A Randomized, Double-Blind, Placebo-Controlled 52-Week Study to Assess Adverse Events of Special Interest in Adults With Active, Autoantibody-Positive Systemic Lupus Erythematosus Receiving Belimumab
Phase: PHASE4
Conditions: Systemic Lupus Erythematosus
Sponsor: GlaxoSmithKline

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CLINICAL PROTOCOL HGS1006-C1113 
Protocol Amendment: 04 
EudraCT Number: 2011-005667-25 
Date: 25 NOV 2020 
 
 
TITLE OF STUDY: A Randomized, Double-Blind, Placebo-Controlled 52-Week 
Study to Assess Adverse Events of Special Interest in Adults with Active, 
Autoantibody-Positive Systemic Lupus Erythematosus Receiving Belimumab  
 
 
 
 
 
STUDY SPONSOR: 
GlaxoSmithKline, LLC 
 
5 Crescent Drive 
 
Philadelphia, Pennsylvania 19112 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.   
Unauthorised copying or use of this information is prohibited. 
 
 

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REVISION CHRONOLOGY FOR HGS1006-C1113 (BEL115467) 
 
Date 
Document* 
 
Global 
 
08 March 2012 
Original 
Global 
 
01 August 2012 
Amendment No 01 
Local 
2013N162025_00 
15 March 2013 
Local Amendment No 01 for Lithuania 
Global 
2016N273856_00 
13 July 2016 
Amendment No 02 
 
Global 
2016N273856_01 
22 May 2017 
Amendment No 03 
Global 
2016N273856_02 
25 Nov 2020 
Amendment No 04 
 
*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 and any other institutional requirements. 
 
 
Principal Investigator: 
 
 
 
Signature  
 
 
 
 
 
 
 
Date 
 
 
 
Name (please type or print) 
 
 
 
Institution 
 
 
 
Address (must include country name) 
 
 
 
 
 

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Study Synopsis 
Study Number: HGS1006-1113  
Title of the Study: A Randomized, Double-Blind Placebo-Controlled 52-Week Study to 
Assess Adverse Events of Special Interest in Adults with Active, Autoantibody-Positive 
Systemic Lupus Erythematosus Receiving Belimumab 
Objectives: 
The objectives of this study are to evaluate the following in adult SLE subjects receiving 
belimumab plus standard therapy versus subjects receiving placebo plus standard therapy: 
• Mortality and adverse events of special interest over 1 year (52 weeks). 
• Corticosteroid reduction during Weeks 40-52. 
 
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria: 
1. Males or females ≥ 18 years. 
2. Have a diagnosis of SLE, refer to ACR revised criteria for the classification of SLE 
(Appendix 1) as a guide for diagnosis of SLE. 
3. Active, autoantibody positive SLE (autoantibody positive is defined as the presence of 
ANA or anti-dsDNA antibodies). 
4. Are on a SLE treatment regimen consisting of any of the following medications (alone 
or in combination):  
• Corticosteroids 
• Other 
immunomodulatory 
agents 
including 
methotrexate, 
azathioprine, 
leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate 
mofetil hydrochloride, and mycophenolate sodium), calcineurin inhibitors (eg, 
tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine, or 
thalidomide. 
• Anti-malarials [eg, hydroxychloroquine, chloroquine, quinacrine (mepacrine)] 
5. A female subject is eligible to enter the study if she is:  
• Not pregnant or nursing;  
• Of non-childbearing potential defined as: 
• pre-menopausal females with a documented tubal ligation,  hysterectomy, 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, or documented bilateral 
oophorectomy or 
• postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile [e.g., > 45 years, in the absence of hormone 
replacement therapy or other cause for amenorrhea]; in questionable cases 
obtain a blood sample for follicle stimulating hormone (FSH) and estradiol 
simultaneously to confirm. Diagnostic levels for FSH and estradiol vary by 
specific laboratories/assays; 

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• OR is of child-bearing potential with negative pregnancy test as determined by 
urine human chorionic gonadotrophin (hCG) test at screening and urine hCG test 
prior to dosing AND 
• Agrees to use one of the contraception methods listed in the protocol (see 
Section 4.3) for 2 weeks prior to the day of dosing to sufficiently minimize the 
risk of pregnancy at that point.  Female subjects must agree to use contraception 
until 16 weeks following the last dose of study agent. 
• OR has only same-sex partners, when this is her preferred and usual lifestyle. 
6. 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 data collection procedures [including 
annual contacts from Years 2 through 5 (Week 260) to assess mortality and 
malignancy]. 
 
Exclusion Criteria: Subjects will be excluded from participating in the study if they meet 
any of the following exclusion criteria: 
1. Have received any prior treatment with belimumab, either as a marketed product or as 
an investigational agent. 
2. Have received treatment with B cell targeted therapy (eg, rituximab, other anti-CD20 
agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion 
protein [BR3], TACI-Fc, anti-BAFF [LY2127399]) within 364 days of Day 0. 
3. Have received any of the following within 90 days of Day 0:  
• Any biologic agent (eg, adalimumab, etanercept, infliximab, anakinra) other than 
B cell targeted therapy (see Exclusion Criterion 2). 
• Plasmapheresis. 
4. Have received any of the following within 60 days of Day 0: 
• A non-biologic investigational agent.  
5. Have received any of the following within 30 days of Day 0: 
• A live vaccine.  
6. 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.  
7. Have required management of acute or chronic infections, as follows: 
• Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria). 
• Hospitalization for treatment of infection within 60 days of Day 0. 
• Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of Day 0. 
8. Have severe lupus kidney disease (defined by proteinuria > 6 g/24 hour or equivalent 
using spot urine protein to creatinine ratio, or serum creatinine > 2.5 mg/dL), or have 
severe active nephritis requiring acute therapy, or have required hemodialysis or 
high-dose prednisone or equivalent (> 100 mg/day) within 90 days of Day 0.  

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9. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, 
organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) 
requiring therapeutic intervention. 
10. Known HIV infection.  
11. Current or history of hepatitis B or hepatitis C infection.  
12. Only applicable to Lithuanian sites: 
• Have hypogammaglobulinaemia (IgG <400 mg/dL) or a deficiency in 
immunoglobulin A (IgA <10 mg/dL). 
• Have had renal, stem cell/marrow or other major organ transplant. 
• Have a chronic infection or a history of recurrent infections, which in the opinion 
of the investigator poses a significant risk to the subject. 
• Have received cyclophosphamide via any route of administration within 90 days of 
Day 0. 
 
Study Design and Schedule:  
This is a global, multi-center, randomized, placebo-controlled study to evaluate adverse 
events of special interest in adults with active, autoantibody-positive systemic lupus 
erythematosus (SLE) treated with belimumab plus standard therapy vs placebo plus 
standard therapy. It was initially planned that approximately 5,000 subjects would be 
randomized to 1 of 2 treatment groups: belimumab 10 mg/kg (2,500 subjects) or placebo 
(2,500 subjects) plus standard therapies. Subseqent to the completion of 2 additional 
placebo-controlled trials, it was estimated based on data from all 5 of the completed Phase 
2/3 trials that adverse event rates could be assessed with the same planned level of precision 
with a total sample size of 4,000 subjects. Consequently, a sample size reduction was 
proposed to and accepted by the FDA and EMA regulatory authorities. 
Subjects will receive study agent (belimumab or placebo) on Days 0, 14, 28 and 
approximately every 28 days thereafter through Week 48 with a final visit conducted at 
Week 52. Subjects who discontinue treatment at any time during the 52-week study will 
be followed for mortality and malignancy including non-melanoma skin cancers (NMSC) 
at 1 year (through Week 52) and annually for Years 2 through 5.  
Subject data will be collected at randomization and subsequently at approximately 28-day 
intervals for 52 weeks. Subjects will be assessed for malignancies including NMSC, 
serious infections, opportunistic infections and other infections of interest, selected serious 
psychiatric events, suicidality, and serious infusion and hypersensitivity reactions. All 
cause mortality will be reported. All other serious adverse events (SAEs), irrespective of 
causality, will also be recorded. Medical history will be collected on all subjects. 
Immunomodulatory agents used to treat SLE at baseline and during study, hospitalizations, 
and organ damage (SLICC/ACR Damage Index) will also be assessed through Week 52. 
All subjects will have a follow-up visit performed approximately 4 weeks after the last 
dose of study agent. In the event that a subject withdraws consent to participate in the first 
year monthly study visits, an attempt should be made at the time of consent withdrawal to 
obtain consent to contact the subject at Week 52 and annually for Years 2 through 5 (Week 
260) to assess mortality and malignancy (including NMSC).  

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Subjects may continue to receive their other SLE medications including corticosteroids, 
immunomodulatory agents and antimalarials; changes in these SLE medications during the 
trial will be permitted as clinically indicated. No concomitant biological therapies will be 
allowed during the 52-week study. In the event that the treating physician decides that a 
subject requires the addition of a biologic agent before Week 52, the subject is withdrawn 
from study agent treatment, but is followed on the study through Week 52 and annually for 
Years 2 through 5 (Week 260).  
Following the 52-week study, all subjects will be contacted annually through Year 5 (Week 
260) to assess mortality and malignancy (including NMSC). 
At the end of the 52-week study, subjects who wish to continue treatment may be able to 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may be able to 
receive belimumab under a separate continuation protocol. A separate informed consent 
will need to be provided for the continuation protocol. 
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data 
for this study on an ongoing basis until the data are locked and analyzed. The IDMC will 
include at least 3 physicians, and a statistician, none of whom are affiliated with the 
sponsor. The first IDMC meeting will review the data after approximately 500 subjects 
have been treated or 6 months from randomization of the first patient, whichever is first. 
After the initial review, the IDMC will continue to review the data approximately every 6 
months. Events to be monitored during the safety review will include at a minimum all 
serious adverse events (including deaths, serious psychiatric events and serious infections), 
opportunistic infections (serious and nonserious) and other infections of interest, 
malignancies (including NMSC), and serious infusion and hypersensitivity reactions. 
Investigators and IRBs/IECs will be notified of the outcome of each IDMC meeting.  
Endpoints and Statistical Analysis: 
The main purpose of this study is to provide an evaluation of the difference in the rates of 
all prespecified AESI and all cause mortality between the belimumab and the placebo 
groups with a 2-sided 95% confidence interval (CI). SAEs will be analyzed descriptively 
only.  

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Safety Endpoints: 
The table below describes the safety endpoints and measures collected in the study.  
All-cause mortality 
Serious Infections (including serious opportunistic infections and any event of TB or TB reactivation) 
Non-serious opportunistic infections and other infections of interest (Appendix 2) 
Malignancies (excluding NMSC) 
Non-melanoma skin cancers 
Psychiatric events suggesting serious mood disorders and anxiety 
Suicidality (using C-SSRS; Appendix 4 and Appendix 5) 
Serious Infusion and Hypersensitivity Reactions 
All SAEs 
 
Efficacy Endpoints: 
The major efficacy endpoint is: 
• Percent of subjects whose average prednisone (or equivalent) dose has been reduced 
by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 (in the subgroup 
of subjects receiving > 7.5 mg/day of prednisone (or equivalent) at baseline). 
 
Other efficacy endpoints include: 
• Use of immunomodulatory medications to treat SLE over 1 year. 
• Number of hospitalizations per patient.  
• Percent of patients hospitalized. 
 
SLICC/ACR Damage Index will be recorded at baseline and at Week 52 to allow 
assessment of accrual of damage in subjects who may be followed in a subsequent study. 
Sample Size Considerations: 
The sample size is based on the feasibility of enrolling a large number of SLE subjects in 
a global trial that will provide a reasonable estimate for mortality and other AESI rates. 
Originally, the sample size was approximated at 5,000 subjects to be randomized (1:1 
randomization; 2,500 per treatment group) to thereby allowing the difference in mortality 
rate between the belimumab- and placebo-treated groups to be established with a 95% CI 
of  0.46% (see Section 8.4 of the protocol).  
Following completion of two additional placebo-controlled trials (each comprising 1 year 
of treatment), a revised mortality estimate based on data from all 5 of the completed 2/3 
trials enabled the same level of precision (i.e., a 95% CI of  0.46%) for the difference in 
mortality between placebo and belimumab to be achieved with 4,000 subjects. 

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Consequently, a proposal to reduce the sample size from 5,000 to 4,000 subjects was 
accepted by regulatory authorities. 
The randomization will be stratified for region (US/Canada vs Central America/South 
America/Mexico vs Europe/Australia/Israel vs Asia), SELENA SLEDAI score (≤ 9 vs ≥ 
10), and steroid dose (≤7.5 mg/day vs >7.5 mg/day prednisone or equivalent). 
Safety Analysis: 
Mortality and AESI will be summarized descriptively using number and percentage of 
subjects and will be analyzed using an estimation paradigm. The difference in the rates of 
all prespecified AESI and all cause mortality, between the belimumab and the placebo 
groups will be evaluated with a 2-sided 95% CI. SAEs will be analyzed descriptively only. 
Deaths will also be described in detail, including, in the belimumab group, assessment of 
relationship to belimumab treatment. The frequency and rate of serious adverse events will 
be tabulated by MedDRA system organ class (SOC) and preferred term. The SAE rates 
may also be reported adjusted for subject years.   
For all cause mortality, the hazard ratio (and its 95% CI) for belimumab vs placebo will be 
estimated using the Cox proportional hazard model, adjusted for baseline randomization 
factors. The time to death will be censored at the last follow-up by the end of the study for 
subjects who are alive.  
Safety analyses will be performed using the As-Treated population, defined as all 
randomized subjects who receive a dose of study agent, grouped according to the actual 
treatment administered to the subject for more than 50% of the doses.  
Analysis of Major Efficacy Endpoint: 
The percent of subjects with average prednisone (or equivalent) dose that has been reduced 
by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 will be compared 
between the belimumab and the placebo groups using a logistic regression model, adjusted 
for baseline prednisone (or equivalent) dose level, baseline SELENA SLEDAI score (≤ 9 
vs ≥ 10), and region (US/Canada or Central America/South America/Mexico or 
Europe/Australia/Israel or Asia). The analysis will be performed on subjects who were 
using prednisone (or equivalent) at a dose > 7.5 mg/day at baseline and were in the intent-
to-treat (ITT) population. In the analysis, all subjects who drop out and/or add new 
immunosuppressive agents before the Week 52 visit will be considered having no steroid 
reduction. However, switching immunomodulatory agents for toxicity reasons or lack of 
availability (eg, no longer manufactured or no longer reimbursed) is permitted and will not 
be imputed as no steroid reduction. To examine the robustness of the results, a sensitivity 
analysis of the steroid reduction may be performed without considering any information 
related to the use of new immunomodulatory agents. 
Study Calendar: 
See Section 6 for a calendar of study visits and assessments. 

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Table of Contents 
Study Synopsis ...............................................................................................................4 
Table of Contents .........................................................................................................10 
List of Tables ...............................................................................................................12 
List of Abbreviations ...................................................................................................13 
1 
Background ......................................................................................................15 
1.1 Disease Background Relevant to Clinical Study .............................................15 
1.2 Study Agent Background Relevant to Clinical Study......................................17 
1.3 Rationale for the Study ....................................................................................19 
1.4 Benefit-Risk Assessment .................................................................................20 
1.4.1 
Risk Assessment ..............................................................................20 
1.4.2 
Benefit Assessment ..........................................................................25 
1.4.3 
Overall Benefit:Risk Conclusion .....................................................25 
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 
4.3 Contraception Requirements for Female Subjects ...........................................29 
5 
Study Treatment Regimen ...............................................................................30 
5.1 Study Agent Name and Formulation ...............................................................30 
5.2 Packaging, Labeling, Preparation, and Storage ...............................................30 
5.3 Dose, Route of Administration, and Schedule .................................................31 
5.4 Alteration of Dose/Schedule Due to Toxicity ..................................................32 
5.5 Concurrent Medications ...................................................................................32 
5.5.1 
Prohibited Medications ....................................................................32 
5.5.2 
Allowable Medications ....................................................................33 
6 
Study Procedures .............................................................................................33 
6.1 Screening Procedures (Day -30 to Day 0) .......................................................33 
6.2 Study Enrollment Procedures ..........................................................................34 
6.3 Treatment Period ..............................................................................................34 
6.4 Post-Treatment Follow-Up ..............................................................................34 
6.5 Discontinuation of Study Agent.......................................................................34 
6.6 Withdrawal from Study....................................................................................35 
6.7 Subject Unblinding ..........................................................................................38 
6.8 Laboratory Tests (Liver Stopping Criteria) .....................................................38 
6.8.1 
Study Agent Restart or Rechallenge ................................................40 
7 
Adverse Event Reporting .................................................................................40 

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7.1 Definitions........................................................................................................40 
7.2 Reporting Adverse Events to the Sponsor .......................................................42 
7.2.1 
Adverse Events of Special Interest ..................................................42 
7.2.2 
Serious Adverse Events ...................................................................42 
7.3 Progressive Multifocal Leukoencephalopathy .................................................43 
7.4 Suicidality Assessment ....................................................................................43 
7.5 Reporting a Pregnancy .....................................................................................44 
7.6 Investigator Evaluation of Adverse Events......................................................44 
7.7 Follow-Up of Adverse Events of Special Interest and Serious Adverse Events
....................................................................................................................45 
7.8 Reporting Serious Adverse Events to the Regulatory Authorities and 
Institutional Review Boards/Ethics Committees .......................................45 
7.9 Regulatory Reporting Requirements for SAEs ................................................46 
8 
Endpoints and Statistical Analysis ...................................................................47 
8.1 General Statistical Considerations ...................................................................47 
8.2 Randomization Procedure and Assignment to Treatment Groups ...................47 
8.3 Independent Data Monitoring Committee (IDMC) .........................................48 
8.4 Sample Size Rationale .....................................................................................48 
8.4.1 
Sample Size Re-Estimation..............................................................48 
8.5 Endpoints and Analysis....................................................................................49 
8.5.1 
Safety Endpoint Definitions and Measurements..............................49 
8.5.2 
Analysis of Safety Endpoints ...........................................................49 
8.5.3 
Efficacy Endpoint Definitions and Measurements ..........................49 
8.5.4 
Analysis of Major Efficacy Endpoint ..............................................50 
9 
Pharmacogenetics (PGx) ..................................................................................50 
10 
Study Administration .......................................................................................50 
10.1 
Informed Consent.......................................................................................50 
10.2 
Institutional Review Board Review/Independent Ethics Committee 
Review and Approval ................................................................................51 
10.3 
Protocol Compliance ..................................................................................51 
10.4 
Protocol Revisions .....................................................................................51 
10.5 
Data Collection and Management ..............................................................52 
10.6 
Study Monitoring .......................................................................................52 
10.7 
Drug Accountability...................................................................................53 
10.8 
Retention of Records..................................................................................53 
10.9 
Financial Disclosure...................................................................................53 
10.10 Publication Policy ......................................................................................53 
10.11 Study or Study Site Termination................................................................54 
11 
References ........................................................................................................55 
List of Appendices .......................................................................................................60 

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List of Tables 
Table 1-1  
Deaths in Belimumab IV and SC SLE Controlled Repeat Dose 
Studies ..............................................................................................17 
Table 1-2  
AESIs in Belimumab IV and SC SLE Controlled Repeat Dose 
Studies ..............................................................................................18 
Table 1-3 
Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
 
21 
Table 6-1 
Study Calendar .................................................................................36 
 

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List of Abbreviations 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANA 
Anti-nuclear antibody 
Anti-dsDNA 
Anti-double-stranded DNA 
Anti-TNF 
Anti-tumor necrosis factor 
BAFF 
B cell activating factor belonging to the THF family 
BEL 
Belimumab 
BLyS 
B lymphocyte stimulator 
°C 
degrees Celsius 
CI 
Confidence Interval 
CMV 
Cytomegalovirus 
CRD 
Controlled repeat dose 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HGS 
Human Genome Sciences 
HIV 
human immunodeficiency virus 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
Kg 
kilogram 
LOCF 
last observation carried forward 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
NHL 
non-Hodgkins lymphoma 
NMSC 
non-melanoma skin cancer 
PGx 
pharmacogenetics 
PML 
progressive multifocal leukoencephalopathy 
PSRQ 
possible suicidality related questionnaire 
SAE 
serious adverse event 
SC 
subcutaneous, subcutaneously  
SELENA 
Safety of Estrogen in Lupus National Assessment 

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SLE 
systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SLICC 
Systemic Lupus International Collaborating Clinics 
SIR 
standardized incidence ratio 
SRI 
SLE responder index 
SWFI 
sterile water for injection 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
US 
United States 
USAN/INN 
United States adopted names/international nonproprietary name 

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1 
Background 
1.1 
Disease Background Relevant to Clinical Study 
SLE is a chronic debilitating autoimmune disease that primarily affects young women of 
childbearing age, although men, children and teenagers also can develop lupus. SLE is 
characterized by the presence of autoreactive B cells resulting in elevated levels of 
autoantibodies, which directly damage the body’s cells and tissues or form immune 
complexes which cause inflammation and tissue damage. A range of organ systems may 
be involved simultaneously or sequentially. The manifestations of lupus include arthritis, 
pleuritis, pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia, 
alopecia, photosensitivity, and malar rash. Over time, patients with lupus accrue 
irreversible organ damage which contributes to an increased mortality rate in these patients. 
Despite advances over the past 40 years in both diagnosis and treatment, patients with SLE 
have a 2 - 5-fold greater risk of mortality. 
SLE most often develops between the ages of 15 – 44 with an insidious onset 
(Danchenko et al, 2006). In the US, the estimated average of the reported prevalence is 
approximately 10 cases per 10,000 persons, representing about 300,000 patients, and the 
incidence has increased 2.5-fold between 1950 and 1979 (Uramoto et al, 1999; Somers et 
al, 2007; Balluz et al, 2001; Naleway et al, 2005; Ward, 2004; Helmick et al, 2008). In the 
European Union, an estimated overall average of the reported prevalence is 4 to 5 cases 
per 10,000 persons (Alamanos et al, 2003; Benucci et al, 2005; Eilertsen et al, 2006; 
Gourley et al, 1997; Govoni et al, 2006; Gudmundson et al, 1990; Hopkinson et al, 1993; 
Johnson et al, 1995; Lopez et al, 2003; Nightingale et al, 2007; Nossent, 2001; Piette et al, 
2004; Samanta et al, 1992; Stahl-Hallengren et al, 2000; Voss et al, 1998). Recent studies 
by Bernatsky et al, have emphasized the increased risk of mortality in SLE and have 
provided data comparing all cause and disease-specific relative mortality across groups 
characterized by age, sex, SLE duration, calendar-year period, geographic location, and 
race (Bernatsky et al, 2006). A 2.4-fold greater risk of mortality (95% CI 2.3–2.5) was 
identified in SLE compared with the general population and there was an increased risk of 
death due to cardiovascular causes, malignancy, infections, and renal disease.  
In an attempt to answer the question as to whether patients with SLE have an increased risk 
of malignancy in comparison to the general population, several large studies have recently 
been conducted. In a Swedish cohort of patients with SLE, Bjornadal et al (2002) used 
hospital discharge data to demonstrate an increased relative risk of any malignancy in SLE 
patients that was 25% higher than the general population. Of note, this finding was driven 
primarily by the higher incidence of non-Hodgkin’s lymphoma (NHL) in the SLE 
population which had a relative risk that was 2.86-fold higher (95% CI 1.96, 4.04) than 
that of the general population. These findings have been subsequently confirmed by the 
Systemic Lupus International Collaborating Clinics (SLICC) research group in a larger 
international multi-center cohort study. Using standardized incidence ratio (SIR) estimates, 
a small increase in all malignancies combined was observed (SIR, 1.15, 95% CI 1.05, 1.27) 
for SLE compared to that expected for the general population based on data from regional 
cancer registry linkages (Bernatsky et al, 2005). Similarly, the increased risk for NHL was 
also demonstrated (SIR, 3.64, 95% CI 2.63, 4.93) in the SLE population compared with 
the general population. Unfortunately, no investigations have been able to establish the 
reason for the close association between SLE and malignancy. Potential considerations for 

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this association include abnormal immune activity early in the course of the disease, as 
well as cumulative exposure to immunosuppressive medications. In the SLICC 
international multi-center cohort study, the adjusted hazard ratio (HR) for overall risk of 
malignancy after administration of any immunosuppressive drug was 0.82 (95% CI 0.50 
1.36). However, when specifically considering hematological malignancies, there was a 
suggestion of an increased risk after immunosuppressive drug exposures particularly when 
the medication exposures were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 
1.02-5.15).  
Infections are responsible for morbidity and mortality in 25-50% of SLE patients; they are 
an important cause of death in SLE patients in developing countries (Alarcón et al, 2001; 
Cervera et al, 1999; Graciela et al, 2006). In a multi-center European study in which 1,000 
SLE patients were followed for more than 5 years, infections and disease activity were 
found to be responsible for more than half of all deaths. Moreover, patients with SLE have 
higher rates of infections and poorer outcomes compared to the general population (Doria 
et al, 2008; Petri, 1998). The microorganisms responsible for the overwhelming majority 
of infections in patients with SLE are bacteria with gram negative and gram positive being 
the most common. However, there are many reports of infections occurring in patients with 
SLE with various outcomes as a consequence of other microorganisms. The increased 
susceptibility to infections may be multifactorial. Disease activity has been shown to be an 
independent risk factor for the occurrence of infections (Petri et al, 1992; Zonana-Nacach 
et al, 2001) presumably because of the abnormal cellular function and complement 
abnormalities that are more pronounced in the affected patients. The use of corticosteroids 
and other immunosuppressive medications has also been associated with the increased 
occurrence of infections in SLE (Gladman et al, 2002; Noel et al, 2001; Petri et al, 1992). 
Consequently, the possibility exists that the increased occurrence of infections may be a 
consequence of cytokine suppression, resulting in multiple cellular functional 
abnormalities (Boumpas et al, 1993).  
Neuropsychiatric events are well recognized in the SLE population, with a wide range of 
incidence. In an international inception cohort study (Hanly, 2007), neuropsychiatric 
events occurred in 28% of subjects near the time of SLE diagnosis, and the incidence of 
mood disorders attributed to SLE ranged from 4% to 13% depending on the attribution 
model used. Another study (Bachen et al, 2009) found the prevalence rates of many 
psychiatric disorders (major depressive disorder, bipolar disorder, panic disorder, etc.) 
were significantly higher in patients with SLE than the general population. The rate of 
major depression reported in the literature for patients with SLE ranges from 22.5%-39.1% 
(Nery et al, 2007; Brey et al, 2002; Ainiala et al, 2001). Severe depression requiring 
hospitalization was found to be 0.26% (14/5371 SLE patients in a Swedish cohort followed 
from 1973 to 2004) (Sundquist et al, 2008). Chronic physical illness is also an important 
risk factor for suicide (Karassa et al, 2003). Patients with SLE are at almost 5 times greater 
risk for suicide than expected (Harris et al, 1994). Suicide attempts among SLE patients 
was 5/300 SLE patients who visited a UK Rheumatology Clinic over a 20-year period 
(1979-1999) (Karassa et al, 2003) with deaths attributed to suicide ranging from 0.23-
0.95% (Mok et al, 2008; Nossent, 2001; Karassa et al, 2003).  

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1.2 
Study Agent Background Relevant to Clinical Study 
Belimumab (BENLYSTATM) is a recombinant human IgG1λ monoclonal antibody that 
binds to soluble human B-lymphocyte stimulator (BLyS; also known as B cell activating 
factor belonging to the tumor necrosis factor (TNF) family [BAFF] and TNFSF13B) and 
inhibits its biological activity (Baker, 2003). GlaxoSmithKline (GSK) received its first 
approval of belimumab on 09 March 2011 in United States (US) for treatment of SLE at a 
dosage regimen of 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals 
thereafter. Belimumab is currently approved in the US, all EU Member States, as well as 
40 further countries. These approvals were based on the data from two Phase 3 trials in 
1,684 patients 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. Reduction in steroid use and risk 
of severe flare was also observed, but not consistently across trials. Reductions in anti-
dsDNA antibodies and increases in complement levels were observed. 
The current primary belimumab safety population, includes safety data from the double-
blind portion of the Phase 2/3 studies submitted with the original IV marketing application, 
as well as double-blind studies of beliumumab administered subcutaneously (SC) in SLE 
subjects and IV in SLE subjects located in the North East region of Asia. A summary of 
adverse events of special interest, including deaths, in this dataset is provided below. 
Additional information is provided in the Investigator’s Brochure. 
Deaths from belimumab SLE studies are summarized in Table 1-1; this includes a 3 study 
pooled IV dataset (data presented in the original marketing authorization submissions), and 
more recent data generated from studies performed with IV belimumab in North East Asia 
(BEL113750) and from a study in which belimumab was administered SC (BEL112341). 
A total of 20 deaths have occurred in this primary safety population: 6/1190 (0.504%) 
received placebo, and 14/2484 (0.564%) received belimumab. No single cause of death has 
predominated and etiologies included infection, cardiovascular disease and suicide. 
Table 1-1  
Deaths in Belimumab IV and SC SLE Controlled Repeat Dose 
Studies 
C1056/C1057/LBSL02 
Pooled IV 
BEL112341 SC 
BEL113750 IV 
Pbo 
N=675 
Bel  
N=1458 
Pbo 
N=280 
Bel  
N=556 
Pbo 
N=235 
Bel  
N=470 
n 
3 
11 
2 
3 
1 
0 
n/N% 
0.4% 
0.8% 
0.7% 
0.5% 
0.4% 
0% 
n=number of subjects 
 
Likewise, rates of adverse events of special interest (AESIs), including malignancy, 
infection and psychiatric events are summarized in Table 1-2 for data generated in IV and 
SC controlled, repeat dose belimumab studies.   

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Table 1-2  
AESIs in Belimumab IV and SC SLE Controlled Repeat Dose Studies 
C1056/C1057/LBSL02 
Pooled IV 
BEL112341 SC 
BEL113750 IV 
Pbo 
N=675 
Bel  
N=1458 
Pbo 
N=28
0 
Bel 
N=556 
Pbo 
N=23
5 
Bel  
N=470 
Malignancies including NMSC 
 
 
n 
2 
5 
1 
2 
0 
1 
n/N% 
0.3% 
0.3% 
0.4% 
0.4% 
0% 
0.2% 
Malignancies excluding NMSC 
 
 
 
 
 
 
n 
1 
2 
1 
2 
0 
1 
n/N% 
0.1% 
0.1% 
0.4% 
0.4% 
0% 
0.2% 
Serious Infections of Special 
Interest 
 
 
 
 
 
 
n 
5 
19 
3 
8 
7 
11 
n/N% 
0.7% 
1.3% 
1.1% 
1.4% 
3.0% 
2.3% 
Opportunistic Infections 
 
 
 
 
 
 
n 
8 
15 
1 
2 
5 
13 
n/N% 
1.2% 
1.0% 
0.4% 
0.4% 
2.1% 
2.8% 
Depression/Suicide/Self Injury 
 
 
 
 
 
 
n 
56 
146 
10 
17 
6 
10 
n/N% 
8.3% 
10.0% 
3.6% 
3.1% 
2.6% 
2.1% 
 
Malignancies (excluding NMSC) assessed across all IV and SC SLE belimumab studies as 
of 08 March 2016, including safety data from double-blind and open-label studies/portions 
of studies and adjusted for patient-years exposure were compared with the malignancy rate 
in SLE patients reported in a large international cohort study of cancer in SLE (Bernatsky 
et al, 2005). Excluding NMSC, the malignancy rate per 100 patient-years with belimumab 
is 0.45 (95% CI 0.33, 0.59) compared with a background rate in SLE patients of 0.53 (95% 
CI 0.48, 0.59). Excluding NMSC is appropriate given that they are generally nonserious 
events with a high cure rate and it is known that NMSC is underreported in observational 
studies compared with prospective clinical trials (Great Britain National Cancer Statistics, 
2010; Young et al, 2007). No pattern of malignancies or increase in any particular type of 
malignancy was identified in patients receiving belimumab other than would be expected 
in an SLE population with a predominance of women. 
In the randomized-controlled IV SLE trials, infections occurred slightly more often in 
belimumab groups compared with the placebo group; although, severe and serious events 
occurred at similar rates across the placebo and the belimumab groups. In the randomized-
controlled SC SLE study, similar rates of infections, including severe and serious events, 
occurred in the belimumab 200 mg SC group and placebo group. The rate of opportunistic 
infections to date among belimumab study subjects and post-marketing approval patients 
appears less than the range reported in the literature for patients with SLE, 1.10 per 100 
patient-years (95% CI: 0.67, 1.7) as compared to 2.50 per 100 patient years (95% CI: 1.21, 
4.55) (Gladman, 2002; Zonana-Nacach, 2001). 
 
Across all SLE studies of belimumab through 08 March 2016, the incidence rate of 
completed suicide for belimumab-treated subjects was 36 per 100,000 subject-years (95% 
CI: 9.83, 92.38). The incidence rate of suicidal behavior (suicide attempt and completed 
suicide) was 180 per 100,000 subject-years (95% CI: 110.20, 278.62). The incidence rate 
of suicidal ideation was 108 per 100,000 subject-years (95% CI: 55.93, 189.08). These 

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estimates are consistent with the background rates for completed suicide (10 to 2181 per 
100,000 patient-years (Cervera, 2003; Li-Yu, 2007) and for suicide and suicide attempts 
(117 per 100,000 patient-years; 95% CI: 46.9, 240) reported for SLE patients in 
observational studies or retrospective chart reviews (Karassa, 2003). Furthermore, review 
of clinical trial, as well as postmarketing data, of suicide and suicidal thoughts and/or 
behavior did not identify a pattern or establish an association with belimumab. It is known 
that SLE is associated with increased incidence of depression and suicide/suicidal ideation 
than in the general population.  
 
Across all SLE studies of belimumab through 08 March 2016, the proportion of subjects 
with serious hypersensitivity reactions or infusion/injection-related  reactions was 31/5366 
subjects (0.58%) or 0.28 per 100 subject-years (95% CI: 0.19, 0.40). The estimated 
incidence rate of serious hypersensitivity reactions or infusion/injection-related reactions 
in spontaneous and postmarketing reports was 0.32 per 100 patient-years (95% CI: 0.26, 
0.38). The majority of serious hypersensitivity events have occurred on the 1st infusion, 
although there have been reports of hypersensitivity events occurring after several 
infusions of belimumab. Most clinical trial and spontaneous cases of serious 
hypersensitivity occurred during or within the first hour after the completion of the 
infusion. The majority of reports of infusion-related and hypersensitivity reactions were 
non-serious and included symptoms such as nausea, vomiting, diarrhea, chills, fever, rash, 
urticaria, pruritus, headache, dizziness, and dyspnoea. However, infusion and 
hypersensitivity reactions can be severe and fatal.   
 
1.3 
Rationale for the Study 
The primary goal of lupus treatment is to control or halt the inflammatory disease process 
while minimizing the side effects and the risk of infection that are associated with current 
therapies. The treatments historically and currently used for SLE have broad effects on 
immune and inflammatory pathways. Standard therapies for SLE include corticosteroids, 
antimalarial agents, non-steroidal anti-inflammatory drugs, and immunosuppressive 
agents. The available therapies are similar in US, Europe and the rest of the world. In 
addition to the disease itself, these treatments also cause short- and long-term morbidity. 
Agents such as cyclophosphamide are both cytotoxic and immunosuppressive and can 
result in increased risk of premature ovarian failure, serious infection, and cancer. 
Long-term use of high-dose corticosteroids can cause cataracts, osteoporosis, avascular 
necrosis, metabolic disorders, increased infections, edema, weight gain, and 
hyperlipidemia. Belimumab is approved in numerous markets world wide and is a 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.  
In Phase 3 clinical trials belimumab was shown to be effective in the treatment of patients 
with active, autoantibody-positive SLE; patients with severe active lupus nephritis and 
severe active central nervous system lupus were excluded from the studies, as were patients 
receiving intravenous cyclophosphamide and other biologics. Furthermore, belimumab 
was generally safe and well-tolerated, including with long term use in a subset of patients, 
albeit in an uncontrolled setting. While substantial information exists about the safety of 

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belimumab from these clinical trials, the present study is intended to evaluate a larger 
number of subjects in a controlled setting. The safety objectives of the study are intended 
to focus on areas where a numerical imbalance in the frequency and rates were observed 
across treatment groups in the controlled trials included with the original marketing 
applications (i.e., mortality, selected psychiatric events/suicidality, serious infusion and 
hypersensitivity reactions) or where there is a theoretical basis for increased risk with an 
immunomodulatory treatment (ie, serious/opportunistic infections, malignancy).  
The study design is considered optimal to address these safety objectives. The study is 
double-blind, placebo-controlled for 1 year. During this time, all safety endpoints as 
described in Section 8.5.1 will be evaluated. This study also affords the opportunity to 
evaluate steroid reduction at Weeks 40-52.  
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, infections, and symptoms 
consistent with SLE.  The majority of reports of infusion-related and hypersensitivity 
reactions were non-serious and include symptoms such as nausea, vomiting, diarrhea, 
chills, fever, rash, urticaria, pruritus, headache, dizziness, and dyspnoea.  However, 
infusion and hypersensitivity reactions can be severe and fatal.  Most clinical trial and 
spontaneous cases of serious hypersensitivity occurred during or within the first hour after 
the completion of the infusion, although some cases report delayed acute onset (>4 hours 
but <4 days) or a delayed non-acute onset (4-21 days) hypersensitivity reactions.   
Infections have been reported with administration of belimumab and are also associated 
with both SLE and immunosuppressant medication used to treat SLE. The mechanism of 
action of belimumab may increase the potential risk for the development of infections.   
Table 1-3 provides a summary of key issues, their impact, and strategy to mitigate risk in 
this study. 

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

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Identified Risks 
Summary of Data 
Impact – Eligibility Criteria 
Strategy and Monitoring 
placebo were nasopharyngitis, bronchitis, 
pharyngitis, cystitis, and gastroenteritis 
viral. Serious infections, occurred in 5% of 
patients receiving either belimumab or 
placebo. 
antibiotics within 60 days of Day 0; 
a history of or positive test at 
screening for HIV, hepatitis B or 
hepatitis C;  
 
Potential Risks 
Summary of Data 
Impact – Eligibility Criteria 
Strategy and Monitoring 
Progressive 
multifocal 
leukoencephalopa
thy (PML) 
No association between belimumab and the 
risk of opportunistic infections, including 
PML, has been indentified to date, but data 
are limited. PML resulting in neurological 
deficits, including fatal cases, has been 
reported 
in 
SLE 
patients 
receiving 
immunosuppressant 
pharmacotherapy, 
including belimumab. 
This potential risk does not directly 
impact eligibility criteria. 
Subjects should be made aware of this 
potential risk, the signs and symptoms of PML, 
and the importance of immediately seeking 
medical attention. A diagnosis of PML should 
be considered in any subject presenting with 
new-onset or deteriorating neurological signs 
and symptoms. The subject should be referred 
to a neurologist or other appropriate specialist 
for evaluation. If PML is confirmed, study 
agent 
should 
be 
discontinued 
and 
consideration should be given to stopping 
immunosuppressant therapy. If PML is 
suspected, this should be immediately 
reported to the Medical Monitor. The 
appropriateness of continuing study agent, 
while the case is being assessed, should be 
discussed. 
Malignancies 
As with other immunomodulating agents, 
the mechanism of action of belimumab may 
increase the potential risk for the 
development of malignancies. 
Exclude patients with a history of 
malignant neoplasm within the last 
5 years, except for adequately 
treated basal or squamous cell 
Monitor patients for signs and symptoms of 
malignancy. Subjects should be made aware 
of the potential risk, and the importance of 

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Potential Risks 
Summary of Data 
Impact – Eligibility Criteria 
Strategy and Monitoring 
cancers of the skin, or carcinoma 
in situ of the uterine cervix. 
immediately seeking medical attention with 
any related signs or symptoms.  
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.  
This potential risk does not directly 
impact eligibility criteria. 
Monitor adverse events.  
Effects 
on 
immunizations 
including reactions 
with live vaccines 
No data are available on the secondary 
transmission of infection from persons 
receiving live vaccines to patients receiving 
belimumab. Because of its mechanism of 
action, belimumab may interfere with the 
response to immunisations. 
However, in a study evaluating the 
response to a 23-valent pneumococcal 
vaccine, overall immune responses to the 
Exclude 
patients 
who 
have 
received a live vaccine within 30 
days of Day 0. 
Live vaccines are prohibited during the study 
conduct. Subjects should be made aware of 
the potential risk for impact of belimumab on 
vaccine response. 

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Potential Risks 
Summary of Data 
Impact – Eligibility Criteria 
Strategy and Monitoring 
different serotypes were similar in SLE 
patients receiving belimumab compared 
with those not receiving treatment at the 
time of vaccination. Limited data suggest 
that belimumab does not significantly affect 
the ability to maintain a protective immune 
response to immunisations received prior to 
administration of belimumab.  
Potential 
psychiatric events 
- Depression and 
suicidality 
There have been reports of depression and 
suicidality in patients receiving belimumab. 
The estimated rates of suicidality for 
belimumab remain consistent with the rates 
of the background SLE population. The 
background rate for completed suicide 
identified in the literature ranged from 0.01 
to 2.17 per 100 PY and varied by study type 
(clinical trial or observational study) [Li-Yu 
2007; Cervera 2003]. The background rate 
for suicidal behavior (completed suicide and 
attempts) is 0.12 (95% CI 0.05, 0.24)/100 
patient years [Karassa 2003]. 
This potential risk does not directly 
impact eligibility criteria.  
Perform suicidality assessment by using the 
Columbia Suicidality-Severity Rating Scale (C-
SSRS) Screening form at baseline and every 
visit, and monitor results. Subjects should be 
made aware of the potential risk and should 
report signs and symptoms.  
 

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Refer to Section 8.3 for information about the Independent Data Monitoring Committee 
(IDMC) being used in the study. 
1.4.2 
Benefit Assessment 
The primary data supporting efficacy and the approval of IV belimumab were the Phase 3 trials 
(C1056 and C1057) in which 1,684 subjects were treated for up to 52 weeks (C1057) or 76 
weeks (C1056) (Belimumab IB, Section 5.3.1.2). Belimumab produced significant 
improvements in the SLE Responder Index as well as in individual component SELENA-
SLEDAI score in both studies. Pooled analyses demonstrated steroid sparing, delay in median 
time to first flare, and decreased risk of severe flares over 52 weeks. Clinical trial data for 
belimumab since approval continue to show efficacy in the treatment of SLE through decreased 
SLE flares and decreased disease activity across multiple organ systems (Belimumab IB, 
Section 5.3.1.3). 
1.4.3 Overall Benefit:Risk Conclusion 
The safety profile of belimumab remains consistent with that known at approval and is 
consistent with expected events based on the mechanism of action and the disease under study. 
Appropriate risk mitigation measures are in place; rare and long-term risks will be further 
evaluated via the large safety study and registry, ongoing and future studies, and routine 
pharmacovigilance. Review of safety data is conducted on a continual basis in order to identify 
new safety signals which may arise from clinical trial and/or post-marketing reports. The 
benefit: risk profile of belimumab for SLE continues to be favorable. 
2 
Study Objectives 
The objectives of this study are to evaluate the following in adult SLE subjects receiving 
belimumab plus standard therapy versus subjects receiving placebo plus standard therapy: 
• Mortality and adverse events of special interest over 1 year (through 52 weeks). 
• Corticosteroid reduction during Weeks 40-52. 
 
3 
Study Design 
3.1 
Basic Design Characteristics 
This is a global, multi-center, randomized, placebo-controlled study to evaluate adverse events 
of special interest in adults with active, autoantibody-positive systemic lupus erythematosus 
(SLE) treated with belimumab plus standard therapy vs placebo plus standard therapy. 
Originally, approximately 5,000 subjects were planned to be randomized to 1 of 2 treatment 
groups: belimumab 10 mg/kg (2,500 subjects) or placebo (2,500 subjects) plus standard 
therapies. Subsequent to the reporting of additional placebo controlled data, the sample size was 
reduced to 4,000 subjects in total.  
Subjects will receive study agent (belimumab or placebo) on Days 0, 14, 28 and approximately 
every 28 days thereafter through Week 48 with a final visit conducted at Week 52. Subjects 

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who discontinue treatment at any time during the 52-week study will be followed for mortality 
and malignancy (including NMSC) at 1 year (through Week 52) and annually for Years 2 
through 5.  
Subject data will be collected at randomization and subsequently at approximately 28-day 
intervals for 52 weeks. Subjects will be assessed for malignancies, including NMSC, serious 
infections, opportunistic infections and other infections of interest, selected serious psychiatric 
events, suicidality, and serious infusion and hypersensitivity reactions. All cause mortality will 
be reported. All other serious adverse events (SAEs), irrespective of causality, will also be 
recorded. Medical history will be collected on all subjects. Immunomodulatory agents used to 
treat SLE at baseline and during study, hospitalizations, and organ damage (SLICC/ACR 
Damage Index) will also be assessed through Week 52. 
All subjects will have a follow-up visit performed approximately 4 weeks after the last dose of 
study agent. In the event that a subject withdraws consent to participate in the first year monthly 
study visits, an attempt should be made at the time of consent withdrawal to obtain consent to 
contact the subject at Week 52 and annually for Years 2 through 5 (Week 260) to assess 
mortality and malignancy (including NMSC).   
Subjects may continue to receive their other SLE medications including corticosteroids, 
immunomodulatory agents, and antimalarials. Changes in these SLE medications during the 
trial will be permitted as clinically indicated. No concomitant biological therapies will be 
allowed during the 52-week study. In the event that the treating physician decides that a subject 
requires the addition of a biologic agent before Week 52, the subject is withdrawn from study 
agent but is followed on study through Week 52 and annually for Years 2 through 5 (Week 
260).  
Following the 52-week study, all subjects will be contacted annually through Year 5 (Week 
260) to assess mortality and malignancy (including NMSC). 
At the end of the 52-week study, subjects who wish to continue treatment may be able to do so 
by being prescribed commercially available belimumab. If belimumab is not commercially 
available in a subject’s country of participation, the subject may be able to receive belimumab 
under a separate continuation protocol. A separate informed consent will need to be provided 
for the continuation protocol. 
An Independent Data Monitoring Committee (IDMC) will review unblinded safety data for this 
study on an ongoing basis until the data are locked and analyzed. The IDMC will include at 
least 3 physicians, and a statistician, none of whom are affiliated with the sponsor. The first 
IDMC meeting will review the data after approximately 500 subjects are enrolled or 6 months 
from randomization of the first patient, whichever is first. After the initial review, the IDMC 
will continue to review data approximately every 6 months. Events to be monitored during the 
safety review will include at a minimum all serious adverse events (including deaths, serious 
psychiatric events and serious infections), opportunistic infections (serious and nonserious) and 
other infections of interest, malignancies (including NMSC), and serious infusion and 

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hypersensitivity reactions. Investigators and IRBs/IECs will be notified of the outcome of each 
IDMC meeting.  
4 
Inclusion and Exclusion Criteria 
4.1 
Inclusion Criteria 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Males or females ≥ 18 years. 
2. Have a diagnosis of SLE, refer to ACR revised criteria for the classification of SLE 
(Appendix 1) as a guide for diagnosis of SLE. 
3. Active, autoantibody positive SLE (autoantibody positive is defined as the presence of ANA 
or anti-dsDNA antibodies). 
4. Are on a SLE treatment regimen consisting of any of the following medications (alone or 
in combination):  
• Corticosteroids 
• Other immunomodulatory agents including methotrexate, azathioprine, leflunomide, 
mycophenolate 
(including 
mycophenolate 
mofetil, 
mycophenolate 
mofetil 
hydrochloride, and mycophenolate sodium), calcineurin inhibitors (eg, tacrolimus, 
cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine, or thalidomide. 
• Anti-malarials [eg, hydroxychloroquine, chloroquine, quinacrine (mepacrine)]. 
5. A female subject is eligible to enter the study if she is:  
• Not pregnant or nursing;  
• Of non-childbearing potential defined as: 
• pre-menopausal females with a documented tubal ligation,  hysterectomy, 
documented hysteroscopic tubal occlusion procedure with follow-up confirmation 
of bilateral tubal occlusion, or documented bilateral oophorectomy or 
• post-menopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile [e.g., > 45 years, in the absence of hormone replacement 
therapy or other cause for amenorrhea]; in questionable cases obtain a blood sample 
for follicle stimulating hormone (FSH) and estradiol simultaneously to confirm. 
Diagnostic levels for FSH and estradiol vary by specific laboratories/assays; 
• OR is of child-bearing potential with negative pregnancy test as determined by urine 
human chorionic gonadotrophin (hCG) test at screening and urine hCG test prior to 
dosing AND 
• Agrees to use one of the contraception methods listed in the protocol (see 
Section 4.3) for 2 weeks prior to the day of dosing to sufficiently minimize the risk 
of pregnancy at that point.  Female subjects must agree to use contraception until 
16 weeks following the last dose of study agent. 
• OR has only same-sex partners, when this is her preferred and usual lifestyle. 

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6. 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 data collection procedures [including annual 
contacts from Years 2 through 5 (Week 260) to assess mortality and malignancy]. 
 
4.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Have received any prior treatment with belimumab, either as a marketed product or as an 
investigational agent. 
2. Have received treatment with B cell targeted therapy (eg, rituximab, other anti-CD20 
agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein 
[BR3], TACI-Fc, anti-BAFF [LY2127399]) within 364 days of Day 0. 
3. Have received any of the following within 90 days of Day 0:  
• Any biologic agent (eg, adalimumab, etanercept, infliximab, anakinra) other than B cell 
targeted therapy (see Exclusion Criterion 2). 
• Plasmapheresis. 
4. Have received any of the following within 60 days of Day 0: 
• A non-biologic investigational agent.  
5. Have received any of the following within 30 days of Day 0: 
• A live vaccine.  
6. 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.  
7. Have required management of acute or chronic infections, as follows: 
• Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria). 
• Hospitalization for treatment of infection within 60 days of Day 0. 
• Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents) within 60 days of Day 0. 
8. Have severe lupus kidney disease (defined by proteinuria > 6 g/24 hour or equivalent using 
spot urine protein to creatinine ratio, or serum creatinine > 2.5 mg/dL), or have severe active 
nephritis requiring acute therapy, or have required hemodialysis or high-dose prednisone or 
equivalent (> 100 mg/day) within 90 days of Day 0.  
9. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, 
organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) 
requiring therapeutic intervention. 
10. Known HIV infection.  
11. Current or history of hepatitis B or hepatitis C infection.  

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12. Only applicable to Lithuanian sites: 
• Have 
hypogammaglobulinaemia 
(IgG 
<400 
mg/dL) 
or 
a 
deficiency 
in 
immunoglobulin A (IgA <10 mg/dL). 
• Have had renal, stem cell/marrow or other major organ transplant. 
• Have a chronic infection or a history of recurrent infections, which in the opinion of the 
investigator poses a significant risk to the subject. 
• Have received cyclophosphamide via any route of administration within 90 days of Day 
0. 
4.3 
Contraception Requirements for Female Subjects 
Female subjects of childbearing potential must not become pregnant during the study and so 
must be sexually inactive by abstinence or use contraceptive methods with a failure rate of 
< 1%.  Female subjects of childbearing potential with same sex partners (when this is their 
preferred and usual lifestyle) are not required to be abstinent or to use contraception. 
 
Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.  
 
Contraceptive Methods with a Failure Rate of < 1% 
• 
Oral contraceptive, either combined or progestogen alone 
• 
Injectable progestogen 
• 
Implants of levonorgestrel or etonogestrel 
• 
Estrogenic vaginal ring 
• 
Percutaneous contraceptive patches 
• 
Intrauterine device (IUD) or intrauterine system (IUS) with  <1% failure rate as stated in 
the product label 
• 
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the 
female subject's entry into the study, and this male is the sole partner for that subject.  For 
this definition, “documented” refers to the outcome of the investigator's/designee’s review 
of the subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records. 
• 
Double barrier method:  condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent (foam/gel/film/cream/suppository). 
NOTE: MMF and other forms of mycophenolate affect the metabolism of oral contraceptives 
and may reduce their effectiveness. As such, women receiving mycophenolate who are using 
oral contraceptives for birth control should employ an additional method (e.g., barrier method). 

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

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• Investigational drug statement 
• Sponsor’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) obtained at each visit prior to 
dosing. At sites where it is impractical to use the subject’s current body weight to calculate the 
dose, it is permissible for the Week 2 visit onward to use the subject’s body weight from the 
previous visit (e.g., the Day 0 weight can be used to calculate the dose for the Week 2 visit). 
The current visit body weight must still be measured prior to dosing and if the current weight 
varies by more than 10% from the previous visit weight, then the weight measured at the current 
visit must be used to calculate the dose. 
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, 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. 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 preparation, storage, handling, and 
drug accountability. 
5.3 
Dose, Route of Administration, and Schedule 
There are 2 treatment groups: 10 mg/kg belimumab and placebo. Both treatment groups will 
receive other standard therapies, including steroids, immunomodulatory agents and 
antimalarials, as appropriate.  
Once randomized, subjects will be dosed with study agent on Days 0, 14, 28 and then 
approximately every 28 days through Week 48.  
Study agent should be administered by healthcare providers prepared to manage anaphylaxis. 
Prior to dosing with study agent, administration of premedication for prophylaxis against 
infusion reactions and hypersensitivity reactions may be considered. In the Phase 3 trials, 13% 
of subjects received premedication, which may have mitigated or masked a hypersensitivity 

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response; however, there is insufficient evidence to determine whether premedication 
diminishes the frequency or severity of hypersensitivity reactions. All study agent treatments 
will be administered intravenously (IV) over no less than 1 hour. The rate of infusion may be 
slowed or interrupted if the subject develops an infusion reaction. In the event of a serious 
hypersensitivity reaction, administration of study agent must be discontinued immediately and 
appropriate medical therapy administered.  
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions. Should symptoms of acute hypersensitivity occur, an 
extended period of monitoring may be appropriate, based on clinical judgment. This may 
include, but is not limited to, monitoring vital signs and observing for any untoward reactions. 
In addition, delayed-type, non-acute hypersensitivity reaction have also been observed and 
included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial edema. Beyond 
the first 2 infusions, subjects should be monitored during and for an appropriate period of time 
after infusion according to study sites’ guidelines or standard operating procedure for IV 
infusions. 
Subjects should be made aware of the potential risk, the signs and symptoms of such reactions, 
and the importance of immediately seeking medical attention. For further information, see the 
belimumab Investigator’s Brochure. 
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. 
5.5 
Concurrent Medications 
5.5.1 Prohibited Medications 
Subjects who require any prohibited medications during the 52-week study will have study 
agent discontinued, they will, however, remain on study and continue to be assessed according 
to the schedule outlined in the Study Calendar (Table 6-1). The following medications are 
prohibited during the study:  
• Other investigational agents (biologic or non-biologic). Investigational applies to any drug 
not approved for sale in the country it is being used. 
• Anti-TNF therapy (eg, adalimumab, etanercept, infliximab) 
• Other biologicals (eg, commercial belimumab, rituximab, abatacept, interleukin-1 receptor 
antagonist [anakinra]) 
• Live vaccines 
 

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5.5.2 Allowable Medications 
Subjects are enrolled on their current standard therapy for SLE. The medications used to treat 
SLE will be recorded at each visit during the study. These data will include the dose and 
frequency of corticosteroids as well as immunomodulatory and antimalarial agents.  
6 
Study Procedures 
The nature of this study and the potential risks and benefits associated with participation in the 
study will be explained to all potential study subjects. Written informed consent 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 
(see Section 9 and Appendix 7) must sign the PGx informed consent prior to any PGx samples 
being drawn from the subject. 
Refer to the Study Calendar (Table 6-1) and the Study Procedures Manual. 
6.1 
Screening Procedures (Day -30 to Day 0) 
The following should be performed within 30 days of the first dose of study agent (Day 0) as 
outlined in the Study Calendar (Table 6-1): 
• Record demographics. 
• Obtain medical history. 
• Obtain history of and current SLE medications. 
• Confirm diagnosis of SLE disease based on ACR criteria (Appendix 1) by reviewing 
previously documented clinical records. 
• Perform suicidality assessment by using the Columbia Suicidality-Severity Rating Scale (C-
SSRS) “Baseline/Screening” form (see Section 7.4 and Appendix 4). 
• Complete SELENA SLEDAI (see Appendix 6). 
Note: To complete the SELENA SLEDAI, the following laboratory tests must be performed 
within 30 days prior to the SELENA SLEDAI assessment (within 60 days prior to 
randomization at Day 0):  Hematology (WBC, platelets), complement (C3, C4), 
anti-dsDNA, routine urinalysis, and spot urine for macroscopic/microscopic/proteinuria 
assessments. [A dipstick for urine protein is NOT sufficient, measurement of 24 hr urine 
protein or a protein/creatinine ratio on a spot urine collection MUST be completed.] 
• Pregnancy test (urine). 
• Confirm subject meets study entry criteria. 
• Subjects can be rescreened, if deemed appropriate by the Principal Investigator, but only 
once. 
 

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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 a central Interactive Web Response System 
(IWRS). Subjects will be randomized in a 1:1 ratio and stratified by region (US/Canada vs 
Central America/South America/Mexico vs Europe/Australia/Israel vs Asia), their screening 
SELENA SLEDAI score (≤ 9 vs ≥ 10), and steroid dose (≤ 7.5 mg/day or > 7.5 mg/day 
prednisone or equivalent). 
6.3 
Treatment Period 
Subjects will be evaluated at the study site for the scheduled study visits outlined in the 
Study Calendar (Table 6-1). On Day 0, the subject will be randomized and receive the first dose 
of study agent. Subjects will be dosed at Week 2, Week 4 and approximately every 28 days 
(calculated from the Day 0 dose) thereafter through Week 48. The final treatment period 
evaluation for the study will occur at Week 52. Time windows are defined as ± 3 days for visits 
at Week 2 and Week 4, and ± 7 days for visits from Week 8 though Week 52. All study visits 
should occur within the visit window of the scheduled study visit. In rare circumstances, when 
the scheduled visit cannot be done within the visit window the Medical Monitor may be 
contacted for advice. Similarly, while all assessments for a dosing visit should be performed 
same day, in rare circumstances, an investigator may be permitted to conduct the assessments 
over two consecutive days so long as the infusion of the study agent is performed on the second 
day and after all other assessments. 
All subjects who do not withdraw consent to participate in the first year monthly study visits 
and regardless of whether they continue to receive study agent will be followed on-study 
through Week 52 and annually for Years 2 through 5 (Week 260). All subjects will have a 
follow-up visit performed approximately 4 weeks after the last dose of study agent. In the event 
that a subject withdraws consent to participate in the first year monthly study visits, an attempt 
should be made at the time of consent withdrawal to obtain consent to contact the subject at 
Week 52 and annually for Years 2 through 5 (Week 260) to assess mortality and malignancy 
(including NMSC). 
6.4 
Post-Treatment Follow-Up 
All subjects will be contacted annually through Year 5 (Week 260) to assess mortality 
and  malignancy (including NMSC) as outlined in the Study Calendar (Table 6-1). Annual 
follow-up also applies to subjects who discontinued study agent before Week 48. Time windows 
are ± 30 days for annual follow-up contacts from Year 2 to Year 5. 
6.5 
Discontinuation of Study Agent 
Subjects will be free to discontinue study agent treatment at any time, for any reason, or the 
investigator may discontinue study agent treatment, if necessary, to protect the subject’s health 
(see reasons for study agent discontinuation below). Subjects who discontinue study agent after 
receiving at least 1 dose of study agent will not be replaced. Subjects who discontinue study 
agent will continue to be followed on-study through Week 52 (regardless of changes in 

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background medications) and annually for Years 2 through 5 (Week 260) according to the 
schedules outlined in Table 6-1. All subjects will have a follow-up visit performed 
approximately 4 weeks after the last dose of study agent (i.e., the follow-up visit is Week 52 for 
a subject who completes all dosing visits, and the follow-up visit is the next scheduled visit for 
a subject who discontinues study agent). 
Subjects may have study agent discontinued for any of the following reasons: 
• At the investigator’s discretion. 
• Requires: 
- 
Other investigational agents.  
- 
Anti-TNF therapy (eg, adalimumab, etanercept, infliximab). 
- 
Other biologicals (eg, commercial belimumab, rituximab, abatacept, interleukin-1 
receptor antagonist [anakinra]). 
- 
Live vaccines. 
• Lost to follow-up. 
 
6.6 
Withdrawal from Study 
Subjects will be free to withdraw from the study at any time, for any reason. It is understood by 
all concerned that an excessive rate of withdrawals can render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects from study should be avoided. 
If a subject withdraws consent to participate in the first year monthly study visits, at the time of 
consent withdrawal it is requested that the site attempt to obtain consent to contact the subject 
at Week 52 and annually for Years 2 through 5 (Week 260) to assess mortality and malignancy 
(including NMSC). 

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Table 6-1 
Study Calendar 
Study Week 
Screening visit 
(within 30 days of Day 
Day 0 visit 
Wk 2 visit 
(Day 14  3 d) 
Wk 4 visit 
(Day 28  3 d) 
Wk 8 visit 
(Day 56  7 d) 
Wk 12 visit 
(Day 84  7 d) 
Wk 16  visit 
(Day 112  7 d) 
Wk 20  visit 
(Day 140  7 d) 
Wk 24 visit 
(Day 168  7 d) 
Wk 28 visit 
(Day 196  7 d) 
Wk 32 visit 
(Day 224  7 d) 
Wk 36 visit 
(Day 252  7 d) 
Wk 40 visit 
(Day 280  7 d) 
Wk 44 visit 
(Day 308  7 d) 
Wk 48 visit 
(Day 336  7 d) 
Wk 52 visit 
(Day 364  7 d) 
Annual Follow-up 
Years 2-511 
Written Informed Consent, Demographics, Medical History, 
SLE History/Diagnosis, Eligibility Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SELENA SLEDAI (related laboratory tests within 30 days 
prior to screening date) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Weight2 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Baseline/screening suicidality assessment (C-SSRS 
Appendix 4) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Since last visit suicidality assessment (C-SSRS Appendix 
5)3 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study Agent Administration4 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Record Concurrent Medications used to treat SLE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Assess/Record Serious Adverse Events5 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Assess/Record all Opportunistic Infections and Other 
Infections of Interest 
(including TB reactivation)6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Assess/Record all Malignancies (including NMSC) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Assess/Record Serious Infusion and Hypersensitivity 
Reactions 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Record Hospitalizations7 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pharmacogenetic Sampling  
(consenting subjects only)8 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC/ACR Damage Index9 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
X9 
 
Survival Assessment10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Footnotes for the study calendar appear on the following page. 
 
1 
A urine pregnancy test is required for women of child bearing potential. The results of urine pregnancy test must be available prior to dosing.   

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2 
The weight at the current visit should be used to calculate dose. Refer to Section 5.2 for further information. 
3 
Suicidality is to be assessed prior to study agent infusion using the “Since Last Visit” C-SSRS (Appendix 5). 
4 
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. 
5 
All SAEs will be recorded. These data will be used to analyze serious infections and selected serious psychiatric events. 
6 
Guidelines for opportunistic infections and other infections of interest are provided in Appendix 2. 
7 
A hospitalization is an inpatient admission for any length of time. An admission 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 recorded as a hospitalization. 
8 
Pharmacogenetic sampling informed consent must be obtained prior to any blood being taken for PGx research. Sample should be drawn prior to dosing on Day 0.  However, the sample 
may be collected at any time during the study. 
9 
Refer to Appendix 3. SLICC/ACR Damage Index is only performed at Screening and Week 52 (but not earlier if a subject discontinues study agent). 
10 
If asubject withdraws consent to participate in the first year monthly study visits, it is requested that the site attempt to obtain consent to contact the subject at Week 52 and annually for 
Years 2 through 5 (Week 260) to assess mortality and malignancy (including NMSC)..  
11 
Following the study, all subjects will be contacted annually through Year 5 (Week 260) to assess mortality and malignancy (including NMSC).  
 

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6.7 
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.  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. 
6.8 
Laboratory Tests (Liver Stopping Criteria) 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). 
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf 
 
Although routine safety laboratory is not required per protocol, in the event the investigator 
becomes aware that liver function test (LFT) monitoring was performed, the LFT results should 
be evaluated against the liver stopping criteria and the GSK Medical Monitor must be contacted. 

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Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm 
 
 
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued Therapy 
for ALT 3xULN but <8xULN 
 
 
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*
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 
9. 
 
6.8.1 Study Agent Restart or Rechallenge 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with study 
treatment unless: 
• 
GSK Medical Governance approval is granted 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
Refer to Appendix 10 for full guidance. 
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 (EXPERIENCE): 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 
• 
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.   

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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 
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, 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 

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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 
7.2.1 Adverse Events of Special Interest 
All adverse events of special interest, AESIs, (see Section 8.5.1 for details) that are identified 
from the start of study medication (Day 0) through Week 52 and regardless if study agent is 
discontinued early will be recorded on the Adverse Event Case Report Form (AE eCRF). All 
deaths will be recorded as an outcome from the event that is considered to be the primary event 
leading to death. All data fields on the AE eCRF should be completed.  
7.2.2 Serious Adverse Events 
Serious Adverse Events (SAEs) that occur from the start of study agent at Day 0 through Week 
52 and regardless if study agent is discontinued early must be recorded on the SAE eCRF within 
24 hours of site personnel becoming aware of a SAE, regardless of expectedness. All fields of 
the SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the SAE 
eCRF within 24 hours of site personnel becoming aware of the follow-up information as 
described in the ePharmaSolutions document portal. 
SAEs that occur after Week 52 (or 4 weeks after the last dose of IP if a subject has withdrawn 
consent to participate in the first year monthly study visits) and that are assessed by the 
investigator as possibly related to study agent taken the first year must be reported to the 
Sponsor as outlined in the ePharmaSolutions document portal. 
Prior to study drug administration, any SAE assessed as related to study participation (e.g., 
protocol mandated procedures, invasive tests) will be recorded on the SAE worksheet and 
reported as described above from the time a subject consents to participate in the study. Pre-
treatment SAEs will not be documented on the SAE eCRF. 

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7.3 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, including 
fatal cases, has been reported in SLE patients receiving immunosuppressant pharmacotherapy, 
including belimumab. A diagnosis of PML should be considered in any subject presenting with 
new-onset or deteriorating neurological signs and symptoms. The subject should be referred to 
a neurologist or other appropriate specialist for evaluation. If PML is confirmed, study agent 
should be discontinued and consideration should be given to stopping immunosuppressant 
therapy.  
If PML is suspected, this should be immediately reported to the Medical Monitor. The 
appropriateness of continuing study agent, while the case is being assessed, should be discussed. 
7.4 
Suicidality Assessment 
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation (Bachen, 
2009; Timonen, 2003; Stenager, 1992). In order to objectively assess suicidality in belimumab 
clinical programs the C-SSRS (Appendix 4 and Appendix 5) will be utilized to collect 
information on suicidal behavior and ideation. ‘Baseline’ C-SSRS (Appendix 4) will be used at 
screening ONLY; whereas, ‘Since Last Visit’ C-SSRS (Appendix 5) will be used at all other 
designated study visits. 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 
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 a SAE worksheet.  The medical monitor should be notified when these events occur.  In 
addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation questions 3, 4, or 5 on 
the C-SSRS prompts the completion of a Possible Suicidality Related History Questionnaire 
(PSRHQ) eCRF (PSRHQ, only the first time this condition is met), and a Possible Suicidality 
Related Questionnaire (PSRQ) eCRF at all times this condition is met. 
Baseline/Screening and during treatment (Since Last Visit) assessment of suicidality will be 
performed during the blinded portion of this study using C-SSRS (refer to Appendix 4 and 
Appendix 5 for C-SSRS). The C-SSRS is a brief measure which is designed to assess severity 
and change of suicidality by integrating both behavior 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 blinded 
portion of the study. 

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7.4.1.1 
Possible Suicidality Related Questionnaire (PSRQ) 
The investigator will be prompted to complete the PSRQ (in addition to the AE, SAE pages, 
and PSRHQ as appropriate) if a “yes” response is given to any suicidal behavior or a “yes” 
response to suicidal ideation questions 3, 4 or 5 on the C-SSRS. If the adverse event meets the 
definition of an SAE, which includes a “yes” answer to any suicidal behavior or a “yes” to 
suicidal ideation questions 4 or 5 on the C-SSRS, the site must ensure that there are no 
significant discrepancies between the PSRQ and SAE. 
7.5 
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, Drug Safety sends an acknowledgement memorandum to the principal 
investigator along with a Pregnancy Assessment Form. A Pregnancy Assessment Form must be 
completed every 3 months until live birth, elective termination of the pregnancy, or miscarriage. 
The site is responsible for following the subject’s pregnancy to final outcome.  
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 7.2. 
7.6 
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: 
SEVERITY 
Grade 1 - Mild 
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities (Grade 1 
DMID). 
Grade 2 - Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID). 
Grade 3 - 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.  

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An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE. 
CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated. The investigator will also consult the IB and/or Product 
Information, for marketed products, in the determination of his/her assessment. 
For each AE/SAE the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.  The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool accordingly.  
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.  
7.7 
Follow-Up of Adverse Events of Special Interest and Serious 
Adverse Events 
AESIs (see Section 8.5.1 for details) and SAEs that occur from the start of study agent 
administration (Day 0) through Week 52 are reported. 
After the initial AESI/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All AESIs/SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-
up. Follow-up of AESI/SAE reports applies to all subjects, including those withdrawn 
prematurely.  
7.8 
Reporting Serious Adverse Events to the Regulatory Authorities 
and Institutional Review Boards/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 (eg, 15-Day) reports to the appropriate 
regulatory authorities AND to all participating investigators (exceptions discussed below). In 
addition, the sponsor or designee follows all applicable local and national regulatory 
requirements regarding safety reporting. Each investigator must also comply with the applicable 

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regulatory requirements related to the reporting of SAEs to the IRBs/IECs responsible for 
reviewing the study at their site, as well as the regulatory authority(ies) (if applicable).  
All SAEs, including disease-related events that meet the definition of a SAE (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 meet 
the definition of a SAE (ie, when the event is more severe than expected for the subject’s SLE 
condition and meets the regulatory definition of being an SAE), they must be reported to the 
sponsor within 24 hours of site personnel becoming aware as described in Section 7.2. The 
sponsor will not submit these events as expedited reports to regulatory authorities, investigators, 
or IRBs/IECs (unless considered by the sponsor to be related to study agent). 
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 
 
In addition, AESI that are study endpoints (Section 8.5.1) generally will not be submitted as 
expedited reports to regulatory authorities or participating investigators. Specifically, serious 
infections, malignancies (including NMSC), serious psychiatric events suggesting serious mood 
disorders/anxiety, suicide, serious infusion and hypersensitivity reactions, and all-cause 
mortality will not be reported to regulatory authorities or participating investigators as expedited 
single case reports. These events will be monitored by treatment group by an IDMC (Section 
8.3). Investigators will be notified of the outcome of each IDMC meeting, and any 
recommendations made. 
7.9 
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 

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comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/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 
This main purpose of this study is to provide an evaluation of the difference in the rates of all 
prespecified AESI and all cause mortality between the belimumab and the placebo groups with 
a 2-sided 95% confidence interval (CI). SAEs will be analyzed descriptively only.  
Safety analyses will be performed on the as-treated population defined as all subjects who are 
randomized and received at least 1 dose of study agent, grouped according to the treatment that 
was received for >50% of doses. Secondary efficacy endpoints will be analyzed using the ITT 
population, grouped  according to the treatment that a subject was randomized to receive, 
regardless of the actual treatment received.  
The final analysis for the 52-week study will be performed when all the data have been 
collected, verified and validated for all subjects through the Week 52 visit. 
An interim analysis will be conducted once at least 2000 randomized subjects have completed 
through Week 52. The interim analysis is solely for monitoring patients’ safety and reporting 
event rates to health authorities. It will be descriptive in nature and no comparative statistical 
inferences for claims will be made. Therefore, there will be no adjustment to Type I error for 
the interim or the final analyses. To minimize bias and to maintain data integrity, the interim 
analysis will be performed by a statistician who is not affiliated with the study conduct. 
Similarly, sponsor staff who have access to the interim results will not be involved in subject 
level monitoring of the study. Site personnel, investigators, and subjects will remain blinded 
until the study is complete and the final results are made public. 
8.2 
Randomization Procedure and Assignment to Treatment Groups 
Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system) to 1 of 2 treatment groups (10 mg/kg belimumab or placebo) in a 1:1 ratio. 
The randomization will be stratified for region (US/Canada vs Central America/South 
America/Mexico vs Europe/Australia/Israel vs Asia), SELENA SLEDAI score (≤ 9 vs ≥ 10), 
and steroid dose (≤ 7.5 mg/day vs > 7.5 mg/day prednisone or equivalent). 

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8.3 
Independent Data Monitoring Committee (IDMC) 
An IDMC will review unblinded safety data for the study on an ongoing basis until the data are 
locked and analyzed. The IDMC will include at least 3 physicians, and a statistician, none of 
whom are affiliated with the sponsor. The first IDMC data review meeting will after 
approximately 500 are enrolled or 6 months from randomization of the first patient, 
whichever is first. After initial review, the IDMC will review the data approximately every 
6 months. Events to be monitored during the safety review will include at a minimum 
all serious adverse events (including deaths, serious psychiatric events, and serious 
infections), opportunistic infections (serious and nonserious), malignancies (including 
NMSC), and serious infusion and hypersensitivity reactions. Investigators and IRBs/IECs will 
be notified of the outcome of each IDMC meeting.  
The IDMC will receive information within 72 hours of the sponsor or designee receiving 
notification of all SAEs that are life threatening or result in death. Other SAEs will be provided 
monthly to the IDMC. 
8.4 
Sample Size Rationale 
It was originally planned that a target of 5,000 SLE subjects would be enrolled in this safety 
study. The sample size was based on the feasibility of enrolling a large number of SLE subjects 
in a global trial that would provide a reasonable estimate for mortality and other AESI rates. 
The study design was designed to allow the difference in mortality rates between the placebo 
and the belimumab treated groups to be established with a 95% confidence interval (CI) of  
0.46% (ie, within -0.46% and 0.46%), assuming the estimated first year mortality rate was the 
same 0.68% in the 2 treatment groups. The estimated reference AE mortality rates were based 
on the annual AE mortality rates in the pooled primary safety database in SLE subjects 
(integrated database of LBSL02 [placebo-controlled treatment phase only], HGS1006-C1056, 
and HGS1006-C1057).  
8.4.1 Sample Size Re-Estimation 
Following the completion of  2 additional placebo-controlled trials (BEL112341/C1115, 
BEL113750), revised mortality estimates based on data from all 5 of the completed studies 
were as follows: 0.504% (6/1,190 for the placebo group) and 0.564% (14/2,484 for the 
belimumab group) with a delta of 0.060%.  
 
Using a conservative revised mortality rate of 0.564%, the 95% CI for a 4,000 subject sample 
size with 1:1 randomization was also 0.46%. As a result, given the revised mortality estimate, 
a sample size of 4,000 subjects would not result in any loss of precision (i.e., the width of the 
95% CI remains unchanged). Therefore,  agreement was reached with regulatory authorities to 
reduce the sample size from 5,000 to 4,000 subjects. 

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8.5 
Endpoints and Analysis 
8.5.1 Safety Endpoint Definitions and Measurements 
The table below describes the safety endpoints and measures collected in the study. All events 
shown in the table will be collected. 
All-cause mortality 
Serious Infections (including serious opportunistic infections and any event of TB or TB reactivation) 
Non-serious opportunistic infections and other infections of interest (Appendix 2) 
Malignancies (excluding NMSC) 
Non-melanoma skin cancers 
Psychiatric events suggesting serious mood disorders and anxiety  
Suicidality (using C-SSRS; Appendix 4 and Appendix 5) 
Serious Infusion and Hypersensitivity Reactions 
All SAEs 
 
8.5.2 Analysis of Safety Endpoints 
Mortality and AESI will be analyzed using an estimation paradigm. The difference in the rates 
of all prespecified AESI and all cause mortality, between the belimumab and the placebo groups 
will be evaluated with a 2-sided 95% CI. Deaths will also be described in detail, including, in 
the belimumab group, assessment of relationship to belimumab treatment.   
For all cause mortality, the hazard ratio (and its 95% CI) for belimumab vs placebo will be 
estimated using the Cox proportional hazard model, without adjustment for baseline 
randomization factors. The time to death will be censored at the last follow-up by the end of the 
study for subjects who are alive.  
SAEs will be analyzed descriptively only.  The frequency and rate of serious adverse events 
will be tabulated by MedDRA system organ class (SOC) and preferred term. The SAE rates 
may also be reported adjusted for subject years.   
8.5.3 Efficacy Endpoint Definitions and Measurements 
The major efficacy endpoint is: 
• Percent of subjects whose average prednisone (or equivalent) dose has been reduced by 
≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 (in the subgroup of 
subjects receiving > 7.5 mg/day of prednisone (or equivalent) at baseline). 
 
Other efficacy endpoints include: 
• Use of immunomodulatory medications to treat SLE. 
• Number of hospitalizations per patient.  

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• Percent of patients hospitalized. 
SLICC/ACR Damage Index will be recorded at baseline and at Week 52 to permit assessment 
of accrual of damage in subjects who may be followed a subsequent study. 
8.5.4 Analysis of Major Efficacy Endpoint 
The percent of subjects with average prednisone (or equivalent) dose that has been reduced by 
≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 through 52 will be compared between 
the belimumab and the placebo groups using a logistic regression model, adjusted for baseline 
prednisone (or equivalent) dose level, baseline SELENA SLEDAI score (≤ 9 vs ≥ 10), and 
region (US/Canada or Central America/South America/Mexico or Europe/Australia/Israel or 
Asia). The analysis will be performed on subjects who were using prednisone (or equivalent) at 
a dose > 7.5 mg/day at baseline. In the analysis, all subjects who drop out and/or add new 
immunomodulatory agents before the Week 52 visit will be considered having no steroid 
reduction. However, switching immunomodulatory agents for toxicity reasons or lack of 
availability (eg, no longer manufactured or no longer reimbursed) is permitted and will not be 
imputed as no steroid reduction. To examine the robustness of the results, a sensitivity analysis 
of the steroid reduction may be performed without considering any information related to the 
use of new immunomodulatory agents. 
Analysis of other efficacy endpoints will be described in the analytical plan. 
9 
Pharmacogenetics (PGx) 
This is an optional sub-study. 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 7). 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. 
In consenting subjects, a blood sample for PGx research will be drawn to better characterize 
genetic variability (eg, HLA typing) that may affect efficacy or safety endpoints. Information 
regarding PGx research is included in Appendix 7.  
10 
Study Administration 
This study is sponsored by GlaxoSmithKline (GSK) LLC. GSK will lead the operational 
conduct of this study on a world-wide basis working with contract research organizations. 
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 

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

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

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10.7 Drug Accountability 
Upon receipt, the investigator or their designee, 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 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 GSK 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 polled and analyzed. The investigators 
acknowledge that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and the sponsor’s representatives. Neither the 
participating institutions nor the principal investigators shall publish or present the results of 
the study prior to the publication of the multi-center study publication. The investigators agree 
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 

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information determined by the 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. 
 
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 GSK, 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 ...................... 61 
Appendix 2 
Infections of Interest ..................................................................................... 62 
Appendix 3 
SLICC/ACR Damage Index ......................................................................... 64 
Appendix 4 
Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline/Screening .... 66 
Appendix 5 
Columbia- Suicide Severity Rating Scale (C-SSRS) Since Last Visit ......... 82 
Appendix 6 
SELENA SLEDAI Score .............................................................................. 94 
Appendix 7 
Pharmacogenetic Research ........................................................................... 95 
Appendix 8 
Adverse Event Severity Grading Tables ....................................................... 99 
Appendix 9 
Liver Safety Required Actions and Follow up Assessments ...................... 108 
Appendix 10 
Liver Safety – Study Treatment Restart or Rechallenge Guidelines Liver 112 
 

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
6 1  
 
A p p e n di x 1  
A m eri c a n C oll e g e of R h e u m at ol o g y ( A C R)  Crit eri a f or 
S L E  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht 
l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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Appendix 2 
Infections of Interest 
 
“Infections of Interest” include opportunistic infections and other infections of interest 
generally not considered opportunistic.  Opportunistic infections are a subset of infections that 
are caused by organisms that usually do not cause disease in immunocompetent individuals but 
which may cause illness, or more severe illness, when the immune system is suppressed. Since 
there are no general guidelines for labeling pathogens as opportunistic without considering the 
host's immune condition, identification of opportunistic infections and other infections of 
interest in this study is based on the following list of pathogens which when present may 
indicate immune suppression in a subject. These pathogens and infections in general are rarely 
observed in immunocompetent individuals and will be considered opportunistic. Pathogens 
considered to cause opportunistic infections and other infections of interest include but are not 
limited to the following: 
Acinetobacter infection 
Aspergillosis 
Blastomycosis, extrapulmonary 
Candidiasis of esophagus, bronchi, trachea, or lungs 
Coccidioidomycosis, dissemintaed or extrapulmonary 
Cryptococcosis, extrapulmonary 
Cryptosporidiosis infection, chronic intestinal (> 1 month duration) 
Cytomegalovirus disease (other than liver, spleen, or nodes) 
Herpes simplex bronchitis, pneumonitis, or esophagitis 
Disseminated herpes zoster or involving at least 2 distinct episodes (see other infections of 
interest below) 
Histoplasmosis disseminated or extrapulmonary 
Human polyomavirus infection  
Isosporiasis, chronic intestinal (> 1 month’s duration) 
Listeriosis 
Mycobacterium avium complex or M. Kansasii, disseminated or extrapulmonary 
Mycobacterium infections, other species or unidentified species, disseminated or 
extrapulmonary (eg, M. haemophilium, M. fortuitum, or M. marinum)  
Nocardiosis 
Polyomavirus (JC virus or BK virus)-associated nephropathy (including progressive 
multifocal leukoencephalopathy) 
Pneumocystis jiroveci infection 
Toxoplasmosis of brain 
 

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Other infections of interest that will be recorded in this study, but which are not generally 
considered opportunistic, include: 
Mycobacterium tuberculosis, any site, latent or active 
Salmonella sepsis 
Hepatitis B  
Hepatitis C 
All other (ie, non-disseminated or single episode) herpes zoster (shingles) 

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
6 4  
 
A p p e n di x 3  
S LI C C/ A C R D a m a g e I n d e x  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s 
a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
6 5  
 
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht 
l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
6 6  
 
A p p e n di x 4  
C ol u m bi a - S ui ci d e  S e v erit y R ati n g S c al e ( C -S S R S) 
B a s eli n e/ S cr e e ni n g  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
6 7  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
6 8  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
6 9  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
7 0  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
7 1  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
7 2  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
7 3  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
7 4  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
7 5  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
7 6  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
7 7  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
7 8  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
7 9  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
8 0  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
8 1  
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h 
ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
8 2  
 
A p p e n di x 5  
C ol u m bi a - S ui ci d e  S e v erit y R ati n g S c al e ( C -S S R S) 
Si n c e L a st Vi sit  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h 
ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
8 3  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
8 4  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
8 5  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
8 6  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
8 7  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
8 8  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
8 9  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
9 0  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
9 1  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
H G S 1 0 0 6 -C 1 1 1 3 ( B E L 1 1 5 4 6 7)  
9 2  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 1 6 N 2 7 3 8 5 6 _ 0 2   
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
H G S 1 0 0 6 -C 1 1 1 3  ( B E L 1 1 5 4 6 7) 
 
9 3  
 
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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Appendix 6 
SELENA SLEDAI Score 
 
Score if descriptor is present at time of visit or in the preceding 30 days. 
 
 
Wgt. 
 
Descriptor 
 
Definition 
 
8 
Seizure 
Recent onset (last 30 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. 
 
Touma Z, Urowitz MB, Gladmann DD. SLEDAI-2K for a 30-day window. Lupus 2010; 19:49-50. 
 
Touma Z, Urowitz MB, Ibañez D, et al. SLEDAI-2K 10 day versus SLEDAI-2K 30 days in a longitudinal 
evaluation. Lupus 2011; 20:67-70. 

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Appendix 7 
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 8 
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 9 
Liver Safety Required Actions and Follow up 
Assessments 
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf 

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Phase III-IV liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria - Liver Stopping Event 
ALT-absolute 
ALT  8xULN 
ALT Increase 
ALT  5xULN but <8xULN  persists for 2 weeks 
ALT  3xULN but <5xULN  persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 ALT   3xULN associated with symptoms (new or worsening) believed to be related 
to  liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue  study treatment 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments 
• Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below) 
• Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (refer to Appendix 10) 
• If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
• Viral hepatitis serology4 
• Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5 
• Blood sample for pharmacokinetic (PK) 
analysis, obtained within approximately 1 to 
2 weeks after the liver event6 
• 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 

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MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs 
• Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs  
• Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline 
including acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: not 
required in China  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN. Additionally, if serum bilirubin 
fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to subjects 
receiving anticoagulants. 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).    
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);  Hepatitis E IgM antibody. 
5. If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where 
needed) [Le Gal, 2005]. 
6. PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  Record 
the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood sample 
draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time 
of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not 
obtain a PK sample. Instructions for sample handling and shipping are in the study reference manual. 
 

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Phase III-IV liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT 5xULN and <8xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3xULN and <5xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
 
• Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss subject 
safety.  
• Subject can continue study treatment 
• Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
• If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and 
Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns 
of Virological Response to Interferon Therapy in Chronically Infected Patients.  J Clin 
Microbiol. 2005;43(5):2363–2369.  

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Appendix 10 
Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines Liver 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with study 
treatment unless: 
• 
GSK Medical Governance approval is granted (as described below), 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
If GSK Medical Governance approval to restart/rechallenge subject with study treatment is 
not granted, then subject must permanently discontinue study treatment and may continue 
in the study for protocol-specified follow up assessments, 
Rechallenge Following Liver Stopping Events that are Possibly Related to Study 
Treatment 
Following drug-induced liver injury, drug rechallenge is associated with a 13% mortality 
across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes vary by drug, with 
nearly 50% fatality with halothane readministered within one month of initial injury. However, 
some drugs seldom result in recurrent liver injury or fatality. Risk factors for a fatal drug 
rechallenge outcome include: 
• 
Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, eosinophilia)  
• 
jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of total) 
• 
subject currently exhibits severe liver injury defined by: ALT 3xULN, bilirubin 2xULN 
(direct bilirubin >35% of total), or INR1.5 
• 
serious adverse event or fatality has earlier been observed with drug rechallenges [Hunt, 
2010;  Papay, 2009] 
• 
evidence of drug-related preclinical liability (e.g. reactive metabolites;  mitochondrial 
impairment [Hunt, 2010]. 
Rechallenge refers to resuming study treatment following drug induced liver injury (DILI). 
Because of the risks associated with rechallenge after DILI this should only be considered for 
a subject for whom there is compelling evidence of benefit from a critical or life-saving 
medicine, there is no alternative approved medicine available, and a benefit:risk assessment of 
rechallenge is considered to be favourable. 
 
Approval by GSK for rechallenge with study treatment can be considered where: 
• 
Principal Investigator (PI) requests consideration of rechallenge with study treatment for a 
subject who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available.   
• 
Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.    

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• 
If the rechallenge 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 rechallenge with 
study treatment.  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 rechallenge with study treatment must 
return to the clinic twice a week for liver chemistry tests until stable liver chemistries have 
been demonstrated and then standard laboratory monitoring may resume as per protocol. 
• 
If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued.  
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment rechallenge.  
• 
GSK to be notified of any adverse events, as per Section 7.2.  
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment 
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, pancreatic 
events, hypotension, acute viral hepatitis). Furthermore, there should be no evidence of 
alcoholic hepatitis or hypersensitivity, and the study treatment should not be associated with 
HLA markers of liver injury. 
 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator  requests consideration for study treatment restart if liver chemistries have a 
clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries have 
improved to normal or are within 1.5 x baseline and ALT <3xULN). 
• 
Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic hepatitis, 
possible study treatment-induced liver injury) or study treatment has an HLA genetic 
marker associated with liver injury (e.g. lapatinib, abacavir, amoxicillin/clavulanate) are 
reviewed and excluded. 
• 
Ethics Committee or Institutional Review Board approval of study treatment restart must 
be obtained, as required. 
• 
If restart of study treatment is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver injury or 
death.   
• 
The subject must also provide signed informed consent specifically for the study treatment 
restart.  Documentation of informed consent must be recorded in the study chart.   

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• 
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. 
 
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.