symptoms of acute 
hypersensitivity reactions as well as recurrence of clinically significant reactions after 
initial appropriate treatment has been observed. Subjects will remain at the clinic for 
3 hours following the first 2 infusions for observation. Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment. Subjects should be made aware of the potential risk for severe or life-
threatening hypersensitivity reactions, the signs and symptoms of such reactions, the 
potential for delayed onset or recurrence of symptoms, and the importance of 
immediately seeking medical attention should they occur. Belimumab should be 
administered by a healthcare professional prepared to treat hypersensitivity reactions 
including anaphylaxis.
Table 1-2 provides a summary of key issues, their impact, and strategy to mitigate risk in 
this study.

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Table 1-2
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Post-injection 
systemic reactions 
and Hypersensitivity 
Administration of belimumab may result in 
infusion and hypersensitivity reactions, 
which can be severe and can be fatal.  
Non-serious infusion reactions and 
hypersensitivity reactions are common in 
SLE clinical trials with IV belimumab.  
Serious infusion and hypersensitivity 
reactions affected less than 1% of patients 
and included anaphylactic reaction, 
bradycardia, hypotension, angioedema, 
and dyspnea. Delay in the onset of 
hypersensitivity reactions have been 
observed. Infusion reactions following 
administration of belimumab occurred 
more frequently on the first 2 infusion days 
and tended to decrease with subsequent 
administrations.
Delayed-type, non-acute hypersensitivity 
reactions have also been observed and 
included symptoms such as rash, nausea, 
fatigue, myalgia, headache, and facial 
oedema.
Exclusion of subjects with a 
history of an anaphylactic 
reaction to parenteral 
administration of contrast agents, 
human or murine proteins or 
monoclonal antibodies. 
Subjects should remain under clinical 
supervision for 3 hours after completion of 
the first 2 infusions. Should symptoms of 
acute hypersensitivity occur, an extended 
period of monitoring may be appropriate, 
based on clinical judgment. Otherwise, 
subjects will be monitored during and after 
each infusion according to study sites’ 
guidelines or standard operating procedure 
for IV infusions. This may include, but is not 
limited to, monitoring vital signs and 
observing for any untoward reactions.
Subjects should be made aware of the 
potential risk, the signs and symptoms of 
such reactions, and the importance of 
immediately seeking medical attention.  
Belimumab should be administered by a 
healthcare professional prepared to treat 
hypersensitivity reactions including 
anaphylaxis.
Premedication including an antihistamine, 
with or without an antipyretic, may be 
administered before the infusion.

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Infections
Infections occurred in a slightly greater 
proportion of subjects treated with 
belimumab compared with placebo. 
Infections occurring in at least 3% of 
patients receiving belimumab and at least 
1% more frequently than patients 
receiving placebo were nasopharyngitis, 
bronchitis, pharyngitis, cystitis, and 
gastroenteritis viral.  Serious infections 
occurred in 5% of patients receiving either 
belimumab or placebo.
Exclude patients who are 
currently on any suppressive 
therapy for acute or chronic 
infection, hospitalized for 
treatment of infection within 60 
days of Day 0, or who used 
parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-
fungals, or anti-parasitic agents) 
within 60 days prior to Day 0.,a 
history of or positive test at 
screening for HIV, Grade 3 or 4 
lymphopenia, Grade 3 or 4 IgG or 
IgA deficiency, serologic 
evidence of Hepatitis B viral 
(HBV) infection based on the 
results of testing for HBsAg and 
Anti-HBc including HBsAg 
positive, HBsAg negative but 
positive for Anti-HBc regardless 
of Anti-HBs antibody status 
requiring  clarification by HBV 
DNA, HBV DNA HCV positive at 
screening.
Monitor patients for signs and symptoms of 
infection, monitor laboratory values, request 
that patients report signs of infection.  Treat 
infections immediately and appropriately. 
Delay or withhold the dose of study agent, or 
discontinue study treatment when 
necessary.

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Progressive 
multifocal 
leukoencephalopathy
No association between belimumab and 
the risk of opportunistic infections, 
including PML, has been indentified to 
date, but data are limited. PML resulting in 
neurological deficits, including fatal cases, 
has been reported in SLE patients 
receiving immunosuppressant 
pharmacotherapy, including belimumab.
Exclude patients who have acute 
or chronic infection including 
PML.
A diagnosis of PML should be considered in 
any subject presenting with new-onset or 
deteriorating neurological signs and 
symptoms. The subject should be referred to 
a neurologist or other appropriate specialist 
for evaluation. If PML is confirmed, study 
agent should be discontinued and 
consideration should be given to stopping 
immunosuppressant therapy. If PML is 
suspected, this should be immediately 
reported to the Medical Monitor.  The 
appropriateness of continuing study agent, 
while the case is being assessed, should be 
discussed.
Malignancies
As with other immunomodulating agents, 
the mechanism of action of belimumab 
may increase the potential risk for the 
development of malignancies. Across all 
SLE trials as of 08 March 2013, the 
relative rate of malignant neoplasms per 
100-subject years (excluding non-
melanoma skin cancer [NMSC]) for 
belimumab was 0.527, 95% CI: 0.365-
0.736. This rate is consistent with the rate 
of malignant neoplasms, excluding NMSC, 
observed in the SLE international cohort 
(0.53, 95% CI: 0.48, 0.59); incidence ratio 
0.87 (0.59, 1.29) (Bernatsky et al, 2005). 
Incidence rates of malignancy for 
Exclude patients with a history of 
malignant neoplasm within the 
last 5 years, except for 
adequately treated basal or 
squamous cell cancers of the 
skin, or carcinoma in situ of the 
uterine cervix.
Monitor patients for signs and symptoms of 
malignancy, monitor laboratory values, 
request that patients report signs and 
symptoms.  Treat appropriately.

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Potential risk 
Summary of data
Impact- eligibility criteria
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spontaneous SLE cases were not 
reported, as the number of cases is too 
few.
Immunogenicity
As with other monoclonal antibodies, 
treatment with belimumab could lead to 
the development of anti-drug antibodies 
(ADA). Among SLE subjects treated with 
belimumab, the proportion of subjects who 
developed persistently positive ADA was 
low and very few of the persistently 
positive antibodies were found to be
neutralizing. Neither development of ADA 
nor persistent ADA was associated with 
infusion or hypersensitivity reactions. As 
expected, the proportions of subjects with 
persistent ADA increased slightly over 
time in belimumab-treated subjects but 
(there was no increase in the number of 
subjects with neutralizing antibodies or the 
number reporting infusion-related adverse 
events.
Not applicable
Analyse anti-drug antibody laboratory values 
at the end of the study to further investigate 
clinical relevance.

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
Effects on 
immunizations 
including reactions 
with live vaccines
No data are available on the secondary 
transmission of infection from persons 
receiving live vaccines to patients 
receiving belimumab. 
Because of its mechanism of action, 
belimumab may interfere with the 
response to immunizations. The efficacy 
of concurrent vaccination in patients 
receiving belimumab is not known.  
Limited data suggest that belimumab does 
not significantly affect the ability to 
maintain a protective immune response to 
immunizations received prior to 
administration of belimumab. 
Exclude patients who have 
received a live vaccine within 
30 days of Day 0.
Live vaccines should not be given for 30 
days before or concurrently as clinical safety 
has not been established. Subjects who 
require a live vaccine during the study 
should have study agent discontinued prior 
to receiving the live vaccine.
Potential psychiatric 
events - Depression 
and suicidality
There have been reports of depression 
and suicidality in patients receiving 
belimumab. Based on an estimated 
current clinical trial exposure of 7117.3 
patient-years (PY) in belimumab studies 
(as of 08 March 2013), the rate of 
completed suicide in patients exposed to 
belimumab in clinical trials is estimated to 
be 4/7117.3 or 0.056/100 PY (0.015, 
0.144). The rate of suicidal behavior 
(completed suicide and attempt; including 
overdose) is 15/7117.3 or 0.211/100PY 
(0.118, 0.348). The rate of suicidal 
ideation (including all events of suicidality, 
Exclude patients who have 
evidence of serious suicide risk 
including any history of suicidal 
behavior in the last 6 months 
and/or any suicidal ideation of 
type 4 or 5 on the Columbia 
Suicide Severity Rating Scale [C-
SSRS in the last 2 months or who 
in the investigator's judgment, 
pose a significant suicide risk.
Monitor patients for signs and symptoms of 
psychiatric events including depression and 
suicidality, request that patients report signs 
and symptoms.  Treat appropriately

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Potential risk 
Summary of data
Impact- eligibility criteria
Strategy-monitoring 
suicidal thoughts and behavior) is 
19/7117.3 or 0.267/100PY (0.161, 0.417).  
The estimated rates of suicidality for 
belimumab remain consistent with the 
rates of the background SLE population. 
The background rate for completed 
suicide identified in the literature ranged 
from 0.02 to 2.18 per 100 PY and varied 
by study type (clinical trial or observational 
study) (Li-Yu, 2007; Cervera, 2003; 
Cervera, 2006; Cervera, 2009).  The 
background rate for suicidal behavior 
(completed suicide and attempts) is 0.12 
(95% CI 0.05, 0.24)/100 patient years 
(Karassa 2003).

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An Independent Data Monitoring Committee (IDMC) reviews unblinded safety data for
this Phase 3 study on an ongoing basis until the data are locked and analyzed through 
Week 104. At all times the sites and sponsor will remain blinded to treatment allocation. 
Events to be monitored during the safety review include, at a minimum, all serious 
adverse events (including deaths, serious psychiatric events, and serious infections), 
Grade 3 and Grade 4 laboratory abnormalities, opportunistic infections (serious and 
nonserious), malignancies, and hypersensitivity/ anaphylactic reactions during the 
double-blind and open-label extension portions of the study. Investigators (and 
IRBs/IECs, as appropriate,) will be notified of the outcome of each IDMC meeting.
1.4.2.
Benefit Assessment
The primary data supporting efficacy of belimumab were the Phase 3 trials (C1056 and 
C1057) in which 1,684 subjects including those patients with renal manifestations were 
treated for up to 52 weeks (C1057) or 76 weeks (C1056) (Belimumab IB, Section 
5.3.1.2). Belimumab produced significant improvements in the SLE Responder Index as 
well as in individual component SELENA-SLEDAI score in both studies. Pooled 
analyses demonstrated steroid sparing, delay in median time to first flare, and decreased 
risk of severe flares over 52 weeks. In a post hoc analysis of the pooled data in subjects 
with renal involvement at baseline, there were favorable trends of greater reduction in 
proteinuria, hematuria, pyuria, and lower renal flare rate with belimumab. These 
preliminary findings in patients with renal involvement support that belimumab may 
provide potential benefit to these patients (Dooley et al, 2013). Clinical trial data for 
belimumab since approval continue to show efficacy in the treatment of SLE through 
decreased SLE flares and decreased disease activity across multiple organ systems 
(Belimumab IB, Section 5.3.1.3; Dooley et al, 2013).  
1.4.3.
Overall Benefit:Risk Conclusion
The safety profile of belimumab remains consistent with that known at approval and is 
consistent with expected events based on the mechanism of action and the disease under 
study. Appropriate risk mitigation measures are in place; rare and long-term risks will be 
further evaluated via the large safety study and registry, ongoing and future studies, and 
routine pharmacovigilance. Review of safety data is conducted on a continual basis in 
order to identify new safety signals which may arise from clinical trial and/or post-
marketing reports. The benefit: risk profile of belimumab for SLE continues to be 
favorable. In addition, the preliminary evidence suggests that patients with lupus 
nephritis may potentially benefit from belimumab.
2.
STUDY OBJECTIVES
•
To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV, or V using the 2003 ISN/RPS criteria.
•
To assess the safety and tolerability of belimumab plus standard of care versus 
placebo plus standard of care in adult subjects with lupus nephritis Class III, IV, or V 
using the 2003 ISN/RPS criteria.

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

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The primary endpoint will be measured using the Primary Efficacy Renal Response 
(PERR) based on study defined criteria (see Section 8.5). Week 104 PERR will be 
defined by a response at Week 100 that is confirmed by a repeat measurement at Week 
104. Likewise, for the relevant major secondary endpoints, complete and ordinal renal 
responses at Week 104 will be defined by the complete and ordinal renal response at 
Week 100 that is confirmed by a repeat measurement at Week 104.
All subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104. 
In the event that a subject withdraws consent from the study, an attempt should be made 
to obtain consent to collect follow-up safety data (at an exit visit approximately 4 weeks 
after the last dose of study agent as well as a follow-up visit approximately 8 weeks after 
the last dose of study agent) and to obtain survival status at Week 104. Any subject that 
withdraws consent for use and disclosure of research-related health information will be 
considered withdrawn from the study and will not be followed for mortality. 
Subjects who receive treatment with study agent through Week 100 and complete Week 
104 assessments in the double-blind period may enter into a 6-month open-label 
extension. The Week 104 visit of the double-blind period will serve as the Day 0 visit for 
subjects entering the 6-month open-label extension. In the open-label extension, all 
subjects will receive 10 mg/kg belimumab every 28 days until Week 24, with a final 
evaluation at Week 28 (4 weeks after the last dose). The first dose on the open-label 
extension will be given at the Week 104 visit of the double-blind period following the 
completion of all Week 104 assessments. Subjects participating in the open-label 
extension will continue to be monitored for efficacy and safety as per the study calendar 
(see Table 6-3). Subjects who complete the 104-week double-blind period, but do not 
enter the open-label extension will be required to return for an additional follow up visit 8 
weeks after the last dose of study agent. All subjects who enter the open-label extension 
period and withdraw early will return for an Exit visit approximately 4 weeks after their 
last dose of study agent as well as a follow-up visit approximately 8 weeks after the last 
dose of study agent. 
At the end of the 6-month open-label extension period, subjects who wish to continue 
treatment may do so by being prescribed commercially available belimumab. If 
belimumab is not commercially available in a subject’s country of participation, the 
subject may continue to receive belimumab under a separate continuation protocol if 
permissible according to local regulations. A separate informed consent will need to be 
provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.

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4.
INCLUSION AND EXCLUSION CRITERIA
4.1.
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Males or females at least 18 years of age.
2. Have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the 
American College of Rheumatology (ACR) criteria (Appendix 1).
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding 
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or 
pure Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy 
must be performed in the 6 months prior to the screening visit or during the screening 
period. The local biopsy report will be used to confirm subject eligibility. A tissue 
sample from the renal biopsy used to qualify the subject for randomization needs to 
be sent to a central reading center after Day 0 (baseline).
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an 
ANA titer ≥ 1:80 (based on Hep-2 immunofluorescence assay or equivalence by 
enzyme immunoassay assay) and/or a positive anti-dsDNA (≥30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results.
5. Have documentation of active renal disease at screening requiring induction therapy 
with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) or 
mycophenolate mofetil (MMF) or other oral forms of mycophenolate. The following 
factors will be used to define active renal disease at screening:

Urinary protein:creatinine ratio of ≥ 1.0 AND 

Active urinary sediment as defined by at least 1 of the following (in absence 
of menses and genitourinary tract infection).  

> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory 
reference range

> 5 white blood cell (WBC)/hpf or above the laboratory reference range.

Presence of cellular casts (RBC or WBC).

Subjects without active urinary sediment are eligible if they meet at least 1 of 
the following criteria: 

Have a confirmatory biopsy performed within 3 months prior to the 
screening visit or during the screening period meeting the criteria 
outlined in Inclusion Criterion 3.

Have proteinuria ≥ 3.5 grams/day (or urinary protein:creatinine ratio≥ 
3.5).
6. Have active renal disease defined as above which requires induction therapy with 
high dose corticosteroids (HDCS) with either intravenous (IV) cyclophosphamide 
(CYC) or mycophenolate mofetil (MMF) or other oral forms of mycophenolate:

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Induction therapy may begin before Screening but should be initiated within 60 days 
prior to or on Day 0 (baseline). Initiation of induction is when both HDCS and either 
MMF or CYC have been started.
The study recommended doses for induction therapy are as follows, adjustments may 
be made for tolerability issues (refer to Section 5.5.1 Standard of Care Medication for 
details): 
-
MMF 1-3g/day orally or Mycophenolate sodium 720 - 2160 mg/day orally 
-
corticosteroids: 0-3 IV pulses of methylprednisolone 500 -1000 mg/pulse 
followed by oral prednisone 0.5-1.0 mg/kg/day with total daily dose up to 60 
mg/day (or equivalence)
-
CYC 500 mg by IV infusion every 2 weeks (3 days) for 6 infusions 
Subjects who have been on MMF for SLE including lupus renal disease may be 
eligible if they have received, or will receive, the following induction therapy within 
60 days prior to or on Day 0 (baseline): 
-
initiation of HDCS with MMF dose increase to reach the target dose for induction 
in the subject (if the subject did not previously fail MMF induction based on the 
investigator’s opinion), OR 
-
initiation of HDCS with discontinuation of MMF and initiation of CYC.  
Note: It is recommended that subject eligibility should be discussed with the Medical 
Monitor if a subject initiated but did not complete an induction therapy within 6 
months prior to the initiation of current induction therapy for the study.
7. A female subject is eligible to enter the study if she is:  

Not pregnant or nursing; 

Of non-childbearing potential (ie, women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed, or have current documented tubal ligation or any other 
permanent female sterilization procedure); or

Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This 
category includes women with oligomenorrhoea [even severe], women who are 
perimenopausal, or have just begun to menstruate. These women must have a 
negative serum pregnancy test at screening, and agree to 1 of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of 
the 1st dose of study agent until 16 weeks after the last dose of study agent; or

Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during study, and for 
16 weeks after the last dose of study agent: 
◦
Implants of levonorgestrel or etonogestrel; 
◦
Ethinyl estradiol/Etonogestrel vaginal ring;

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Injectable progesterone; 
◦
Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
◦
Oral contraceptives (either combined or progesterone only); 
◦
Double barrier method: condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; 
◦
Transdermal contraceptive patch; 
◦
Male partner sterilisation with documentation of azoospermia prior to the 
female subject’s entry into the study, and this male is the sole partner for that 
subject. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
Note: If stricter female or male contraception requirements are specified in the 
country-specific label for induction and/or maintenance standard of care 
medications, they must be followed.
8. Have the ability to understand the requirements of the study, provide written 
informed consent (including consent for the use and disclosure of research-related 
health information), and comply with the study protocol procedures (including 
required study visits). 
4.2.
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the 
following exclusion criteria:
1. Subjects who have previously failed both CYC and MMF (or other forms of 
mycophenolate) induction therapies based on the investigator’s opinion. If a subject 
has failed only 1 of the 2 therapies for induction, they may be eligible for study 
inclusion if the other induction therapy is initiated within 60 days prior to or on Day 0 
(ie, a subject who failed MMF is eligible if newly initiating induction therapy with 
CYC or a subject who failed CYC is eligible if newly initiating induction therapy 
with MMF).
2. Subjects who received an induction therapy with CYC within 3 months prior to the 
planned initiation of the current induction for the study.
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 
based on the Adverse Event Severity Grading Tables (Appendix 7).
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, AZA, corticosteroids).
5. Have a history of an anaphylactic reaction to parenteral administration of contrast 
agents, human or murine proteins or monoclonal antibodies.
6. Have received treatment with belimumab within 364 days of baseline (Day 0). 
7. Received the following within 364 days of  baseline (Day 0):   

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Nitrogen mustard

Chlorambucil

Vincristine

Procarbazine

Etoposide

Abatacept

Treatment with any B cell targeted therapy (eg, rituximab, other anti-CD20 
agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor 
fusion protein [BR3], TACI-Fc, or LY2127399 [anti-BAFF])

A biologic investigational agent (eg, abetimus sodium, anti-CD40L antibody 
[BG9588/ IDEC-131]). Investigational agent applies to any drug not approved 
for sale in the country in which it is being used.

Treatment with interleukin-6 targeted therapy (e.g., tocilizumab, sirukumab).
8. Received any of the following within 90 days of baseline (Day 0):  

Anti-TNF therapy (eg, adalimumab, etanercept, infliximab, certolizumab, 
golimumab pegol)

Interleukin-1 receptor antagonist (anakinra).

Intravenous immunoglobulin (IVIG).

Plasmapheresis.
9. Received a non-biological investigational agent within 60 days of baseline (Day 0).
10. Received a live vaccine within 30 days of baseline (Day 0).
11. Have severe active central nervous system (CNS) lupus (including seizures, 
psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis, or 
CNS vasculitis) requiring therapeutic intervention within 60 days of baseline (Day 0).
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant or are due to receive transplantation.
13. Subjects who have been on dialysis within 364 days of baseline (Day 0).
14. An estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit 
(using the simplified Modification of Diet in Renal Disease [MDRD] equation).
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic 
diseases not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, 
hepatic, renal, neurological, malignancy, or infectious diseases) which, in the opinion 
of the principal investigator, could confound the results of the study or put the subject 
at undue risk.
16. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) 
that, in the opinion of the principal investigator, makes the subject unsuitable for the 
study.
17. Have a history of malignant neoplasm within the last 5 years, except for adequately 
treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine 
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18. Have acute or chronic infection requiring management, as follows:

Currently on any suppressive therapy for a chronic infection (such as 
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes 
zoster, or atypical mycobacteria).

Hospitalization for treatment of infection within 60 days of baseline (Day 0).

Have had infection requiring treatment with parenteral (IV or IM) antibiotics 
(antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days 
of baseline (Day 0).
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within 364 days prior to baseline (Day 0). 
20. Have a historically positive test or test positive at screening for HIV antibody.  
21. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:

Patients positive for HBsAg are excluded.

Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-
HBs antibody status, will require clarification of their status by testing for 
HBV DNA

o
if HBV DNA positive, patients will be excluded from participation

o
if HBV DNA negative, patients will be eligible to enrol.

NOTE: For those subjects randomised, additional ongoing assessment during 
the study is required (see Section 6.7.5).
22. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate. Subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing.
23. Have an IgA deficiency (IgA level < 10 mg/dL).
24. Have a Grade 3 or greater laboratory abnormality (including serum IgG level) based 
on the Adverse Event Severity Grading Tables (Appendix 7) except for the following 
that are allowed:

Urinalysis (eg, proteinuria)

Hematuria

Pyuria

Casts

Hypoalbuminemia due to lupus nephritis.

Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.

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
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant 
and not related to liver disease or anti-coagulant therapy.

Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus 
hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes or 
viral hepatitis. If present, any abnormalities in the ALT and/or AST must be ≤ 
Grade 2.

Stable Grade 3 reduction in hemoglobin levels due to SLE

Stable Grade 3 neutropenia or stable Grade 3 white blood cell count [with the 
exception of subjects receiving CYC who will be excluded if WBC is Grade 3 
or 4 per Exclusion Criterion 3]. Note that WBC count should be obtained 
immediately prior to starting induction therapy. If immediate pre-induction 
WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used. 

Hyperuricemia or blood urea nitrogen (BUN) elevation due to lupus nephritis 
or SLE.
25. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Appendix 8) in the last 2 months 
or who, in the investigator's opinion, pose a significant suicide risk.
5.
STUDY TREATMENT REGIMEN
5.1.
Study Agent Name and Formulation
The common name of the study agent is BENLYSTA™. The generic (USAN/INN) name 
is belimumab.
Belimumab is a recombinant, human, IgG1λ monoclonal antibody specific for soluble 
human B lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13B). 
Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced 
by recombinant DNA technology in a mammalian cell expression system. 
Belimumab drug product is provided as a sterile, lyophilized product. Upon 
reconstitution with 4.8 mL sterile water for injection (SWFI), each vial will contain 80 
mg/mL belimumab in 0.16 mg/mL citric acid, 2.7 mg/mL sodium citrate, 80 mg/mL 
sucrose, 0.4 mg/mL polysorbate 80, pH 6.5. Each lyophilized vial is single use.
The placebo control is prepared as a sterile and lyophilized product.  Upon reconstitution 
with 4.8 mL SWFI, each vial will contain 0.16 mg/mL citric acid, 2.7 mg/mL sodium 
citrate, 80 mg/mL sucrose, 0.4 mg/mL polysorbate 80, pH 6.5.  Each lyophilized vial is 
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5.2.
Packaging, Labeling, Preparation, and Storage
Belimumab will be supplied in a 20 mL vial containing 400 mg belimumab (deliverable).
Placebo control will be supplied in a 20 mL vial.
Lyophilized belimumab and placebo should be stored at 2-8°C. After reconstitution and 
dilution in normal saline, the material is stable for up to 8 hours at 2-8°C, or at room 
temperature. Refer to the Pharmacy Manual for detailed instructions on the preparation, 
administration, and storage of study agent.
The 400 mg single use vial of study agent will be reconstituted with 4.8 mL SWFI, to 
yield a final concentration of 80 mg/mL of belimumab. Placebo will be reconstituted with 
4.8 mL SWFI.
In addition to any country-specific requirements, the study agent label will contain, at a 
minimum, the following information:
•
Product name
•
Concentration
•
Lot number
•
Storage conditions
•
Investigational drug statement
•
Manufacturer’s name and address
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) using the subject’s current body weight in kilograms (kg) which should 
be obtained at each visit prior to dosing. 
The reconstituted study agent will be diluted in 250 mL normal saline for IV infusion. 
An amount of normal saline, equal to the calculated amount of product to be added (refer 
to the Pharmacy Manual for additional details), should be removed from the infusion bag 
prior to adding the product. After adding the reconstituted product, gently invert the bag 
to mix the solution. 
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will 
be employed. The study agent will be reconstituted and diluted by the unblinded site 
pharmacist or designee, independent of the study (person responsible for receiving and 
dispensing study agent). Except for a limited number of safety oversight personnel, all 
other site personnel, the subject, the sponsor, and contract research organization (CRO) 
will remain blinded to the study agent received and to certain biomarkers and 
pharmacodynamic laboratory results (see Section 6.7 and Section 6.9). Separate monitors 
will be responsible for the clinical (blinded monitor) and study agent (unblinded monitor) 
aspects of the study.
Study agent inventory/accountability forms will be examined and reconciled by the 
unblinded monitor or designee as long as the study is blinded. After the end of the study 

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all used and unused study agent must be accounted for on a study agent accountability 
form provided to the investigator by the sponsor, or its designee.
Refer to the Pharmacy Manual for more details regarding storage, handling, and drug 
accountability.
5.3.
Dose, Route of Administration, and Schedule
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a 
placebo arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over at least
1 hour. Once randomized, subjects will be dosed with study agent on Days 0, 14, and 28 
and every 28 days days thereafter through 100 weeks of double-blind treatment.
Following the final double-blind visit at Week 104, subjects who complete 100 weeks of 
treatment with study agent and complete Week 104 assessments, will have the option to 
continue in the 6-month open-label extension period (with first dose given at the Week 
104 visit).
Premedication including an antihistamine, with or without an antipyretic, may be 
administered before the infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) 
are also permitted.
Study agent should be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. In the post-marketing setting, delayed onset of 
symptoms of acute hypersensitivity reactions has been observed. Subjects should remain 
under clinical supervision for 3 hours after completion of the first 2 infusions in the 
double-blind treatment period and the open-label extension. The infusion rate may be 
slowed or interrupted if the subject develops an infusion reaction. Investigators/site 
personnel should be aware of the risk of hypersensitivity reactions, which may present as 
infusion reaction, and monitor subjects closely.
Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment. In the event of a serious reaction, study agent administration must be 
discontinued immediately and the appropriate medical therapy administered. In addition, 
delayed-type, non-acute hypersensitivity reaction have also been observed and included 
symptoms such as rash, nausea, fatigue, myalgia, headache, and facial edema Beyond the 
first 2 infusions, subjects should be monitored during and for an appropriate period of 
time after infusion according to study sites’ guidelines or standard operating procedure 
for IV infusions. This may include, but is not limited to, monitoring vital signs and 
observing for any untoward reactions. Subjects should be made aware of the potential 
risk, the signs and the symptoms of such reactions, and the importance of immediately 
seeing medical attention.
5.4.
Alteration of Dose/Schedule Due to Toxicity
The dose of study agent administered may not be altered. The rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or 
infusion-associated symptoms. At later visits, these subjects may continue to be infused 
over a longer infusion period at the investigator’s clinical discretion. 

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If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to study agent and could potentially be 
exacerbated by the next dose, the investigator may delay the dose by up to 2 weeks or 
withhold 1 dose. If a similar concern is present at the time of the next scheduled dose, the 
investigator should contact the Medical Monitor to determine whether treatment with 
study agent should be discontinued.  
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE 
that the investigator believes may be definitely, possibly or probably related to study 
agent, then treatment with study agent will be discontinued. The subject should be 
withdrawn from study agent, and followed at regularly scheduled study visits as specified 
by protocol and also until resolution of the AE(s) (whichever is longer). All subjects 
should be monitored closely for infection. Increased vigilance for infection is 
recommended in subjects whose serum IgG concentrations are < 250 mg/dL. Clinical 
judgment should be applied with respect to the appropriateness of continuing study 
therapy in these subjects. If a subject experiences IgG levels < 250 mg/dL, the dose of 
study agent must be withheld and the Medical Monitor must be consulted before 
administering any subsequent dose of study agent. Study agent will be discontinued in 
subjects with IgG levels < 250 mg/dL that are associated with a severe or serious 
infection.
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and symptoms. 
The subject should be referred to a neurologist or other appropriate specialist for 
evaluation. If PML is confirmed, study agent should be discontinued and consideration 
should be given to stopping immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.
The appropriateness of continuing study agent, while the case is being assessed, should 
be discussed.
5.5.
Concurrent Medications During the Double-blind Treatment 
Period
This section reviews medications which are required or allowed provided the guidelines 
below are followed. Anytime the concurrent medication requirements are not followed, 
the subject will have study agent discontinued and will be considered a treatment failure 
(non-responder).
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, SLE 
Flare Index and PGA) and laboratory assessments (hematology, chemistry, urinalysis, 
anti-dsDNA, and complement) should be performed to document renal flare prior to 
instituting treatment that results in treatment failure designation.
Comprehensive education and guidance regarding the use of concurrent standard of care
medications (including escalations and tapers, as appropriate) must be provided to the 

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

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

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

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

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

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return for scheduled visits through Week 104. The following medications and therapies 
are prohibited at any time during the double-blind treatment period:
•
New immunosuppressant agents (other than described in Section 5.5.1 as part of the
induction and maintenance regimens).
•
Corticosteroid use outside of the limits described in Section 5.5.6.
•
Other investigational agents (biologic or non-biologic). Investigational applies to any 
drug not approved for sale in the country in which it is being used. 
•
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).
•
Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist 
[anakinra]).
•
Intravenous immunoglobulin (IVIG).   
•
Plasmapheresis.
Whenever a subject has worsening nephritis or SLE, a complete disease activity 
assessment (SELENA SLEDAI, SLE Flare Index, and PGA) and laboratory assessments 
(hematology, chemistry, urinalysis, urinary microscopy, spot urine, anti-dsDNA, and 
complement) should be performed to document disease activity prior to instituting 
treatment that results in treatment failure designation as defined in Section 5.5 and 
Section 5.6.
5.6.1.
Live Vaccines
Live vaccines are not permitted in the study. Subjects who require a live vaccine during 
the study should have study agent discontinued prior to receiving the live vaccine. These 
subjects should continue to return for the scheduled visits through Week 104.
5.7.
Prohibited Medications During Open-Label Extension
During the open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited 
medications during this phase are live vaccines, biological therapies, and other 
investigational agents.
6.
STUDY PROCEDURES
The nature of potential risks and benefits associated with participation in the study will be 
explained to all potential study subjects. Written informed consent (including consent for 
the use and disclosure of research-related health information) must be obtained before the 
subject can begin any screening procedures that are not considered part of standard 
patient care. 
Subjects participating in the pharmacogenetics (PGx) research portion of the protocol 
(Appendix 6) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject.

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Refer to the Study Calendar (Table 6-1, Table 6-2, and Table 6-3), Study Procedures 
Manual, and Central Laboratory Manual for additional information.
6.1.
Screening Procedures (Day -35 to Day 0)
The following assessments are required at screening:
•
Demographics.
•
Medical history.
•
Therapy History.
•
Complete physical examination (including vital signs).
•
Confirm diagnosis of SLE disease (based on ACR criteria) by reviewing previously 
documented clinical records (see Appendix 1).
•
Record concurrent medications.
•
Blood samples for: (see Appendix 5 – Laboratory Tests)

Hematology.

Modified Chem 20 (non-fasting).

Serum pregnancy test - for all women with an intact uterus, unless exempted 
from pregnancy testing (ie, of non-childbearing potential - women who had a 
hysterectomy, are post-menopausal which is defined as 1 year without 
menses, have both ovaries surgically removed or have current documented 
tubal ligation or any other permanent female sterilization procedure).

Autoantibodies (ANA and anti-dsDNA).

Biological markers (Complement C3, C4).

Serum immunoglobulin isotypes (IgG, IgM, IgA).

HIV antibody testing, serologic investigations for Hepatitis B (HB) infection 
(HBsAg, anti-HBc, and anti-HBs, HBV DNA, NOTE: if anti-HBc result is 
reactive, the sample drawn for HBV DNA will be tested for viral DNA; 
otherwise, the sample will be destroyed), and Hepatitis C antibody testing ± 
confirmatory HCV RNA-PCR testing. (NOTE: see Section 4.2, subjects in 
China with positive test for Hepatitis C antibody will be excluded without 
confirmatory Hepatitis C RNA-PCR testing). 

PT/PTT
•
Urine sample for:

Urinary protein: urinary creatinine ratio.

Locally performed urinary microscopy and routine urinalysis. Note: Urine 
collection may be postponed up to 14 days at the investigators discretion if 
menstrual bleeding or a genitourinary tract infection is present at the time of 
urinalysis.

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•
Renal biopsy result (should be from a renal biopsy obtained in the 6 months prior to 
the screening visit or during the screening period. The local biopsy reports will be 
used for the purposes of randomization. A tissue sample from the renal biopsy used to 
qualify the subject for randomization needs to be sent to a central reading center after 
Day 0 (baseline). 
•
Pre-flare GFR and/or serum creatinine – most recent GFR and/or serum creatinine 
values obtained prior to screening and before first manifestations of the current renal 
flare.
•
Suicidality assessment by using the Columbia-Suicide Severity Rating Scale (C-
SSRS) Screening assessment form (see Section 7.6 and Appendix 8).
•
For subjects in China, SAEs will be collected from the time a subject consents to 
participate in the study (see Section 7.2).
•
Confirm subject meets study entry criteria.
6.2.
Study Enrollment Procedures
Subjects who have undergone all screening procedures and have met the entry criteria 
will be enrolled into the study and assigned to treatment by Interactive Web Response 
System (IWRS). Subjects will be randomized in a 1:1 ratio to treatment with either 10
mg/kg belimumab plus standard of care or placebo plus standard of care. Randomization 
of all eligible subjects will be stratified by their induction regimen (HDCS plus CYC vs 
HDCS plus MMF) and race (black race vs other). There is race stratification in this study 
because race may be an important factor related to outcomes in patients with lupus 
nephritis. Race should be self-designated.
6.3.
Double-Blind Treatment Period
Subjects will be evaluated during the scheduled study visits as outlined in the Study 
Calendar (Table 6-1 and Table 6-2). Time windows are provided for each study visit to 
allow flexibility in site and subject scheduling. All study visits should occur within the 
visit window of the scheduled study visit.
At baseline (Day 0), the subject will be randomized and receive the first dose of study 
agent. Visits to the study site for clinical evaluation, disease activity assessment, and 
laboratory sampling will occur approximately every 28 days (calculated from the Day 0 
dose) through Week 104. All efforts should be made to retain subjects on schedule, based 
on the date of their Day 0 dose. During the double-blind treatment period, study agent is 
administered at every scheduled visit through Week 100. The final efficacy evaluation for 
the double-blind portion of the study will occur at Week 104. Subjects should remain 
under clinical supervision for 3 hours after completion of the first 2 infusions. Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment.  
Subjects who complete the double-blind period through Week 104 will be given the 
option to receive belimumab in the 6-month open-label extension.  

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

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

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

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BMost recent GFR prior to the current renal flare.
C The Columbia-Suicidality Severity Rating Scale (C-SSRS) Since Last Visit form (see Appendix 9) will be used at Day 0 and all subsequent visits. The C-SSRS Baseline/Screening form 
(see Appendix 8) is only used at Screening. 
DThe weight at the current visit should be used to calculate dose.
EFor subjects who discontinue treatment with study agent during the double-blind period (for reasons other than withdrawal of consent), all adverse events will be collected through 8 weeks 
following the administration of the last dose of study agent. After this time, SAEs, regardless of relationship to study drug, will be collected through Week 104.
F Refer to Appendix 5 for a listing of laboratory assessments to be completed. 
GTwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  baseline, Weeks 24, 48 and 52.  Serum creatinine for these visits will be collected at 
the initial visit which will take place within 3 days prior to or on the day of the scheduled visit, and then 3 days after the initial visit. For urinary sediment assessments, both menstrual 
cycles and genitourinary tract infections may be confounders.  Urine collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract 
infection is present at time of urinalysis or anytime during the 24 hour urine collection.
HRoutine urinalysis and urinary microscopy will be performed locally.
IFor women of child-bearing potential, serum pregnancy test is required at screening. At subsequent visits, a urine pregnancy test is required. Results of the pregnancy test must be 
available prior to dosing.
JSamples will only be analyzed in subjects with positive results at baseline.
KFor PK sampling times, see Section 6.7.1.
LPharmacogenetic sampling informed consent must be obtained prior to any blood being taken for PGx research. Sample should be drawn prior to dosing.
MSubjects who are withdrawn from treatment with study agent prior to Week 100 (for reasons other than withdrawl of consent) should continue to follow the study calendar and have all 
assessments completed through Week 104 (with the exception of study agent administration).
N Subjects should remain under clinical supervision for 3 hours after completion of the first 2 study agent infusions.  Should symptoms of acute hypersensitivity occur, an extended period of          
monitoring may be appropriate, based on clinical judgment.
OInduction therapy may begin before Screening but should be initiated within 60 days prior to or on Day 0 (baseline).
P Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs are to be performed prior to dosing.
QNote: if anti-HBc result is reactive, the sample drawn for HBV DNA will be tested for viral DNA; otherwise, the sample will be destroyed. Subjects in China with positive hepatitis C 
screening results will be excluded without confirmatory hepatitis C RNA-PCR testing.
RNote: For subjects in China, SAEs will be collected from the time a subject consents to participate in the study (see Section 7.2).

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

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

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6.4.
Open-Label Extension
Subjects who receive treatment with study agent through Week 100 and complete the 
Week 104 assessments in the double-blind period may enter into a 6-month open-label 
extension. The Week 104 visit of the double-blind period will serve as the Day 0 visit for 
subjects entering the 6-month open-label extension. In the open-label extension, all 
subjects will receive 10 mg/kg belimumab approximately every 28 days until Week 24,
with a final evaluation at Week 28 (4 weeks after the last dose). The first dose on the 
open-label extension will be given at the Week 104 visit of the double-blind period after 
the completion of Week 104 assessments. Subjects participating in the open-label 
extension will continue to be monitored for efficacy and safety as per the study calendar 
(see Table 6-3). Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgment.
All subjects who withdraw early from the open-label extension will return for an Exit 
visit approximately 4 weeks after their last dose of study agent as well as a follow-up 
visit approximately 8 weeks after the last dose of study agent. 
At the end of the 6-month open-label extension period, subjects who wish to continue 
treatment may do so by being prescribed commercially available belimumab. If 
belimumab is not commercially available in a subject’s country of participation, the 
subject may continue to receive belimumab under a separate continuation protocol if 
permissible according to local regulations. A separate informed consent will need to be 
provided for the continuation protocol. The 8-week follow-up visit is not required for 
subjects entering the continuation protocol.
Note that a urine pregnancy test is required at the 8-week follow-up visit for all women 
with an intact uterus, unless exempted from pregnancy testing (see Section 6.1). Women 
of child-bearing potential must be reminded of the requirement to report any pregnancy 
that occurs through 16 weeks following the last dose of study agent (see Section 7.7).

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

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ADay 0 of the open-label extension is the Week 104 study visit of the double-blind treatment period, and represents the first belimumab administration for those subjects continuing on the 
6 month open-label extension.  
B For subjects who discontinue from the study, an Exit visit should be completed 4 weeks after the last dose of study agent.
C For subjects who discontinue from the study, a Follow-up visit should be completed 8 weeks after the last dose of study agent. The 8-week follow up visit is not required for subjects 
entering the separate continuation protocol.
D The weight at the current visit should be used to calculate dose.
ERefer to Appendix 5 for a listing of laboratory assessments to be completed. 
FRoutine urinalysis and urinary microscopy will be performed locally.
GFor women of child-bearing potential, a urine pregnancy test is required. Results of the urine pregnancy test must be available prior to dosing.
HSamples will only be analyzed for anti-Sm and anti-C1q in subjects with positive results at baseline.
IFor PK sampling times, see Section 6.7.1.
J AZA/MMF continued at the discretion of the investigator.
K Subjects should remain under clinical supervision for 3 hours after completion of the first 2 study agent infusions.  Should symptoms of acute hypersensitivity occur, an extended period of 
monitoring may be appropriate, based on clinical judgment.
L Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate. On days on which study agent is administred, vital signs are to be performed prior to dosing.

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6.5.
Unscheduled Visits
Unscheduled visits may be necessary during the course of the study to capture a subject’s 
status between regularly scheduled visits. Examples include, but are not limited to, a 
worsening of lupus nephritis symptoms, AE reporting, or follow-up to a previously 
reported AE.
When a subject has worsening nephritis or SLE, a complete disease activity assessment 
(SELENA SLEDAI, SLE Flare Index and PGA), and laboratory assessments 
(hematology, chemistry, urinalysis, urinary microscopy, spot urine, anti-dsDNA, and 
complement) should be performed to document disease activity worsening (eg, renal 
flare/relapse) prior to instituting treatment that results in treatment failure designation as 
defined in Section 5.5 and Section 5.6.
Refer to the Study Calendar (Table 6-2) for a list of procedures required at this visit. 
Other assessments should be performed as clinically indicated. 
6.6.
Renal Biopsies
The local biopsy reports will be used for the purposes of randomization. A tissue sample 
from the renal biopsy used to qualify the subject for randomization needs to be sent to a 
central reading center after Day 0 (baseline). Tissue from any renal biopsies performed as 
part of routine care anytime after baseline (Day 0) will also be collected, where possible, 
for a similar central reading. 
6.7.
Laboratory Tests
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): aCL (IgM, IgG, IgA isotypes), ANA, anti-Sm, anti-C1q, 
serum immunoglobulin isotypes IgM/IgA, and the results from the biological markers 
measured by FACS analysis listed below.
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis):
•
Peripheral B lymphocytes: 
CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+
plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, CD19+/CD24HIGH/CD38HIGH
regulatory B cells, and CD20-/138+ plasma cells.
For the renal function assessments at all study visits, the simplified MDRD formula 
(below) will be used to estimate GFR (Levey et al, 2006):

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

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Table 6-4
PK Visit Days and Sample Times
Day (Week)
Time (Related to Dosing of Study Agent)
Day 0
Before the start of infusion
Day 3
Anytime during visit
Day 14 (Week 2)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 28 (Week 4)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 56 (Week 8)
Prior to dosing
Day 168 (Week 24)
Prior to dosing, 0 - 4 hours after the end of infusion
Day 171 (Week 24 + 3 days)
Anytime during visit
Day 364 (Week 52)
Prior to dosing
Day 728/Exit (Week 104)
Anytime during visit (or prior to dosing if going into the open-label 
treatment period of the study)
8-week follow-up
Any time during visit
Open Label 8-week follow-up
Any time during visit 
On days study agent is administered and blood samples for pharmacokinetic analysis are 
obtained after infusion, blood samples for pharmacokinetic analysis should not be taken 
from the same arm used for the administration of study agent. Samples may be obtained 
by venipuncture.  
If a subject withdraws from treatment with study agent, a blood sample for 
pharmacokinetic analysis will be drawn any time during visit at 4 weeks and 8 weeks
after the last dose of study agent is administered. If a subject withdraws consent from the 
study, an attempt should be made to obtain a blood sample for pharmacokinetic analysis 
at the follow-up visits approximately 4 and 8 weeks after the last dose of study agent.
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.
6.7.2.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity

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1) Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2) All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
3) New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).
6.7.2.1.
Required Actions and Follow up Assessments following ANY Liver 
Stopping Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the 
event also meets the criteria for an SAE (All events of ALT 3xULN and 
bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), 
must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 10).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return 
to within baseline

A specialist or hepatology consultation is recommended

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For All other criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up assessments within 24-72 hours

Monitor subjects weekly until liver chemistries resolve, stabilize or return to 
within baseline
FOLLOW UP ASSESSMENTS

Viral hepatitis serology (includes: Hepatitis A IgM antibody; Hepatitis B surface 
antigen and Hepatitis B Core Antibody (IgM) and HBV DNA (see Section 
6.7.5); Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral 
capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing);  Hepatitis E IgM antibody)

Blood sample for pharmacokinetic (PK) analysis, obtained within approximately 
one to two weeks after last dose (PK sample may not be required for subjects 
known to be receiving placebo or non-GSK comparator treatments.)  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the CRF. If the date or time of the 
last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report 
form including acetaminophen, herbal remedies, other over the counter 
medications

Record alcohol use on the liver event alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use 
in the preceding week [James, 2009]). NOTE: not required in China 

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.

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6.7.3.
Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms 
believed to be related to liver injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks OR

ALT 3xULN and <5xULN  and bilirubin <2xULN without symptoms 
believed to be related to liver injury or hypersensitivity, and who can be 
monitored weekly for 4 weeks
6.7.3.1.
Required Actions and Follow Up Assessments for Increased 
Monitoring with Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality 
to discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following 
ANY Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within 
baseline.
6.7.4.
Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than drug induced liver injury [DILI]) of the liver event 
(e.g. biliary obstruction, pancreatic events, hypotension,
acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity.
Approval by GSK for study treatment restart can be considered where:

Investigator  requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic
hepatitis, or possible study treatment-induced liver injury) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

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
If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 7.2.
6.7.5.
Additional Hepatitis B Monitoring
Safety assessment for Hepatitis B during the trial will be as follows:
•
ALT and/or AST elevations of greater than 2.5 x ULN will require:
•
Sites to review laboratory results for anti-HBc from Screening visit:

If Screening anti-HBc result was reactive, then obtain HBV DNA.

If HBV DNA returns reactive, withdraw subject from further treatment and 
enter follow up visit schedule.  Investigator will determine the extent of 
required attention for proper follow up of potential hepatitis B re-activation.

If anti-HBc result from Screening visit was negative, then repeating hepatitis 
B testing is optional per investigator upon investigating for other causes.
•
Refer to the SPM for guidance on documenting the suspected reason for ALT and/or 
AST elevations of greater than 2.5 x ULN.
6.7.6.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at baseline (Day 0), and at any 
time on Week 8, Week 24, Week 52, Week 76 and Week 104 in the double-blind portion 
of the study. During the open-label extension, a sample will be collected at Week 24. 
Additionally, a sample will be collected at the 8-week follow-up visit. 

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6.8.
Withdrawal of Subjects from Treatment
In addition to the reasons for withdrawal detailed below, subjects are free to withdraw 
from treatment or from the study at any time, for any reason, or may be 
withdrawn/removed, if necessary, to protect their health. It is understood by all concerned 
that an excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. Subjects who withdraw from 
treatment/study after receiving at least 1 dose of study agent will not be replaced. 
Subjects should be withdrawn from treatment with study agent for any of the following 
reasons:
•
Missing 3 or more consecutive doses of study agent
•
Prohibited concurrent medication or prohibited dose of concurrent medication 
(see Section 5.5 and Section 5.6).
•
Prohibited therapy.
•
Unacceptable toxicity (see Section 5.4).
•
Pregnancy.
•
Withdrawal of consent (including use and disclosure of research-related health 
information).
•
Subjects positive for Anti-HBc at Screening who develop elevated LFTs >2.5 x ULN 
during the study followed by an HBV DNA test that shows detectable viral load (see 
Section 6.7.5).
All subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent) should return for all scheduled visits 
through Week 104.
In the event that a subject withdraws consent during the double-blind period, an attempt 
should be made to obtain consent to collect follow-up safety data (at an exit visit 
approximately 4 weeks after the last dose of study agent as well as a follow-up visit 
approximately 8 weeks after the last dose of study agent) and to obtain survival status at 
Week 104. Any subject that withdraws consent for use and disclosure of research-related 
health information will be considered withdrawn from the study and will not be followed 
for mortality.
All subjects who discontinue treatment during the open-label extension should return for 
an Exit visit (4 weeks after the last dose of study agent) and a follow up visit 8 weeks 
after the last dose of study agent. The follow-up visit is not required for subjects entering 
the separate continuation protocol.
6.9.
Subject Unblinding
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will 
be employed. The study agent will be reconstituted and diluted by the unblinded site 
pharmacist or qualified designee, independent of the study (person responsible for 

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receiving and dispensing study agent). Except for a limited number of safety oversight 
personnel, all study site personnel, the subject, the sponsor, and the Contract Research 
Organization (CRO) will remain blinded to the study agent received and to the results of 
certain biomarker and pharmacodynamic laboratory results (see Section 6.7). Separate 
monitors will be responsible for the clinical (blinded monitor) and study agent (unblinded 
monitor) aspects of the study.
In the case of a medical emergency when knowledge of the study treatment is essential 
for the appropriate clinical management or welfare of the subject, the study blind may be 
broken for the specific subject. Whenever possible, the investigator should discuss 
options with the Medical Monitor prior to unblinding any subject. If this is impractical, 
the investigator must notify the Medical Monitor as soon as possible of any broken blind, 
but without revealing the treatment assignment of the unblinded subject, unless that 
information is important for the safety of subjects currently in the study. Any broken 
blind will be clearly justified and explained by a comment in the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
7.
ADVERSE EVENT REPORTING
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.
Definitions
ADVERSE EVENT Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

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
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
SERIOUS ADVERSE EVENT: A serious adverse event is any untoward medical 
occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation
NOTE:  In general, hospitalisation signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalisation are AEs.  
If a complication prolongs hospitalisation or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 

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vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency 
or drug abuse.
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.   
7.2.
Reporting Adverse Events to the Sponsor
All adverse events (AEs) that are identified from the start of study agent administration 
(Day 0) through 8 weeks following administration of the last dose of study agent will be 
recorded on the Adverse Event Case Report Form (AE eCRF). All data fields on the AE 
eCRF must be completed. 
For subjects who discontinue treatment with study agent during the double-blind period 
(for reasons other than withdrawal of consent), all adverse events will be collected 
through 8 weeks following the administration of the last dose of study agent. After this 
time, all SAEs, regardless of relationship to study drug, will be collected through Week 
104.
Serious Adverse Events (SAEs) must be recorded on the SAE eCRF within 24 hours of 
site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
SAE eCRF within 24 hours of site personnel becoming aware of the event as described in 
the Study Procedures Manual. 

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

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pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and symptoms. 
The subject should be referred to a neurologist or other appropriate specialist for 
evaluation. If PML is confirmed, study agent should be discontinued and consideration 
should be given to stopping immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.
The appropriateness of continuing study agent, while the case is being assessed, should 
be discussed.
7.6.
Suicidality Assessment
Some autoimmune diseases have an increased risk of suicidal behaviour and/or ideation
(Bachen et al, 2009; Timonen et al, 2003; Stenager et al, 1992). In order to objectively 
assess suicidality in belimumab clinical programs the C-SSRS (Appendix 8 and
Appendix 9) will be utilized to collect information on suicidal behavior and ideation. SLE 
patients have an increased prevalence of mood and anxiety disorders compared with the 
general population and disease activity may contribute to this higher risk. The incidence 
of major depressive disorder (MDD) among SLE patients has been reported to be as high 
as 47% (Bachen et al, 2009). Since active SLE and MDD may increase the risk of 
suicidal ideation or behavior before or during clinical studies, subjects participating in the 
double-blind portion of this study will be assessed for suicidality at every visit. 
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation 
questions 4 or 5 on the C-SSRS should be referred to appropriate psychiatric care and 
prompts the completion of an SAE worksheet. The Medical Monitor should be notified 
when these events occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal 
ideation question 3, 4 or 5 on the C-SSRS prompts the completion of the Possible 
Suicidality Related History Questionnaire (PSRHQ, only the first time this condition is 
met; refer to Appendix 11 for the PSRHQ) eCRF and a Possible Suicidality Related 
Questionnaire (PSRQ) eCRF (at all times this condition is met; refer to Appendix 12 for 
the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed 
during the blinded portion of this study using C-SSRS (refer to Appendix 8 and Appendix 
9 for C-SSRS).  The C-SSRS is a brief measure which is designed to assess severity and 
change of suicidality by integrating both behaviour and ideation (Posner et al, 2007). The 
C-SSRS is administered by a qualified clinician and is designed to address the need for a 
summary measure to track change in the severity/density of suicidality across both 
clinical settings and treatment trials. It assesses intensity of ideation (a potentially 
important marker of severity) by specifically asking about frequency, duration, 
intrusiveness, controllability, and deterrents. In addition, it captures both the modal and 
most severe forms of ideation. The C-SSRS is to be completed by the investigator or 
his/her qualified designee at every visit during the double-blind portion of the study. 
Although assessment of suicidality using the C-SSRS will take place only during the 
blinded portion of the study, investigators are reminded of the importance to clinically 

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assess for suicidality at every visit given that SLE patients are at increased risk of suicidal 
behavior and/or ideation.
7.6.1.
Possible Suicidality Related Questionnaire (PSRQ)
The investigator will be prompted to complete the PSRQ (in addition to the AE, SAE 
pages, and PSRHQ as appropriate) if a “yes” response is given to any suicidal behaviour 
or a “yes” response to suicidal ideation questions 3, 4 or 5 on the C-SSRS. Refer to 
Appendix 12 for the PSRQ. If the adverse event meets the definition of an SAE, which 
includes a “yes” answer to any suicidal behaviour or a “yes” to suicidal ideation 
questions 4 or 5 on the C-SSRS, the site must ensure that there are no significant 
discrepancies between the PSRQ and SAE. 
7.7.
Reporting a Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor within 24 hours of learning of its occurrence. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child.  Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the Sponsor.
7.8.
Investigator Evaluation of Adverse Events
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to 
study agent). The investigator will make an assessment of intensity based on the Division 
of Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading 
Tables (see Appendix 7) where possible:

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SEVERITY:

Mild
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities (Grade 1 
DMID).

Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).

Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID).

Not applicable
Those event(s) where intensity is meaningless or impossible to 
determine (i.e., blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the pre-
defined outcomes as described in the definition of an SAE.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.  The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
7.9.
Follow-up of Adverse Events
Serious and non-serious adverse events that occur from the start of study agent 
administration through 8 weeks after the date of last administration of study agent are 
reported. In addition, prior to study drug administration, any SAE assessed as related to 
study participation (eg, protocol mandated procedures, invasive tests) will be reported as 
an SAE from the time a subject consents to participate in the study For subjects in China, 
prior to study drug administration, SAE(s) regardless of relationship to study 

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participation (eg, protocol mandated procedures, invasive tests) or study treatment will be 
reported from the time a subject consents to participate in the study. For subjects who 
discontinue treatment with study agent during the double-blind period (for reasons other 
than withdrawal of consent), all SAEs, regardless of relationship to study drug, will be 
collected through Week 104.
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs and non-serious AEs of special interest 
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up.  This applies to 
all subjects, including those withdrawn prematurely.
PSEs (see Section 7.3) that occur after Screening visit through 8 weeks after the date of 
last administration of study agent are reported and followed as described above for 
AEs/SAEs.
7.10.
Disease Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs
The following disease related events (DREs) (preferred terms; MedDRA v. 14.0) are 
common in subjects with SLE and can be serious/life-threatening:
Butterfly rash
Cutaneous lupus erythematosus
Glomerulonephritis membranoproliferative
Glomerulonephritis membranous
Glomerulonephritis proliferative
Lupus encephalitis
Lupus endocarditis
Lupus enteritis
Lupus hepatitis
Lupus myocarditis
Lupus nephritis
Lupus pancreatitis
Lupus pneumonitis
Lupus vasculitis
Nephritic syndrome
Nephritis
Neuropsychiatric lupus
Pericarditis lupus
Peritonitis lupus
SLE arthritis
Systemic lupus erythematosus
Systemic lupus erythematosus rash
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to the 
Sponsor (even though the event may meet the definition of a serious adverse event).  
These events will be recorded on the DRE page in the subject’s eCRF. However, if one 
or both of the following conditions apply, then the event should be reported as an SAE 
using the standard process:
•
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual subject, or
•
The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the study agent

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If either of the above conditions is met then record the DRE on the SAE page rather 
than the DRE page and report promptly (i.e., expedited reporting, see Section 7.2) to 
the Sponsor.
7.11.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  The 
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and the Sponsor’s policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will file 
it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.
ENDPOINTS AND STATISTICAL ANALYSIS
8.1.
General Statistical Considerations
Unless otherwise specified, all analyses will be performed on the intention to treat (ITT)
population defined as all subjects who are randomized and receive at least 1 dose of study 
agent. The ITT analysis will be performed according to the treatment that a subject was 
randomized to receive, regardless of the actual treatment received.
The database will be locked for the primary analysis after data through the Week 104
visit for all subjects have been collected, verified and validated. All subjects and study 
site personnel will remain blinded until the final database lock, which will occur after 
data have been collected, verified and validated for all subjects completing the 8 week 
follow-up after the open-label extension.
For the analysis of the primary and the major secondary efficacy endpoints, a step-down 
sequential testing procedure will be used to control the overall type 1 error. With this 
procedure, the primary and 4 major secondary efficacy endpoints will be evaluated for 
statistical significance based on a pre-specified sequence for interpretation: (1) primary 
efficacy renal response (PERR) at Week 104, (2) complete renal response (CRR) at Week 
104, (3) PERR at Week 52, (4) time to death or renal-related event, and (5) ordinal renal 
response (ORR) at Week 104. Specifically, endpoints will be tested in the sequence 
above (2-sided alpha=0.05) provided that statistical significance is achieved by all prior 
tests. If at any point in the sequence statistical significance is not met, then subsequent 

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endpoints in the sequence cannot be deemed statistically significant, although nominal p-
values may be reported and considered descriptive.
Analyses of other efficacy endpoints other than the major secondary efficacy endpoints 
will not be subject to any multiple testing procedure. All statistical tests will be 2-sided 
and performed at an overall significance level of 0.05.
Received dose for all systemic corticosteroids will be converted to prednisone equivalent. 
As such, when “prednisone” is used throughout this protocol, it refers to prednisone dose 
or equivalent.
8.2.
Randomization Procedure and Assignment to Treatment 
Groups
This is a Phase 3, multi-center, multi-national, randomized, double-blind, placebo-
controlled study. Once subjects have consented, have undergone all screening procedures 
and have been determined to be eligible for the study, they will return for the baseline 
(Day 0) visit to be randomized in a 1:1 ratio (via an Interactive Web Response System) to 
1 of 2 treatment groups (10 mg/kg belimumab plus standard of care or placebo control 
plus standard of care. The randomization of all eligible subjects will be stratified by their 
induction regimen (HDCS plus CYC vs HDCS plus MMF) and race (black race vs other).
8.3.
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this Phase 3 program on an ongoing basis until the data are locked and analyzed
through Week 104 (after which monitoring may be assumed by an internal GSK/HGS 
committee). The IDMC will include physicians with expertise in infectious disease, 
rheumatology or nephrology and a statistician, none of whom are affiliated with the 
sponsor. The first review will occur 6 months after the first subject is randomized or after 
the first 20 subjects are randomized and have completed a Week 8 visit, whichever is 
sooner. Thereafter, the IDMC will review the data approximately every 6 months. At all 
times the sites and sponsor will remain blinded to treatment allocation. Events to be 
monitored during the safety review will include, at a minimum, all serious adverse events 
(including deaths, serious psychiatric events, and serious infections), Grade 3 and Grade 
4 laboratory abnormalities, opportunistic infections (serious and nonserious), 
malignancies, and hypersensitivity/ anaphylactic reactions during the double-blind and 
open-label extension portions of the study. Investigators (and IRBs/IECs, as appropriate,)
will be notified of the outcome of each IDMC meeting.
The IDMC will receive information within 72 hours of the sponsor or designee receiving 
notification of all SAEs that are life threatening or result in death. Other SAEs will be 
provided to the IDMC within 15 calendar days. In addition, the IDMC will receive 
information on all serious infections and all opportunistic infections, irrespective of 
relationship to study agent, within 15 calendar days.

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

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

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

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8.5.2.3.
Subgroup Analysis
Subgroup analysis of the primary efficacy endpoint (ie, PERR at Week 104) will be 
performed in the following subgroups:
•
Induction regimen (HDCS plus CYC vs HDCS plus MMF).
•
Race (Black vs Non-Black).
•
Region (US/Canada, Europe/Australia/Israel, Asia, Americas excluding US and 
Canada).
•
Baseline anti-dsDNA (anti-dsDNA ≥ 30 IU/mL vs other).
•
Baseline complement (C3 and/or C4 low vs other).
•
Baseline complement and anti-dsDNA (C3 and/or C4 low AND anti-dsDNA ≥ 30 
IU/mL vs other).
•
Baseline Renal Biopsy Class (Class III or Class IV Only; Class V Only; Class V plus 
Class III or Class IV; Other).
8.5.3.
Secondary Efficacy Endpoints
8.5.3.1.
Major Secondary Efficacy Endpoints
•
Complete renal response (CRR) at Week 104 (see definition under ORR).
•
PERR at Week 52.
•
Time to death or renal-related event defined as any of the following: i) end stage renal 
disease (ESRD), ii) doubling of serum creatinine, iii) renal worsening as evidenced by 
increased proteinuria and/or impaired renal function, or iv) renal disease-related 
treatment failure. Further definition details will be provided in the analysis plan.
•
ORR (complete, partial or no response) at Week 104 defined as follows:
•
CRR:
Estimated glomerular filtration rate (GFR) is no more than 10% below the 
pre-flare value or within normal range 
AND
Urinary protein:creatinine ratio < 0.5 
AND
No receipt of prohibited (rescue) therapy resulting in treatment failure (see 
Section 5.5 and Section 5.6).
•
Partial Renal Response (PRR):
Estimated GFR no more than 10% below the baseline value or within normal 
range 
AND

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

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•
Individual components of CRR.  Proportion of subjects with the following by visit:

Urinary protein:creatinine ratio < 0.5.

Estimated GFR no more than 10% below the pre-flare value or within the 
normal range
•
Percent change in proteinuria by visit.
•
Change in proteinuria by visit.
•
Proportion of subjects with a doubling of the serum creatinine or progression to end 
stage renal disease (ESRD) as defined below:

Doubling of serum creatinine compared with baseline that is confirmed with a 
second measurement at least 3 weeks later.

Progression to ESRD defined as the need for chronic dialysis or renal 
transplantation.
•
Time to first PERR that is maintained through Week 52.
•
Time to the first PERR that is maintained through Week 104.
•
Time to the first CRR that is maintained through Week 52.
•
Time to the first CRR that is maintained through Week 104.
•
Proportion of subjects with PERR by visit.
•
Proportion of subjects with CRR by visit.
Corticosteroid Use
•
Proportion of subjects receiving ≤5 mg/day prednisone by visit.
•
Proportion of subjects receiving ≤7.5 mg/day prednisone by visit.
SLICC Damage Index (SDI)
•
SDI change from baseline at Week 104
•
Percent of patients with any SDI worsening (change >0) at Week 104 compared with 
baseline.
Biomarkers
1. Median/mean percent change and median/mean absolute change from baseline in 
absolute B cell subsets (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+
activated, CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 
CD19+/CD24HIGH/CD38HIGH regulatory B cell, and CD20-/138+ plasma cells) by visit. 
Only in regions/countries where assessment of B cells is feasible. 
2. Median/mean percent change and median/mean absolute change from baseline by 
visit 

Total serum immunoglobulin (IgG and other isotypes: IgM and IgA).

Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q).

Complement (C3, C4) levels.

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3. Percent of patients with normalized serological activity at Week 104 and over time

IgG, IgM and IgA (high to normal/low).

Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q) present to 
absent.

Complement (C3, C4, and C3 AND C4) levels low to normal/high.
* Anti-dsDNA will be collected monthly throughout the double-blind treatment period. 
Other autoantibodies will be collected from all patients at baseline, then at regular 
intervals during the study.
Data collection and analysis of the exploratory renal biomarkers will be performed 
independently of the main study and will form the basis of a separate report. 
8.5.5.
Secondary Efficacy Analyses
8.5.5.1.
Major Secondary Efficacy Analyses
Time to death or renal-related event will be compared between belimumab vs. placebo
using a Cox proportional hazards model controlling for induction regimen (CYC vs. 
MMF), race (Black vs. Non-Black) baseline proteinuria, and baseline eGFR.
CRR at Week 104 and PERR at Week 52 will be compared between belimumab and 
placebo using logistic regression controlling for induction regimen (CYC vs. MMF), race 
(Black vs. Non-Black), baseline proteinuria, and baseline eGFR.
Analysis of ORR (complete, partial or no response) at Week 104 will be compared 
between belimumab vs. placebo using rank analysis of covariance (ANCOVA) 
controlling for induction regimen (CYC vs. MMF), race (Black vs. Non-Black), baseline 
proteinuria, and baseline eGFR. 
8.5.6.
Other Efficacy Analyses
The analysis of all other efficacy endpoints will be described in the statistical analysis 
plan.
8.6.
Safety
8.6.1.
Definition of Safety Variables
Safety will be evaluated by adverse events, changes in laboratory parameters, and 
immunogenicity.
8.6.2.
Analysis of Safety Variables
AEs will be graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 7) or the grades in Section 7.8, as appropriate. The frequency and 
incidence of AEs will be tabulated by MedDRA system organ class (SOC) and preferred 

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term. Additional analysis may be performed based on event rates adjusting for subject-
years on study agent if the dropout rates are unbalanced across treatment groups. AEs 
will also be summarized by MedDRA SOC and preferred terms for those that are 
considered to be severe (Grade 3 and Grade 4) and those that are considered serious. 
Discontinuations due to AEs will be summarized. 
The frequency and incidence of laboratory abnormalities will be tabulated by treatment 
group. Laboratory values will be assessed for significant changes from baseline. 
Laboratory toxicity will be graded using Adverse Event Severity Grading Tables
(Appendix 7) when possible. Shift tables will be used to determine if subjects move from 
normal to abnormal during the course of the study. Shifts of ≥2 grades and Grade 3 or 4 
laboratory abnormalities will be summarized.
Safety Endpoints of Special Interest
•
All cause mortality
•
Serious and/or severe infections
•
Opportunistic infections
•
Malignant neoplasms
•
Selected serious psychiatric events
•
Suicidality assessment (see Appendix 8 and Appendix 9)
•
Hypersensitivity reactions/anaphylaxis
•
Immunogenicity
The analyses of these safety endpoints will be described in the statistical analysis plan.
8.7.
Pharmacokinetics
8.7.1.
Definition of Pharmacokinetic Evaluation
All randomized subjects will be sampled for serum belimumab levels. Serum belimumab 
concentration data will be used in a population PK analysis. Assessment of belimumab 
concentrations will be performed at the timepoints indicated in Section 6.7.1.
8.7.2.
Analysis of Pharmacokinetics
Serum belimumab concentration will be determined by an electrochemiluminescence 
(ECL)-based assay. Results for this study will be presented using appropriate graphic and 
tabular summaries. Serum belimumab concentration data obtained from this study will be 
used in a population PK analysis, which will be reported separately. Potential effects of 
demographic and disease characteristics, concurrent medications or renal function on 
belimumab PK will be evaluated.

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9.
PHARMACOGENETICS (PGX)
In consenting subjects, a blood sample for PGx research should be drawn predose at 
baseline (Day 0) to better characterize genetic variability (eg, HLA typing) that may 
affect efficacy or safety endpoints. Information regarding PGx research is included in
Appendix 6.
The IEC/IRB and, where required, the applicable regulatory agency must approve the 
PGx assessments before these can be conducted at the study site. The approval(s) must be 
in writing and clearly specify approval of the PGx assessments (ie, approval of Appendix 
6). In some cases, approval of the PGx assessments can occur after approval is obtained 
for the rest of the study. If so, then the written approval will clearly indicate that approval 
of the PGx assessments is being deferred and the study, except for PGx assessments, can 
be initiated. When PGx assessments are not approved, then approval for the rest of the 
study will clearly indicate this and that PGx assessments will not be conducted.
10.
STUDY ADMINISTRATION
Belimumab is under development by GlaxoSmithKline Pharmaceuticals. Human Genome 
Sciences, Inc. a wholly owned subsidiary of GlaxoSmithKline Pharmaceuticals is the 
sponsor of this study.
10.1.
Informed Consent
A copy of the proposed informed consent document must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The 
consent form must be approved by the IRB/IEC and contain all elements required by 
national, state, local, and institutional regulations or requirements.
It is the responsibility of the investigator to provide each subject with full and adequate 
verbal and written information using the IRB/IEC approved informed consent 
document(s), including the objective and procedures of the study and the possible risks 
involved before inclusion in the study. Each subject must voluntarily provide written 
informed consent (including consent for the use and disclosure of research-related health 
information). The consent must be obtained prior to performing any study-related
procedures that are not part of normal patient care, including screening and changes in 
medications including any washout of medications. A copy of the signed informed 
consent must be given to the study subject.
10.2.
Institutional Review Board Review/Independent Ethics 
Committee Review and Approval
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with the ICH Guideline for Good Clinical Practice 
(GCP), will provide initial and continuing review of the study.

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Prior to shipment of the study agent and enrollment of study subjects, documented 
IRB/IEC approval of the protocol, informed consent form, and any advertisement for 
subject recruitment must be obtained and provided to the sponsor or designee.
The IRB/IEC must also be informed of all protocol amendments prior to implementation. 
The investigator must provide reports of any change in research activity (ie, the 
completion, termination, or discontinuation of a study) to the IRB/IEC.
10.3.
Protocol Compliance
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC.
10.4.
Protocol Revisions
Protocol amendments will be prepared and approved by the sponsor. All protocol 
amendments will be signed by the investigator and submitted to the IRB/IEC for review 
prior to implementation. Documentation of IRB/IEC approval must be forwarded to the 
sponsor or designee. If an amendment significantly alters the study design, increases 
potential risk to the subject or otherwise affects statements in the informed consent form, 
the informed consent form must be revised accordingly and submitted to the IRB/IEC for 
review and approval. The approved consent form must be used to obtain informed 
consent from new subjects prior to enrollment and must be used to obtain informed 
consent from subjects already enrolled if they are affected by the amendment.
10.5.
Data Collection and Management
The investigator is responsible for maintaining accurate, complete, and up-to-date records 
for each subject. The investigator is also responsible for maintaining any source 
documentation related to the study, including any films, tracings, computer discs, or 
tapes.
The anonymity of participating subjects must be maintained. For data collection and 
management purposes, subjects are to be identified by a subject number only. Documents 
that identify the subject beyond subject number will not be submitted to the sponsor (eg, 
the signed informed consent document; subject initials) and must be maintained in strict 
confidence by the investigator, except to the extent necessary to allow auditing by the 
regulatory authorities, study monitor, or sponsor representatives.
Site personnel record all data for each study subject through electronic case report forms 
(eCRFs) using an Electronic Data Capture (EDC) system provided and approved by the 
sponsor. Refer to the Study Procedures Manual for additional information regarding 
CRFs that will be used as source documentation. Sites must complete the eCRFs in a 
timely manner and the investigator must promptly review the completed eCRFs after 
every visit for each subject. As the person ultimately responsible for the accuracy of all 
eCRF data, the investigator must sign the Investigator's Statement in each subject's eCRF.

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The EDC system automatically generates queries resulting from the computer checks 
embedded into the system, so as to ensure accuracy, quality, consistency, and 
completeness of the database. Manual queries resulting from review by monitors, medical 
coders, and other Data Management staff are also generated from within the EDC system, 
where they are tracked. Sites resolve the queries and correct the entered data when 
necessary. Every change to data is captured in the EDC system audit trail. Upon 
completion of the study, or after reaching a pre-specified point in the study, Data 
Management will lock the database and generate the SAS datasets necessary for data 
analysis and reporting. Upon completion of the study, each site will be provided with a 
compact disc (CD) containing the eCRFs for each of their subjects.
10.6.
Study Monitoring
The study sponsor or designee will monitor the study. Study monitors representing the 
sponsor will visit study sites routinely throughout the trial. The sponsor will review 
eCRFs and compare them with source documents to verify accurate and complete 
collection of data and confirm that the study is being conducted according to the protocol. 
Auditors representing the sponsor may also similarly evaluate the study and its monitors. 
For these purposes, the investigator will make eCRFs and source documents available 
when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 
promptly notify GlaxoSmithKline Pharmaceuticals / Human Genome Sciences of any 
audits they have scheduled with any regulatory authority.
10.7.
Drug Accountability
Upon receipt of the study agents, the designated pharmacy personnel at the study site is
responsible for taking an inventory of the study agent, including any buffers or diluents. 
A record of this inventory must be kept and usage must be documented on study agent 
inventory forms provided by the sponsor.
Study agent inventory forms will be examined and reconciled by a sponsor’s unblinded
monitor, or designee. At the end of the study, all used and unused study agent must be 
accounted for on a study agent accountability form provided to the investigator by the 
sponsor or its designee.
10.8.
Retention of Records
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs or tapes. They will be retained for the 
longer of the maximum period required by the country and institution in which the study 
is conducted, or the period specified by the sponsor at the time the study is completed, 
terminated or discontinued.

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If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall 
be documented in writing and provided to the sponsor.
10.9.
Financial Disclosure
The Investigator and all Sub-Investigators will provide the sponsor sufficient and 
accurate information on financial interests (proprietary or equity interests, payments 
exclusive of clinical trial costs) to allow complete disclosure to regulatory authorities.
The investigators shall promptly update this information if any relevant changes occur 
during the course of the investigation and for a period of 1 year following study 
completion.
10.10.
Publication Policy
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The 
investigator acknowledges that an independent, joint publication is anticipated to be 
authored by the investigators of the multi-center study and sponsor’s representatives. 
Neither institution nor principal investigator shall independently publish or present the 
results of the study prior to the publication of the multi-center study publication. The 
investigator agrees that the sponsor will be the coordinator and arbitrator of all multi-
center study publications. For multi-center trials, no investigator will be authorized to 
publish study results from an individual center until the earlier of the multi-center trial 
results are published or 12 months after the end or termination of the multi-center trial at 
all sites.
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until all of 
the sponsor’s comments on the proposed publication or presentation have been 
considered and any information determined by sponsor to be confidential information has 
been removed. If requested in writing by the sponsor, the investigator shall withhold 
material from submission for publication or presentation for an additional 60 days to 
allow for the filing of a patent application or the taking of other measures to establish and 
preserve the sponsor’s proprietary rights.
10.11.
Study or Study Site Termination
If the sponsor, the investigator, IRB/IEC or a regulatory authority discovers conditions 
arising during the study that indicate that the study should be halted or that the study 
center should be terminated, this action may be taken after appropriate consultation 
between the sponsor and the investigator. Conditions that may warrant termination of the 
study include, but are not limited to, the following:
•
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.

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•
A decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
The study site may warrant termination under the following conditions:
•
Failure of the investigator to enroll subjects into the study at an acceptable rate.
•
Failure of the investigator to comply with pertinent regulatory authority regulations.
•
Submission of knowingly false information from the research facility to the sponsor, 
study monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.

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11.
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LIST OF APPENDICES
Appendix 1
American College of Rheumatology (ACR) Criteria for SLE.................101
Appendix 2
International Society of Nephrology/Renal Pathology Society 
(ISN/RPS) 2003 Classification of Lupus Nephritis.................................102
Appendix 3
SELENA SLEDAI Disease Assessment Scales ......................................103
Appendix 4
SLICC/ACR Damage Index ....................................................................106
Appendix 5
Laboratory Tests ......................................................................................108
Appendix 6
Pharmacogenetic Research ......................................................................109
Appendix 7
Adverse Event Severity Grading Tables..................................................113
Appendix 8
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening...................................................................................122
Appendix 9
Columbia- Suicide Severity Rating Scale (C-SSRS) Since Last Visit ....138
Appendix 10
Algorithm for Liver Chemistry Stopping and Follow-up Criteria...........149
Appendix 11
Possible Suicidality Related History Questionnaire (PSRHQ)................151
Appendix 12
Possible Suicidality Related Questionnaire (PSRQ)................................153
Appendix 13
Country-specific Requirements: Thailand...............................................155

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Appendix 1
American College of Rheumatology (ACR) Criteria 
for SLE
The ACR Criteria for the Classification of Systemic Lupus Erythematosus
(Tan et al, 1982, and Hochberg, 1997)
Criterion
Definition
1. Malar "butterfly" rash 
Fixed erythema, flat or raised, over the malar eminences, tending to 
spare the nasolabial folds.
2. Discoid rash 
Erythematosus raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions.
3. Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation.
4. Oral ulcers 
Oral or nasopharyngeal ulceration usually painless observed by 
physician.
5. Arthritis 
Nonerosive arthritis involving 2 or more peripheral joints characterized 
by tenderness, swelling, or effusion.
6. Serositis 
a. Pleuritis (convincing history or pleuritic pain or rub heard by 
physician or evidence of pleural effusion), OR
b. Pericarditis (documented by ECG, rub, or evidence or pericardial 
effusion).
7. Renal disorder 
a. Persistent proteinuria (> 0.5 grams/day or > 3 + if quantitation not 
performed) OR
b. Cellular casts (may be red cell, hemoglobin, granular, tubular, or 
mixed).
8. Neurologic disorder 
a. Seizures (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance) 
OR
b. Psychosis (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance.
9. Hematologic disorder 
a. Hemolytic anemia (with reticulocytosis)
OR
b. Leukopenia (< 4000/mm3 total on 2 or more occasions), OR
c. Lymphopenia (<1500/mm3 on 2 or more occasions), OR
d. Thrombocytopenia (< 100,000/mm3 in the absence of offending 
drugs).
10. Immunologic disorder 
a. Anti-DNA (antibody to native DNA in abnormal titer), OR
b. Anti-Sm (presence of antibody to Sm nuclear antigen), OR
c. Positive-finding of antiphospholipid antibodies based on 1) an 
abnormal serum level of IgG or IgM anticardiolipin antibodies, 2) a 
positive test result for lupus anticoagulant using a standard method, 
or 3) a false-positive serologic test for syphilis known to be positive 
for at least 6 months and confirmed by Treponema pallidum 
immobilization (TPI) or fluorescent treponemal antibody (FTA) 
absorption test.
11. Antinuclear antibody (ANA)
Abnormal titer of ANA by immunofluorescence or an equivalent assay at 
any point in time and in the absence of drugs known to be associated 
with "drug-induced lupus" syndrome.
*The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical 
studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are 
present, serially or simultaneously, during any interval or observation.

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

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

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

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

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

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

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Appendix 5
Laboratory Tests
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)
Partial thromboplastin time (PTT)
Serum Pregnancy 
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Dysmorphic RBC
Casts (specified by type 
eg, RBC, WBC)
Urine Pregnancy
Spot urine
24-hour urine
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase
(GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
Infectious Disease Screening
HIV-1/2 antibody
Hepatitis C antibody
Hepatitis B surface antigen
Hepatitis B surface and core 
antibodies
Hepatitis B Viral DNA PCR 
Quantitative (HBV DNA)
Autoantibodies
ANA 
Anti-dsDNA
aCL (IgG, IgA and IgM isotypes)
Anti-Sm
Anti-c1q
Immunoglobulins
Serum immunoglobulin isotypes: IgG, 
IgM, IgA
Belimumab PK and Immunogenicity
*The urine microscopy and 
routine 
urinalysis 
will 
be 
performed locally. All other 
tests will be performed by a 
central laboratory. 
Biological Markers
BLyS protein 
Serum complement (C3 and C4) 
FACS of peripheral lymphocytes: B lymphocytes (CD20+, 
CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, 
CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset 
CD19+/CD24HIGH/CD38HIGH regulatory B cell and CD20-/138+ 
plasma cells)   Note: May be collected in selected sites/regions.
Urinary Biomarkers 
Include, but are not limited to, MCP-1, hepcidin, NGAL, LFABP, 
Angiogenin, Angiopoietin 2, Angiostatin, IL-6r, Osteopontin, PAI-1, 
PF4, RAGE, RANK, Sgp130, Siglec 5, Siglec 9, Tgf-beta1, TIM1, 
TIMP-2, TLSP, TNFR-II, Trem1, VCAM-1, Vegf-C and VEGF-R3.
Other:
Alcohol and drug screen

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Appendix 6
Pharmacogenetic Research
Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in different populations. There is increasing evidence that an individual's genetic 
composition 
(ie, genotype) 
may 
impact 
pharmacokinetics, 
pharmacodynamics 
(relationship between concentrations and pharmacologic effects or the time course of 
pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and 
tolerability).
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies. 
Research Rationale
Blood samples for pharmacogenetics will be drawn as described in Section 9. Collection 
of whole blood samples, even when no a priori hypothesis has been identified, may 
enable PGx analyses to be conducted if there is unexplained or unexpected variation in 
response to belimumab.
If at any time it appears there is potential variability in response in this clinical study or in 
a series of clinical studies with belimumab that may be attributable to genetic variations 
of subjects, the following objectives may be investigated: 
•
Relationship between genetic variants and the pharmacokinetics of belimumab.
•
Relationship between genetic variants and safety and/or tolerability of belimumab.
•
Relationship between genetic variants and efficacy of belimumab.
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives belimumab may take part in the 
PGx research. 
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood being taken for 
PGx research.

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Study Assessments and Procedures
In addition to any blood samples drawn for the clinical study, a whole blood sample (~10 
mL) will be collected for the PGx research at baseline. The PGx sample is labeled (or 
coded) with a study specific number that can be traced or linked back to the subject by 
the investigator or site staff. Coded samples do not carry personal identifiers (such as 
name or social security number). The blood sample will be taken on a single occasion 
unless a duplicate sample is required due to inability to utilize the original sample. The 
blood samples should be drawn on Day 0 (baseline), provided informed consent for PGx 
research has been obtained from the subject, but the sample may be taken at any time 
while the subject is participating in the clinical study.
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA will be 
subjected to sample quality control analysis. This analysis will involve the genotyping of 
several genetic markers to confirm the integrity of individual samples. If inconsistencies 
are noted in the analysis, then those samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
belimumab has been completed and the study data reviewed. In some cases, the samples 
may not be studied. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or the sponsor may destroy the samples sooner. The sponsor or those 
working with the sponsor (for example, other researchers or a contract lab) will use 
samples collected from the study for the purpose stated in this protocol and in the subject 
informed consent form.
Subjects may request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:
1. The sample is retained for PGx research.
2. The sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by the sponsor and maintain the 
documentation in the site study records. In either case, the sponsor will only use study 
information collected/generated up to that point.

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

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

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

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

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

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

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

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

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

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

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

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Appendix 8
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.

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

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Appendix 9
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit
CCI - This section contained Clinical Outcome Assessment data collection questionnaires
or indices, which are protected by third party copyright laws and therefore have been
excluded.

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

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Appendix 10
Algorithm for Liver Chemistry Stopping and Follow-
up Criteria
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 6.7.2.1 and Section 6.7.3.1. 

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

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Appendix 11
Possible Suicidality Related History Questionnaire 
(PSRHQ)

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Appendix 12
Possible Suicidality Related Questionnaire (PSRQ)

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

 
 
 
 
CLINICAL PROTOCOL HGS1006-C1121 
 
Protocol Amendment: 00 
 
 
EudraCT Number: 2011-004570-28 
Date: 19 October 2011 
 
 
TITLE OF STUDY:  
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus Standard 
of Care in Adult Subjects with Active Lupus Nephritis 
 
 
 
 
STUDY SPONSOR: 
Human Genome Sciences, Inc. 
 
14200 Shady Grove Road 
 
Rockville, Maryland 20850 
 
U.S.A. 
 
 
 
 
 
 
Confidential and Proprietary 
This document contains proprietary and confidential information of Human Genome 
Sciences, Inc. Acceptance of this document constitutes agreement by the recipient that 
no unpublished information contained herein will be published or disclosed without 
prior written approval from Human Genome Sciences, Inc., except that this document 
may be disclosed to study personnel under your supervision who need to know the 
contents for conducting the study and appropriate Institutional Review Boards under 
the condition that they are requested to keep it confidential. The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, Human 
Genome Sciences, Inc. must be promptly informed of any such disclosure. 
 

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

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Study Synopsis 
Study Number: HGS1006-C1121 
Title of the Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus 
Standard of Care in Adult Subjects with Active Lupus Nephritis 
Clinical Development Phase: 3 
Objectives:  
• To evaluate the efficacy of belimumab in combination with standard of care in adult 
subjects with lupus nephritis Class III, IV or V using the 2003 ISN/RPS criteria. 
• To assess the safety and tolerability of belimumab plus standard of care versus  placebo 
plus standard of care in adult subjects with lupus nephritis Class III, IV or V using the 
2003 ISN/RPS criteria. 
 
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria: 
1. Males or females at least 18 years of age. 
2. Have a clinical diagnosis of SLE according to the American College of Rheumatology 
(ACR) criteria (Appendix 1). 
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV (excluding 
Class III(C), IV-S(C) and IV-G(C)) either with or without the presence of Class V, or pure 
Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy must be 
performed in the 6 months prior to baseline (Day 0). Whenever possible, a tissue sample 
from the renal biopsy used to qualify the subject will be collected and sent to a central 
reading center; however, the tissue sample will not be shipped prior to nor be used for the 
purposes of randomization. 
4. Have unequivocally positive ANA test results defined as an ANA titer ≥ 1:80 (based on 
Hep-2 immunofluorescence assay) and/or a positive anti-dsDNA (≥ 30 IU/mL based on 
ELISA assay) serum antibody test at the screening visit based on the study’s central 
laboratory results. 
5. Have documentation of active renal disease at screening requiring initiation of induction 
therapy with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) 
or mycophenolate mofetil (MMF) or other oral forms of mycophenolate. Induction 
therapy should be started no more than 14 days prior to the baseline visit (Day 0). The 
following factors will be used to define active renal disease: 
 
Urinary protein:creatinine ratio of ≥ 1.0 AND active urinary sediment as defined by at 
least 1 of the following (in absence of menses and genitourinary tract infection).   

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 
> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory reference 
range. 
 
> 5 white blood cell (WBC)/hpf (or above the laboratory reference range). 
 
Presence of cellular casts (RBC or WBC). 
• Subjects without active urinary sediment are eligible if they meet at least 1 of the 
following criteria:  
 Have a confirmatory biopsy performed within 3 months prior to the baseline visit 
meeting the criteria outlined in criterion 3 
 Have proteinuria ≥ 3.5 grams/day. 
6. A female subject is eligible to enter the study if she is:   
 
Not pregnant or nursing;  
 
Of non-childbearing potential (ie, women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented tubal ligation or any other permanent 
female sterilization procedure); or  
 
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are perimenopausal 
or have just begun to menstruate. These women must have a negative serum 
pregnancy test at screening, and agree to 1 of the following: 
 
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or 
 
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during study and 16 weeks 
after the last dose of study agent:  
◦ 
Implants of levonorgestrel or etonogestrel;  
◦ 
Ethinyl estradiol/Etonogestrel vaginal ring; 
◦ 
Injectable progesterone;  
◦ 
Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year; 
◦ 
Oral contraceptives (either combined or progesterone only);  
◦ 
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermidical foam/gel/film/cream/suppository;  
◦ 
Transdermal contraceptive patch;  
◦ 
Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject. 
7. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).  
 

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Exclusion Criteria: Subjects will be excluded from participating in the study if they meet any 
of the following exclusion criteria: 
1. Subjects who have previously failed induction therapy with both CYC and MMF (or other 
forms of mycophenolate) based on the investigator’s opinion. If a subject has failed only 
1 of the 2 therapies for induction, they may be eligible for study inclusion if they are 
newly initiating the other induction therapy (ie, a subject who failed MMF is eligible if 
newly initiating induction therapy with CYC or a subject who failed CYC is eligible if 
newly initiating induction therapy with MMF). 
2. Subjects who have previously received an induction therapy within 6 months prior to the 
screening visit. 
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 based on 
the Adverse Event Severity Grading Tables (Appendix 7). 
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, azathioprine (AZA), 
corticosteroids). 
5. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies. 
6. Have received treatment with belimumab at anytime.  
7. Received any of the following within 364 days of baseline (Day 0):   
- 
Nitrogen mustard 
- 
Chlorambucil 
- 
Vincristine 
- 
Procarbazine 
- 
Etoposide 
- 
Abatacept 
- 
Treatment with any B cell targeted therapy (eg, rituximab, other anti-CD20 agents, 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein 
[BR3], TACI-Fc, or LY2127399 [anti-BAFF]) 
- 
A biologic investigational agent (eg, abetimus sodium, anti-CD40L antibody 
[BG9588/ IDEC-131]). Investigational agent applies to any drug not approved for sale 
in the country in which it is being used. 
8. Received any of the following within 90 days of baseline (Day 0):   
- 
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab) 
- 
Interleukin-1 receptor antagonist (anakinra). 
- 
Intravenous immunoglobulin (IVIG). 
- 
Plasmapheresis. 
9. Received a non-biological investigational agent within 60 days of baseline (Day 0). 
10. Received a live vaccine within 30 days of baseline (Day 0). 
11. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, 
organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) 
requiring therapeutic intervention within 60 days of baseline (Day 0). 
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic 
stem cell/marrow transplant or are due to receive transplantation. 
13. Subjects who have been on dialysis within 364 days of baseline (Day 0). 

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14. An estimated glomerular filtration rate < 30 ml/min at the screening visit (using the 
simplified Modification of Diet in Renal Disease [MDRD] equation). 
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious diseases) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk. 
16. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study. 
17. Have a history of malignant neoplasm within the last 5 years, except for adequately treated 
cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.   
18. Have required management of acute or chronic infections, as follows: 
- 
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria). 
- 
Hospitalization for treatment of infection within 60 days of baseline (Day 0). 
- 
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of baseline (Day 0). 
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to baseline (Day 0).  
20. Have a historically positive test or test positive at screening for HIV antibody, hepatitis B 
surface antigen, or hepatitis C antibody.   
21. Have an IgA deficiency (IgA level < 10 mg/dL). 
22. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event Severity 
Grading Tables (Appendix 7) except for the following that are allowed: 
- 
Urinalysis (eg, proteinuria) 
- 
Hematuria 
- 
Pyuria 
- 
Casts 
- 
Hypoalbuminemia due to lupus nephritis 
- 
Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment. 
- 
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not 
related to liver disease or anti-coagulant therapy. 
- 
Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus hepatitis, 
and not related to alcoholic liver disease, uncontrolled diabetes or viral hepatitis. If 
present, any abnormalities in the ALT and/or AST must be ≤ Grade 2. 
- 
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. (Note that WBC 
count should be obtained immediately prior to starting induction therapy. If immediate 
pre-induction WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used).  
23. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia- 
Suicide Severity Rating Scale (C-SSRS) (Appendix 8) in the last 2 months or who in the 
investigator's opinion, pose a significant suicide risk. 
 

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

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

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

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Sample Size Calculation: 
It is expected that approximately 50% subjects on placebo plus standard of care will have 
complete (10%) or partial renal response (40%) at the Week 104 visit (Appel et al, 2009; 
Sinclair, 2007). It is expected that renal response in subjects on belimumab plus standard of 
care will be approximately 65% (Complete = 15%, Partial = 50%). Approximately 
464 subjects will be randomized to achieve a target of 232 subjects in each treatment arm 
providing approximately 90% power to detect the difference in the primary endpoint, based 
on a 2-sided Van Elteren test at the 5% significance level (Zhao et al, 2008).  
Analysis of Primary Efficacy Endpoint: 
Renal response (complete, partial, or no renal response) at the Week 104 visit will be 
compared between the belimumab plus standard of care treatment group and placebo plus 
standard of care using the Van Elteren test, stratified by the baseline randomization factors. 
Any subject who receives a protocol-prohibited medication or protocol prohibited dose (as 
defined in Sections 5.5 and 5.6) will be considered a treatment failure (ie, non-responder) for 
the primary endpoint. 
Analysis of Major Secondary Efficacy Endpoints: 
Renal response (complete, partial or no response) at the Week 52 visit will be analyzed using 
the same method as for the primary endpoint. The proportion of subjects who achieve a 
complete renal response at the Week 104 visit, will be compared between the belimumab 
treatment group and placebo group using a logistic regression model. The independent 
variables in the model will include treatment group (ie, 10 mg/kg belimumab vs placebo) and 
the baseline randomization stratification factors.  
For the analysis of the primary and the major secondary efficacy endpoints, a step-down 
sequential testing procedure will be used to control the overall type 1 error (Section 8.1).  
Other efficacy endpoints are described in Section 8.5.4. 
Safety Endpoints and Analysis: 
Descriptive statistics will be used to summarize adverse events (AEs), changes in laboratory 
parameters and immunogenicity. The frequency and rate of laboratory abnormalities will be 
tabulated by treatment group. The frequency and rate of adverse events will be tabulated by 
MedDRA system organ class (SOC) and preferred term and compared between placebo and 
the belimumab treatment group.  
An independent Data Monitoring Committee (DMC) will review unblinded safety data on an 
ongoing basis until data through Week 104 of the double-blind treatment period are locked 
and analyzed (after which time monitoring may be assumed by an internal HGS committee). 
The DMC will include at least 3 physicians and a statistician, none of whom are affiliated 
with the sponsor. The DMC will review the data approximately every 4 months. At all times 
the sites and sponsor will remain blinded to treatment allocation. Events to be monitored 
during the safety review will include at a minimum all serious adverse events (including 
deaths, serious psychiatric events, and serious infections), Grade 3 and Grade 4 laboratory 

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abnormalities, opportunistic infections (serious and nonserious), malignancies, and 
hypersensitivity/anaphylactic reactions during the double-blind Week 104 and open-label 
extension portions of the study. Investigators and IRBs/IECs will be notified of the outcome 
of each DMC meeting.  
Pharmacokinetics Endpoints and Analysis: 
Blood samples will be collected during the study and analyzed to determine serum belimumab 
concentrations. Serum belimumab concentration data will be used in a population PK 
analysis, which will be reported separately. 
Immunogenicity: 
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at the baseline visit (Day 0), 
Week 8, Week 24, Week 52, Week 76 and Week 104. During the 6 month open-label 
extension, samples will be obtained at Week 24. Additionally, a sample will be collected at 
the 8-week follow-up visit. For any subject who had a positive antibody response at the 
8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-week 
follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or 
after completion and/or unblinding of the study, whichever is later. 
Biological Markers and Autoantibodies:  
The following biomarkers will be measured from baseline (Day 0) and at selected timepoints 
thereafter: 
• Autoantibodies: ANA, anti-dsDNA, aCL (IgG, IgM, IgA isotypes), anti-Sm, and anti-C1q 
• Serum immunoglobulin isotypes: IgA, IgG, IgM  
• Serum complement (C3,C4) 
• BLyS protein (baseline only) 
 
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis) at baseline (Day 0) and at multiple time points thereafter: 
• Peripheral B lymphocytes:  
- 
CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ 
plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, CD19+/CD24HIGH/CD38HIGH 
regulatory B cell and CD20-/138+ plasma cells. 
 
Study Calendar: 
See Table 6-1, Table 6-2, and Table 6-3 for a calendar of study visits and assessments. 
Study Schematic:  See Figure 1-1. 
 

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

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

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

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

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

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

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List of Abbreviations 
aCL 
anticardiolipin 
ACE 
angiotensin converting enzyme 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody  
ARB 
angiotensin receptor antagonists/blockers 
Anti-dsDNA anti-double-stranded DNA 
Anti-Sm 
anti-Smith antibody  
Anti-TNF 
anti-Tumor Necrosis Factor 
AST 
aspartate aminotransferase  
AUC 
area under the serum drug concentration-time curve 
AUCi 
area under the curve for an individual subject 
AZA 
Azathioprine 
bid 
twice a day 
BILAG 
British Isles Lupus Assessment Group of SLE Clinics 
BLyS 
B lymphocyte Stimulator 
BR3 
BLyS-receptor fusion protein 
BUN 
blood urea nitrogen 
ºC 
degrees Celsius 
CD 
compact disc 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CRR 
complete renal response 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
CYC 
Cyclophosphamide 
CVA 
cerebrovascular accident 
dL 
deciliter 
DMC 
Data Monitoring Committee 
DMID  
Division of Microbiology and Infectious Diseases 
DNA 
deoxyribonucleic acid 
dsDNA 
double stranded DNA 
eCRF 
electronic case report form 
ECL 
electrochemiluminescence 
EDC 
electronic data capture 
ELISA 
Enzyme-linked immunosorobent assay 
ESRD 
end stage renal disease 
EU 
European Union 
FACS 
florescence activated cell sorting 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 

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

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PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell 
RPS 
Renal Pathology Society 
SAE 
serious adverse event 
SAS 
statistical analysis system 
SC 
subcutaneous 
SELENA 
Safety of Estrogen in Lupus National Assessment trial 
SLE  
systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SLICC 
Systemic Lupus International Collaborating Clinics 
SOC 
System Organ Class 
SRI 
systemic lupus erythematosus responder index 
SWFI 
sterile water for injection 
TACI-Fc 
transmembrane activator attached to Fc portion of an immunoglobulin  
tid 
three times daily 
TNF 
tumor necrosis factor 
ULN 
upper limits of normal 
USA 
United States of America 
USAN/INN 
United States adopted names/international nonproprietary name 
WBC 
white blood cell 
WHO 
World Health Organization 
 

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1 Background 
1.1 
Disease Background Relevant to Clinical Study 
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by 
autoantibody production and abnormal B lymphocyte function (Pisetsky, 2001). The etiology 
of SLE is unknown, although genetics, sex hormones, and environmental conditions are 
thought to play a role (Kotzin, 1996; Pisetsky, 1998; Sobel et al, 1999). This disease is more 
common in women (~90% of patients) than men (NWHIC, 2003) and more prevalent in 
African-Americans than Caucasians (OMHRC, 2001; NWHIC, 2003). In the United States the 
reported prevalence is 100,000 to 500,000 patients with some estimates of 1 million as the 
incidence increased 2-3 fold between 1950 and 1979. In the European Union (EU), prevalence 
rates have been reported ranging from 25 to 39 cases per 100,000 persons (Jimenez et al, 
2003). In community-based studies among Asians, the prevalence (per 100,000) of SLE 
ranged from 3.2 to 70.4 (Thumboo and Wee, 2006). The disease onset is generally between 
the ages of 20 and 40. Patients with SLE have about a 3-fold greater risk of mortality than the 
general population. Approximately 70% of SLE patients survive 20 years from time of 
diagnosis (Houssiau et al, 2004). 
SLE can lead to arthritis, kidney failure, heart and lung inflammation, central nervous system 
(CNS) changes, vasculitis, severe skin rash, and blood dyscrasias such as anemia, leukopenia, 
and thrombocytopenia. The manifestations of SLE vary from patient to patient and it may take 
many years to render the proper diagnosis. The American College of Rheumatology (ACR) 
criteria that define a diagnosis of this heterogeneous disease require 4 of 11 criteria that 
include SLE-associated signs or symptoms, lab abnormalities, and the presence of specific 
anti-nuclear autoantibodies (Tan et al, 1982). 
Approximately 35% of all adult patients with SLE develop clinically significant lupus 
nephritis and despite improvements in both diagnosis and treatment over the last few decades 
it remains an indicator of poor prognosis (Gordon et al, 2009; Waldman and Appel, 2006). 
Manifestations of lupus nephritis include proteinuria, elevations in serum creatinine and the 
presence of urinary sediment. Alongside these clinical manifestations, morphological changes 
can be observed in renal biopsy specimens. In 1975 the WHO proposed a classification 
system for renal biopsies in SLE which was continually revised by them up until 1995. In 
2004 updated criteria jointly developed by the International Society of Nephrology and the 
Renal Pathology Society were published (Weening et al, 2004). Within the 5 overall classes, 
Classes I and II reflect disease restricted to mesangial abnormalities. Classes III and IV 
represent either focal (< 50% glomeruli involved - Class III) or diffuse (≥ 50% glomeruli 
involved - Class IV) segmental or global glomerulonephritis. Class V represents membranous 
disease with Class VI representing advanced sclerosis. Classes I and II are rarely accompanied 
by clinical manifestations and there is no activity in Class VI only damage, so therapy has 
traditionally focused on Classes III-V. 
Belimumab (BENLYSTA™) administered IV is approved in the United States (US), Canada, 
and the European Union (EU) for the treatment of adult patients with active autoantibody-
positive SLE who are receiving standard therapy; patients with severe active lupus nephritis 

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and severe active CNS lupus were excluded, as were patients receiving other biologics and IV 
cyclophosphamide (Refer to specific country labeling for additional information regarding the 
approved indication).  Approval of IV belimumab for SLE is being sought in other regions of 
the world.  
1.2 
Belimumab 
1.2.1 Mechanism of Action 
Belimumab (also known as LymphoStat-B™; BENLYSTA™) is a B-lymphocyte stimulator 
(BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to 
its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, 
belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the 
differentiation of B cells into immunoglobulin-producing plasma cells.  
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology data generated with 
belimumab are provided in the Investigator’s Brochure (IB).  
1.2.2 Clinical Experience with Belimumab 
Belimumab administered as an IV infusion has been studied in SLE patients in 1 Phase 1 trial 
(LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial (LBSL02) and 
2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 (HGS1006-C1057) 
and BLISS 76 (HGS1006-C1056)], and in RA patients in a Phase 2 double-blind, 
placebo-controlled trial (LBRA01).  
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the basis 
of the approval of IV belimumab in the US, Canada and the EU. The Phase 3 trials included 
1,684 subjects where belimumab 10 mg/kg plus standard therapy demonstrated superiority 
over placebo plus standard therapy in reduction in disease activity as measured by the SLE 
responder index (SRI) with an acceptable safety profile. The primary safety population 
supporting approval also included data from a Phase 2 study in 449 subjects with SLE. 
Evidence of benefit in other clinical measures such as reductions in disease activity as 
measured by SELENA SLEDAI, severe flare, and reduced steroid use was also observed. 
Treatment with belimumab plus standard of care was generally well tolerated, with rates of 
adverse events (AEs), severe AEs, serious AEs, AEs leading to discontinuation, and 
serious/severe infections generally comparable to the rates observed in the placebo plus 
standard of care group. Mortality rates in the controlled clinical trials were low, although 
numerically higher in the belimumab groups: 0.4% and 0.8% in the placebo and belimumab 
groups, respectively. Causes of death were as expected in an SLE population with active 
disease receiving a wide range of standard therapies, such as steroids and 
immunosuppressants, and included infection, cardiovascular disease, and suicide. Serious 
infections were observed in 5.2% and 6.0% of subjects receiving placebo and belimumab, 
respectively. The rate of malignancy (excluding non-melanoma skin cancer) was the same 
between the placebo and belimumab groups at 0.4%; however as with other 
immunomodulating agents, the mechanism of action of belimumab could increase the risk for 
the development of malignancies. Hypersensitivity and infusion reactions were observed. 

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Anaphylaxis was also observed, though rare (< 1%). Depression-related events, common in 
patients with SLE, were observed more frequently with belimumab than with placebo; it is 
unknown if belimumab treatment is associated with an increased risk for these events. The 
most commonly-reported adverse reactions, occurring in ≥ 5% of patients in clinical trials 
were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, 
depression, migraine, and pharyngitis.  
Experience from open-label, long-term continuation trials of belimumab in SLE subjects 
suggests that prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence rate of AEs or serious adverse events (SAEs) over time, 
including important events such as infections and malignancies. The prevalence rate of AEs 
and SAEs has also remained relatively stable over time. Long term belimumab treatment 
through 6 years appears to provide sustained improvement in SLE disease activity. 
Results of the clinical trials of belimumab administered IV are described in further detail in 
the Investigator’s Brochure.  
1.3 
Rationale for the Study 
Current standard of care treatment for lupus nephritis consists of corticosteroids and 
immunosuppressants. Several studies have now been conducted in lupus nephritis; however at 
this time no therapies have been approved for lupus nephritis. In the Euro-lupus trial, a low 
dose IV cyclophosphamide (CYC) regimen achieved similar clinical results with respect to 
treatment failures, renal remission and renal flares when compared to a high dose IV CYC 
regimen (Houssiau et al, 2002). A recent systematic review of recent trials in lupus nephritis 
concluded that MMF is as effective as CYC in inducing disease remission (Touma et al, 
2011). 
Belimumab treatment at a dose of 10 mg/kg in combination with standard SLE therapy 
demonstrated a statistically significant and clinically meaningful reduction in SLE disease 
activity vs placebo plus standard SLE therapy at week 52 in 2 Phase 3 clinical studies 
(C1056/BLISS76 and C1057/BLISS52) in subjects with active, autoantibody-positive SLE. 
While the 2 Phase 3 studies did explore the effect of belimumab on individual organ systems, 
these findings were limited for the renal organ domain as subjects were excluded if they had 
severe active lupus nephritis. However, 267 subjects (16%) included in the Phase 3 trials had 
renal involvement by SELENA SLEDAI (comprising hematuria, proteinuria, pyruia and/or 
urinary casts). In a post-hoc analysis of the pooled data (Table 1-1), there were trends towards 
SELENA SLEDAI renal organ domain improvement, especially in the subgroup of subjects 
who were anti-dsDNA positive and had low C3 and/or low C4 at baseline. There were 
favorable trends of greater reduction in proteinuria, hematuria, pyuria, and lower renal flare 
rate in the belimumab treatment groups versus placebo. Understanding whether belimumab 
plus standard of care can reduce the disease activity in subjects with active lupus nephritis 
subjects is of interest to prescribing physicians and health authorities.  

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

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

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

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

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6. A female subject is eligible to enter the study if she is:   
 
Not pregnant or nursing;  
 
Of non-childbearing potential (ie, women who had a hysterectomy, are 
postmenopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented tubal ligation or any other permanent 
female sterilization procedure); or  
 
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are perimenopausal 
or have just begun to menstruate. These women must have a negative serum 
pregnancy test at screening, and agree to 1 of the following: 
 
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or 
 
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during study and 16 weeks 
after the last dose of study agent:  
◦ 
Implants of levonorgestrel or etonogestrel;  
◦ 
Ethinyl estradiol/Etonogestrel vaginal ring; 
◦ 
Injectable progesterone;  
◦ 
Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year; 
◦ 
Oral contraceptives (either combined or progesterone only);  
◦ 
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermidical foam/gel/film/cream/suppository;  
◦ 
Transdermal contraceptive patch;  
◦ 
Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject. 
7. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).  
 
4.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria:  
1. Subjects who have previously failed induction therapy with both CYC and MMF (or other 
forms of mycophenolate) based on the investigator’s opinion. If a subject has failed only 1 
of the 2 therapies for induction, they may be eligible for study inclusion if they are newly 
initiating the other induction therapy (ie, a subject who failed MMF is eligible if newly 
initiating induction therapy with CYC or a subject who failed CYC is eligible if newly 
initiating induction therapy with MMF). 

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2. Subjects who have previously received an induction therapy within 6 months prior to the 
screening visit. 
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 based on 
the Adverse Event Severity Grading Tables (Appendix 7). 
4. Known hypersensitivity or contraindication to any drug products or any component of 
these drug products they plan to receive (eg, CYC, MMF, AZA, corticosteroids). 
5. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies. 
6. Have received treatment with belimumab at anytime.  
7. Received the following within 364 days of  baseline (Day 0):    
- 
Nitrogen mustard 
- 
Chlorambucil 
- 
Vincristine 
- 
Procarbazine 
- 
Etoposide 
- 
Abatacept 
- 
Treatment with any B cell targeted therapy (eg, rituximab, other anti-CD20 agents, 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein 
[BR3], TACI-Fc, or LY2127399 [anti-BAFF]) 
- 
A biologic investigational agent (eg, abetimus sodium, anti-CD40L antibody 
[BG9588/ IDEC-131]). Investigational agent applies to any drug not approved for sale 
in the country in which it is being used. 
8. Received any of the following within 90 days of baseline (Day 0):   
- 
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab) 
- 
Interleukin-1 receptor antagonist (anakinra). 
- 
Intravenous immunoglobulin (IVIG). 
- 
Plasmapheresis. 
9. Received a non-biological investigational agent within 60 days of baseline (Day 0). 
10. Received a live vaccine within 30 days of baseline (Day 0). 
11. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, 
organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) 
requiring therapeutic intervention within 60 days of baseline (Day 0). 
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic 
stem cell/marrow transplant or are due to receive transplantation. 
13. Subjects who have been on dialysis within 364 days of baseline (Day 0). 
14. An estimated glomerular filtration rate < 30 ml/min at the screening visit (using the 
simplified Modification of Diet in Renal Disease [MDRD] equation). 
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious diseases) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk. 
16. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study. 

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17. Have a history of malignant neoplasm within the last 5 years, except for adequately treated 
cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.   
18. Have required management of acute or chronic infections, as follows: 
- 
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria). 
- 
Hospitalization for treatment of infection within 60 days of baseline (Day 0). 
- 
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of baseline (Day 0). 
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to baseline (Day 0).  
20. Have a historically positive test or test positive at screening for HIV antibody, hepatitis B 
surface antigen, or hepatitis C antibody.   
21. Have an IgA deficiency (IgA level < 10 mg/dL). 
22. Have a Grade 3 or greater laboratory abnormality based on the Adverse Event Severity 
Grading Tables (Appendix 7) except for the following that are allowed: 
- 
Urinalysis (eg, proteinuria) 
- 
Hematuria 
- 
Pyuria 
- 
Casts 
- 
Hypoalbuminemia due to lupus nephritis. 
- 
Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment. 
- 
Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not 
related to liver disease or anti-coagulant therapy. 
- 
Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus hepatitis, 
and not related to alcoholic liver disease, uncontrolled diabetes or viral hepatitis. If 
present, any abnormalities in the ALT and/or AST must be ≤ Grade 2. 
- 
Stable Grade 3 neutropenia or stable Grade 3 white blood cell count. (Note that WBC 
count should be obtained immediately prior to starting induction therapy. If immediate 
pre-induction WBC is not available, a WBC count obtained within 28 days prior to 
induction may be used).  
23. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS 
(Appendix 8) in the last 2 months or who in the investigator's opinion, pose a significant 
suicide risk. 
 

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5 Study Treatment Regimen 
5.1 
Study Agent Name and Formulation 
The common name of the study agent is BENLYSTA™. The generic (USAN/INN) name is 
belimumab. 
Belimumab is a recombinant, human, IgG1λ monoclonal antibody specific for soluble human 
B lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a 
molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA 
technology in a mammalian cell expression system.  
Belimumab drug product is provided as a sterile, lyophilized product. Upon reconstitution 
with sterile water for injection (SWFI), each vial will contain 80 mg/mL belimumab in 
0.16 mg/mL citric acid, 2.7 mg/mL sodium citrate, 80 mg/mL sucrose, 0.4 mg/mL polysorbate 
80, pH 6.5. Each lyophilized vial is single use. 
The placebo control is prepared as a sterile and lyophilized product.  Upon reconstitution with 
4.8 mL SWFI, each vial will contain 0.13 mg/mL citric acid, 2.8 mg/mL sodium citrate, 
80 mg/mL sucrose, 0.4 mg/mL polysorbate 80, pH 6.5.  Each lyophilized vial is single use. 
5.2 
Packaging, Labeling, Preparation, and Storage 
Belimumab will be supplied in a 20 mL vial containing 400 mg belimumab (deliverable). 
Placebo control will be supplied in a 20 mL vial. 
Lyophilized belimumab and placebo should be stored at 2-8°C. After reconstitution and 
dilution in normal saline, the material is stable for up to 8 hours at 2-8°C, or at room 
temperature. Refer to the Pharmacy Manual for detailed instructions on the preparation, 
administration, and storage of study agent. 
The 400 mg single use vial of study agent will be reconstituted with 4.8 mL SWFI, to yield a 
final concentration of 80 mg/mL of belimumab. Placebo will be reconstituted with 4.8 mL 
SWFI. 
In addition to any country-specific requirements, the study agent label will contain, at a 
minimum, the following information: 
• Product name 
• Concentration 
• Lot number 
• Storage conditions 
• Investigational drug statement 
• Manufacturer’s name and address 
 

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The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's body weight in kilograms 
(kg) at baseline (Day 0) of this study. If a subject’s weight increases or decreases by more 
than 5% from their baseline (Day 0) weight on this study, the current weight should be used to 
calculate the dose of study agent administered. 
The reconstituted study agent will be diluted in 250 mL normal saline for IV infusion. 
An amount of normal saline, equal to the calculated amount of product to be added 
(see Section 5.1), should be removed from the infusion bag prior to adding the product. After 
adding the reconstituted product, gently invert the bag to mix the solution.  
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will be 
employed. The study agent will be reconstituted and diluted by the unblinded site pharmacist 
or designee, independent of the study (person responsible for receiving and dispensing study 
agent). Except for a limited number of safety oversight personnel, all other site personnel, the 
subject, the sponsor and contract research organization (CRO) will remain blinded to the 
study agent received and to certain biomarkers and pharmacodynamic laboratory results (see 
Section 6.12). Separate monitors will be responsible for the clinical (blinded monitor) and 
study agent (unblinded monitor) aspects of the study. 
Study agent inventory/accountability forms will be examined and reconciled by the unblinded 
monitor or designee as long as the study is blinded. After the end of the study all used and 
unused study agent must be accounted for on a study agent accountability form provided to 
the investigator by the sponsor, or its designee. 
Refer to the Pharmacy Manual for more details regarding storage, handling, and drug 
accountability. 
5.3 
Dose, Route of Administration, and Schedule 
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving standard of care therapy (as described in 
Section 5.5.1). All study agent treatments will be administered intravenously over 1 hour. 
Once randomized, subjects will be dosed with study agent on Days 0, 14, and 28 and every 
28 days days thereafter through 100 weeks of double-blind treatment. Following the final 
double-blind visit at Week 104, subjects who will have the option to continue in the 6-month 
open-label extension period (with first dose given at Week 104 visit). 
Premedication including an antihistamine, with or without an antipyretic, may be administered 
before the infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 
Study agent should be administered by Investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 
closely. In the event of a serious reaction, study agent administration must be discontinued 
immediately and the appropriate medical therapy administered.  Subjects should be monitored 

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during and for an appropriate period of time after infusion according to study sites’ guidelines 
or standard operating procedure for IV infusions. This may include, but is not limited to, 
monitoring vital signs and observing for any untoward reactions. Subjects should also be 
informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek 
medical care should a reaction occur.   
5.4 
Alteration of Dose/Schedule Due to Toxicity 
The dose of study agent administered may not be altered. The rate of infusion may be slowed 
or interrupted if the subject appears to develop signs of adverse reaction or infusion-associated 
symptoms. At later visits, these subjects may continue to be infused over a longer infusion 
period at the investigator’s clinical discretion.  
If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to study agent and could potentially be exacerbated by 
the next dose, the investigator may delay the dose by up to 2 weeks or withhold 1 dose. If a 
similar concern is present at the time of the next scheduled dose, the investigator should 
contact the Medical Monitor to determine whether treatment with belimumab should be 
discontinued.   
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE that 
the investigator believes may be definitely, possibly or probably related to study agent, then 
treatment with study agent will be discontinued. The subject should be withdrawn from the 
study agent, and followed at regularly scheduled study visits as specified by protocol and also 
until resolution of the AE(s) (whichever is longer). All subjects should be monitored closely 
for infection. Increased vigilance for infection is recommended in subjects who experience 
IgG levels < 250 mg/dL, especially for prolonged periods; clinical judgment should be applied 
with respect to the appropriateness of continuing study therapy in these subjects. The Medical 
Monitor must be consulted before administering subsequent doses of study agent in subjects 
with IgG levels < 250 mg/dL. Study agent will be discontinued in subjects with IgG levels 
< 250 mg/dL that are associated with a severe or serious infection.  
5.5 
Concurrent Medications 
This section reviews medications which are allowed during the course of the study provided 
the guidelines below are followed. Anytime the concurrent medication guidelines are not 
followed, the subject will have study agent discontinued and will be considered a treatment 
failure (non-responder). 
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, SLE Flare 
Index and PGA) and laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, 
and complement) should be performed to document renal flare prior to instituting treatment 
that results in treatment failure designation.  
Received dose for all systemic corticosteroids will be converted to prednisone equivalent. As 
such, when “prednisone” is used throughout this protocol, it refers to prednisone dose or 
equivalent. 

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

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

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

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

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• Other biologics (eg, rituximab, abatacept, interleukin-1 receptor antagonist [anakinra]). 
• Intravenous immunoglobulin (IVIG).    
• Plasmapheresis. 
 
Whenever possible, a complete disease activity assessment (SELENA SLEDAI, PGA, and 
laboratory assessments (hematology, chemistry, urinalysis, anti-dsDNA, and complement) 
should be performed to document renal flare prior to instituting treatment that results in 
treatment failure designation as defined in Sections 5.5 and 5.6. 
5.6.1.1 
Live Vaccines 
Live vaccines are not permitted in the study. Subjects who require a live vaccine during the 
study should have study agent discontinued prior to receiving the live vaccine. These subjects 
should be followed according to the study protocol until the study endpoint is reached 
(Week 104 or until receipt of a prohibited medication or dose resulting in treatment failure 
designation). 
6 Study Procedures 
The nature of potential risks and benefits associated with participation in the study will be 
explained to all potential study subjects. Written informed consent (including consent for the 
use and disclosure of research-related health information) must be obtained before the subject 
can begin any screening procedures that are not considered part of standard patient care.  
Subjects participating in the pharmacogenetics (PGx) research portion of the protocol 
(Appendix 6) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject. 
Refer to the Study Calendar (Table 6-1, Table 6-2, and Table 6-3), Study Procedures Manual 
and Central Laboratory Manual for additional information. 
6.1 
Screening Procedures (Day -28 to Day 0) 
The following assessments are required at screening: 
• Demographics. 
• Medical history. 
• Complete physical examination (including vital signs). 
• Confirm diagnosis of SLE disease (based on ACR criteria) by reviewing previously 
documented clinical records (see Appendix 1). 
• Record concurrent medications. 
• Blood samples for: (see Appendix 5 – Laboratory Tests) 
- 
Hematology. 
- 
Modified Chem 20 (non-fasting). 

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- 
Serum pregnancy test - for all women with an intact uterus, unless exempted from 
pregnancy testing (ie, of non-childbearing potential - women who had a hysterectomy, 
are post-menopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented tubal ligation or any other permanent 
female sterilization procedure). 
- 
Autoantibodies (ANA and anti-dsDNA). 
- 
Biological Markers (Complement C3, C4). 
- 
Serum Immunoglobulin isotypes (IgG, IgM, IgA). 
- 
HIV antibody, hepatitis B surface antigen, and hepatitis C antibody testing. 
- 
PT/PTT 
• Urine sample for: 
- 
Urinary protein: urinary creatinine ratio. 
- 
Locally performed urinary microscopy and routine urinalysis. 
• Renal biopsy result (should be from a renal biopsy obtained in the 6 months prior to 
baseline (Day 0). Whenever possible, a tissue sample from the renal biopsy used to qualify 
the subject will be collected and sent to a central reading center; however, the tissue 
sample will not be shipped prior to nor be used for the purposes of randomization. 
• Suicidality assessment by using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Screening assessment form (see Section 7.6 and Appendix 8). 
• Confirm subject meets study entry criteria. 
 
6.2 
Study Enrollment Procedures 
Subjects who have undergone all screening procedures and have met the entry criteria will be 
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Subjects will be randomized in a 1:1 ratio to treatment with either 10 mg/kg 
belimumab plus standard of care or placebo plus standard of care. Randomization of all 
eligible subjects will be stratified by their induction regimen (HDCS plus CYC vs HDCS plus 
MMF) and race (black race vs other). There is race stratification in this study because race 
may be an important factor related to outcomes in patients with lupus nephritis. Race should 
be self-designated.  
6.3 
Double-Blind Treatment Period 
Subjects will be evaluated at the study site during the scheduled study visits as outlined in the 
Study Calendar (Table 6-1 and Table 6-2). Time windows are provided for each study visit to 
allow flexibility in site and subject scheduling. All study visits should occur within the visit 
window of the scheduled study visit. 
At baseline (Day 0), the subject will be randomized and receive the first dose of study agent. 
Visits to the study sites for clinical evaluation, disease activity assessment, and laboratory 
sampling will occur every 28 days (calculated from the Day 0 dose) through Week 104. 
All efforts should be made to retain subjects on schedule, based on the date of their Day 0 
dose. During the double-blind treatment period, study agent is administered at every 

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

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

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

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

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AFor subjects completing all 100 weeks of treatment and continuing into the 6-month open-label extension, the Week 104 visit will also serve as Day 0 visit of the 6-month open-label 
extension. For subjects discontinued from the double-blind study early or subjects who are not continuing into the open label extension, the Week 104/Exit visit will occur approximately 4 
weeks after the last dose of study agent. Only subjects who wish to continue in the open-label extension study will have study agent administered at the Week 104 visit after the completion of 
Week 104 assessments. 
BThe 8-week follow-up visit is to occur approximately 8 weeks after last dose of study agent for subjects withdrawing early and those subjects who do not continue into the 6-month open-label 
extension 
CIf weight changes by more than 5% from their Baseline (Day 0) weight, the weight at the current visit should be used for calculating the dose. 
D Refer to Appendix 5 for a listing of laboratory assessments to be completed.  
ETwo 24 hour urine and serum creatinine collections will be performed for each of the following visits:  Weeks 76, 100 and 104. The serum creatinine for these visits will be collected on the day 
of the initial visit and then 3 days after the initial visit. For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections may be confounders.  The urine 
collection may be postponed up to 14 days at the investigators discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during the 24 hour urine collection. 
F Routine urinalysis and urinary microscopy will be performed locally. 
GFor women of child-bearing potential, a urine pregnancy test is required. The results of the urine pregnancy test must be available prior to dosing. 
HSamples will only be collected in subjects with positive results at baseline. 
IFor PK sampling times, see Section 6.10.1. 
 

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6.4 
Open-Label Extension 
Subjects who successfully complete the initial 104-week double blind period and complete the 
Week 104 assessments may enter into a 6-month open-label extension. The Week 104 visit of 
the double-blind period will serve as the Day 0 visit for subjects entering the 6-month 
open-label extension. In the open-label extension, all subjects will receive 10 mg/kg 
belimumab every 28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the 
last dose). The first dose on the open-label extension will be given at the Week 104 visit of the 
double-blind period after the completion of Week 104 assessments. Subjects participating in 
the open-label extension will continue to be monitored for efficacy and safety as per the study 
calendar (see Table 6-3).  
During the open-label extension, the investigator may adjust concurrent medications (add, 
eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications and 
prohibited doses of medications as outlined in Sections 5.5 and 5.6 will still apply. 
All subjects who withdraw early from the open-label extension will return for an Exit visit 
approximately 4 weeks after their last dose of study agent as well as a follow-up visit 
approximately 8 weeks after the last dose of study agent.  
6.5 
Continuation Phase – For Subjects in Countries where Belimumab 
is not Commercially Available 
Subjects who complete dosing in the 6-month open-label extension and wish to continue 
treatment may do so by being prescribed commercially available product.  
If belimumab is not commercially available in a subject’s country of participation, subjects 
may continue to receive belimumab under this protocol until belimumab becomes 
commercially available. The Day 168/Week 24 visit from the 6-month open-label extension 
will serve as the Day 0 visit for subjects entering the continuation phase. Subjects will 
continue to receive belimumab every 28 days until belimumab becomes commercially 
available. The schedule of assessments representing a 48 week treatment period is provided in 
Table 6-4.   
During the continuation phase, the investigator may adjust concurrent medications (add, 
eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications as 
outlined in Section 5.6 will still apply. 

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

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Table 6-4  
Study Calendar- Continuation Phase (For Subjects in Countries where Belimumab is not Commercially Available)  
Study Day 
Day 0A 
Day 28 visit  
 3 days 
Day 56 visit 
 7 days 
Day 84 visit  
 7 days 
Day 112 visit 
  7 days 
Day 140 visit 
 7 days 
Day 168 visit 
 7 days 
Day 196 visit  
 7 days 
Day 224 visit 
 7 days 
Day 252 visit 
 7 days 
Day 280 visit 
 7 days 
Day 308 visit 
 7 days 
Day 336 visit  
 7 daysE 
ExitB 
8-week 
Follow-up  
+ 7 DaysC 
Study Week 
See Week 28 
Visit  
in Open-Label 
Extension 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
 
 
Record Concurrent Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record/Assess Adverse Events   
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy TestD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Immunogenicity (anti-belimumab antibody) 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Study Agent Administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ADay 0 of the extension portion of the trial is the Week 28 visit of the open-label extension, and represents the first belimumab administration for those subjects participating in the continuation 
phase. 
BAny visit in which the subject discontinues treatment will become the Exit visit. Study agent should not be administered, and all Exit assessments must be completed. 
C The 8-week follow-up visit is to occur approximately 8 weeks after last dose of study agent for subjects who withdraw from the continuation phase and will not be receive commercially 
available belimumab. 
DFor women of child-bearing potential, a urine pregnancy test is required. The results of the urine pregnancy test must be available prior to dosing 
 
This calendar represents a yearly (48 week) ongoing visit schedule until the subject terminates the study.  Week 4 of this calendar represents the next visit (after Week 28 from the 6-month 
open-label extension) for subjects continuing in this protocol where belimumab is not commercially available. Following completion of the Week 48 visit, for subjects in countries where 
belimumab is still not commercially available and wish to continue treatment, the study calendar will be repeated for subsequent years starting with the Week 4 visit. 
 

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

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6.10 Laboratory Tests 
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2, and Table 6-3). 
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): aCL (IgM, IgG, IgA isotypes), ANA, anti-Sm, anti-C1q, and 
serum immunoglobulin isotypes IgM/IgA.  
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis): 
• Peripheral B lymphocytes:  
CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ 
plasmacytoid, 
CD19+/27BRIGHT/38BRIGHT 
SLE 
subset, 
CD19+/CD24HIGH/CD38HIGH 
regulatory B cell and CD20-/138+ plasma cells. 
For the renal function assessments at Baseline (Day 0), Week 24, 48, 52, 76, 100 and 104, the 
glomerular filtration rate (GFR) will be based on creatinine clearance determined from the 
mean creatinine value of 2 contiguous 24 hour urine collections and 2 serum creatinine 
measurements (first serum creatinine collected at initial visit and the second sample taken 
3 days later at the follow-up visit). Subjects will be provided with the materials for collecting 
the two 24 hour urine collections beginning the next morning following their initial clinic 
visit. On the third day following the initial visit, subjects will return to the clinic for the 
second serum creatinine sample. For all other study visits, the simplified MDRD formula 
(below) will be used to estimate GFR (Levey et al, 2000): 
 
eGFR = 186 x serum creatinine-1.154x Age-0.203 x [1.212 if Black] x [0.742 if Female] 
 
The serum creatinine concentration is expressed in mg/dL. 
 
 
It has been demonstrated that there is a strong correlation between the protein content of a 
24-hour urine collection and the urinary protein: urinary creatinine ratio in a single urine 
sample (Ginsberg et al, 1983; Ruggenenti et al, 1998; KDOQI Clinical Practice Guidelines for 
Chronic Kidney Disease 2002; Price et al, 2005). Given this information, spot urinary protein: 
urinary creatinine ratio will be used for determining proteinuria in this study for renal 
response assessments and the SELENA SLEDAI (Appendix 3) disease activity indices when a 
24-hour urine sample is not collected.  
For the urinary sediment assessments, both menstrual cycles and genitourinary tract infections 
may be confounders. The urine collection may be postponed up to 14 days at the investigators 
discretion if menstrual bleeding or a genitourinary tract infection is present at anytime during 
the 24 hour urine collection. 

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Additional instructions regarding collection procedures are provided in the Study Procedures 
Manual and Central Laboratory Manual.  
6.10.1 Pharmacokinetics 
All randomized subjects will be sampled for serum belimumab levels. A blood sample for 
pharmacokinetic analysis will be drawn according to the time schedule below. 
Table 6-5  
PK Visit Days and Sample Times 
Day (Week) 
Time (Related to Dosing of Study Agent) 
Day 0 
Before the start of infusion 
Day 3 
Anytime during visit 
Day 14 (Week 2) 
Prior to dosing, 0-4 hours after the end of infusion 
Day 28 (Week 4) 
Prior to dosing, 0-4 hours after the end of infusion 
Day 56 (Week 8) 
Prior to dosing 
Day 168 (Week 24) 
Prior to dosing, 0 - 4 hours after the end of infusion 
Day 171 (Week 24 + 3 days) 
Anytime during visit 
Day 364 (Week 52) 
Prior to dosing 
Day 728/Exit (Week 104) 
Anytime during visit (or prior to dosing if going into the open-label 
treatment period of the study) 
8-week follow-up 
Any time during visit  
 
On days study agent is administered and blood samples for pharmacokinetic analysis are 
obtained after infusion, blood samples for pharmacokinetic analysis should not be taken from 
the same arm as that used for the administration of study agent. Samples may be obtained by 
venipuncture.   
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.  
6.10.2 Immunogenicity 
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study agent at baseline (Day 0), and at any time 
on Week 8, Week 24, Week 52, Week 76 and Week 104 in the double-blind portion of the 
study. During the open-label extension, a sample will be collected at Week 24. Additionally, a 
sample will be collected at the 8-week follow-up visit. For any subject who had a positive 
antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity 
was assessed if 8-week follow-up immunogenicity sample is not available), an attempt will be 
made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last 
dose of study agent or after completion and/or unblinding of the study, whichever is later.  
6.11 Withdrawal of Subjects from Treatment 
In addition to the reasons for withdrawal detailed below, subjects are free to withdraw from 
treatment or from the study at any time, for any reason, or may be withdrawn/removed, if 
necessary, to protect their health. It is understood by all concerned that an excessive rate of 

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withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of 
subjects should be avoided. Subjects who withdraw from treatment/ study after receiving at 
least 1 dose of study agent will not be replaced.  
Subjects may be withdrawn from treatment for any of the following reasons: 
• Prohibited concurrent medication or prohibited dose of concurrent medication 
(see Sections 5.5 and 5.6). 
• Prohibited therapy. 
• Unacceptable toxicity (see Section 5.4). 
• Pregnancy. 
• Withdrawal of consent (including use and disclosure of research-related health 
information). 
 
All subjects who discontinue treatment during the double-blind period (for reasons other than 
receipt of prohibited medications or doses of medication that result in treatment failure 
designation or withdrawal of consent) should return for all scheduled visits through 
Week 104. 
All subjects who discontinue treatment during the double-blind period for receipt of 
prohibited medications or doses of medication that result in treatment failure designation, or 
discontinue treatment during the open-label extension or continuation phase must complete 
the Exit visit (4 weeks after the last dose of study agent) and a follow up visit 8 weeks after 
the last dose of study agent.  
In the event that a subject withdraws consent during the double-blind period, an attempt 
should be made at the time of consent withdrawal to obtain consent to obtain survival status at 
Week 104. Any subject that withdraws consent for use and disclosure of research-related 
health information will be considered withdrawn from the study and not followed for 
mortality.  
6.12 Subject Unblinding 
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will be 
employed. The study agent will be reconstituted and diluted by the unblinded site pharmacist 
or designee, independent of the study (person responsible for receiving and dispensing study 
agent). Except for a limited number of safety oversight personnel, all study site personnel, the 
subject, the sponsor and the Contract Research Organization (CRO) remain blinded to the 
study agent received and to the results of certain biomarker and pharmacodynamic laboratory 
results. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study. 
If a medical emergency occurs and a decision regarding the subject’s condition requires 
knowledge of the treatment assignment, the study blind may be broken for the specific 
subject. Unless the medical emergency is deemed to be life-threatening, the Medical Monitor 

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

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7.2 
Reporting Adverse Events to the Sponsor 
All adverse events (AEs) that are identified from the start of study agent administration 
(Day 0) through 8 weeks following administration of the last dose of study agent will be 
recorded on the Adverse Event Case Report Form (AE eCRF). All data fields on the AE eCRF 
must be completed.  
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
the Drug Safety designee within 24 hours of site personnel becoming aware of the SAE, 
regardless of expectedness. All pages of the SAE Worksheet should be completed, but the 
SAE Worksheet should not be held until all information is available. Additional information 
and corrections should be provided on subsequent SAE Worksheets as described in the Study 
Procedures Manual. SAE Worksheets should be sent either via the EDC system, if SAE EDC 
functionality is available or by facsimile to the HGS Drug Safety designee using the fax 
number listed on the SAE Worksheet.  
7.3 
Other Events Requiring Rapid Reporting (Protocol Specified 
Events) 
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (See Section 7.1). PSEs are 
recorded on SAE Worksheets and sent to the Drug Safety designee within 24 hours of site 
personnel becoming aware of the event.  
IgG < 250 mg/dL (Grade 4) is a protocol specified event for this protocol.  
7.4 
Laboratory Abnormalities as Adverse Events 
A laboratory abnormality should be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, or concomitant therapy. In addition, any medically important laboratory 
abnormality may be reported as an adverse event at the discretion of the investigator. This 
includes laboratory abnormalities for which there is no intervention but the abnormal value(s) 
suggests a disease or organ toxicity. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC increased). In 
addition, an IgG abnormality < 250 mg/dL (Grade 4) should be recorded as an adverse event 
(and SAE if meeting the criteria in Section 7.1). 
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in the Appendix, the lab test should be graded 
mild, moderate, severe or life-threatening as specified in Section 7.8. 
7.5 
Progressive Multifocal Leukoencephalopathy 
There have been no reported cases of PML in subjects with SLE or RA treated with 
belimumab. However, patients with SLE may be at increased risk for PML secondary to SLE 

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itself, as well as the concurrent use of immunosuppressive drugs. The most common signs and 
symptoms of PML include visual disturbances, ocular movements, ataxia, and mental status 
changes such as disorientation or confusion. Clinical signs and symptoms of PML and SLE 
can be similar. The investigator must exercise best judgment in further workup and clinical 
intervention as appropriate. If PML is suspected, this should be promptly reported to the 
sponsor. 
7.6 
Suicidality Assessment 
Some autoimmune diseases have an increased risk of suicidal behaviour and/or ideation 
(Bachen, 2009; Timonen, 2003; Stenager, 1992). In order to objectively assess suicidality in 
belimumab clinical programs the C-SSRS (Appendix 8 and Appendix 9) will be utilized to 
collect information on suicidal behavior and ideation. SLE patients have an increased 
prevalence of mood and anxiety disorders compared with the general population and disease 
activity may contribute to this higher risk. The incidence of major depressive disorder (MDD) 
among SLE patients has been reported to be as high as 47% (Bachen, 2009). Since active SLE 
and MDD may increase the risk of suicidal ideation or behavior before or during clinical 
studies, subjects participating in the double-blind portion of this study will be assessed for 
suicidality at every visit.  
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 
Questionnaire (PSRHQ, only the first time this condition is met) eCRF and a Possible 
Suicidality Related Questionnaire (PSRQ) eCRF (at all times this condition is met).   
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 and Appendix 9 for 
C-SSRS).  The C-SSRS is a brief measure which is designed to assess severity and change of 
suicidality by integrating both behaviour and ideation (Posner, 2007). The C-SSRS is 
administered by a qualified clinician and is designed to address the need for a summary 
measure to track change in the severity/density of suicidality across both clinical settings and 
treatment trials. It assesses intensity of ideation (a potentially important marker of severity) by 
specifically asking about frequency, duration, intrusiveness, controllability, and deterrents. In 
addition, it captures both the modal and most severe forms of ideation. The C-SSRS is to be 
completed by the investigator or his/her qualified designee at every visit during the double-
blind portion of the study.  
Although assessment of suicidality using the C-SSRS will take place only during the blinded 
portion of the study, investigators are reminded of the importance to clinically assess for 
suicidality at every visit given that SLE patients are at increased risk of suicidal behavior 
and/or ideation. 

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7.6.1 Possible Suicidality Related Questionnaire (PSRQ) 
The investigator will be prompted to complete the PSRQ  (in addition to the AE, SAE pages, 
and PSRHQ as appropriate) if a “yes” response is given to any suicidal behaviour or a “yes” 
response to suicidal ideation questions 3, 4 or 5 on the C-SSRS. If the adverse event meets the 
definition of an SAE, which includes a “yes” answer to any suicidal behaviour or a “yes” to 
suicidal ideation questions 4 or 5 on the C-SSRS, the site must ensure that there are no 
significant discrepancies between the PSRQ and SAE.  
7.7 
Reporting a Pregnancy 
Pregnancies must be reported to the Drug Safety designee within 24 hours of the site 
becoming aware of a pregnancy in a subject. All pregnancies that are identified from the start 
of study agent through 16 weeks following the last dose of study agent should be reported. All 
pregnancies are tracked up to term or delivery following the last study agent treatment. When 
pregnancy is reported, HGS Drug Safety sends an acknowledgement memorandum to the 
principal investigator along with a Pregnancy Assessment Form. A Pregnancy Assessment 
Form must be completed every three months until live birth, elective termination of the 
pregnancy, or miscarriage. The site is responsible for following the subject’s pregnancy to 
final outcome.  
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 7.2 
7.8 
Investigator Evaluation of Adverse Events 
The investigator will evaluate all adverse events with respect to seriousness, severity 
(intensity or grade), and causality (relationship to study agent). The criteria for serious are 
listed in Section 7.1. The severity of an AE is to be evaluated according to the Adverse Event 
Severity Grading Tables in Appendix 7. If an AE does not have Adverse Event Severity 
Grading in Appendix 7, the following severity classifications will be used: 
SEVERITY: 
 
 
Grade 1- Mild 
     - causing no limitation of usual activities. 
 
Grade 2- Moderate  
     - causing some limitation of usual activities. 
 
Grade 3- Severe 
     - causing inability to carry out usual activities. 
 
Grade 4- Life-threatening*   - potentially life-threatening or disabling; significant 
    medical intervention is required. 
 
*Note – a severity assessment of Life-threatening is not necessarily the same as the 
seriousness criterion of Life-threatening. (See “Serious” Criteria Section 7.1.) The former 
means that the event is a potential threat to life. The latter means that the event is an 
immediate threat to life. 

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CAUSALITY: 
Definitely Related  
- reasonable temporal relationship to study agent administration 
- follows a known response pattern (eg, study agent is known to 
  cause this AE) 
- there is no alternative etiology 
 
Probably Related  
- reasonable temporal relationship 
- follows a suspected response pattern (eg, based on similar drugs) 
- no evidence for a more likely alternative etiology  
 
Possibly Related  
- reasonable temporal relationship  
 
 
 
 
 
 
- little evidence for a more likely alternative etiology     
 
Probably Not Related - does not have a reasonable temporal relationship OR 
 
 
 
 
 
 
- good evidence for a more likely alternative etiology    
 
Not Related 
 
 
- does not have a temporal relationship OR 
- definitely due to alternative etiology  
 
The causality assessment must be made by the investigator based on information available at 
the time that the AE eCRF or SAE worksheet is completed. The initial causality assessment 
may be revised as new information becomes available. 
7.9 
Follow-up of Adverse Events 
Adverse events that occur from the start of study agent administration through 8 weeks after 
the date of last administration of study agent are followed until final outcome is known or 
until the end of the 8-week study follow-up period. Adverse events that have not resolved at 
the end of the 8-week study follow-up visit are recorded on the adverse event case report form 
(AE eCRF) as ONGOING.  
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for a particular SAE (eg, the subject is lost to follow-up), then the reason a final 
outcome could not be obtained must be documented by the investigator.  
7.10 Post Study Serious Adverse Events 
SAEs that occur after the follow-up period (ie, 8 weeks after the last dose of the study agent) 
that are assessed by the investigator as having as definitely, possibly or probably related to 
study agent must be reported to the Drug Safety designee on the SAE worksheet as described 
in Section 7.2. Post study SAEs will not be documented on the AE eCRF. 

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7.11 Reporting Serious Adverse Events to Regulatory Authorities and 
Institutional Review Boards/Independent Ethics Committees 
All SAEs that are considered by the sponsor to be unexpected and related to belimumab will 
be reported by the sponsor or designee as expedited (ie, 15-Day) reports to the appropriate 
regulatory authorities AND to all participating investigators (exceptions discussed below). In 
addition, the sponsor or designee follows all applicable local and national regulatory 
requirements regarding safety reporting.  
All unexpected SAEs that are reported to the Sponsor as related to the study agent will be 
reported to investigators and IRBs/IECs irrespective of whether, upon unblinding by the 
Sponsor, the subject is known to have received belimumab or placebo.  This will insure that 
investigators and other investigational site staff do not become unblinded during the study.  
Each investigator must also comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRBs/IECs responsible for reviewing the study at their site, as well as 
the regulatory authority(ies) (if applicable). Regulatory authorities that receive such reports 
directly from the Sponsor will receive unblinded reports for those events where the subject 
was receiving belimumab. 
All serious adverse events, including serious disease-related events (discussed below), will be 
monitored by treatment group by an independent DMC (Section 8.3). Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting, and any recommendations 
made. 
The following conditions (preferred terms; MedDRA v. 14.0) are disease related events that 
can occur in the study population regardless of belimumab exposure. When these conditions 
are considered SAEs, they must be reported to the sponsor within 24 hours of site personnel 
becoming aware as described in Section 7.2. The sponsor will not submit these events as 
expedited reports to regulatory authorities, participating investigators, or IRBs/IECs (unless 
considered by the sponsor to be related to study agent).  
Butterfly rash 
Cutaneous lupus erythematosus 
Glomerulonephritis membranoproliferative  
Glomerulonephritis membranous  
Glomerulonephritis proliferative  
Lupus encephalitis 
Lupus endocarditis 
Lupus enteritis 
Lupus hepatitis 
Lupus myocarditis 
Lupus nephritis 
Lupus pancreatitis 
Lupus pneumonitis 
Lupus vasculitis 
Nephritic syndrome 
Nephritis 
Neuropsychiatric lupus 
Pericarditis lupus 
Peritonitis lupus 
SLE arthritis 
Systemic lupus erythematosus 
Systemic lupus erythematosus rash 
 

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8 Endpoints and Statistical Analysis 
8.1 
General Statistical Considerations 
Unless otherwise specified, all analyses will be performed on the ITT population defined as 
all subjects who are randomized and receive at least 1 dose of study agent. The ITT analysis 
will be performed according to the treatment that a subject was randomized to receive, 
regardless of the actual treatment received. 
The database will be locked for primary analysis after data through the Week 104 visit for all 
subjects have been collected, verified and validated. All subjects and study site personnel will 
remain blinded until the final database lock, which will occur after data have been collected, 
verified and validated for all subjects completing the 8 week follow-up after the open-label 
extension.  
For the analysis of the primary and the major secondary efficacy endpoints, a step-down 
sequential testing procedure will be used to control the overall type 1 error. With this 
procedure, the primary and 2 major secondary endpoints will be evaluated for statistical 
significance based on a pre-specified sequence for interpretation: (1) renal response 
(complete, partial or no response) at Week 104 (2) renal response (complete, partial or no 
response) at Week 52, and (3) complete renal response at Week 104. Specifically, endpoints 
will be tested in the sequence above (2-sided alpha=0.05) provided that statistical significance 
is achieved by all prior tests. If at any point in the sequence statistical significance is not met, 
then subsequent endpoints in the sequence cannot be deemed statistically significant, although 
nominal p values may be reported and considered descriptive. 
Analyses of other efficacy endpoints other than the major secondary efficacy endpoints will 
not be subject to any multiple testing procedure. All statistical tests will be 2-sided and 
performed at an overall significance level of 0.05. 
Received dose for all systemic corticosteroids will be converted to prednisone equivalent. As 
such, when “prednisone” is used throughout this protocol, it refers to prednisone dose or 
equivalent. 
8.2 
Randomization Procedure and Assignment to Treatment Groups 
This is a Phase 3, multi-center, multi-national, randomized, double-blind, placebo-controlled 
study. Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will return for the baseline (Day 0) visit to be 
randomized in a 1:1 ratio (via an Interactive Web Response System) to 1 of 2 treatment 
groups (10 mg/kg belimumab plus standard of care or placebo control plus standard of care.  
The randomization of all eligible subjects will be stratified by their induction regimen (HDCS 
plus CYC vs HDCS plus MMF) and race (black race vs other). 

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8.3 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will review unblinded safety data for 
this Phase 3 program on an ongoing basis until the data are locked and analyzed through 
Week 104 (after which monitoring may be assumed by an internal HGS committee). The 
DMC will include at least 3 physicians and a statistician, none of whom are affiliated with the 
sponsor. The DMC will review the data approximately every 4 months. At all times the sites 
and sponsor will remain blinded to treatment allocation. Events to be monitored during the 
safety review will include, at a minimum, all serious adverse events (including deaths, serious 
psychiatric events, and serious infections), Grade 3 and Grade 4 laboratory abnormalities, 
opportunistic infections (serious and nonserious), malignancies, and hypersensitivity/ 
anaphylactic reactions during the double-blind and open-label extension portions of the study. 
Investigators and IRBs/IECs will be notified of the outcome of each DMC meeting.  
The DMC will receive information within 72 hours of the sponsor or designee receiving 
notification of any IgG < 250 mg/dL and all unexpected causally-related SAEs that are life 
threatening or result in death. Other unexpected, causally-related SAEs will be provided to the 
DMC within 15 calendar days. In addition, the DMC will receive information on all serious 
infections and all opportunistic infections, irrespective of relationship to study agent, within 
15 calendar days. 
8.4 
Sample Size Rationale 
It is expected that approximately 50% subjects on placebo plus standard of care will have 
complete (10%) or partial renal response (40%) at the Week 104 visit (Appel et al, 2009; 
Sinclair et al, 2007). It is expected that renal response in subjects on belimumab plus standard 
of care will be approximately 65% (Complete=15%, Partial=50%). Approximately 464 
subjects will be randomized to achieve 232 subjects in each treatment arm providing 
approximately 90% power to detect the difference in the primary endpoint, based on a 2-sided 
Van Elteren test at the 5% significance level (Zhao et al, 2008).  
8.5 
Efficacy 
8.5.1 Primary Efficacy Endpoint  
The primary efficacy endpoint is renal response at Week 104 measured as an ordinal response 
- complete renal response, partial renal response, or no renal response. Renal response is 
determined by changes in urinary sediment, proteinuria, and renal function. Week 104 renal 
response will be defined by a response at the Week 100 visit that is confirmed by a repeat 
measurement at the Week 104 visit.  Renal response is defined as follows: 
• Complete Renal Response: 
 
Calculated glomerular filtration rate (GFR) is within normal range  
 
AND 
 

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

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

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

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• Baseline complement (C3 and/or C4 low vs other). 
• Baseline complement and anti-dsDNA (C3 and/or C4 low AND anti-dsDNA ≥ 30 IU/mL 
vs other).  
 
8.5.3 Secondary Efficacy Endpoints 
8.5.3.1 
Major Secondary Efficacy Endpoints 
• Renal response measured by complete, partial or no response at Week 52. 
• Proportion of subjects who achieve complete renal response at Week 104. 
 
8.5.4 Other Efficacy Endpoints 
Disease activity 
• Mean and median percentage change from baseline in SELENA SLEDAI score by visit.  
• Proportion of subjects with a > 4 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 5 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 6 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with a > 7 point reduction in SELENA SLEDAI from baseline 
score by visit. 
• Proportion of subjects with improvement and worsening in SELENA SLEDAI organ 
systems (Bombardier, 1992) from baseline by visit. 
• Mean and mean percent change from baseline in SELENA SLEDAI excluding renal items 
by visit. 
 
Flares* 
• Time to first renal flare and the rate of renal flare from Week 24 among subjects with PRR 
or CRR at Week 24. 
• Time to first renal flareand the rate of renal flare from Week 52 among subjects with PRR 
or CRR at Week 52. 
• Time to first severe flare. 
• Time to severe flare after Week 24. 
• Rate of severe flare per 100 subject years over 104 weeks. 
 
*Renal flare will be defined according to FDA Guidance (June 2010); Severe flare will be 
defined by using the modified SLE Flare Index.  Both definitions will be included in full in 
the statistical analysis plan. 

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Renal Specific Measures 
• Individual components of renal response.  Proportion of subjects  with the following by 
visit: 
- 
Inactive urinary sediment (< 5 RBCs/hpf and < 5 WBCs/hpf or within the reference 
range of the laboratory); and no cellular casts (no RBC or WBC casts).  
- 
RBCs/hpf ≥ 50% reduction from baseline and no RBC casts. 
- 
Urinary protein:creatinine ratio < 0.5.  
- 
≥ 50% improvement in the urine protein:creatinine ratio with one of the following:  a 
urine protein:creatinine ratio of < 1.0, if the baseline ratio was ≤ 3.0 OR a urine 
protein:creatinine ratio of < 3.0, if the baseline ratio was > 3.0. 
- 
GFR within the normal range.  
- 
GFR no more than 10% below the baseline value.  
• Percent change in proteinuria by visit. 
• Proportion of subjects with a doubling of the serum creatinine or progression to end stage 
renal disease (ESRD) as defined below: 
- 
Doubling of serum creatinine compared with baseline that is confirmed with a second 
measurement at least 3 weeks later. 
- 
Progression to ESRD defined as the need for chronic dialysis or renal transplantation. 
• Duration of longest complete or partial renal response (CRR/PRR) in all subjects 
achieving at least 1 response. 
• Duration of CRR in all subjects achieving at least 1 CRR. 
• Time to first PRR/CRR that is maintained through Week 52. 
• Time to the first PRR/CRR that is maintained through Week 104. 
• Time to the first CRR that is maintained through Week 52. 
• Time to the first CRR that is maintained through Week 104. 
• Time to sustained (≥ 3months) complete or partial renal response (CRR/PRR) after 
Week 24. 
• Time to sustained (≥ 3months) CRR after Week 24. 
• Proportion of subjects with CRR by visit. 
• Proportion of subjects with CRR and/or PRR by visit. 
 
Corticosteroid Use 
• Proportion of subjects receiving ≤ 5 mg/day prednisone by visit. 
• Proportion of subjects receiving ≤ 10 mg/day prednisone by visit. 
 
Biomarkers 
1. Median/mean percent change and median/mean absolute change from baseline in absolute 
B cell subsets (CD20+, CD20+/27+ memory, CD20+/27– naïve, CD20+/69+ activated, 
CD20+/138+ plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset, 

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CD19+/CD24HIGH/CD38HIGH regulatory B cell, and CD20-/138+ plasma cells) by visit. 
Only in regions/countries where assessment of B cells is feasible.  
2. Median/mean percent change and median/mean absolute change from baseline by visit  
- 
Total serum immunoglobulin (IgG and other isotypes: IgM and IgA). 
- 
Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q). 
- 
Complement (C3, C4) levels. 
3. Percent of patients with normalized serological activity at Week 104 and over time 
- 
IgG, IgM and IgA (high to normal/low). 
- 
Autoantibodies* (anti-dsDNA, ANA, aCL, anti-Sm, and anti-C1q) present to absent. 
- 
Complement (C3, C4, and C3 AND C4) levels low to normal/high. 
 
* Anti-dsDNA will be collected monthly throughout the double-blind treatment period. Other 
autoantibodies will be collected from all patients at baseline, then at regular intervals during 
the study.  
8.5.5 Secondary Efficacy Analyses 
8.5.5.1 
Major Secondary Efficacy Analyses 
Renal response (complete, partial or no response) at the Week 52 visit will be analyzed using 
the same method as for the primary endpoint. The proportion of subjects who achieve a 
complete renal response at the Week 104 visit will be compared between the belimumab 
treatment group and placebo using a logistic regression model. The independent variables in 
the model will include treatment group (ie, 10 mg/kg belimumab vs placebo) and the baseline 
randomization stratification factors.  
8.5.6 Other Efficacy Analyses 
The analysis of all other efficacy endpoints will be described in the statistical analysis plan. 
8.6 
Safety 
8.6.1 Definition of Safety Variables 
Safety will be evaluated by adverse events, changes in laboratory parameters, and 
immunogenicity. 
8.6.2 Analysis of Safety Variables 
AEs will graded for severity by the investigator using Adverse Event Severity Grading Tables 
(Appendix 7) or the grades in Section 7.8, as appropriate. The frequency of AEs will be 
tabulated by MedDRA system organ class (SOC) and preferred term. Additional analysis may 
be performed based on event rates adjusting for subject-years on study agent if the dropout 
rates are unbalanced across treatment groups. AEs will also be summarized by MedDRA SOC 
and preferred terms for those that are considered to be severe (Grade 3 and Grade 4) and those 
that are considered serious. Discontinuations due to AEs will be summarized.  
The frequency of laboratory abnormalities will be tabulated by treatment group. Laboratory 
values will be assessed for significant changes from baseline. Laboratory toxicity will be 

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graded using Adverse Event Severity Grading Tables (Appendix 7) when possible. Shift 
tables will be used to determine if subjects move from normal to abnormal during the course 
of the study. Shifts of ≥ 2 grades and Grade 3 or 4 laboratory abnormalities will be 
summarized. 
Safety Endpoints of Special Interest 
• All cause mortality 
• Serious and/or severe infections 
• Opportunistic infections 
• Malignant neoplasms 
• Selected serious psychiatric events 
• Suicidality assessment (see Appendix 8 and Appendix 9) 
• Hypersensitivity reactions/anaphylaxis 
• Immunogenicity 
 
The analyses of these safety endpoints will be described in the statistical analysis plan. 
 
8.7 
Pharmacokinetics 
8.7.1 Definition of Pharmacokinetic Evaluation 
All randomized subjects will be sampled for serum belimumab levels. Serum belimumab 
concentration data will be used in a population PK analysis. Assessment of belimumab 
concentrations will be performed at the timepoints indicated in Section 6.10.1. 
8.7.2 Analysis of Pharmacokinetics 
Serum belimumab concentration will be determined by an electrochemiluminescence (ECL)-
based assay. Results for this study will be presented using appropriate graphic and tabular 
summaries. Serum belimumab concentration data obtained from this study will be used in a 
population PK analysis, which will be reported separately. Potential effects of demographic 
and disease characteristics, concurrent medications or renal function on belimumab PK will be 
evaluated.  
9 Pharmacogenetics (PGx) 
In consenting subjects, a blood sample for PGx research will be drawn predose at baseline 
(Day 0) to better characterize genetic variability (eg, HLA typing) that may affect efficacy or 
safety endpoints. Information regarding PGx research is included in Appendix 6. 
The IEC/IRB and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the study site. The approval(s) must be in 
writing and clearly specify approval of the PGx assessments (ie, approval of Appendix 6). In 
some cases, approval of the PGx assessments can occur after approval is obtained for the rest 
of the study. If so, then the written approval will clearly indicate that approval of the PGx 

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assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments are not approved, then approval for the rest of the study will clearly 
indicate this and that PGx assessments will not be conducted. 
10 Study Administration 
Belimumab is under joint development by Human Genome Sciences, Inc. and 
GlaxoSmithKline Pharmaceuticals. Human Genome Sciences, Inc. is the sponsor of this 
study. 
10.1 Informed Consent 
A copy of the proposed informed consent document must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 
form must be approved by the IRB/IEC and contain all elements required by national, state, 
local, and institutional regulations or requirements. 
It is the responsibility of the investigator to provide each subject with full and adequate verbal 
and written information using the IRB/IEC approved informed consent document(s), 
including the objective and procedures of the study and the possible risks involved before 
inclusion in the study. Each subject must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information). The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal patient care, including screening and changes in medications including any washout of 
medications. A copy of the signed informed consent must be given to the study subject. 
10.2 Institutional Review Board Review/Independent Ethics Committee 
Review and Approval 
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with the ICH Guideline for Good Clinical Practice (GCP), 
will provide initial and continuing review of the study. 
Prior to shipment of the study agent and enrollment of study subjects, documented IRB/IEC 
approval of the protocol, informed consent form, and any advertisement for subject 
recruitment must be obtained and provided to the sponsor or designee. 
The IRB/IEC must also be informed of all protocol amendments prior to implementation. The 
investigator must provide reports of any change in research activity (ie, the completion, 
termination, or discontinuation of a study) to the IRB/IEC. 
10.3 Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC. 

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10.4 Protocol Revisions 
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form, the informed consent 
form must be revised accordingly and submitted to the IRB/IEC for review and approval. The 
approved consent form must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment. 
10.5 Data Collection and Management 
The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. The investigator is also responsible for maintaining any source documentation 
related to the study, including any films, tracings, computer discs, or tapes.  
The anonymity of participating subjects must be maintained. For data collection and 
management purposes, subjects are to be identified by a subject number only. Documents that 
identify the subject beyond subject number will not be submitted to the sponsor (eg, the 
signed informed consent document; subject initials) and must be maintained in strict 
confidence by the investigator, except to the extent necessary to allow auditing by the 
regulatory authorities, study monitor, or sponsor representatives. 
Site personnel record all data for each study subject through electronic case report forms 
(eCRFs) using an Electronic Data Capture (EDC) system provided and approved by the 
sponsor. Refer to the Study Procedures Manual for additional information regarding CRFs 
that will be used as source documentation. Sites must complete the eCRFs in a timely manner 
and the investigator must promptly review the completed eCRFs for each subject. As the 
person ultimately responsible for the accuracy of all eCRF data, the investigator must sign the 
Investigator's Statement in each subject's eCRF. 
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system, so as to ensure accuracy, quality, consistency, and completeness of 
the database. Manual queries resulting from review by monitors, medical coders, and other 
Data Management staff are also generated from within the EDC system, where they are 
tracked. Sites resolve the queries and correct the entered data when necessary. Every change 
to data is captured in the EDC system audit trail. Upon completion of the study, or after 
reaching a pre-specified point in the study, Data Management will lock the database and 
generate the SAS datasets necessary for data analysis and reporting. Upon completion of the 
study, each site will be provided with a compact disc (CD) containing the eCRFs for each of 
their subjects. 

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10.6 Study Monitoring 
The study sponsor or designee will monitor the study. Study monitors representing the 
sponsor will visit study sites routinely throughout the trial. The sponsor will review eCRFs 
and compare them with source documents to verify accurate and complete collection of data 
and confirm that the study is being conducted according to the protocol. Auditors representing 
the sponsor may also similarly evaluate the study and its monitors. For these purposes, the 
investigator will make eCRFs and source documents available when requested.  
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority. 
10.7 Drug Accountability 
Upon receipt of the study agents, the designated pharmacy personnel at the study site is 
responsible for taking an inventory of the study agent, including any buffers or diluents. A 
record of this inventory must be kept and usage must be documented on study agent inventory 
forms provided by the sponsor.  
Study agent inventory forms will be examined and reconciled by a sponsor’s blinded monitor, 
or designee. At the end of the study, all used and unused study agent must be accounted for on 
a study agent accountability form provided to the investigator by the sponsor or its designee. 
10.8 Retention of Records 
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the sponsor at the time the study is completed, terminated or 
discontinued. 
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor. 
10.9 Financial Disclosure 
The Investigator and all Sub-Investigators will provide the sponsor sufficient and accurate 
information on financial interests (proprietary or equity interests, payments exclusive of 
clinical trial costs) to allow complete disclosure to regulatory authorities. The investigators 
shall promptly update this information if any relevant changes occur during the course of the 
investigation and for a period of 1 year following study completion. 
10.10 Publication Policy 
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 

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acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the sponsor 
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites. 
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until all of the 
sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by sponsor to be confidential information has been removed. If 
requested in writing by the sponsor, the investigator shall withhold material from submission 
for publication or presentation for an additional 60 days to allow for the filing of a patent 
application or the taking of other measures to establish and preserve the sponsor’s proprietary 
rights. 
10.11 Study or Study Site Termination 
If the sponsor, the investigator, IRB/IEC or a regulatory authority discovers conditions arising 
during the study that indicate that the study should be halted or that the study center should be 
terminated, this action may be taken after appropriate consultation between the sponsor and 
the investigator. Conditions that may warrant termination of the study include, but are not 
limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
• A decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
 
The study site may warrant termination under the following conditions: 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory authority regulations. 
• Submission of knowingly false information from the research facility to the sponsor, study 
monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 
 

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11 References 
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Women with Systemic Lupus Erythematosus. Arthritis Rheum (Arthritis Care and Research). 
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Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease 
activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis 
Rheum 1992;35(6):630-40. 
Buyon JP, Petri MA, Kim MY, et al. The Effect of Combined Estrogen and Progesterone 
Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A 
Randomized Trial. Ann Internal Med 2005;142(12 Pt 1):953-62. 
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables, May 2007. 
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lttox.doc  
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables, May 2001.  
Eibl MM and Rosen FS. Intravenous gamma globulin and plasmapheresis. In Frank MM et al 
(eds): Samter's Immunologic Diseases (5th ed.). Boston: Little, Brown, 1995;1529-36. 
Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate 
quantitative proteinuria. N Engl J Med 1983;309(25):1543-6. 
Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development 
and initial validation of the Systemic Lupus International Collaborating Clinics/American 
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Goldfarb NS, Avery RK, Goormastic M, et al. Hypogammaglobulinemia in lung transplant 
recipients. Transplantation 2001;71(2):242-6. 
Gordon C, Hayne D, Pusey C, et al. European Consensus Statement on the Terminology used 
in the Management of Lupus Glomerulonephritis. Lupus 2009;18:257-263.  
Hochberg MC. Updating the American College of Rheumatology revised criteria for the 
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Houssiau FA, Vasconcelos C, D’Cruz D, et al. Early Response to Immunosuppressive therapy 
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Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive Therapy in Lupus 
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Jiménez S, Cervera R, Font J, et al. The epidemiology of systemic lupus erythematosus. Clin 
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Kotzin BL. Systemic lupus erythematosus. Cell 1996;85(3):303-6. 
Levey AS, Greene T, Kusek JW, et al. A simplified equation to predict glomerular filtration 
rate from serum creatinine (Abstr) J Am Soc Nephrol 2000;(11):155A. 
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Human Services. Available on-line at www.hhs.gov. 
Office of Minority Health Resource Center (OMHRC), HHS 2001. Available on-line at 
www.omhrc.gov 
Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. 
Lupus 1999;8:685-91. 
Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic 
lupus erythematosus. N Engl J Med 2005;353:2550-8. 
Pisetsky DS. Immune recognition of DNA in SLE. Clinical Immunology and 
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Posner K, Oquendo MA, Gould M, Stanley, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s Pediatric 
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Price CP, Newall RG, Boyd JC. Use of Protein:Creatinine Ratio measurements on random 
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Ruggenenti P, Gaspari F, Perna A, et al. Cross sectional longitudinal study of spot morning 
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Sinclair A, Appel G, Dooley MA, et al. Mycophenolate mofetil as induction and maintenance 
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Yamani MH, Avery RK, Mawhorter SD, et al. Hypogammaglobulinemia following cardiac 
transplantation: a link between rejection and infection. J Heart Lung Transplant 
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List of Appendices 
Appendix 1 
American College of Rheumatology (ACR) Criteria for SLE ...................... 76 
Appendix 2 
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 
2003 Classification of Lupus Nephritis ........................................................ 77 
Appendix 3 
SELENA SLEDAI Disease Assessment Scales ........................................... 78 
Appendix 4 
SLICC/ACR Damage Index ......................................................................... 81 
Appendix 5 
Laboratory Tests ........................................................................................... 83 
Appendix 6 
Pharmacogenetic Research ........................................................................... 84 
Appendix 7 
Adverse Event Severity Grading Tables ....................................................... 88 
Appendix 8 
Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline/Screening .... 97 
Appendix 9 
Columbia- Suicide Severity Rating Scale (C-SSRS) Since Last Visit ....... 114 
 
 

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Appendix 1 
American College of Rheumatology (ACR) Criteria for 
SLE 
 
The ACR Criteria for the Classification of Systemic Lupus Erythematosus 
(Tan et al, 1982, and Hochberg, 1997) 
 
Criterion 
Definition 
1. Malar "butterfly" rash  
Fixed erythema, flat or raised, over the malar eminences, tending to spare 
the nasolabial folds. 
 
2. Discoid rash  
Erythematosus raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring may occur in older lesions. 
 
3. Photosensitivity  
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation. 
 
4. Oral ulcers  
Oral or nasopharyngeal ulceration usually painless. 
 
5. Arthritis  
Nonerosive arthritis involving 2 or more peripheral joints characterized by 
tenderness. 
 
6. Serositis  
a. Pleuritis (convincing history or pleuritic pain or rub heard by physician or 
evidence of pleural effusion), OR 
b. Pericarditis (documented by ECG, rub, or evidence or pericardial 
effusion). 
 
7. Renal disorder  
a. Persistent proteinuria (> 0.5 grams/day or > 3 + if quantitation not 
performed) OR 
b. Cellular casts (may be red cell, hemoglobin, granular, tubular, or mixed). 
 
8. Neurologic disorder  
a. Seizures (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance) OR 
b. Psychosis (in the absence of offending drugs or known metabolic 
derangements; ie, uremia, ketoacidosis, or electrolyte imbalance. 
 
9. Hematologic disorder  
a. Hemolytic anemia (with reticulocytosis) 
 
OR 
b. Leukopenia (< 4000/mL total on 2 or more occasions), OR 
c. Lymphopenia (<1500/mL on 2 or more occasions), OR 
d. Thrombocytopenia (< 100,000/mL in the absence of offending drugs). 
 
10. Immunologic disorder  
a. Anti-DNA (antibody to native DNA in abnormal titer), OR 
b. Anti-Sm (presence of antibody to Sm nuclear antigen), OR 
c. Positive-finding of antiphospholipid antibodies based on 1) an abnormal 
serum level of IgG or IgM anticardiolipin antibodies, 2) a positive test 
result for lupus anticoagulant using a standard method, or 3) a false-
positive serologic test for syphilis known to be positive for at least 6 
months and confirmed by Treponema pallidum immobilization (TPI) or 
fluorescent treponemal antibody (FTA) absorption test. 
 
11. Antinuclear antibody (ANA) 
Abnormal titer of ANA by immunofluorescence or an equivalent assay at any 
point in time and in the absence of drugs known to be associated with "drug-
induced lupus" syndrome. 
*The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a 
person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, 
serially or simultaneously, during any interval or observation. 
 

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

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

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

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

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

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

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Appendix 5 
Laboratory Tests 
 
Hematology 
 
Urinalysis 
Modified Chem-20 
Total white blood cell count 
Differential: 
 
Absolute Neutrophils 
 
 
Segmented Neutrophils 
 
 
Band Neutrophils 
 
 
Myelocytes 
 
 
Metamylocytes 
 
 
Promyelocytes 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Hemoglobin 
Hematocrit 
Red blood cell (RBC) count 
Platelet count 
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
Serum Pregnancy  
Protein 
Glucose 
Ketones 
Occult blood 
Microscopic examination 
including: 
WBC per hpf 
RBC per hpf 
Dysmorphic RBC 
Casts (specified by type 
eg, RBC, WBC) 
Urine Pregnancy 
Spot urine 
24-hour urine 
Electrolytes: 
 
Sodium 
 
Potassium 
 
Magnesium 
 
Chloride 
 
Carbon dioxide 
 
Calcium adjusted for Albumin 
 
Inorganic Phosphate 
Enzymes: 
 
SGOT (AST) 
 
SGPT (ALT) 
 
Alkaline Phosphatase 
 
Gamma glutamyl transferase (GGT) 
 
Lactic dehydrogenase (LDH) 
Other: 
 
Creatinine 
 
Blood urea nitrogen (BUN) 
 
BUN/creatinine ratio 
 
Bilirubin, total 
 
Protein, total  
 Albumin 
 
Uric acid 
 
Glucose 
  
 
Infectious Disease Screening 
HIV-1/2 antibody 
Hepatitis C antibody 
Hepatitis B surface antigen 
 
 
Autoantibodies 
ANA  
Anti-dsDNA 
aCL (IgG, IgA and IgM isotypes) 
Anti-Sm 
Anti-c1q 
*When 24 hour urines are 
collected, the calculated GFR 
will be based on the mean 
value of two 24 hour urine and 
serum creatinine collections. 
For 
all 
other 
visits, 
the 
simplified MDRD formula will 
be used to estimate GFR and 
the spot urine method will be 
used 
for 
the 
proteinuria 
assessments. 
The 
urine 
microscopy 
and 
routine 
urinalysis will be performed 
locally. All other tests will be 
performed 
by 
a 
central 
laboratory.  
Biological Markers 
BLyS protein  
Serum complement (C3 and C4)  
 
FACS of peripheral lymphocytes: B lymphocytes (CD20+, CD20+/27+ 
memory, CD20+/27– naïve, CD20+/69+ activated, CD20+/138+ 
plasmacytoid, CD19+/27BRIGHT/38BRIGHT SLE subset 
CD19+/CD24HIGH/CD38HIGH regulatory B cell and CD20-/138+ plasma 
cells)   Note: May be collected in selected sites/regions. 
 
 
Immunoglobulins 
Serum immunoglobulin isotypes: IgG, IgM, IgA 
 
Belimumab PK and Immunogenicity 
 

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Appendix 6 
Pharmacogenetic Research 
 
Background 
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors 
in different populations. There is increasing evidence that an individual's genetic composition 
(ie, genotype) may impact pharmacokinetics, pharmacodynamics (relationship between 
concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or 
clinical outcome (in terms of efficacy and/or safety and tolerability). 
A key component to successful PGx research is the collection of samples during the conduct 
of clinical studies.  
Research Rationale 
Blood samples for pharmacogenetics will be drawn as described in Section 9. Collection of 
whole blood samples, even when no a priori hypothesis has been identified, may enable PGx 
analyses to be conducted if there is unexplained or unexpected variation in response to 
belimumab.  
If at any time it appears there is potential variability in response in this clinical study or in a 
series of clinical studies with belimumab that may be attributable to genetic variations of 
subjects, the following objectives may be investigated:  
• Relationship between genetic variants and the pharmacokinetics of belimumab. 
• Relationship between genetic variants and safety and/or tolerability of belimumab. 
• Relationship between genetic variants and efficacy of belimumab. 
 
Study Population 
Any subject who has given informed consent to participate in the clinical study, has met all 
the entry criteria for the clinical study, and receives belimumab may take part in the PGx 
research.  
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or 
loss of benefits to which the subject would otherwise be entitled. 
Informed Consent 
Subjects who do not wish to participate in the PGx research may still participate in the clinical 
study. PGx informed consent must be obtained prior to any blood being taken for PGx 
research. 

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Study Assessments and Procedures 
In addition to any blood samples drawn for the clinical study, a whole blood sample (~10 mL) 
will be collected for the PGx research at baseline. The PGx sample is labeled (or coded) with 
a study specific number that can be traced or linked back to the subject by the investigator or 
site staff. Coded samples do not carry personal identifiers (such as name or social security 
number). The blood sample will be taken on a single occasion unless a duplicate sample is 
required due to inability to utilize the original sample. The blood samples should be drawn on 
Day 0 (baseline), provided informed consent for PGx research has been obtained from the 
subject, but the sample may be taken at any time while the subject is participating in the 
clinical study.  
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA will be 
subjected to sample quality control analysis. This analysis will involve the genotyping of 
several genetic markers to confirm the integrity of individual samples. If inconsistencies are 
noted in the analysis, then those samples may be destroyed.  
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
belimumab has been completed and the study data reviewed. In some cases, the samples may 
not be studied.  
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or the sponsor may destroy the samples sooner. The sponsor or those 
working with the sponsor (for example, other researchers or a contract lab) will use samples 
collected from the study for the purpose stated in this protocol and in the subject informed 
consent form. 
Subjects may request their sample to be destroyed at any time. 
Subject Withdrawal from Study 
If a subject who has consented to participate in PGx research and has a sample taken for PGx 
research withdraws from the clinical study for any reason other than lost to follow-up, the 
subject will be given the following options: 
1. The sample is retained for PGx research. 
2. The sample is destroyed. 
 
If a subject withdraws consent from the PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by the sponsor and maintain the documentation in 
the site study records. In either case, the sponsor will only use study information 
collected/generated up to that point. 

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

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

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

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

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

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

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

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

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

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

Human Genome Sciences, Inc. 
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Belimumab 
 
 
 
 
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 

Human Genome Sciences, Inc. 
Confidential 
Page 97 
Protocol HGS1006-C1121 
 
Belimumab 
 
 
Appendix 8 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening 
 

Human Genome Sciences, Inc. 
Confidential 
Page 98 
Protocol HGS1006-C1121 
 
Belimumab 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices,
which are protected by third party copyright laws and therefore have been excluded.

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

Human Genome Sciences, Inc. 
Confidential 
Page 114 
Protocol HGS1006-C1121 
 
Belimumab 
 
 
Appendix 9 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit 

Human Genome Sciences, Inc. 
Confidential 
Page 115 
Protocol HGS1006-C1121 
 
Belimumab 
 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices,
which are protected by third party copyright laws and therefore have been excluded.

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

PPD
PPD
PPD
PPD
PPD