Clinical trial NCT01663623
Conditions: Vasculitis
Keywords: Wegener's Granulomatosis anti-MPO WG Belimumab GPA anti-proteinase 3 anti-neutrophil cytoplasmic antibody anti-myeloperoxidase Granulomatosis with polyangiitis Vasculitis Autoimmune Diseases Microscopic Polyangiitis anti-PR3 ANCA MPA Systemic Vasculitis
Sponsor: Human Genome Sciences Inc., a GSK Company
Start date: 2013-03-20; Completion date: 2017-02-06
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of belimumab, in combination with azathioprine, for the maintenance of remission following a standard induction regimen in patients with Wegener's granulomatosis or microscopic polyangiitis. The random assignment in this study is "1 to 1" which means that participants have an equal chance of receiving belimumab or placebo.

Detailed description:

Arms: arm 1: Placebo IV plus oral azathioprine 2 mg/kg/day; placebo administered on Days 0, 14, 28, and then every 28 days until the end of the study. If the results in the double-blind period show that belimumab is safe and effective, then participants have the option to receive treatment with belimumab in a 6-month open-label extension phase. Placebo patients who opt to participate in the extension will receive belimumab 10 mg/kg IV every 28 days plus oral azathioprine 2 mg/kg/day for an additional 6 months. arm 2: Belimumab 10 mg/kg IV plus oral azathioprine 2 mg/kg/day; belimumab administered on Days 0, 14, 28, and then every 28 days until the end of the study. If the results in the double-blind period show that belimumab is safe and effective, then participants have the option to continue treatment with belimumab in a 6-month open-label extension phase. Patients who opt to participate in the extension will continue to receive belimumab 10 mg/kg IV every 28 plus oral azathioprine 2 mg/kg/day days for an additional 6 months.
Interventions: intervention 1: Placebo intervention 2: Belimumab 10 mg/kg intervention 3: Azathioprine
Intervention descriptions: intervention 1: Placebo intervention 2: Belimumab 10 mg/kg intervention 3: Azathioprine

Protocol documents:
Prot_000.pdf: 
PPD


CLINICAL PROTOCOL HGS1006-C1100
Protocol Amendment: 04
Date: 26 February 2015
EudraCT 2011-004569-33
TITLE OF STUDY:
A Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
STUDY SPONSOR:
Human Genome Sciences, Inc.
14200 Shady Grove Road
Rockville, Maryland 20850
Confidentiality
This document contains proprietary and confidential information of Human Genome 
Sciences, Inc. Acceptance of this document constitutes agreement by the recipient that 
no unpublished information contained herein will be published or disclosed without 
prior written approval from Human Genome Sciences, Inc., except that this document 
may be disclosed to study personnel under your supervision who need to know the 
contents 
for 
conducting 
the 
study 
and 
appropriate 
Institutional 
Review 
Boards/Independent Ethics Committees under the condition that they are requested to 
keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws however, Human Genome Sciences, Inc. must be 
promptly informed of any such disclosure.
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Revision Chronology for HGS1006-C1100 (BEL115466)
Date
Document*
Global
07 March 2012
Original
Global
22 June 2012
Amendment No 01
Local 
29 January 2013
Addendum 01 for Sweden
Local
DNG2013N160488_01
31 January 2013
Addendum 01 for Ireland
Global
DNG2013N167980_00
25 April 2013
Amendment No 02
Global
DNG2013N167980_01
04 February 2014
Amendment No 03
Local
DNG2014N217970_01
01 October 2014
Local Amendment 01 for France
Local
DNG2014N217970_02
03 February 2015
Local Amendment 02 for France
Global
DNG2013N167980_02
26 February 2015
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


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Study Synopsis
Study Number: HGS1006-C1100
Title of the Study: 
A Multi-Center, Multinational, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Clinical Development Phase: 3
Objectives: 
•
To evaluate the efficacy of belimumab in the maintenance of remission following a 
standard induction regimen in subjects with Wegener’s granulomatosis (WG) or 
microscopic polyangiitis (MPA).
•
To evaluate the safety of belimumab in subjects with WG or MPA.
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria:
1. Are at least 18 years of age.
2. Have a clinical diagnosis of Wegener’s granulomatosis (WG) or a diagnosis of 
microscopic polyangiitis (MPA) according to the Chapel Hill criteria (Appendix 1 and 
Appendix 2).
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:
A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks plus 
high dose corticosteroids (HDCS) OR
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
cyclophosphamide 2 mg/kg/day orally plus HDCS OR
cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
4. Have documented evidence of either anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase 
(anti-MPO) prior to Day 0.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving ≤10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at 
least 14 days apart, between 6 and 26 weeks after the first dose of induction therapy 
(either CYC or RTX, as defined in Section 3.1). A minimum 6 week period should elapse 
between initiation of induction therapy and randomization.
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6. Subjects receiving non-systemic corticosteroids for reasons other than vasculitis must be 
on a stable regimen prior to randomization.
7. A female subject is eligible to enter the study if she is:
Not pregnant or nursing;
Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal 
which is defined as 12 consecutive months with no menses without an alternative medical 
cause, have both ovaries surgically removed or have current documented tubal ligation or 
other permanent sterilization procedure); or
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are peri-menopausal or 
have just begun to menstruate. These women must have a negative serum pregnancy test 
at screening, and agree to 1 of the following:
o
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or
o
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 
16 weeks after the last dose of study agent:
o Implants of levonorgestrel or etonogestrel;
o Injectable progesterone;
o Transdermal contraceptive patch
o Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
o Oral contraceptives (either combined or progesterone only);
o Ethinyl estradiol/Etonogestrel vaginal ring
o Double barrier method: Condom and Occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; or
o Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject.
8. Have the ability to understand the requirements of the study and provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).
Exclusion Criteria: Subjects will be excluded from participating in the study if they meet 
any of the following exclusion criteria:
1. Co-existence of other multisystem autoimmune diseases.
2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance or 
contraindications to methotrexate where methotrexate is being considered as an alternative 
to AZA for maintenance therapy.
3. Have received treatment with a B-cell directed therapy (other than rituximab), for example 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], anti-CD40L antibody [BG9588/ 
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IDEC-131], BLyS-receptor fusion protein [BR3], LY2127399, TACI-Fc, or belimumab at 
any time.
4. Have required 3 or more courses of systemic corticosteroids for concomitant conditions 
not related to their vasculitis (eg, asthma, atopic dermatitis) within 364 days of Day 0.
(Topical or inhaled steroids are permitted.)
5. Have received a non-biologic or biologic investigational agent within 60 days or 
5 half-lives of the agent (whichever is longer) of Day 0.
6. Have received a live vaccine within 30 days of Day 0.
7. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to vasculitis (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious disease) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk.
8. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study.
9. 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.
10. Have required management of acute or chronic infections, as follows:
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, aspergillosis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (intravenous, subcutaneous or intramuscular) antibiotics, antibacterials, 
antivirals, anti-fungals, or anti-parasitic agents within 60 days of Day 0.
11. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to Day 0.
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:
Patients positive for HBsAg are excluded.
Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody 
and with no history of Hepatitis B vaccination are excluded.
Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are 
excluded.
Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are 
excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will 
be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a 
positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the 
subsequent sample will not be eligible to participate.
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15. Have an IgA deficiency (IgA level < 10 mg/dL).
16. Have a Grade 3 or greater laboratory abnormality based on the protocol DMID toxicity 
scale, unless considered by the investigator to be related to the underlying disease or 
induction therapy.
17. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies.
18. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS 
(Refer to Appendix 8 for C-SSRS) in the last 2 months or who in the investigator’s 
opinion, pose a significant suicide risk.
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of normal 
(ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin > 1.5ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%).
Study Design and Schedule:
This is a multi-center, multi-national, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:
•
A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
Cyclophosphamide 2mg/kg/day orally plus HDCS OR
•
Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
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standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Subjects who are between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3 
score of 0 (Appendix 4), and are receiving ≤10 mg/day prednisone (or equivalent) on 2
consecutive measurements at least 14 days apart may be enrolled into the study. A minimum 
6 week period should elapse between initiation of induction therapy and randomization. 
Randomization will be performed on Day 0. A schematic of the study design is shown below.
All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 
2 mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than Day 0. 
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to receive study agent 
(belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.  
Initial randomization will be limited to 40 subjects per induction regimen (40 post-RTX 
induction and 40 post-CYC induction). Once the first 20 patients randomized following 
induction with RTX have had a Week 8 visit, safety data will be reviewed by the independent 
data monitoring committee (DMC), who will make a recommendation regarding whether to 
continue randomization. The same procedure would be applied for the first 20 subjects 
randomized following induction with CYC. At all times the sites and sponsor will remain 
blinded to treatment allocation.
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The study will complete, the database will be locked and the primary 
analysis will be performed when 12 months have elapsed after the last subject is randomized.
Subjects who discontinue study agent prior to relapse/flare (as defined below) are to be 
followed per the double blind visit schedule until relapse/flare or the end of the double-blind 
treatment phase (whichever is earlier). In subjects who withdraw consent from the study prior 
to 1 year an attempt will be made to ascertain survival status at 12 months after the first dose 
of study agent.  
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Schematic of study design:
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Efficacy Endpoints and Analysis:
Primary Efficacy Endpoint:
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as:
•
At least 1 major BVAS item (Appendix 4) OR 
•
A minimum total BVAS score of 6 (Appendix 4) OR
•
Receipt of prohibited medications (as defined in Section 5.5.1).
Major Secondary Efficacy Endpoint:
•
Time from Day 0 to the first major relapse (defined as experiencing at least 1 major BVAS 
item, see Appendix 4).
Other efficacy endpoints are described in Section 8.5.4.
Sample Size Considerations:
Approximately 100 subjects will be randomized. The sample size has been determined based 
on the feasibility of enrolling patients into the study within a reasonable time-frame. The 
sample size was not based on statistical considerations and the analysis of primary and 
secondary endpoints will be exploratory in nature. The primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo group, a 
relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically significant 
(p<0.05) in a study of 100 subjects (50 per arm). 
Analysis of Primary Efficacy Endpoint:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazards model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage
at induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using oral cyclophosphamide
or IV 
cyclophosphamide. For any subject who does not experience a relapse, the time to first relapse 
will be censored at the time of the subject’s last assessment.
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after 12 months have elapsed following randomization of the last subject.
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Analysis of Major Secondary Efficacy Endpoints:
The analysis of the major secondary efficacy endpoint will be performed using the same 
method described for the primary efficacy analysis, but censoring subjects who receive any 
prohibited medication prior to an observation of any major BVAS item.
Safety Endpoints and Analysis:
Descriptive statistics will be used to summarize adverse events (AEs), changes in laboratory 
parameters and immunogenicity. The frequency and rate of laboratory abnormalities will be 
tabulated by treatment group. The frequency and rate of AEs will be tabulated by MedDRA 
system organ class (SOC) and preferred term and presented by treatment group.
Adverse events of special interest that will be analyzed in this protocol include: all-cause 
mortality; serious and/or severe infections; opportunistic infections; infusion reactions 
including hypersensitivity reactions; malignant neoplasms; selected serious psychiatric events; 
suicidality assessment (Appendix 8); and immunogenicity.
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed. The DMC will include at least 3 physicians and a 
statistician, none of whom are affiliated with the Sponsor. The first DMC reviews will occur 
after the first 20 subjects per induction regimen (RTX or IV/oral CYC) have been randomized 
and have had a Week 8 visit. Once the first 20 subjects randomized following induction with 
RTX have had a Week 8 visit, safety data will be reviewed by the DMC, who will make a 
recommendation regarding whether to continue randomization. The same procedure would be 
applied for the first 20 subjects randomized following induction with IV or oral CYC. The 
DMC will review the data approximately every 6 months thereafter across both induction 
regimens. At all times the sites and sponsor will remain blinded to treatment allocation.  The 
DMC will monitor this trial until the data are locked, unblinded, and analyzed for the primary 
efficacy outcome, after which time monitoring may be assumed by an internal Human 
Genome Sciences (HGS) committee. Investigators and IRBs/ECs will be notified of the 
outcome of each DMC meeting.
PK Endpoints and Analysis:
Serum samples will be collected from all randomized subjects who receive a dose of study 
agent during the study and analyzed to determine serum belimumab concentrations. Serum 
belimumab concentration data will be used in a population PK analysis, which will be 
reported separately.
Immunogenicity:
Serum samples for the measurement of anti-belimumab antibodies will be obtained from all 
subjects before administration of study agent on Day 0, Week 8, Week 24, Week 48 and
Exit/8-week Follow-up. Additionally, samples will be obtained from subjects at Weeks 24 and 
48 during additional years. For any subject who had a positive antibody response at the 
8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-week 
follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum 
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sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or 
after completion and/or unblinding of the study, whichever is later. 
Biological Markers and Autoantibodies:
Pharmacogenetic sampling (in consenting subjects) will be taken once during the course of 
this study (see Appendix 9).  
Biological markers will be measured at baseline (Day 0) and at multiple time points 
thereafter:
•
Anti-neutrophil cytoplasmic antibody (ANCA: antiPR3, anti-MPO)
•
Serum complement (C3, C4)
•
Serum immunoglobulin isotypes (IgA, IgM, IgG)
•
C-reactive Protein (CRP)
•
Erythrocyte sedimentation rate (ESR)
•
Urinary protein: urinary creatinine ratio
•
BLyS protein (Day 0 only)
•
FACS of peripheral lymphocytes
Study Calendar
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Table of Contents
Study Synopsis ........................................................................................................................... 4
Table of Contents...................................................................................................................... 13
List of Tables............................................................................................................................ 16
List of Abbreviations................................................................................................................ 17
1
Background................................................................................................................... 20
1.1 Disease Background ..................................................................................................... 20
1.2 Study Agent Background.............................................................................................. 21
1.3 Clinical Experience....................................................................................................... 21
1.3.1
Belimumab Administered Intravenously...................................................... 21
1.4 Rationale for the Study................................................................................................. 22
2
Study Objectives........................................................................................................... 23
2.1 Primary Objective......................................................................................................... 23
3
Study Design................................................................................................................. 23
3.1 Basic Design Characteristics ........................................................................................ 23
4
Inclusion and Exclusion Criteria .................................................................................. 25
4.1 Inclusion Criteria.......................................................................................................... 25
4.2 Exclusion Criteria......................................................................................................... 26
5
Study Treatment Regimen............................................................................................ 28
5.1 Study Agent Name and Formulation............................................................................ 28
5.2 Packaging, Labeling, Preparation, and Storage............................................................ 29
5.3 Dose, Route of Administration, and Schedule ............................................................. 30
5.4 Alteration of Dose/Schedule Due to Toxicity .............................................................. 31
5.5 Concurrent Medications ............................................................................................... 31
5.5.1
Prohibited Medications and Therapies that Result in Treatment Failure ..... 31
5.5.2
Other Prohibited Medications and Therapies ............................................... 32
5.5.3
Allowable Medications................................................................................. 32
6
Study Procedures .......................................................................................................... 33
6.1 Screening Procedures (Day -60 to Day 0).................................................................... 33
6.2 Study Enrollment Procedures ....................................................................................... 34
6.3 Double-Blind Treatment Phase .................................................................................... 34
6.4 Unscheduled Visits....................................................................................................... 41
6.5 Laboratory Tests........................................................................................................... 41
6.5.1
Pharmacokinetics.......................................................................................... 41
6.5.2
Liver Chemistry Stopping and Follow-up Criteria....................................... 42
6.5.3
Increased Monitoring Criteria with Continued Therapy .............................. 44
6.5.4
Study Treatment Restart ............................................................................... 45


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6.5.5
Immunogenicity............................................................................................ 46
6.6 Exit Visit....................................................................................................................... 46
6.7 8-Week Follow-up Visit ............................................................................................... 46
6.8 Withdrawal of Subjects from Treatment ...................................................................... 47
6.9 Subject Unblinding....................................................................................................... 47
7
Adverse Event Reporting.............................................................................................. 48
7.1 Definitions .................................................................................................................... 48
7.2 Reporting Adverse Events to the Sponsor.................................................................... 50
7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events) ....................... 50
7.4 Laboratory Abnormalities as Adverse Events.............................................................. 51
7.5 Progressive Multifocal Leukoencephalopathy ............................................................. 51
7.6 Suicidality Assessment................................................................................................. 51
7.6.1
Possible Suicidality Related Questionnaire (PSRQ) .................................... 52
7.7 Reporting a Pregnancy.................................................................................................. 52
7.8 Investigator Evaluation of Adverse Events .................................................................. 53
7.9 Follow-Up of Adverse Events...................................................................................... 54
7.10
Reporting Serious Adverse Events to Regulatory Authorities and Institutional 
Review Boards/Independent Ethics Committees ................................................... 54
8
Endpoints and Statistical Analysis ............................................................................... 55
8.1 General Statistical Considerations................................................................................ 55
8.2 Randomization Procedure and Assignment to Treatment Groups ............................... 55
8.3 Data Monitoring Committee (DMC)............................................................................ 55
8.4 Sample Size Rationale.................................................................................................. 56
8.5 Efficacy......................................................................................................................... 56
8.5.1
Primary Efficacy Endpoint........................................................................... 56
8.5.2
Primary Efficacy Analysis............................................................................ 56
8.5.3
Major Secondary Efficacy Endpoint ............................................................ 57
8.5.4
Other Efficacy Endpoints ............................................................................. 57
8.5.5
Major Secondary Endpoint analysis and Other Efficacy Analyses.............. 58
8.6 Safety............................................................................................................................ 58
8.6.1
Definition of Safety Variables...................................................................... 58
8.6.2
Analysis of Safety Variables ........................................................................ 58
8.7 Pharmacokinetics.......................................................................................................... 59
8.7.1
Definition of Pharmacokinetic Evaluation ................................................... 59
8.7.2
Analysis of Pharmacokinetics ...................................................................... 59
9
Pharmacogenetics (PGx) .............................................................................................. 59
10
Study Administration.................................................................................................... 59


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10.1
Informed Consent ................................................................................................... 59
10.2
Institutional Review Board Review/Independent Ethics Committee Review and 
Approval ................................................................................................................. 60
10.3
Protocol Compliance .............................................................................................. 60
10.4
Protocol Revisions.................................................................................................. 60
10.5
Data Collection and Management .......................................................................... 61
10.6
Study Monitoring.................................................................................................... 61
10.7
Drug Accountability ............................................................................................... 62
10.8
Retention of Records .............................................................................................. 62
10.9
Financial Disclosure ............................................................................................... 62
10.10 Publication Policy................................................................................................... 62
10.11 Study or Study Site Termination ............................................................................ 63
11
References .................................................................................................................... 64
List of Appendices.................................................................................................................... 64


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List of Tables
Table 6-1
Double-blind Treatment Phase Year One..................................................... 36
Table 6-2
Double-blind Treatment Phase Additional Years......................................... 39
Table 6-3
PK visit days and sample times .................................................................... 42


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List of Abbreviations
AAV
ANCA-associated vasculitis
aCL
anticardiolipin
ACR
American College of Rheumatology
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody 
ANCA
anti-neutrophil cytoplasmic antibodies
Anti-dsDNA
anti-double-stranded DNA
Anti-MPO
anti- myeloperoxidase
Anti-PR3
anti-proteinase 3
Anti-RNP
anti-ribonucleoprotein
Anti-Sm
anti-Smith antibody (see Sm)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the serum drug concentration-time curve
AZA
azathioprine
BAFF
B Cell Activating Factor belonging to the TNF Ligand Family
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BLyS
B lymphocyte Stimulator
BR3
BLyS-receptor fusion protein
BUN
blood urea nitrogen
BVAS
Birmingham Vasculitis Activity Score
ºC
degrees Celsius
C3
Complement Factor 3
C4
Complement Factor 4
C-ANCA
Cytoplasmic antineutrophil cytoplasmic antibodies
CHCC
Chapel Hill consensus Conference
Chem
chemistry
Clcr
creatinine clearance
Coag
Coagulation
CPK
creatine phosphokinase
CRF
case report form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSS
Churg-Strauss Syndrome
C-SSRS
Columbia-Suicide Severity Rating Scale
CYC
cyclophosphamide
dL
deciliter
DMC
Data Monitoring Committee
DMID
Division of Microbiology & Infectious Diseases
DNA
deoxyribonucleic acid
dsDNA
double stranded DNA
DSM
Diagnostic and Statistical Manual


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ECG
electrocardiogram
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme linked immunosorbent assay
ESR
erythrocyte sedimentation rate
EU
Europe
FACS
florescence activated cell sorting
Fc 
immunoglobulin constant region (fragment crystallizable)
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GPA
Granulomatosis with polyangiitis
HB
hepatitis B
HBsAg
hepatitis B surface antigen
HBc
hepatitis B core
HDCS
high dose corticosteroids
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGS
Human Genome Sciences, Inc.
HIV
human immunodeficiency virus
HLA
Human Leukocyte Antigen
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IM
intramuscular
INR
International Normalized Ratio
INN
international nonproprietary Name
IRB
Institutional Review Board
ITT
intention to treat
IUD
intrauterine device
IV
intravenous
IVIG
intravenous immunoglobulin
IWRS
Interactive Web Response System 
kDa
kilodalton
kg
kilogram
LDH
lactate dehydrogenase
m2
meters squared
MDD 
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MPA
microscopic polyangiitis
MPO
myeloperoxidase
MTX
methotrexate


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n
number
μg
microgram
mg
milligram
mL
milliliter
OD
optical density
PAN
polyarteritis nodosa
P-ANCA
perinuclear antineutrophil cytoplasmic antibodies
PGx
pharmacogenetics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PR3
proteinase 3
PSE
protocol specified events
PSRHQ
possible suicidality related history questionnaire
PSRQ
possible suicidality related questionnaire
PT
prothrombin time
PTT
partial thromboplastin time
RA
rheumatoid arthritis
RBC
red blood cell
RF
rheumatoid factor
RTX
rituximab
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SLE
Systemic lupus erythematosus
SOC
System Organ Class
SRI
SLE responder index
SWFI
sterile water for injection
t1/2,term
terminal half-life 
TACI
transmembrane activator and calcium-modulator and cyclophilin ligand 
interactor
TEN
toxic epidermal necrolysis
TNFSF13B
Tumor Necorsis Factor Superfamily Member 13 B
TPMT 
thiopurine methyltransferase
ULN
upper limits of normal
USA
United States of America
USAN
United States Adopted Name
VDI
Vasculitis Damage Index
WBC
white blood cell
WG
Wegener’s Granulmatosis (Granulomatosis with polyangiitis)


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1 Background
1.1
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis (also commonly referred to as granulomatosis 
with polyangiitis [GPA]), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to life-threatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. Historically, ANCA have been classified on the basis of their staining 
patterns in immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear 
(P-ANCA). It is now recognized that in AAV, C-ANCA is usually directed against proteinase 
3 (PR3), and P-ANCA is generally directed against myeloperoxidase (MPO), both of which 
are enzymes that are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel
et al, 1997). Anti-PR3 antibodies are generally associated with WG, while anti-MPO 
autoantibodies are more common in MPA and CSS.  Anti-PR3 antibodies are associated with 
increased morbidity and mortality compared to anti-MPO (Hogan et al, 1996; Franssen et al, 
1998). The most widely used classification criteria for diagnosing the 3 types of AAV are 
those published by the American College of Rheumatology (ACR) for WG and CSS (Leavitt
et al, 1990 and Masi et al, 1990, respectively), and that published by the Chapel Hill 
Consensus Conference (CHCC) for MPA (Jennette et al, 1994; Jennette et al, 2013). Of note, 
none of these diagnostic criteria incorporate the measurement of ANCA. The Chapel Hill 
criteria for WG can be found in Appendix 1 and for MPA in Appendix 2.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007; 
Mahr, 2009). In the case of MPA, in particular, epidemiological studies are confounded by its 
original inclusion as a form of polyarteritis nodosa (PAN). Utilising the ACR or CHCC 
criteria, prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and
0.4-1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes and Nossent, 2008). In the US, the prevalence rates of WG range from 
2.6-9/100000 (Zeft et al, 2005; Mahr et al, 2006). AAV are extremely rare in childhood with 
peak age of onset in those aged 65 to 74 years (Ntatsaki et al, 2010), with other small vessel 
vasculitides being the major concern in childhood (Brogan et al, 2010).
Current therapy is usually determined by severity of the disease, with more severe forms 
warranting more aggressive approaches. These usually involve an initial remission induction 
regimen of high dose corticosteroid administered with either cyclophosphamide or rituximab 
followed by a remission maintenance period usually with azathioprine (Stone et al, 2010; 
Bosch et al, 2007; Jayne et al, 2003). Minor manifestations are usually treated with low dose 
corticosteroid administered with either azathioprine or methotrexate (Belmont, 2006). Even 
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with recent treatment advances the morbidity and mortality of patients with AAV remains 
unacceptably high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2008, Appendix 3). In its current 
form it is a list of 56 items which are considered to be manifestations of vasculitis. A 
weighted numerical score is attached to each item to reflect the importance of each 
manifestation. The items are grouped by organ systems, and each organ system has a 
maximum or ‘ceiling’ score to reflect the relative importance of the organ system 
(Mukhtyar et al, 2008). The tool also makes a distinction between new or worsening disease 
and persistent disease with new or worsening attracting higher scores.
1.2
Study Agent Background
Belimumab (also known as LymphoStat-B; BENLYSTA™) is a B-lymphocyte stimulator 
(BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to 
its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, 
belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the 
differentiation of B cells into immunoglobulin-producing plasma cells.
Nonclinical pharmacologic, pharmacokinetic (PK), and toxicologic data generated with 
belimumab are provided in the Investigator’s Brochure (IB).
1.3
Clinical Experience
1.3.1 Belimumab Administered Intravenously
Belimumab administered as an intravenous (IV) infusion has been studied in SLE subjects in 
1 Phase 1 trial (LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial 
(LBSL02) and 2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 
(HGS1006-C1057) and BLISS 76 (HGS1006-C1056)], and in RA subjects in a Phase 2 
double-blind, placebo-controlled trial (LBRA01).
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the basis 
of IV belimumab in the US, Canada and EU. The Phase 3 trials included 1,684 subjects where 
belimumab 10 mg/kg plus standard therapy demonstrated superiority over placebo plus 
standard therapy in reduction in disease activity as measured by the SLE responder index 
(SRI) with an acceptable safety profile. The primary safety population supporting approval 
also included data from a Phase 2 study in 449 subjects with SLE. Evidence of benefit in other 
clinical measures such as reductions in disease activity as measured by SELENA SLEDAI, 
severe flare, and reduced steroid use was also observed. Treatment with belimumab plus 
standard of care was generally well tolerated, with rates of adverse events (AEs), severe AEs, 
serious AEs, AEs leading to discontinuation and serious/severe infections generally 
comparable to the rates observed in the placebo plus standard of care group. Mortality rates in 
the controlled clinical trials were low, although numerically higher in the belimumab groups: 


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0.4% and 0.8% in the placebo and belimumab groups, respectively. Causes of death were as 
expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as steroids and immunosuppressants, and included infection, cardiovascular 
disease, and suicide. Serious infections were observed in 5.2% and 6.0% of subjects receiving 
placebo and belimumab, respectively. The rate of malignancy (excluding non-melanoma skin 
cancer) was the same between the placebo and belimumab groups at 0.4%; however as with 
other immunomodulating agents, the mechanism of action of belimumab could increase the 
risk for the development of malignancies. Hypersensitivity and infusion reactions were 
observed. Anaphylaxis was also observed, though rare (< 1%). Depression-related events, 
common in patients with SLE, were observed more frequently with belimumab than with 
placebo; it is unknown if belimumab treatment is associated with an increased risk for these 
events. The most commonly-reported adverse reactions, occurring in ≥5% of subjects in 
clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in 
extremity, depression, migraine, and pharyngitis.
Experience from open-label, long-term continuation trials of belimumab in SLE subjects 
suggests that prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence rate of AEs or serious adverse events (SAEs) over time, 
including important events such as infections and malignancies. The prevalence rate of AEs 
and SAEs has also remained relatively stable over time. Long term belimumab treatment 
through 6 years appears to provide sustained improvement in SLE disease activity.
Results of the clinical trials of belimumab administered IV are described in further detail in 
the Investigator’s Brochure.
A benefit-risk evaluation of belimumab in the context of the present study is provided in 
Appendix 12 of this protocol.
1.4
Rationale for the Study
Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 
18 months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the 
most effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al,
2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels.
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20 (Dass et al, 2008; Wang et al 2008), recently showed success in inducing 
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remission in AAV (Stone et al, 2010) and was granted approval for the treatment of WG and 
MPA supports the rationale that belimumab, which down regulates B cells by targeting BLyS, 
may be useful in the treatment of this disease. Finally, limited data from the small (n = 111) 
subset of subjects in the Phase 3 trials of SLE who had vasculitic symptoms as part of their 
SLE (as assessed by the SELENA SLEDAI) showed that more subjects in the belimumab plus 
standard of care treatment arms had resolution of their vasculitic symptoms at Week 52 
compared with subjects receiving placebo plus standard of care. Specifically, 19/36 (52.8%) 
and 28/38 (73.7%) of subjects in the belimumab 1 mg/kg and 10 mg/kg dose groups, 
respectively, had resolution of vasculitic activity at Week 52 compared with 15/37 (40.5%) of 
placebo subjects. Taken together, these data support the evaluation of belimumab in AAV.
2 Study Objectives
2.1
Primary Objective
1. To evaluate the efficacy of belimumab in the maintenance of remission following a 
standard induction regimen in subjects with Wegener’s granulomatosis (WG) or 
microscopic polyangiitis (MPA).
2. To evaluate the safety of belimumab in subjects with WG or MPA.
3 Study Design
3.1
Basic Design Characteristics
This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen. Subjects enrolled into the trial must have had an 
initial or relapsing episode of moderate to severely active WG or MPA that was treated with 
corticosteroids and either cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 
6 months leading up to randomization.
Subjects treated under the following induction 
regimens will be eligible for participation in the study:
•
A single course rituximab (RTX) administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval plus HSCS OR
•
Cyclophosphamide 2mg/kg/day orally plus HDCS OR
•
Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
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For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Subjects who between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3
score of 0 (Appendix 4) and are receiving ≤10 mg/day oral prednisone (or equivalent) on 
2 consecutive visits at least 14 days apart may be enrolled into the study. A minimum 6 week 
period should elapse between initiation of induction therapy and randomization.
Randomization will be performed on Day 0. A schematic of the study design is shown in 
Figure 1.
Figure 1 Schematic of study design
All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 2 
mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than Day 0. 
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to also receive study 
agent (belimumab [10 mg/kg] or placebo) administered intravenously over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
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cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent will be 
administered at Day 0, 14, 28 and every 28 days thereafter.
Initial randomization will be limited to 40 subjects per induction regimen (40 post-RTX 
induction and 40 post-CYC induction). Once the first 20 patients randomized following 
induction with RTX have had a Week 8 visit, safety data will be reviewed by the independent 
data monitoring committee (DMC), who will make a recommendation regarding whether to 
continue randomization. The same procedure would be applied for the first 20 subjects
randomized following induction with CYC. At all times the sites and sponsor will remain 
blinded to treatment allocation.
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1). The study will complete, the database will be locked, and the 
primary analysis will be performed when 12 months have elapsed after the last subject is 
randomized.
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent. 
4 Inclusion and Exclusion Criteria
4.1
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Are at least 18 years of age.
2. Have a clinical diagnosis of Wegener’s granulomatosis or a diagnosis of microscopic 
polyangiitis (MPA) according to the Chapel Hill criteria (Appendix 1 and Appendix 2).
3. In the 26 weeks prior to Day 0, had an episode of moderate to severely active WG or MPA 
requiring treatment under one of the following induction regimens:
A single course of rituximab administered at  a dose of 375 mg /m2/week for 4 weeks plus 
high dose corticosteroids (HDCS) OR
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
cyclophosphamide 2 mg/kg/day orally plus HDCS OR
cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
4. Have documented evidence of either anti-PR3 or anti-MPO prior to Day 0.
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5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving ≤10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at 
least 14 days apart, between 6 and 26 weeks after the first dose of induction therapy 
(either CYC or RTX, as defined in Section 3.1).  A minimum 6 week period should elapse 
between initiation of induction therapy and randomization.
6. Subjects receiving non-systemic corticosteroids for reasons other than vasculitis must be 
on a stable regimen prior to randomization.  
7. A female subject is eligible to enter the study if she is:
Not pregnant or nursing;
Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal 
which is defined as 12 consecutive months with no menses without an alternative medical 
cause, have both ovaries surgically removed or have current documented tubal ligation or 
other permanent sterilization procedure); or
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are perimenopausal or 
have just begun to menstruate. These women must have a negative serum pregnancy test 
at screening, and agree to 1 of the following:
o
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or
o
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 
16 weeks after the last dose of study agent:
o Implants of levonorgestrel or etonogestrel;
o Injectable progesterone;
o Transdermal contraceptive patch
o Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
o Oral contraceptives (either combined or progesterone only);
o Ethinyl estradiol/Etonogestrel vaginal ring;
o Double barrier method: Condom and Occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; or
o Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject.
8. Have the ability to understand the requirements of the study and provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).
4.2
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria:
1. Co-existence of other multisystem autoimmune diseases. 
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2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance or 
contraindications to methotrexate where methotrexate is being considered as an alternative 
to AZA for maintenance therapy.
3. Have received treatment with a B-cell directed therapy (other than rituximab), for example 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], antiCD40L antibody [BG9588/ 
IDEC-131], BLyS-receptor fusion protein [BR3], LY2127399, TACI-Fc, or belimumab at 
any time.
4. Have required 3 or more courses of systemic corticosteroids for concomitant conditions 
not related to their vasculitis (eg, asthma, atopic dermatitis) within 364 days of Day 0.
(Topical or inhaled steroids are permitted.)
5. Have received a non-biologic or biologic investigational agent within 60 days or 
5 half-lives of the agent (whichever is the longer) of Day 0.
6. Have received a live vaccine within 30 days of Day 0.
7. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to vasculitis (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious disease) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk.
8. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study.
9. 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.
10. Have required management of acute or chronic infections, as follows:
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, aspergillosis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (IV, SC or IM) antibiotics, antibacterials, antivirals, anti-fungals, or anti-
parasitic agents within 60 days of Day 0.
11. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to Day 0.
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:
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Patients positive for HBsAg are excluded.
Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody 
and with no history of Hepatitis B vaccination are excluded.
Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are 
excluded.
Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are 
excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood
sample by RNA PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will 
be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a 
positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the 
subsequent sample will not be eligible to participate.
15. Have an IgA deficiency (IgA level < 10 mg/dL).
16. Have a Grade 3 or greater laboratory abnormality based on the protocol DMID toxicity 
scale, unless considered by the investigator to be related to the underlying disease or
induction therapy.
17. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies.
18. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS 
(Refer to Appendix 8 for C-SSRS) in the last 2 months or who in the investigator’s 
judgment, pose a significant suicide risk.
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of normal 
(ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin > 1.5ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%).
5 Study Treatment Regimen
5.1
Study Agent Name and Formulation
The common name of the investigational product is BENLYSTA™. The generic (USAN/INN) 
name is belimumab.
Belimumab is a recombinant, human, IgG1monoclonal antibody specific for soluble human 
B lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a 
molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA 
technology in a mammalian cell expression system.
Belimumab drug product is provided as a sterile, lyophilized product in a 20 mL vial. Upon 
reconstitution with 4.8 mL sterile water for injection (SWFI), each vial will contain 80 mg/mL 
belimumab in 0.16 mg/mL citric acid, 2.7 mg/mL sodium citrate, 80 mg/mL sucrose, 
0.4 mg/mL polysorbate 80, pH 6.5. Each vial is single use.
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The placebo control is prepared as a sterile, lyophilized product in a 20 mL vial. Placebo is
reconstituted with 4.8 mL SWFI. Upon reconstitution with 4.8 mL sterile water for injection 
(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 placebo vial is single use.
5.2
Packaging, Labeling, Preparation, and Storage
Belimumab will be supplied in a 20 mL vial containing 400 mg belimumab (deliverable).
Placebo control will be supplied in a 20 mL vial.
Lyophilized belimumab and placebo should be stored at 2-8°C. After reconstitution and 
dilution in normal saline, the material is stable for up to 8 hours at 2-8°C, or at room 
temperature. Refer to the Pharmacy Manual for detailed instructions on the preparation, 
administration, and storage of study agent.
The 400 mg single use vial of study agent will be reconstituted with 4.8 mL SWFI, to yield a 
final concentration of 80 mg/mL of belimumab. Placebo will be reconstituted with 4.8 mL 
SWFI.
In addition to any country-specific requirements, the study agent label will contain, at a 
minimum, the following information:
•
Product name;
•
Concentration;
•
Lot number;
•
Storage conditions;
•
Investigational drug statement; and
•
Manufacturer’s name and address.
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's body weight in kilograms 
(kg).
The reconstituted study agent will be diluted in 250 mL normal saline for intravenous 
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 and to certain biomarkers and pharmacodynamic laboratory results. 


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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 Sponsor
or designee. At the end of the study, all used and unused study agent must be accounted for on 
a study agent accountability form.
Refer to the Pharmacy manual for more details regarding storage, handling, and drug 
accountability.
5.3
Dose, Route of Administration, and Schedule
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. The intent of this 
instruction is to prevent more rapid infusion of belimumab which may result in a higher
incidence of infusion reactions. Infusion time need not be exactly one hour as it is often 
difficult to so precisely adjust infusion times and there may be clinical reasons for infusions
lasting longer than one hour. Therefore, the instruction should be interpreted as infusion over 
at least one hour. The target infusion time should still be approximately one hour assuming no 
other issues intervene. Once randomized, subjects will be dosed with study agent on Days 0, 
14, and 28 and every 28 days thereafter.
Premedication including an antihistamine, with or without an antipyretic, may be administered 
before the infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted.
Belimumab/placebo should be administered by investigators/site personnel prepared to 
manage infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if 
the subject develops an infusion reaction. Investigators/site personnel should be aware of the 
risk of hypersensitivity reactions, which may present as infusion reaction, and monitor 
subjects closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. 
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase. 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. 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 IB.
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5.4
Alteration of Dose/Schedule Due to Toxicity
The dose of belimumab/placebo administered may not be altered.  The rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or infusion-
associated symptoms. At later visits, these subjects may continue to be infused over a longer 
infusion period at the investigator’s clinical discretion. 
If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo and could potentially be 
exacerbated by the next dose, the investigator may delay the dose by up to 2 weeks or 
withhold 1 dose. If a similar concern is present after 2 weeks, the investigator should contact 
the medical monitor to determine whether treatment should be discontinued.
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE that 
the 
investigator 
believes 
may 
be 
definitely, 
possibly 
or 
probably 
related 
to 
belimumab/placebo, then treatment with study agent will be discontinued. The subject will be 
followed at regularly scheduled study visits as specified by the protocol through the end of the 
double-blind period and also until resolution of the AE(s) (whichever is longer). All subjects 
should be monitored closely for infection. Increased vigilance for infection is recommended 
in subjects who experience IgG levels < 250 mg/dL, especially for prolonged periods; clinical 
judgment should be applied with respect to the appropriateness of continuing study therapy in 
these subjects. The Medical Monitor must be consulted before administering subsequent doses 
of study agent in subjects with IgG levels < 250 mg/dL.  Study agent will be discontinued in 
subjects with IgG levels < 250 mg/dL that are associated with a severe or serious infection.
5.5
Concurrent Medications
5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Subjects who start prohibited medication or therapies at any time during the double-blind 
phase will be considered as having relapsed as of the time of receipt of the prohibited 
medication, and treatment with study agent will be discontinued. However, the subject will 
continue to be followed for survival through at least 12 months after randomization. The 
following medications and therapies are prohibited during the study:
•
Other immunomodulatory investigational agents (biologic or non-biologic);
•
Rituximab;
•
Cyclophosphamide;
•
Other immunosuppressive agents (eg, cyclosporine) with the exception of methotrexate 
for AZA intolerance described in Section 5.5.3;
•
Corticosteroids for vasculitis:


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doses > 20 mg/day prednisone (or equivalent), or
IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 1 week, are only allowable within the first 2 months of the double-blind 
treatment period.
•
Corticosteroids for reasons other than vasculitis:
at an average daily dose of > 20 mg/day prednisone (or equivalent) for > 14 days where 
the average daily dose is calculated as the sum of the dose over 7 consecutive days divided 
by 7, or
IV corticosteroid pulses > 125 mg prednisone (or equivalent)
Note: Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or IV corticosteroid 
pulses ≤ 125 mg prednisone (or equivalent) for reasons other than vasculitis cannot be 
given more than once in any 365 day period (See also Section 5.5.3).
•
Plasmapharesis.
5.5.2 Other Prohibited Medications and Therapies
Due to the mechanism of action of belimumab, it is possible that response to vaccination may 
be impaired. Live vaccines should not be given for 30 days before or concurrently with 
belimumab/placebo infusions.
Other investigational agents are not permitted.
5.5.3 Allowable Medications
The use of stable baseline dose regimens of corticosteroids (≤10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
1 week within the first 2 months of the double-blind treatment period. At other times, subjects 
are restricted to ≤10 mg/day prednisone or equivalent. It is expected that this dose may be 
tapered as clinically appropriate. Inhaled corticosteroids for asthma, or topical corticosteroids 
for atopic dermatitis are also permitted. Doses of prednisone (or equivalent) > 20mg/day for ≤ 
14 days or an IV corticosteroid pulse up to 125 mg prednisone (or equivalent) are permitted 
for reasons other than vasculitis (eg. acute allergic reaction), but a subject cannot receive more 
than 1 such corticosteroid regimen in any 365 day period (See also Section 5.5.1).
5.5.3.1
Azathioprine and Methotrexate
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). For the 
maintenance of remission azathioprine may be initiated as soon as it is clinically indicated 
following administration of induction therapy. Azathioprine must not be initiated any later 
than Day 0. Azathioprine should be started at a dose of 50 mg/day and increased by no more 
than 50 mg/day every week until the target dose is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
Amend 01
22Jun12
Amend 01
22Jun12
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22Jun12
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22Jun12
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25Apr13
Amend 02
25Apr13
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04Feb14
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permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
For subjects previously identified as being intolerant to azathioprine, or for subjects identified 
as having undetectable or reduced activity of thiopurine methyltransferase (TPMT), it may be
permissible for methotrexate to be used as an alternative to azathioprine for the maintenance 
of remission from the outset. This should be discussed with the medical monitor.
Methotrexate would not be recommended for those subjects with significantly impaired renal 
function.
The appropriate local prescribing information (eg, dose adjustments, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine 
or methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator. 
6 Study Procedures
The nature of potential risks and benefits associated with participation in the study will be 
explained to all potential study subjects. Written informed consent (including consent for the 
use and disclosure of research-related health information) must be obtained before the subject 
can begin any screening procedures that are not considered part of standard patient care. 
Subjects participating in the pharmacogenetics (PGx) research portion of the protocol 
(Appendix 9) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject.
Refer to the Study Calendar (Table 6-1, Table 6-2), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
6.1
Screening Procedures (Day -60 to Day 0)
The following assessments are required at screening and must be within 60 days prior to or on 
Day 0:
•
Demographics.
•
Medical history.
•
Lifetime cyclophosphamide exposure.
•
Complete physical examination, including height, weight and vital signs.
•
Document induction regimen and confirm successful induction of remission for WG or 
MPA vasculitis.
•
Document positive history for either anti-PR3 or anti-MPO.
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•
Obtain historical biopsy information for documentation of vasculitis diagnosis as 
available.
•
Confirm subject meets study entry criteria. 
•
Blood samples for: (see Appendix 6 – Laboratory Tests)
-
Hematology
-
Modified Chem20 (non-fasting)
-
Serum pregnancy test – for all women with an intact uterus, unless exempted from 
pregnancy testing (ie, of non-childbearing potential – women who had a hysterectomy, 
are post-menopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented tubal ligation or other permanent 
sterilization procedure)
-
HIV antibody testing, serologic investigations for Hepatitis B (HB) infection (HBsAg, 
anti-HBc, and anti-HBs), and Hepatitis C antibody testing ± confirmatory HCV RNA-
PCR testing
-
Biological markers (Complement C3, C4) 
-
Serum Immunoglobulin isotypes (IgG, IgM, IgA)
-
C-reactive Protein (CRP)
-
Erythrocyte sedimentation rate (ESR)
-
Autoantibodies (ANCA: anti-PR3, anti-MPO)
•
Urine Sample for:
-
Routine urinalysis
-
Spot urine for Urinary protein: urinary creatinine 
•
Suicidality Assessment using the Columbia Suicidality-Severity Rating Scale (C-SSRS) 
Screening assessment form (see Appendix 8).
6.2
Study Enrollment Procedures
Subjects who have undergone all screening procedures and have met the entry criteria will be 
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Azathioprine may be initiated as soon as 
it is clinically indicated following administration of induction therapy. Azathioprine must not 
be initiated any later than Day 0. Female subjects who require pregnancy testing must have a 
negative urine pregnancy test done on Day 0, prior to randomization. Subjects will be 
randomized in a 1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + AZA).
6.3
Double-Blind Treatment Phase
Subjects will be evaluated during the scheduled study visits as outlined in the Study Calendar 
(Table 6-1 and Table 6-2). Time windows are provided for each study visit to allow flexibility 
in site and subject scheduling. All study visits should occur within the visit window of the 
scheduled study visit.
At baseline (Day 0), the subject will be randomized and receive the first dose of study agent. 
Visits to the study site will occur on Day 14, Day 28, and approximately every 28 days 
(calculated from the Day 0 dose) thereafter. All efforts should be made to retain subjects on 
schedule, based on the date of their Day 0 dose. Subjects should remain under clinical 
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supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The study will complete and the primary efficacy analysis will be 
performed when 12 months have elapsed following randomization of the last subject.
Subjects will return for an Exit visit (approximately 4 weeks after the last dose of study 
agent), and a follow-up visit (approximately 8 weeks after the last dose of study agent).
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Table 6-1
Double-blind Treatment Phase Year One
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7
days
Week 
12
± 7
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Written Informed 
Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Eligibility Criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Document Successful 
Induction Regimen
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Obtain Historical Biopsy 
Report (if available)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Randomization
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Clinical Assessments
Complete Physical 
Exam1
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Symptom Driven 
Physical Exam
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs15, 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
12-lead ECG16
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CSSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events3
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X12
X
X
BVAS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-
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Table 6-1
Double-blind Treatment Phase Year One
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7
days
Week 
12
± 7
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Laboratory 
Assessments
Serum Beta hCG
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HIV, Hepatitis B, C17
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology & Modified 
Chem-20 (non fasting)4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
Coagulation – PT/aPTT 
and INR
X
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test5
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and 
creatinine clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X14
Pharmacokinetic 
Sampling (pre/post 
Belimumab dose)
-
X
Pre
X
Post
(0-4
hrs)
-
X
Pre
-
-
-
X
Post
(0-4
hrs)
-
-
-
-
-
X 
Pre
X
X
-
Pharmacogenetic 
Sampling6
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Immunogenicity (anti-
belimumab antibodies)7
-
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
X
-
BLyS Protein 
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
T cells/B cell subset 
-
X
-
X
X
X
-
-
X
-
-
X
-
-
X
X
X
-
C3/C4 and ANCA
X
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum IgG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgA  & IgM
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
CRP & ESR
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
Protocol Treatments
Study agent 
(Belimumab/Placebo)8, 9,
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration10
X
X
←Throughout the Study →
-
-
-
Footnotes on next page:
Amend 01
22Jun12
Amend 01
22Jun12
Amend 02
25Apr13


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Belimumab
Table 6-1 Footnotes:
1.
Complete physical examination, including height and weight.  
2.
Any SAEs occurring prior to the start of study agent administration and assessed as related to study participation (eg, protocol-mandated procedures, invasive tests) will be recorded on the SAE worksheet and 
reported as described in Section 7.2 from the time a subject consents to participate in the study.
3.
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent should 
be recorded on the Adverse Event Case Report Form (AE eCRF).  SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, possibly or probably related to study agent 
must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
4.
Refer to Appendix 6 for laboratory assessments to be completed.
5.
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for definition of those exempted from pregnancy testing.
6.
In consenting subjects only (Appendix 9).
7.
Immunogenicity samples are collected pre-dose at all time points.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-
week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion 
and/or unblinding of the study, whichever is later. 
8.
Subjects who discontinue treatment with study agent (belimumab/placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1.
9.
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.
10.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by severe nausea and 
vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described above a switch to methotrexate at doses of 
up to 25 mg/week as an alternative to azathioprine will be permitted. For subjects previously identified as being intolerant to azathioprine, or for subjects identified as having undetectable or reduced activity of 
thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be used as an alternative to azathioprine for the maintenance of remission from the outset following discussion with the medical 
monitor.
11.
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 4 weeks after the last dose of study agent). The Exit Visit should be completed for subjects who discontinue the double 
blind treatment phase early or when subjects have completed the double-blind treatment phase. Subjects who discontinue treatment but have not relapsed will remain on the double blind study visit schedule. 
12.
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent.  After this time, all SAEs, regardless of 
relationship to study drug, will be collected until relapse or the study is analysed for the primary endpoint, whichever occurs first.
13.
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent.
14.
Hematology and Modified Chem 20, Urinary protein, urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be clinically indicated by 
the Principal Investigator.  
15.
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
16.
Complete prior to dosing.
17.
HIV, Hepatitis B surface antigen, anti-HBc, anti-HBs and hepatitis C antibody (if hepatitis C antibody positive, HCV RNA-PCR assay will be performed on a subsequent blood sample to confirm the results).
Amend 01
22Jun12
Amend 02
22Apr13
Amend 02
25Apr13
Amend 03
04Feb14
Amend 04
26Feb15


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Belimumab
Table 6-2
Double-blind Treatment Phase Additional Years
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events1
X
X
X
X
X
X
X
X
X
X
X
X
X8
X
X
BVAS
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-
Laboratory Assessments
Hematology & Modified Chem- 20 
(non fasting)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X10
Coagulation – PT/aPTT and INR
-
-
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and creatinine 
clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X10
Pharmacokinetic Sampling (pre 
or post Belimumab dose)
-
-
-
-
-
X 
Pre
-
-
-
-
-
X 
Pre
X
X
-
Immunogenicity (anti- belimumab 
antibodies)4
-
-
-
-
-
X
-
-
-
-
-
X
X
X
-
T cells/B cells 
X
-
-
-
-
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgG
-
-
X
-
-
X
-
-
X
-
-
X
X
X
-
Serum IgA & IgM
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-
CRP & ESR
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-
Amend 01
22Jun12
Amend 02
25Apr13


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Belimumab
Table 6-2
Double-blind Treatment Phase Additional Years
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Protocol Treatments
Study Agent 
(Belimumab/Placebo)5
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
-
-
-
Table 6-2 Footnotes:
1
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent should 
be recorded on the Adverse Event Case Report Form (AE eCRF).    SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, possibly or probably related to study agent 
must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
2
Refer to Appendix 6 for laboratory assessments to be completed.
3
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for definition of those exempted from pregnancy testing.
4
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-
week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion 
and/or unblinding of the study, whichever is later.
5
Subjects who discontinue treatment with study agent (belimumab/Placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1.
6
Subjects naïve to  azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by severe nausea and 
vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described above a switch to methotrexate at doses of 
up to 25 mg/week as an alternative to azathioprine will be permitted.
7
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 1-4 weeks after the last dose of study agent). The Exit Visit should be completed for subjects who discontinue the double 
blind treatment phase early or when subjects have completed the double-blind treatment phase.
8
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent. After this time, all SAEs, regardless of 
relationship to study drug, will be collected until relapse or the study is analysed for the primary endpoint, whichever occurs first.
9
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent.
10
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be clinically indicated  by the 
Principal Investigator.
11
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12
Complete prior to dosing.
Amend 01
22Jun12
Amend 02
25Apr13
Amend 04
26Feb15


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Belimumab
6.4
Unscheduled Visits
Unscheduled visits may be necessary during the course of the study to capture a subject’s 
status between regularly scheduled visits. Examples include, but are not limited to, a 
worsening of disease symptoms (eg, flare), AE reporting, or follow-up to a previously 
reported AE.
6.5
Laboratory Tests
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2).
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): serum immunoglobulin isotypes IgM/IgA and the results from the 
FACS analysis listed below.  
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis):
•
T cell subsets: CD3+/CD4+, CD3+/CD8+
•
B lymphocytes: (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived 
plasma, CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, 
CD138+/CD20+ plasmacytoid, CD27−/IgD+/CD10+ transitional)
6.5.1 Pharmacokinetics
All randomized subjects who receive a dose of study agent will be sampled for the assessment 
of serum belimumab levels. A blood sample for pharmacokinetic analysis will be drawn 
according to the time schedule below.


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Table 6-3
PK visit days and sample times
Week
Time (Related to Dosing of Study 
Agent)
0
Prior to the start of infusion
2
0-4 hours after the end of infusion
8
Prior to the start of infusion
24
0-4 hours after the end of infusion
48
Prior to the start of infusion 
24 (of each additional year)
Prior to the start of infusion 
48 (of each additional year)
Prior to the start of infusion 
Exit visit
Any time during visit
8-week follow-up
Any time during visit
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.
6.5.2
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity
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).
Amend 02
25Apr13
Amend 04
26Feb15


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6.5.2.1
Required Actions and Follow up Assessments following ANY Liver 
Stopping Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the event 
also meets the criteria for an SAE (All events of ALT 3xULN and bilirubin 
2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 13).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24-72 hours
Monitor subjects weekly until liver chemistries resolve, stabilize or return to within baseline
FOLLOW UP ASSESSMENTS

Viral hepatitis serology (includes: Hepatitis A IgM antibody; Hepatitis B surface 
antigen and Hepatitis B Core Antibody (IgM); 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)


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
Blood sample for pharmacokinetic (PK) analysis, obtained within approximately one 
to two weeks after last dose (PK sample may not be required for subjects known to 
be receiving placebo or non-GSK comparator treatments.) Record the date/time of 
the PK blood sample draw and the date/time of the last dose of study treatment prior 
to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report form 
including acetaminophen, herbal remedies, other over the counter medications

Record alcohol use on the liver event alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]). 
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.
6.5.3
Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 
weeks OR

ALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 
weeks


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6.5.3.1
Required Actions and Follow Up Assessments for Increased 
Monitoring with Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following ANY 
Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline.
6.5.4
Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, 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
6.5.5 Immunogenicity
Serum samples for the measurement of anti-belimumab antibodies will be obtained from all 
subjects before administration of study agent on Day 0, Week 8, Week 24, Week 48 and 
Exit/8-week Follow-up. Additionally, samples will be obtained from subjects at Weeks 24 and 
48 during additional years. For any subject who had a positive antibody response at the 
8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-week 
follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or 
after completion and/or unblinding of the study, whichever is later. 
6.6
Exit Visit
Subjects who relapse/flare and do not complete the study must return for an Exit visit 4 weeks 
after the final dose of study agent. 
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent.
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
6.7
8-Week Follow-up Visit
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (see Table 6-1, Table 6-2) for a list of procedures required at this 
visit.
Amend 04
26Feb15


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6.8
Withdrawal of Subjects from Treatment
Subjects will be free to withdraw from treatment or from the study at any time, for any reason, 
or they may be withdrawn/removed, if necessary, to protect their health (see reasons for 
withdrawal below). It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of subjects should be 
avoided.
Subjects may be withdrawn from treatment with study agent for any of the following reasons:
•
Unacceptable toxicity (see Section 5.4)
•
Prohibited concurrent medication or therapy (see Section 5.5.1 and Section 5.5.2)
•
Withdrawal of consent (including use and disclosure of research-related health 
information)
•
Pregnancy
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
attempt will be made to ascertain survival status 12 months after the first dose of study agent.  
Any subject that withdraws consent for use and disclosure of research-related health 
information will be considered withdrawn from the study and not followed. 
6.9
Subject Unblinding
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will be 
employed. The study agent will be reconstituted and diluted by the unblinded site pharmacist 
or designee, independent of the study (person responsible for receiving and dispensing study 
agent). Except for a limited number of safety oversight personnel, all study site personnel, the 
subject, the sponsor and the Contract Research Organization (CRO) remain blinded to the 
study agent received and to the results of certain biomarker and pharmacodynamic laboratory 
results. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study.
If a medical emergency occurs and a decision regarding the subject’s condition requires 
knowledge of the treatment assignment, the study blind may be broken for the specific 
subject. Whenever possible, the investigator should consult with the medical monitor prior to 
unblinding any subject. Any broken blind will be clearly justified and explained by a 
comment in the eCRF. The investigator must notify the Medical Monitor of any broken blind, 
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7 Adverse Event Reporting
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1
Definitions
ADVERSE EVENT 
Any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the
use of a medicinal product. For marketed medicinal products, this also includes failure to
produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported
as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from
lack of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen
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
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 hospitalization or prolongation of an existing hospitalization
NOTE: In general, hospitalisation signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-
patient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be 
considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in disability / incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea,
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly / birth defect
f. Medical or scientific judgment should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. Examples 
of such events are invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
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g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ≥ 
3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥3xULN and INR>1.5, if INR 
measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold 
value stated will not apply to patients receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin
elevations and suggesting liver injury. If testing is unavailable and a subject meets the
criterion of total bilirubin ≥2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.
7.2
Reporting Adverse Events to the Sponsor
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start 
of study agent administration (Day 0) through 8 weeks following administration of the last 
dose of study agent will be recorded on the Adverse Event Case Report Form (AE eCRF). All 
data fields on the AE eCRF should be completed.
For subjects who discontinue treatment with study agent during the double-blind period (for 
reasons other than withdrawal of consent), all adverse events will be collected through 
8 weeks following the administration of the last dose of study agent. After this time, all SAEs, 
regardless of relationship to study drug, will be collected until relapse or the study is analysed 
for the primary endpoint and study sites are informed that SAE data collection can cease, 
whichever occurs first.
Serious Adverse Events (SAEs) must ALSO 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 eCRF 
within 24 hours of site personnel becoming aware of the event as described in the Study 
Procedure Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol-mandated procedures, invasive tests) will be reported as an SAE 
from the time a subject consents to participate in the study.  
SAEs that occur off study, after the follow-up period that are assessed by the investigator as
definitely, possibly or probably related to study agent must be reported to the sponsor as 
outlined in the Study Procedures Manual.
7.3
Other Events Requiring Rapid Reporting (Protocol Specified 
Events)
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (See Section 7.1). PSEs are 
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recorded on the PSE page of the eCRF within 24 hours of site personnel becoming aware of 
the event. 
IgG < 250 mg/dL (Grade 4) is a protocol specified event for this protocol. 
7.4
Laboratory Abnormalities as Adverse Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator are to be recorded as AEs or SAEs. However, any clinically 
significant safety assessments that are associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s condition, are not to be 
reported as AEs or SAEs. 
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg,
elevated creatinine, urine RBC increased). In addition, an IgG abnormality < 250 mg/dL 
(Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 mg/dL should 
also be reported as an SAE if it meets one or more of the SAE criteria in Section 7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in the Appendix, the lab test should be graded 
mild, moderate or severe as specified in Section 7.8.
7.5
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
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 all immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.  The 
appropriateness of continuing study agent, while the case is being assessed, should be 
discussed.
7.6
Suicidality Assessment
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation 
(Bachen et al, 2009, Timonen et al, 2003, Stenager et al, 1992). In order to objectively assess 
suicidality in belimumab clinical programs the C-SSRS will be utilized to collect information
on suicidal behavior and ideation. Since major depressive disorder may increase the risk of 
suicidal ideation or behavior before or during clinical studies, subjects participating in this 
study will be assessed at every visit for suicidality.
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Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 
Questionnaire (PSRHQ, only the first time this condition is met; refer to Appendix 10 for the 
PSRHQ) eCRF and a Possible Suicidality Related Questionnaire (PSRQ) eCRF (at all times 
this condition is met; refer to Appendix 11 for the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2007). The C-SSRS is administered 
by a qualified clinician and is designed to address the need for a summary measure to track 
change in the severity/density of suicidality across both clinical settings and treatment trials. It 
assesses intensity of ideation (a potentially important marker of severity) by specifically 
asking about frequency, duration, intrusiveness, controllability, and deterrents. In addition, it 
captures both the modal and most severe forms of ideation. The C-SSRS is to be completed by 
the investigator or his/her qualified designee at every visit during the double-blind portion of 
the study. 
Although assessment of suicidality using the C-SSRS will take place only during the blinded 
portion of the study, investigators are reminded of the importance to clinically assess for 
suicidality at every visit given that study patients are at increased risk of suicidal behavior 
and/or ideation.
7.6.1 Possible Suicidality Related Questionnaire (PSRQ)
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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. Refer to Appendix 11 for the PSRQ. 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 the SAE.
7.7
Reporting a Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form. To ensure subject safety, each pregnancy must be reported to the Sponsor 
within 2 weeks of learning of its occurrence. All pregnancies that are identified from the start 
of study agent through 16 weeks following the last dose of study agent should be reported. 
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child. Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an 
SAE.
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Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to the Sponsor.
7.8
Investigator Evaluation of Adverse Events
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to study 
agent). The investigator will make an assessment of intensity based on the Division of 
Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading Tables (see 
Appendix 7) where possible:
SEVERITY
Mild
An event that is easily tolerated by the subject, causing minimal  
discomfort and not interfering with everyday activities (Grade 1
DMID).
Moderate
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID). 
Not applicable
Those event(s) where intensity is meaningless or impossible to
determine (i.e., blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.  
An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE.
CAUSALITY
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated. The investigator will also consult the Investigator Brochure (IB) 
and/or Product Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
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There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool 
accordingly. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
7.9
Follow-Up of Adverse Events
Serious and non-serious adverse events that occur from the start of study medication 
administration through 8 weeks after the date of last administration of study agent are 
reported.
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAEs and non-serious AEs of special interest (see Section 
8.6.2) will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the subject is lost to follow-up. This applies to all subjects, 
including those withdrawn prematurely. 
PSEs (see Section 7.3) that occur after the Screening visit through 8 weeks after the date of 
last administration of study agent are reported and followed as described above for 
AEs/SAEs.
7.10
Reporting Serious Adverse Events to Regulatory Authorities and
Institutional Review Boards/Independent Ethics Committees
All SAEs that are considered by the sponsor to be unexpected and related to belimumab will 
be reported by the sponsor or designee as expedited (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 regulatory requirements related to the reporting of SAEs to the IRBs/IECs 
responsible for reviewing the study at their site, as well as the regulatory authority(ies) (if 
applicable).
All serious adverse events, including serious disease-related events (discussed below), will 
be monitored by treatment group by an independent DMC. Investigators and IRBs/IECs will 
be notified of the outcome of each DMC meeting, and any recommendations made.
The conditions listed in Appendix 3 are disease related events that can occur in the study 
population regardless of belimumab exposure. When these conditions are considered SAEs, 
they must be reported to the Sponsor within 24 hours of site personnel becoming aware as 
described in Section 7.2. Where these are clearly related to the underlying vasculitis, the 
Sponsor may not submit them as expedited reports to regulatory authorities or participating 
investigators.
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8 Endpoints and Statistical Analysis
8.1
General Statistical Considerations
Unless otherwise specified, all analyses will be performed on the intent to treat (ITT) 
population defined as all subjects who are randomized and received at least 1 dose of study 
agent (belimumab or placebo). The ITT analysis will be performed according to the treatment 
that a subject was randomized to receive, regardless of the actual treatment received.
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject. All subjects and study site personnel will remain blinded to original treatment 
assignment until after the final database is locked and the results of the study are made 
publicly available. 
Analysis of primary and secondary endpoints will be exploratory in nature. Nominal p values
may be reported and considered descriptive. Where appropriate point estimates and 95% 
confidence intervals will be constructed.
8.2
Randomization Procedure and Assignment to Treatment Groups
This is a multi-center, multinational, randomized, double-blind, placebo-controlled study. 
Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs.
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  
8.3
Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Initial randomization will be limited to 40 subjects 
per induction regimen (40 post-RTX induction and 40 post-CYC induction). The first DMC 
reviews will occur after the first 20 subjects per induction regimen (RTX or IV/oral CYC) 
have been randomized and have had a Week 8 visit. Once the first 20 subjects randomized 
following induction with RTX have had a Week 8 visit, safety data will be reviewed by the 
DMC, who will make a recommendation regarding whether to continue randomization. The 
same procedure would be applied for the first 20 subjects randomized following induction 
with CYC. The DMC will review the data approximately every 6 months thereafter across 
both induction regimens. At all times the sites and sponsor will remain blinded to treatment 
allocation.  Investigators and IRBs/IECs will be notified of the outcome of each DMC 
meeting.
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The DMC will receive information within 72 hours of the sponsor or designee receiving 
notification of any IgG < 250 mg/dL and all unexpected causally-related SAEs that are life 
threatening or result in death. Other unexpected, causally-related SAEs will be provided to the 
DMC within 15 calendar days.  In addition, the DMC will receive information on all serious 
infections and all opportunistic infections, irrespective of relationship to study agent, within 
15 calendar days.
8.4
Sample Size Rationale
Approximately 100 subjects will be randomized. The sample size has been determined based 
on the feasibility of enrolling patients into the study within a reasonable time-frame. The 
sample size was not based on statistical considerations and the analysis of primary and 
secondary endpoints will be exploratory in nature. The primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo group, a 
relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically significant 
(p<0.05) in a study of 100 subjects (50 per arm). 
8.5
Efficacy
8.5.1 Primary Efficacy Endpoint
The primary endpoint is time from Day 0 to the first relapse, defined as 
•
at least 1 major BVAS item (Appendix 4) OR 
•
a minimum total BVAS score of 6 (Appendix 4) OR
•
receipt of prohibited medications (as defined in Section 5.5.1).
8.5.2 Primary Efficacy Analysis
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using the oral or IV cyclophosphamide. If there are 
then still less than 5 patients with an event (relapse) in any of the levels of this or any other 
stratification factor then the stratification term may be removed from the model. For any 
subject who does not experience a relapse, the time to first relapse will be censored at the time 
of the subject’s last assessment. Subjects who discontinue study agent prior to relapse/flare 
(as defined in primary efficacy endpoint) are to be followed per protocol for inclusion in the 
primary efficacy analysis until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). The database will be locked and the primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
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8.5.3 Major Secondary Efficacy Endpoint
1. Time from Day 0 to the first major relapse (defined as experiencing at least 1 major 
BVAS item).
8.5.4 Other Efficacy Endpoints
1. Time from Day 0 to first minor or major relapse (defined as experiencing at least 1 minor 
BVAS item and/or using a dose of rescue medication).
2. Absolute change in Vasculitis Damage Index (VDI) at double-blind Week 48 of Year 1 
and double-blind Week 28 of Year 2 and by visit;
3. Proportion of subjects with any increase in VDI at double-blind Week 48 of Year 1 and 
double-blind Week 28 of Year 2 and by visit;
4. Absolute change in BVAS at double-blind Week 48 of Year 1 and double-blind Week 28 
of Year 2 and by visit; 
5. Proportion of subjects with any increase in BVAS at double-blind Week 48 of Year 1 and 
double-blind Week 28 of Year 2 and by visit; and 
6. Proportion of subjects with any increase in BVAS organ domains at double-blind Week 48
of Year 1 and double-blind Week 28 of Year 2 and by visit and by domain.
7. Proportion of patients in remission (defined as BVAS=0 and corticosteroid dose 
< 10 mg/day) at double-blind Week 48 of Year 1, double-blind Week 28 of Year 2 and by 
visit.
8. Proportion of patients with no relapse at double-blind Week 48 of Year 1, double-blind 
Week 28 of Year 2 and by visit.
Biological Markers and Autoantibodies:
Pharmacogenetic sampling (in consenting subjects) will be taken once during the course of 
this study (see Appendix 9).  
Biological markers will be measured at baseline (Day 0) and at multiple time points 
thereafter:
•
Anti-neutrophil cytoplasmic antibody (ANCA – anti-PR3, anti-MPO)
•
Serum complement (C3, C4)
•
Serum immunoglobulin isotypes (IgA, IgM, IgG)
•
C-reactive Protein (CRP)
•
Erythrocyte sedimentation rate (ESR)
•
Urinary protein: urinary creatinine ratio
•
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•
FACS of peripheral lymphocytes:
B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived 
plasma, CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, 
CD138+/CD20+ plasmacytoid,  CD27−/IgD+/CD10+ transitional)
T cell subsets: CD3+/CD4+, CD3+/CD8+
8.5.5 Major Secondary Endpoint analysis and Other Efficacy Analyses
The exploratory analysis of the major secondary efficacy endpoint will be performed using the
same method described for the primary efficacy endpoint, but censoring subjects who receive 
any prohibited medication (as defined in Section 5.5.1) prior to an observation of any major 
BVAS item. Any censoring will be applied on the date prohibited medications are received.
The analysis of other efficacy endpoints, biomarkers, and auto-antibodies measurements will 
be described in the statistical analysis plan.
8.6
Safety
8.6.1 Definition of Safety Variables
Safety will be evaluated by adverse events, changes in laboratory parameters, suicidality 
assessment (Appendix 8), and immunogenicity.
8.6.2 Analysis of Safety Variables
AEs will be graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 7) or as described in Section 7.8, as appropriate. The frequency and rate of 
AEs will be tabulated by MedDRA system organ class (SOC) and preferred term. Additional 
analyses may be performed based on event rates adjusting for subject-years on study agent if 
the time on study agent is imbalanced across treatment groups. Serious and severe (Grade 3 
and Grade 4) AEs will also be summarized by MedDRA SOC and preferred term. 
Discontinuations due to AEs will be summarized. 
The frequency of laboratory abnormalities will be tabulated by treatment group. Laboratory 
values will be assessed for changes from baseline. Laboratory toxicity will be graded using 
Adverse Event Severity Grading Tables when possible. Shift tables will be used to determine 
if subjects move from normal to abnormal during the course of the study. Shifts of ≥ 2 grades 
and Grade 3 or 4 laboratory abnormalities will be summarized.
Safety Endpoints of Special Interest
•
All cause mortality
•
Serious and/or severe infections
•
Opportunistic infections
•
Malignant neoplasms
•
Selected serious psychiatric events
•
Suicidality assessment (see Appendix 8)
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•
Infusion reactions including hypersensitivity reactions
•
Immunogenicity
The analyses of these safety endpoints will be described in the statistical analysis plan.
8.7
Pharmacokinetics
8.7.1 Definition of Pharmacokinetic Evaluation
All randomized subjects who receive a dose of study agent will be sampled for the assessment 
of serum belimumab levels. Assessment of belimumab concentrations will be performed at the 
timepoints indicated in Section 6.5.1.
8.7.2 Analysis of Pharmacokinetics
Serum belimumab concentration will be determined by an electrochemiluminescence (ECL) -
based assay. Results for this study will be presented using appropriate graphic and tabular 
summaries. Serum belimumab concentration data obtained from this study will be used in a 
population PK analysis, which will be reported separately. Potential effects of demographic 
characteristics, concurrent medications, renal function or disease state on belimumab PK will 
be evaluated.
9 Pharmacogenetics (PGx)
In consenting subjects, a blood sample for PGx research will be drawn at baseline (Day 0) to 
better characterize genetic variability (eg, HLA typing) that may affect efficacy or safety 
endpoints. Information regarding PGx research is included in Appendix 9.
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 9). In 
some cases, approval of the PGx assessments can occur after approval is obtained for the rest 
of the study. If so, then the written approval will clearly indicate that approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments are not approved, then approval for the rest of the study will clearly 
indicate this and that PGx assessments will not be conducted.
10 Study Administration
Belimumab is under joint development by Human Genome Sciences, Inc and 
GlaxoSmithKline Pharmaceuticals. Human Genome Sciences, Inc. is the sponsor of the study.
10.1
Informed Consent
A copy of the proposed informed consent document must be submitted to the Sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 


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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.
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 using
an Electronic Data Capture (EDC) system provided and approved by the Sponsor. Refer to the 
Study Procedures Manual for additional information regarding CRFs that will be used as 
source documentation. Sites must complete the eCRFs in a timely manner and the investigator 
must promptly review the completed eCRFs for each subject. As the person ultimately 
responsible for the accuracy of all eCRF data, the investigator must sign the Investigator's 
Statement in each subject's eCRF.
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system, so as to ensure accuracy, quality, consistency, and completeness of 
the database. Manual queries resulting from review by monitors, medical coders, and other 
Data Management staff are also generated from within the EDC system, where they are 
tracked. Sites resolve the queries and correct the entered data when necessary. Every change 
to data is captured in the EDC system audit trail. Upon completion of the study, or after 
reaching a pre-specified point in the study, Data Management will lock the database and 
generate the SAS datasets necessary for data analysis and reporting. Upon completion of the 
study, each site will be provided with a compact disk containing the eCRFs for each of their 
subjects.
10.6
Study Monitoring
The study Sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the Sponsor will visit study sites routinely throughout the trial. The 
Sponsor will review CRFs and compare them with source documents to verify accurate and 
complete collection of data and confirm that the study is being conducted according to the 
protocol. Auditors representing the Sponsor may also similarly evaluate the study and its 
monitors. For these purposes, the investigator will make CRFs and source documents 
available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 
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 is responsible for taking an inventory of the study agent, 
including any buffers or diluents. A record of this inventory must be kept and usage must be 
documented on study agent inventory forms provided by the Sponsor.
Study agent inventory forms will be examined and reconciled by a Sponsor’s unblinded 
monitor, or designee. At the end of the study, all used and unused study agent must be 
accounted for on a study agent accountability form.
10.8
Retention of Records
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the Sponsor at the time the study is completed, terminated, or 
discontinued.
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the Sponsor.
10.9
Financial Disclosure
The investigator and all sub-investigators will provide HGS sufficient and accurate 
information on financial interests (proprietary or equity interests, payments exclusive of 
clinical trial costs) to allow complete disclosure to regulatory authorities. The investigator 
shall promptly update this information if any relevant changes occur during the course of the 
investigation and for a period of 1 year following study completion.
10.10 Publication Policy
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and Sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the Sponsor
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites.
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 


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Sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by Sponsor to be confidential information has been removed. If 
requested in writing by the Sponsor, the investigator shall withhold material from submission 
for publication or presentation for an additional 60 days to allow for the filing of a patent 
application or the taking of other measures to establish and preserve the Sponsor’s proprietary 
rights.
10.11 Study or Study Site Termination
If HGS, the investigator, IRB/IEC, or a regulatory authority discovers conditions arising 
during the study that indicate that the study should be halted or that the study center should be 
terminated, this action may be taken after appropriate consultation between HGS and the 
investigator. Conditions that may warrant termination of the study include, but are not limited 
to, the following:
•
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study.
•
A decision on the part of HGS to suspend or discontinue testing, evaluation, or 
development of the product for WG or MPA.
The study site may warrant termination under the following conditions:
•
Failure of the investigator to enroll subjects into the study at an acceptable rate.
•
Failure of the investigator to comply with pertinent regulatory authority regulations.
•
Submission of knowingly false information from the research facility to HGS, study 
monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.


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Amend 04
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List of Appendices
Appendix 1
Chapel Hill Consensus Definition for Granulomatosis with polyangiitis 
(GPA) (Wegener’s Granulomatosis) (Jennette et al, 2013).......................... 69
Appendix 2
Chapel Hill Consensus Definition for Microscopic Polyangiitis (MPA) 
(Jennette et al, 2013)..................................................................................... 70
Appendix 3
BVAS Activity Assessment Form ................................................................ 71
Appendix 4
BVAS Item Scoring...................................................................................... 72
Appendix 5
Vasculitis Damage Index.............................................................................. 75
Appendix 6
Laboratory Tests1.......................................................................................... 82
Appendix 7
Adverse Event Severity Grading Tables....................................................... 83
Appendix 8
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening/Since Last Visit............................................................. 91
Appendix 9
Pharmacogenetic Research ......................................................................... 111
Appendix 10
Possible Suicidality Related History Questionnaire (PSRHQ)................... 116
Appendix 11
Possible Suicidality Related Questionnaire (PSRQ)................................... 118
Appendix 12
Protocol Addendum – Benefit and Risk Assessment ................................. 120
Appendix 13
Algorithm for Liver Chemistry Stopping and Follow-up Criteria.............. 132


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Appendix 1
Chapel Hill Consensus Definition for Granulomatosis 
with polyangiitis (GPA) (Wegener’s Granulomatosis)
(Jennette et al, 2013)
The CHCC Definition requires:
Necrotizing granulomatous inflammation usually involving the upper and lower respiratory 
tract, and necrotizing vasculitis affecting predominantly small to medium-sized vessels (eg,
capillaries, venules, arterioles, and arteries) for a diagnosis of Wegener’s.
Another feature that may be commonly present in GPA, but which is not required according 
to the CHCC definition, is necrotizing glomerulonephritis.
Amend 02
25Apr13
Amend 03
04Feb14


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Appendix 2
Chapel Hill Consensus Definition for Microscopic 
Polyangiitis (MPA) (Jennette et al, 2013)
The CHCC definition requires:
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels 
(ie, capillaries, venules, or arterioles) for a diagnosis of MPA. Granulomatous inflammation is 
absent.
Other features that may be present in MPA, but that are not required according to the CHCC 
definition, are: necrotizing arteritis involving small- and medium-sized arteries; commonly 
necrotizing glomerulonephritis; and often pulmonary capillaritis.
Amend 02
25Apr13
Amend 03
04Feb14


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Appendix 3
BVAS Activity Assessment Form
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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Appendix 4
BVAS Item Scoring
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws and therefore have been excluded.


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


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Amend 03
04Feb14
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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


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Appendix 6
Laboratory Tests1
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)
Partial thromboplastin time (PTT)
INR
Serum Pregnancy 
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Casts (specified by 
type eg, RBC, WBC)
Spot Urine (protein : creatinine 
ratio)
Urine Pregnancy
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
HIV-1/2 antibody
Hepatitis C antibody (± HCV RNA 
PCR for confirmation of positive antibody 
test)
Hepatitis B surface antigen
Hepatitis B surface and core antigen 
antibodies
Estimated Creatinine Clearance/ GFR 
(Cockcroft-Gault)
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM 
antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal 
antibodies
Biological Markers
FACS of peripheral lymphocytes: 
T cell subsets: CD3+/CD4+, CD3+/CD8+
B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, 
CD27hi/CD20- short-lived plasma, CD27+/CD20+ memory, CD27-
/CD20+ naïve, CD138+/CD20- 138 plasma cells, CD138+/CD20+ 
plasmacytoid, CD27−/IgD+/CD10+ transitional)
BLyS protein 
Serum complement (C3 and C4) 
C-Reactive Protein (CRP)
Erythrocyte sedimentation rate (ESR)
Immunoglobulins
Serum immunoglobulin isotypes: IgG, IgM, IgA
PK and Immunogenicity
Autoantibodies
ANCA (anti-PR3; anti-MPO)
1Institution or country specific guidelines for blood sample volume limits must be followed in collection of the 
subsequent blood sample.
Amend 01
22Jun12
Amend 02
25Apr13
Amend 02
25Apr13
Amend 02
25Apr13
Amend 02
25Apr13


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Appendix 7
Adverse Event Severity Grading Tables
HEMATOLOGY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Hemoglobin
9.5-11.0 g/dL
> 8.0-9.5 g/dL
6.5-8.0 g/dL
6.5 g/dL
Leukocytes
3000-3999/mm3
2000-2999/mm3
1000-1999/mm3
< 1000/mm3
Absolute Neutrophil Count
1500-1999/mm3
1000-1499/mm3
500-999/mm3
< 500/mm3
Platelets
75,000-99,999/mm3
50,000–74,999/mm3
25,000-49,999/mm3
< 25,000/mm3
Prothrombin Time (PT)
> 1.0-1.25 x ULN*
> 1.25-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0 x ULN
Partial Thromboplastin Time (PTT)
> 1.0-1.66 x ULN
> 1.66-2.33 x ULN
> 2.33-3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0-10.0 %
10.1-15.0 %
15.1-20.0 %
> 20%
*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
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
*(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
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
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
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
Modified from DMID Adult Toxicity Tables, 2001


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


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Appendix 9
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
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for 
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations (Monach and Merkel, 2010).
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach and Merkel, 2010) for example the association of alpha 1-antitrypsin 
deficiency in WG. 
Blood samples for pharmacogenetics will be drawn as described in Section 9. Insights into the 
genetic pathways underlying AAV may help identify subgroups of patients that may have 
additional benefit from therapies from specific therapies. Fc Receptor polymorphism analysis 
may further define the interaction between underlying genetic heterogeneity and the 
therapeutic endpoints utilized in this trial.  
Collection of whole blood samples may enable PGx analyses to be conducted if there are any 
unexplained or unexpected results. 
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.
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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.
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 using a DNA tube. 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 
will be drawn on Day 0 (baseline) visit provided informed consent for PGx research has been 
obtained from the subject, but 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 may 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 ie, no questions are raised about how people respond to belimumab. 
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) 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.


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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. Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by the sponsor and maintain the documentation in 
the site study records. In either case, the sponsor will only use study information 
collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the clinical study, then the 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.
Pharmacogenetics Analyses
Specific sections of DNA may be selected from areas of the genome (ie, candidate genes)
known to encode the drug target, drug metabolizing enzymes, areas associated with 
mechanisms underlying adverse events, and those linked to study disease and, thus, linked to 
drug response. 
Generally, two approaches will be utilized to explore genetic variation in drug response.
The candidate genes that may be selected and investigated in this study are the following: 
•
HLA alleles
•
Alpha-1 anti-trypsin (A1AT)
•
Fc receptors
•
Cytokines, immune receptors and chemokines related to immune cell function
In addition, 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.
By evaluating large numbers of polymorphic markers (eg, single nucleotide polymorphisms or 
SNPs) throughout the genome, sets of markers may be identified that correspond to 
differential drug response. These will include:


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
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 
genotype (or haplotype) and selected parameters (eg, pharmacokinetics, SLE disease 
activity and safety). Where such genotypic tests are inappropriate (eg, where the number 
of marker genotypes is too large and/or the frequency of individual genotypes too small), 
allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker 
allele is the same in responders and non-responders.

Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the 
selected parameters, the possibility of a treatment group by genotype (haplotype or allele) 
interaction will also be explored. If appropriate, the joint effects of multiple markers 
(gene-gene interactions) may also be evaluated.

Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the 2 sites are correlated 
(linkage disequilibrium) may also be evaluated. If the genotypes at 2 polymorphic sites 
within a gene are shown to be statistically associated with a response to investigational 
product, the degree of linkage disequilibrium will aid interpretation in that it will indicate 
the extent to which the 2 sites are exerting independent effects.

Multiple Comparisons and Multiplicity
Adjustment to observed p-values may be made to limit erroneous conclusions due to 
multiple tests when multiple markers are evaluated (especially in the case of a genome 
scan for association). 

Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site 
depends on the total number of subjects genotyped and the frequency distribution of the 
different genotypes. Consequently, genotyping analyses are plausible for those 
polymorphic sites where the number of subjects comprising the genotypic groups is 
sufficiently large; however, these frequencies will not be known until sufficient samples 
have been collected and genotyping is complete. 


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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. 
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 10
Possible Suicidality Related History Questionnaire 
(PSRHQ)
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Appendix 11
Possible Suicidality Related Questionnaire (PSRQ)
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Appendix 12
Protocol Addendum – Benefit and Risk Assessment
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis; also known as granulomatosis with 
polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to lifethreatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. 
Historically, ANCA have been classified on the basis of their staining patterns in 
immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear (P-ANCA). It is 
now recognized that in AAV, C-ANCA is usually directed against proteinase 3 (PR3), and P-
ANCA is generally directed against myeloperoxidase (MPO), both of which are enzymes that 
are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel et al, 1997). 
Anti-PR3 antibodies are generally associated with WG, while anti-MPO autoantibodies are 
more common in MPA and CSS. Anti-PR3 antibodies are associated with increased morbidity 
and mortality compared to anti-MPO. The most widely used classification criteria for 
diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994). Of note, none of these diagnostic criteria incorporate the measurement 
of ANCA.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007). 
In the case of MPA, in particular, epidemiological studies are confounded by its original 
inclusion as a form of polyarteritis nodosa (PAN). Utilizing the ACR or CHCC criteria, 
prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and 0.4-
1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes et al, 2008). AAV are extremely rare in childhood with peak age of onset in 
those aged 65 to 74 years (Ntatsaki et al, 2010), with other small vessel vasculitides being the 
major concern in childhood (Brogan et al, 2010).Current therapy is usually determined by 
severity of the disease, with more severe forms warranting more aggressive approaches. These 
usually involve an initial remission induction regimen of high dose corticosteroid 
administered with either cyclophosphamide (CYC) or rituximab (RTX) followed by a 
remission maintenance period usually with azathioprine (Stone et al, 2010; Bosch et al, 2007; 
Jayne et al, 2003). Minor manifestations are usually treated with low dose corticosteroid 
administered with either azathioprine or methotrexate (Belmont, 2006). Even with recent 
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treatment advances the morbidity and mortality of patients with AAV remains unacceptably 
high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG 
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2009). In its current form it is a list of 
56 items which are considered to be manifestations of vasculitis. A weighted numerical score 
is attached to each item to reflect the importance of each manifestation. The items are grouped 
by organ systems, and each organ system has a maximum or ‘ceiling’ score to reflect the 
relative importance of the organ system (Mukhtyar et al, 2009). The tool also makes a 
distinction between new or worsening disease and persistent disease with new or worsening 
attracting higher scores.
IV Belimumab
Over 2,000 individuals with SLE have been treated with belimumab in clinical studies. In two 
global Phase 3 studies, belimumab 10 mg/kg met the primary efficacy endpoint (SRI at 
Week 52). Evidence of other possible benefits in these trials included reductions in risk of 
severe flare and corticosteroid use, and improvements in patient reported quality of life and 
fatigue. Serological activity was reduced as measured by reductions in autoantibodies and 
normalization of hypergammaglobulinemia and complement levels. B cells, including 
autoreactive B cells, were also reduced, but not severely depleted, consistent with what would 
be expected from inhibition of BLyS (reference belimumab IB, Section 5.3.1). These results 
supported the approval of belimumab in the EU, US, Canada and other countries.
In the United States belimumab is approved for the following indication:
BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, 
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard 
therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with 
severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA 
has not been studied in combination with other biologics or intravenous 
cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
In the EU, the approved indication focuses on patients with high disease activity (where 
belimumab offered the greatest benefit):
Benlysta 
is 
indicated 
as 
add-on 
therapy 
in 
adult 
patients 
with 
active, 
autoantibodypositive systemic lupus erythematosus (SLE) with a high degree of disease 
activity (e.g positive anti-dsDNA and low complement) despite standard therapy.
The EU SPC also includes special warnings and precautions for use similar to the US 
labeling, including that belimumab has not been studied in and is thus not recommended in 


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patients with severe active central nervous system lupus or severe active lupus nephritis. In 
addition, caution should be exercised if belimumab is co-administered with other B cell 
targeted therapy or cyclophosphamide. Reference Section 4.4 of the SPC for the complete list 
of specials warnings and precautions.
Treatment with belimumab plus standard therapy was generally well tolerated, with rates of 
AEs, severe AEs, SAEs, AEs leading to discontinuation, and serious/severe infections 
generally comparable to the rates observed in the placebo plus standard therapy group. The 
most commonly-reported adverse reactions, occurring in ≥ 3% of patients receiving 10 mg/kg 
belimumab IV in clinical trials (and at a ≥ 1% greater rate than placebo) were nausea, 
diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, 
migraine, pharyngitis, cystitis, leukopenia, and gastroenteritis viral. In clinical trials, 
hypersensitivity and infusion reactions were observed more frequently with belimumab, with 
anaphylaxis observed in ≤ 1% of subjects. Data from the post-marketing setting indicate that 
hypersensitivity reactions may be serious or result in death, that the onset of such reactions 
may be delayed, and that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. In addition, it is also known from clinical trials and 
the post-marketing setting that the vast majority of hypersensitivity reactions occur with the 
1st or 2nd infusion. The product labeling, belimumab IB, protocol, and informed consent forms 
have been updated to include this new information, as applicable.
Other risks that may be associated with belimumab based on its mechanism of action include 
serious infections and malignancy, although no increases in the rates of serious infections or 
malignancies have been observed. Psychiatric events including depression and suicide were 
observed more frequently with belimumab than with placebo, although it is unknown if 
belimumab treatment is associated with an increased risk for these events. Finally, mortality 
rates in the controlled clinical trials were low, although numerically higher in the belimumab 
groups (0.4% and 0.8% in the placebo and belimumab groups, respectively). Causes of death 
were as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as corticosteroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide.
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving immunosuppressant 
pharmacotherapy, including belimumab. Although the benefit-risk profile for belimumab 
remains unchanged following these events, the Sponsor considers that knowledge of these 
cases is important and has updated the clinical investigator’s brochure (IB) for belimumab and 
revised the informed consent form (ICF) to communicate that development of PML is a 
potential risk.  
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence of AEs or SAEs over time, including important events such 
as infections and malignancies. Long-term belimumab treatment appears to provide sustained 
improvement in SLE disease activity and reduction of flares.
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Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Belimumab at a dose of 10 mg/kg in combination with standard SLE therapy demonstrated a 
statistically significant and clinically meaningful reduction in SLE disease activity versus 
placebo plus standard SLE therapy at Week 52 in two Phase 3 clinical studies in subjects with 
active, autoantibody-positive SLE.
Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 18 
months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the most 
effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al, 2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels. Therefore, 
for the proposed study, subjects are required to have documented evidence of anti-PR3 or 
anti-MPO autoantibodies prior to randomization, as this population is considered the most 
likely to benefit from treatment with a B cell modulating agent like belimumab. This is 
consistent with the Phase 3 SLE results for belimumab where the subjects who benefitted 
from treatment were those who were antinuclear antibody (ANA/anti-dsDNA) autoantibody 
positive at baseline.
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval in the US for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease. Finally, limited data from the small (n = 111) subset of subjects in the Phase 3 
trials of SLE who had vasculitic symptoms as part of their SLE (as assessed by the SELENA 
SLEDAI) showed that more subjects in the belimumab plus standard of care treatment arms 
had resolution of their vasculitic symptoms at Week 52 compared with subjects receiving 
placebo plus standard of care. Specifically, 19/36 (52.8%) and 28/38 (73.7%) of subjects in 
the belimumab 1 mg/kg and 10 mg/kg dose groups, respectively, had resolution of vasculitic 
activity at Week 52 compared with 15/37 (40.5%) of placebo subjects. Taken together, these 
data support the evaluation of belimumab in AAV.
The safety of the proposed study is supported by data from the Phase 2 and 3 trials in SLE in 
which subjects who were receiving belimumab in combination with significant background 
therapies, including steroids and immunosuppressants, had an adverse event profile similar to 
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This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen. Subjects enrolled into the study must have a clinical 
diagnosis of WG or MPA according to the Chapel Hill criteria and must have had an initial or 
relapsing episode of moderate to severely active WG or MPA that was treated with 
corticosteroids and either CYC or RTX in the 6 months leading up to randomization. Subjects 
treated with 1 of the following induction regimens will be eligible for participation in the 
study:
•
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
CYC 2 mg/kg/day orally plus HDCS OR
•
CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Approximately 100 subjects with ANCA-vasculitis who are between 6 and 26 weeks from 
starting induction therapy, who achieve a BVAS v.3 score of 0 (ie, are in remission), and are 
receiving ≤10 mg/day prednisone (or equivalent) on 2 consecutive measurements at least 14 
days apart will be enrolled into the study. Subjects who meet the eligibility criteria will be 
randomized in a 1:1 ratio to receive study agent (belimumab [10 mg/kg] or placebo) 
administered intravenously (IV) over 1 hour. Study agent (belimumab/placebo) will be 
administered at Day 0, 14, and every 28 days thereafter. Randomization will be performed on 
Day 0. 
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. For the maintenance of remission, azathioprine may be 
initiated as soon as it is clinically indicated following administration of induction therapy. 
Azathioprine must not be initiated any later than Day 0. For subjects previously identified as 
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being intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be 
used as an alternative to azathioprine for the maintenance of remission from the outset. 
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above, a switch to methotrexate at a target dose of 25 
mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. As 
azathioprine is among the better tolerated immunomodulatory agents, it is not anticipated that 
many subjects will need to substitute methotrexate for azathioprine (Walters et al, 2010). 
Subjects for whom methotrexate is substituted for azathioprine will be included in the primary 
analysis.
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease), and induction regimen (IV 
CYC vs. oral CYC vs. RTX). It is anticipated that no more than 25% of the patients would be 
newly diagnosed and anti-MPO positive, and as such enrollment of these patients may be 
capped if they exceed this proportion. Refer to Section 4 of Protocol HGS1006-C1100 for a 
complete list of inclusion and exclusion criteria.
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as at least 
1 major BVAS item or a minimum total BVAS score of 6 or receipt of prohibited medications 
according to the protocol. Subjects will receive study agent (belimumab/placebo) plus AZA 
until the results from the primary efficacy analysis are available or until they experience a 
flare (relapse) as defined in the primary efficacy endpoint. The database will be locked and 
the primary analysis will be performed when 12 months have elapsed after the last subject is 
randomized. Subjects who discontinue study agent prior to relapse/flare are to be followed per 
the double blind visit schedule until relapse/flare or the end of the double-blind treatment 
phase (whichever is earlier). In subjects who withdraw consent from the study prior to 1 year 
an attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent.
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
Dose and Schedule
Investigational Study Agent (Belimumab or Placebo)
The dose and schedule of belimumab proposed for use in the ANCA-associated vasculitis 
study is the same dosage (10 mg/kg every 2 weeks for 3 doses and every 4 weeks thereafter) 
and route of administration (IV) as that approved for marketing. The belimumab BDS and 
FDP that will be used for this study is the same as that approved for marketing.
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In the Phase 3 IV SLE studies, several clinical measures of improvement including the 
primary efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, there
appeared to be a greater dose response in subjects with high disease and serological activity. 
There was no apparent dose-response in the safety profile of belimumab with both doses 
being generally well-tolerated. These data supported the selection of 10 mg/kg belimumab as 
the marketed dose in general SLE, and also support its continued evaluation in combination 
with standard maintenance therapies in patients with WG or MPA.
The use of placebo in this trial is considered appropriate and does not put placebo patients at 
undue risk because all subjects in both the placebo group and the belimumab group will 
receive standard of care maintenance therapies for vasculitis (ie, azathioprine or methotrexate) 
and, if needed, subjects will receive appropriate rescue therapy in accordance with standard 
clinical practice as described above.
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:
•
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
CYC 2mg/kg/day orally plus HDCS OR
•
CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
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Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX dosing regimen of 4 infusions of 375 mg/m2 each 
given 1 week apart reflects the dosing regimen that is approved by the FDA for this indication.
An alternative RTX induction regimen (2 infusions of 1 gram each administered 2 weeks 
apart) is also offered in the protocol. Although the latter regimen is not licensed as an 
induction therapy for ANCA-vasculitis, it is very widely used in clinical practice and clinical 
evidence suggests that there is no difference between the two dosing regimens in terms of 
duration of B-cell depletion or therapeutic efficacy efficacy (Jones et al, 2009).
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including
infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements at least 14 days
apart: a BVAS v3 score of 0 and be receiving ≤10 mg/day of oral prednisone [or equivalent], 
between 6 and 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2 
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. For the maintenance of remission, 
azathioprine may be initiated as soon as it is clinically indicated following administration of 
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induction therapy and no later than Day 0. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced activity 
of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be used as 
an alternative to azathioprine for the maintenance of remission from the outset. Subjects naive 
to azathioprine and who experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or 
thrombocytopenia, AST or ALT 2 times ULN, or a several gastrointestinal hypersensitivity 
reaction characterized by severe nausea and vomiting), following initiation of azathioprine 
will be permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience toxicities, a switch to methotrexate at doses of up to 25 mg/week as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis. The protocol instructs 
physicians to follow the appropriate local prescribing information for azathioprine or 
methotrexate (as applicable) prior to and during treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Safety Considerations
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Belimumab has not yet been studied following use of 
IV cyclophosphamide (CYC) or rituximab (RTX); there is limited experience with the 
combination of belimumab and oral CYC. As an added safety precaution, initial 
randomization will be limited to 40 subjects per induction regimen (40 post-RTX induction 
and 40 post-CYC induction). The first DMC reviews will occur after the first 20 subjects per 
induction regimen (RTX or IV/oral CYC) have been randomized and have had a Week 8 visit. 
Once the first 20 subjects randomized following induction with RTX have had a Week 8 visit, 
safety data will be reviewed by the DMC, who will make a recommendation regarding 
whether to continue randomization. The same procedure would be applied for the first 
20 subjects randomized following induction with CYC. The DMC will review the data 
approximately every 6 months thereafter across both induction regimens. At all times the 
patients, study sites and sponsor will remain blinded to treatment allocation. Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting.
The DMC will be notified of:


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•
all unexpected causally-related SAEs that are life-threatening or result in death;
•
other unexpected causally-related SAEs;
•
all reports of serious infections and opportunistic infections, irrespective of relationship to 
study agent; and
•
subjects experiencing IgG < 250 mg/dL; 
within protocol-specified timeframes. Based on these data, an ad hoc DMC meeting may be 
called at any time (see Section 8.3 of Protocol HGS1006-C1100 for additional detail 
regarding the DMC).
Based on the large body of safety data from SLE patients treated with belimumab and/or the 
mechanism of action of belimumab as a B cell immunosuppressant, anticipated potential risks 
of belimumab treatment in vasculitis patents include serious infusion and hypersensitivity 
reactions, infections, depression-related events, and malignancy. These risks are briefly 
reviewed here and are detailed more fully in the belimumab Investigator’s Brochure. Both 
investigators and subjects will be appropriately informed regarding these risks. It is noted that 
because of the older patient population affected by this disease, the average age of subjects 
anticipated to participate in this study will be older than the average age of the SLE 
population studied to date (mean age of ~53 years at the time of diagnosis in vasculitis (Stone
et al, 2010) compared with an average age of ~38 years in controlled Phase 3 studies of 
belimumab in SLE). As such, patients with vasculitis may be at a greater risk for infection 
than the SLE patients; however, the increased monitoring for infections by both the DMC 
(described above) and recommended to investigators (see below) will help to ensure subject 
safety through timely detection, treatment and reporting of infections.
The protocol states that all subjects should be monitored closely for infection and increased 
vigilance for infection is recommended in subjects who experience IgG levels < 250 mg/dL, 
especially for prolonged periods; clinical judgment should be applied with respect to the 
appropriateness of continuing study therapy in these subjects. The Medical Monitor must be 
consulted before administering subsequent doses of study agent in subjects with IgG levels 
< 250 mg/dL. Study agent will be discontinued in subjects with IgG levels < 250 mg/dL that 
are associated with a severe or serious infection. If a subject experiences a clinically 
significant, potentially life-threatening (Grade 4) AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo, then treatment with study agent 
will be discontinued. The subject will be followed at regularly scheduled study visits as 
specified by the protocol through the end of the double-blind period and also until resolution 
of the AE(s) (whichever is longer).
In order to ensure subject safety with respect to infusion and hypersensitivity reactions, the 
protocol excludes patients with known history of allergic reactions to human or murine 
proteins or monoclonal antibodies. There is currently insufficient evidence to determine 
whether premedication diminishes the frequency or severity of hypersensitivity reactions to 
belimumab. The protocol recommends that based on clinical judgment, premedication 
including an antihistamine, with or without an antipyretic, may be administered before the 
infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 


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Belimumab/placebo will be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 
closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. Per protocol, 
subjects are to remain under clinical supervision for 3 hours after completion of the first 
2 infusions in the double-blind treatment phase. 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. 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.
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving immunosuppressant 
pharmacotherapy, including belimumab. Therefore, a diagnosis of PML should be considered 
in any subject presenting with new-onset or deteriorating neurological signs and symptoms. 
The protocol requires that subjects 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.
The protocol recommends that subjects with persistent or worsening disease should receive 
appropriate rescue therapy in accordance with standard clinical practice, but if exceeding what 
is allowed per protocol, treatment with study agent (ie, belimumab or placebo) will be 
discontinued and the subject will be considered as having relapsed for the primary analysis. 
The list of prohibited medications that results in the subjects being considered as relapsed for 
the primary endpoint (Protocol Section 5.5.2.1), was developed because the need for the use 
of these agents (eg, RTX or CYC) is indicative of treatment failure (ie, disease relapse).
Moreover, concomitant use of such medications (eg, high-dose steroids) can be associated 
both with potent disease-modifying activity and/or significant toxicity that may introduce bias 
and confound interpretation of results. As such, no subject will be denied appropriate medical 
care for their condition due to their participation in this clinical study.
In addition, the Sponsor notes that although this is a placebo controlled trial, the sponsor does 
not consider that placebo patients are at undue risk because all subjects in both the placebo 
group and the belimumab group will receive standard of care maintenance therapies for 
vasculitis (ie, azathioprine or methotrexate) and, if needed, subjects will receive appropriate 
rescue therapy in accordance with standard clinical practice as described above.
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Risk:Benefit Conclusions
In summary, the proposed Phase 3 study is a superiority study evaluating the safety and 
efficacy of belimumab for the maintenance of disease remission in patients with a clinical 
diagnosis of Wegener’s granulomatosis or microscopic polyangiitis. The risk:benefit profile of 
10 mg/kg IV belimumab in patients with active, autoantibody-positive SLE was demonstrated 
to be positive in the two Phase 3 SLE studies, thereby supporting its approval in Canada, the 
US, and the EU. Belimumab has already been shown to be effective in treating patients with 
active, autoantibody-positive SLE, a B cell mediated autoimmune disease. Like SLE, WG and 
MPA are also B cell mediated autoimmune diseases in which autoantibodies (in this case, 
against neutrophil components), are considered to be pathogenic (Popa et al, 1999). In each of 
these diseases, the general purpose of the therapy is similar – reducing disease activity by 
down regulating B cells (including autoreactive B cells) and reducing the level autoantibodies 
produced by those autoreactive B cell clones. Down regulating B cell numbers may also 
reduce inflammatory processes because of the role of B cells in antigen presentation. A 
limited amount of data from the IV Phase 3 studies suggests that belimumab may reduce 
vasculitic symptoms.
There are potential risks associated with belimumab treatment including serious infusion and 
hypersensitivity reactions, infections, depression-related events, and malignancy; however, in 
view of the serious and potentially life threatening nature of disease flares in WG and MPA, it 
is believed that the overall risk:benefit analysis for belimumab in the maintenance of 
remission in WG and MPA is favorable, especially in view of the nature of the trial as a 
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Appendix 13
Algorithm for Liver Chemistry Stopping and Follow-up 
Criteria
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 6.5.2.1. 
Amend 02
25Apr13
Amend 04
26Feb15


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Liver Monitoring Event Algorithm with Continued Therapy for 
ALT≥3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 6.5.2.1.
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the attractive 
hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver injury 
following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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Protocol HGS1006-C1100 Amend 04 Summary of Modifications
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Protocol Amendment 04, 26 February 2015
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The proposed modifications to the protocol reflect a change by the sponsor to the strategic 
objectives for the evaluation of belimumab in ANCA-associated vasculitis (AAV). It is 
proposed that the trial should be changed from a Phase 3 study to allow for an exploratory 
evaluation of belimumab in AAV only. There is no longer the intention to seek a licensed 
indication for belimumab as an adjunctive maintenance therapy in AAV on the basis of 
the data emerging from this study. The term “Phase 3” has been removed from the study 
title.
Enrolment of subjects onto the current trial has progressed at a much slower than expected 
rate. Based on current enrolment projections, data outputs from the current trial would 
unlikely be available for review until mid-2018.
Having reviewed the timing of the study in the context of the evolving therapy area for 
ANCA-associated vasculitis, the sponsor feels that the current format and design of the 
BREVAS trial, if driven to completion as a Phase 3 investigation, would no longer 
provide significant and timely new information for the vasculitis community. On the basis 
of the BREVAS trial data alone, even in the event of a successful outcome, it is not felt 
that belimumab can be sufficiently well differentiated as a concomitant therapy for 
remission maintenance in AAV to fulfill a significant unmet need for patients where other 
therapeutic options are now available (e.g., rituximab). 
As such, GSK is proposing to modify the strategic objective of the trial such that it will be 
conducted as an exploratory study, in which global enrolment would be restricted to 
approximately 100 patients (compared to the original target of approximately 300). It is 
planned that the data will be published in descriptive format with exploratory analyses on 
efficacy endpoints undertaken as appropriate. It is expected that the safety data emerging 
from the smaller cohort of patients in BREVAS will contribute to our understanding of 
belimumab safety. 
2. The study design and schedule has been modified throughout the protocol to clarify that 
the study will no longer be driven by the requirement to achieve at least 66 relapse events. 
The study will complete and the primary analysis will be undertaken once 12 months have 
elapsed following enrolment of the last subject.
3. The protocol has been modified throughout such that subjects completing the study will no 
longer have the option to participate in a 6-month open-label extension following 
completion of the double-blind treatment phase. The section entitled “open label extension 
phase” (6.4) and the related time and events table (Table 6-3) has been removed.
4. The study design schematics have been modified in the protocol by removal of the 
expected number of enrolled subjects; ‘N=300-400’ has been removed from the 
schematic.


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5. In the statistical sections of the protocol, the sample size considerations have been 
modified to reflect the fact that approximately 100 patients will be recruited. The sample 
size is based largely on the feasibility of recruitment within a reasonable time-frame. 
Sample size calculations based on expected relapse rates have been removed from the 
protocol. The minimum detectable effect for a sample size of N=100 subjects has been 
determined. 
For the purposes of reporting the data, analysis of primary and secondary endpoints will 
be exploratory in nature. Nominal ‘p’ values may be reported and considered descriptive. 
Where appropriate point estimates and 95% confidence intervals will be constructed.
The section on “Subgroup analyses” (7.5.2.1) has been removed as this is no longer 
considered relevant in the context of the smaller expected total sample size of 
approximately 100 subjects.
In the section “Primary Efficacy Analysis” (8.5.2), we have clarified how stratification 
terms may be handled in the analysis if there are fewer than 5 events (relapses) in any of 
the stratification levels.
6. In the section “Dose, route of administration and schedule”, we have clarified that the 
administration of belimumab/placebo should be over approximately one hour, but not less 
than one hour for reasons of safety.
7. The section on liver chemistry stopping and follow-up criteria, which describes how 
patient care should be managed if a liver event occurs during the study, has been updated 
with the most recent GSK-specified protocol for managing these events. The section also 
defines the circumstances and criteria that may allow a study treatment restart following a 
liver event. The section also includes the criteria for more intensive monitoring with 
continued therapy following a liver event. Accompanying figures have been placed in 
Appendix 13.
8. The adverse event reporting section (Section 7) has been modified throughout for 
consistency with AE, SAE or PSE data collection procedures and forms.
9. The text on progressive multifocal leukoencephalopathy (PML) has been updated to 
provide further guidance on the management of suspected cases.
10. The section “Reporting a pregnancy” has been modified to provide scope for following up 
the outcomes of a pregnancy (including premature termination) as well as the status of 
mother and child.
11. The section “Randomization procedure and assignment to treatment requirements” has 
been modified to remove the requirement for subjects to be randomised within 2 weeks of 
achieving remission. This corrects an error in the protocol and ensures consistency with 
wording across other sections of the protocol. 
12. The reference list has been updated in the protocol.
13. Appendix 12 (Benefit-Risk assessment) has been updated to reflect the change in study 
status to an exploratory trial and to reflect the changes in the main protocol as outlined 
above.


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Associated Protocol Modifications: 
Protocol Cover Page
Change from:
Protocol Amendment: 03
Date: 04 February 2014
Change to:
Protocol Amendment 04
Date: 26 February 2015
Title of Study, Cover Page and Synopsis
Change from:
A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Change to:
A Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy 
and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance 
of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Revision Chronology for HGS1006-C1100 (BEL115466)
Added rows:
Date
Document*
Local
DNG2014N217970_01
01 October 2014
Local Amendment 01 for France
Local
DNG2014N217970_02
03 February 2015
Local Amendment 02for France
Global
DNG2013N167980_02
26 February 2015
Amendment No 04


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Study Design and Schedule, Synopsis and Section 3.1, Basic Design Characteristics
Change from:
This is a Phase 3, multi-center, multi-national, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multi-national, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
Subjects will receive study agent (belimumab/placebo) plus AZA until the results from the 
primary efficacy analysis are available or until they experience a flare (relapse) as defined in 
the primary efficacy endpoint (see below). The database will be locked and the primary 
analysis will be performed after at least 66 subjects have experienced a relapse and at least
when 12 months have elapsed after the last subject is randomized.
Change to:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The study will complete, the database will be locked and the primary 
analysis will be performed when 12 months have elapsed after the last subject is randomized.
Study Design and Schedule, Synopsis
Deleted:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 6 
months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 


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protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8-week follow-up visit is not required for subjects entering the continuation protocol.
Schematic of study design, Synopsis and Section 3.1, Basic Design Characteristics
Change from:
Change to (removed number of subjects randomized from graphic):
Sample Size Considerations, Synopsis and Section 8.4, Sample Size Rationale
Deleted:
The relapse rate in the study is anticipated to be approximately 20% in the control group. 
However, there is some uncertainty around this relapse event rate which could be 30% or 


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higher. This study is designed to target at least 66 subjects experiencing a relapse (as defined 
in the primary endpoint), which will provide 85% power to detect a reduction in relapse rates 
of 20 vs. 10% (hazard ratio = 0.472). With this same hazard ratio and a 30% event rate, a 
study with 66 subjects experiencing a relapse will provide 85% power to detect a reduction in 
the relapse rate from 30% to 15.5%. A target of 300 to 400 subjects will be randomized to 
achieve the required number of events.
After approximately 300 subjects have been randomized, the relapse rate in the overall 
population will be evaluated in a blinded manner internally by HGS while the enrollment 
continues. If the relapse rate is consistent with the 20% control rate assumption, enrollment 
will continue to 400 subjects to ensure timely accrual of the 66 events. However, if there is 
evidence that the relapse rate is higher than 20% control rate assumption, enrollment may be 
stopped at approximately 300 subjects. The primary efficacy analysis will be performed after 
at least 66 subjects have experienced a relapse and at least 12 months have elapsed after the 
last subject is randomized.
Added:
Approximately 100 subjects will be randomized. The sample size has been determined 
based on the feasibility of enrolling patients into the study within a reasonable time-
frame. The sample size was not based on statistical considerations and the analysis of 
primary and secondary endpoints will be exploratory in nature. The primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the 
last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo 
group, a relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically 
significant (p<0.05) in a study of 100 subjects (50 per arm). 
Analysis of Primary Efficacy Endpoint, Synopsis
Change from:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized. 
Change to:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after 12 months have elapsed following randomization of the last subject. 


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Analysis of Major Secondary Efficacy Endpoints, Synopsis
Deleted:
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error (Section 8.1).
Section 3.1, Basic Design Characteristics
Deleted:
If the result on the primary efficacy endpoint from the double blind portion of this trial shows 
that belimumab is superior to placebo, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 
protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8 week follow-up visit is not required for subjects entering the continuation protocol. 
Section 5.3 Dose, Route of Administration, and Schedule
Change from:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. Once randomized, 
subjects will be dosed with study agent on Days 0, 14, and 28 and every 28 days thereafter. 
Following the final double-blind visit, eligible subjects (see Section 6.4) will have the option 
to continue in the 6-month open-label extension period.
Change to:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. The intent of this 
instruction is to prevent more rapid infusion of belimumab which may result in a higher 
incidence of infusion reactions. Infusion time need not be exactly one hour as it is often 
difficult to so precisely adjust infusion times and there may be clinical reasons for 
infusions lasting longer than one hour. Therefore, the instruction should be interpreted 
as infusion over at least one hour. The target infusion time should still be approximately 


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one hour assuming no other issues intervene. Once randomized, subjects will be dosed with 
study agent on Days 0, 14, and 28 and every 28 days thereafter.
Change from:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase and the open-label 
extension.
Change to:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase.
Section 6.3 Double-Blind Treatment Phase
Change from:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until top 
line data from the primary analysis are available. If top line data from the double blind portion 
of this trial show that belimumab is superior to placebo on the primary efficacy endpoint, and 
the safety profile of belimumab is acceptable, subjects who received treatment with study 
agent until completion of the double-blind treatment period and have not relapsed (as defined 
by the primary endpoint) will be given the option to receive treatment with belimumab in the 
6-month open-label extension phase.
Subjects who do not enter the open-label extension, will return for an Exit visit 
(approximately 4 weeks after the last dose of study agent), and a follow-up visit 
(approximately 8 weeks after the last dose of study agent).
Change to:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The study will complete and the primary efficacy analysis will be 
performed when 12 months have elapsed following randomization of the last subject.
Subjects will return for an Exit visit (approximately 4 weeks after the last dose of study 
agent), and a follow-up visit (approximately 8 weeks after the last dose of study agent).


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Table 6-1 Footnotes:
Change from:
11.  Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase. Subjects who discontinue treatment but have not relapsed 
will remain on the double blind study visit schedule. For subjects who complete the 
double blind phase and enter the open label phase, refer to Table 6-3 for visit details.
Change to:
11. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should be completed for subjects 
who discontinue the double blind treatment phase early or when subjects have completed 
the double-blind treatment phase. Subjects who discontinue treatment but have not 
relapsed will remain on the double blind study visit schedule.  
Change from:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 
month open-label extension phase.
Change to:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent. 
Table 6-2 Footnotes
Change from:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase.  For subjects who complete the double blind phase and 
enter the open label phase, refer to Table 6-3 for visit details.


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Change to:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should be completed for 
subjects who discontinue the double blind treatment phase early or when subjects have 
completed the double-blind treatment phase. 
Change from:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 month 
open-label extension phase.
Change to:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent.
Deleted: Section 6.4 “Open-Label Extension Phase” has been deleted and all subsequent 
sections have been renumbered accordingly.
6.4 Open-Label Extension Phase
In the 6-month open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the last dose). The 
first dose on the open-label extension will be given 4 weeks after completion of the 
double-blind period. Day 0 is the first visit in the extension phase of the trial and represents 
the first belimumab administration for placebo subjects. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-3). 
During the 6-month open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications 
during this phase are live vaccines, biological therapies and other investigational agents. 
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.


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After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
need to be provided for the continuation protocol. The 8 week follow-up visit is not required 
for subjects entering the continuation protocol.
Deleted:
Table 6-3 Open Label Extension Phase and all associated footnotes have been deleted
and the subsequent table has been renumbered accordingly.
Section 6 Study Procedures
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3), Study Procedures Manual, 
and Central Laboratory Manual for additional information.
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
Section 6.5 Laboratory Tests
Change from:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Change to:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2).
Section 6.6.2 Phase III-IV Liver Chemistry Stopping and Follow-up Criteria
The section “Phase III-IV Liver Chemistry Stopping and Follow-up Criteria” has been 
deleted. The deleted text is not shown here. The section has been replaced by the following 
sections (6.5.2-6.5.3) and text:


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6.5.2 Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity
1) Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury. 
2) All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants.
3) New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).
6.5.2.1 Required Actions and Follow up Assessments following ANY Liver Stopping 
Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the event 
also meets the criteria for an SAE (All events of ALT 3xULN and bilirubin 
2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 13).


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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 hours

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 hours
Monitor subjects weekly until liver chemistries resolve, stabilize or return to within baseline
FOLLOW UP ASSESSMENTS

Viral hepatitis serology (includes: Hepatitis A IgM antibody; Hepatitis B surface 
antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody)

Blood sample for pharmacokinetic (PK) analysis, obtained within approximately one 
to two weeks after last dose (PK sample may not be required for subjects known to 
be receiving placebo or non-GSK comparator treatments.) Record the date/time of 
the PK blood sample draw and the date/time of the last dose of study treatment prior 
to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report form 
including acetaminophen, herbal remedies, other over the counter medications

Record alcohol use on the liver event alcohol intake case report form


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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]). 
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.
6.5.3 Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 
weeks OR

ALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 
weeks
6.5.3.1 Required Actions and Follow Up Assessments for Increased Monitoring with 
Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following ANY 
Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline.
Added:
6.5.4 Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 


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should be no evidence of alcoholic hepatitis or hypersensitivity, and the study treatment 
should not be associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries have a 
clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries have 
improved to normal or are within 1.5 x baseline and ALT <3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic hepatitis, 
possible study treatment-induced liver injury or study treatment has an HLA genetic 
marker associated with liver injury (e.g., lapatinib, abacavir, amoxicillin/clavulanate) are
reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart must 
be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries have 
been demonstrated and then laboratory monitoring may resume as per protocol. 

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
Section 6.6 Exit Visit
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  


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Section 6.7 8-Week Follow-up Visit
Change from:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent, unless entering the long-term continuation protocol. 
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
Section 7 Adverse Event Reporting
Added:
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Section 7.1 Definitions
Change from:
ADVERSE EVENT (EXPERIENCE): Any unfavorable or unintended sign, symptom, or 
disease that is temporally associated with the use of a study agent but is not necessarily caused 
by the study agent. This includes worsening (eg, increase in frequency or severity) of 
preexisting conditions.
SERIOUS ADVERSE EVENT: An adverse event resulting in any of the following 
outcomes:

death

is life-threatening (ie, an immediate threat to life)

inpatient hospitalization*

prolongation of an existing hospitalization

persistent or significant disability/incapacity

congenital anomaly/birth defect

is medically important+
*An inpatient hospitalization is defined as an admission for any length of time. A 
hospitalization for administration of study agent, for routine or planned clinical procedures, or 


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for “social” reasons (not the result of any adverse change in the subject’s condition) should 
not be considered an adverse event and should not be reported as a serious adverse event. If 
the subject experiences any adverse change in condition during hospitalization, the condition 
must be reported as an adverse event or serious adverse event according to the above 
definitions. 
+Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above (eg, 
possible drug-induced liver injury). These should also usually be considered serious. (ICH 
guidelines, March 1995)
UNEXPECTED ADVERSE EVENT: An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means the event has previously been observed with the study 
agent and is identified and/or described in the applicable product information. It does not 
mean that the event is expected with the underlying disease(s) or concomitant medications.
Change to:
ADVERSE EVENT
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (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.


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“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition
SERIOUS ADVERSE EVENT: A serious adverse event is any untoward medical 
occurrence that, at any dose:
a. Results in death
b. Is life-threatening
c.
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.
d. Requires hospitalisation or prolongation of existing hospitalisation
e.
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.
f.
Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
g. Results in disability/incapacity, or
h. 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.
i.
Is a congenital anomaly/birth defect


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j.
Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.  Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation, or 
development of drug dependency or drug abuse.
k. 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).
l.
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then the 
event is still reported as an SAE. If INR is obtained, include values on the SAE 
form. INR elevations >1.5 suggest severe liver injury.   
Section 7.2 Reporting Adverse Events to the Sponsor
Change from:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
the HGS Drug Safety designee within 24 hours of site personnel becoming aware of the SAE, 
regardless of expectedness. All pages of the SAE Worksheet should be completed, but the 
SAE Worksheet should not be held until all information is available. Additional information 
and corrections should be provided on subsequent SAE Worksheets as described in the Study 
Procedures Manual. SAE Worksheets should be sent either via the EDC system, if SAE EDC 
functionality is available or by facsimile to the HGS Drug Safety designee using the fax 
number listed on the SAE Worksheet.
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be recorded on the SAE 
worksheet and reported as described  above from the time a subject consents to participate in 
the study. Pre-treatment SAEs will not be documented on the AE eCRF.
SAEs that occur off study, after the follow-up period, that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the Drug Safety 
designee on the SAE worksheet. Post study SAEs will not be documented on the AE eCRF.


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Change to:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE eCRF within 24 hours 
of site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
eCRF within 24 hours of site personnel becoming aware of the event as described in the 
Study Procedures Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an SAE 
from the time a subject consents to participate in the study.
SAEs that occur off study, after the follow-up period that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the sponsor as 
outlined in the Study Procedures Manual.
Section 7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events)
Change from:
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (see Section 7.1). PSEs are 
recorded on SAE Worksheets and sent to the Drug Safety designee within 24 hours of site 
personnel becoming aware of the event. 
Change to:
Protocol Specified Events (PSEs) are additional events that must be reported in an expedited 
manner. A PSE may or may not be an SAE. PSEs are considered SAEs if they meet 1 or more 
of the criteria for an SAE (see Section 7.1). PSEs are recorded on the PSE page of the eCRF
within 24 hours of site personnel becoming aware of the event. 
Section 7.4 Laboratory Abnormalities as Adverse Events
Change from:
A laboratory abnormality should be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, or concomitant therapy. In addition, any medically important laboratory 
abnormality may be reported as an adverse event at the discretion of the investigator. This 
includes laboratory abnormalities for which there is no intervention but the abnormal value(s) 
suggests a disease or organ toxicity. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC increased). In 


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addition, an IgG abnormality < 250 mg/dL (Grade 4) should be recorded as an adverse event 
(and SAE if meeting the criteria in Section 7.1).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, severe, or life-threatening as specified in Section 7.8.
Change to:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, 
elevated creatinine, urine RBC increased). In addition, an IgG abnormality < 250 mg/dL 
(Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 mg/dL
should also be reported as an SAE if it meets one or more of the SAE criteria in Section 
7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, or severe as specified in Section 7.8.
Section 7.5 Progressive Multifocal Leukoencephalopathy
Change from:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping immunosuppressant therapy.
Change to:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping all immunosuppressant therapy.


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Section 7.7 Reporting a Pregnancy
Change from:
Pregnancies must be reported to the HGS Drug Safety designee within 24 hours of the site 
becoming aware of a pregnancy in a study subject. All pregnancies that are identified from the 
start of study agent through 16 weeks following the last dose of study agent should be 
reported. All pregnancies are tracked up to term or delivery following the last study agent
treatment. When pregnancy is reported, HGS Drug Safety sends an acknowledgement 
memorandum to the principal investigator along with a Pregnancy Assessment Form. A 
Pregnancy Assessment Form must be completed every three months until live birth, elective 
termination of the pregnancy, or miscarriage. The site is responsible for following the 
subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 7.1 and 
Section 7.2.
Change to:
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor within 2 weeks of learning of its occurrence. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE 
or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the Sponsor.
Section 7.8 Investigator Evaluation of Adverse Events
Change from:
The investigator will evaluate all adverse events with respect to seriousness, severity 
(intensity or grade), and causality (relationship to study agent). The criteria for serious are 
listed in Section 7.1. The severity of an AE is to be evaluated according to the Adverse Event 
Severity Grading Tables in Appendix 7. If an AE does not have Adverse Event Severity 
Grading in Appendix 7, the following severity classifications will be used:


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SEVERITY:
Grade 1- Mild
     - causing no limitation of usual activities.
Grade 2- Moderate 
     - causing some limitation of usual activities.
Grade 3- Severe
    - causing inability to carry out usual activities.
Grade 4- Life-threatening*
  - potentially life-threatening or disabling; significant medical 
intervention is required.
*Note – a severity assessment of Life-threatening is not necessarily the same as the 
seriousness criterion of Life-threatening (see “serious” criteria Section 7.1). The former means 
that the event is a potential threat. The latter means that the event is an immediate threat to 
life.
CAUSALITY:
It is a regulatory requirement for investigators to assess relationship between the 
investigational product(s) and the occurrence of each AE/SAE based on the information 
available. The assessment should be reviewed on receipt of any new information and amended 
if necessary. A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship. Facts/evidence or arguments that may support a 
“reasonable possibility” include, e.g., a temporal relationship, a pharmacologically-predicted 
event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant 
medication, a concurrent illness, or relevant medical history, should also be considered.
Change to:
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to study 
agent). The investigator will make an assessment of intensity based on the Division of 
Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading Tables (see 
Appendix 7) where possible:
SEVERITY:

Mild
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities (Grade 1 
DMID).

Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).

Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID).

Not applicable
Those event(s) where intensity is meaningless or impossible to 
determine (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 


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severe.  An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. The investigator will also consult the 
Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK. The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Section 7.9 Follow-up of Adverse Events
Change from:
Adverse events that occur from the start of study medication through 8 weeks after the date of 
last administration of study agent are followed until final outcome is known or until the end of 
the 8-week study follow-up period. Adverse events that have not resolved at the end of the 8-
week study follow-up visit are recorded on the adverse event case report form (AE eCRF) as 
ONGOING. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for an SAE (eg, the subject is lost to follow-up), the reason a final outcome 
could not be obtained will be documented by the investigator. 
Change to:
Serious and non-serious adverse events that occur from the start of study medication 
administration through 8 weeks after the date of last administration of study agent are 
reported. 


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After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up. This applies to all 
subjects, including those withdrawn prematurely. 
PSEs (see Section 7.3) that occur after the Screening visit through 8 weeks after the date 
of last administration of study agent are reported and followed as described above for 
AEs/SAEs.
Section 8.1 General Statistical Considerations
Change from:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject or when 66 events (relapse as defined for the primary efficacy endpoint) have 
been observed, whichever is later. All subjects and study site personnel will remain blinded to 
original treatment assignment until after the final database is locked and the results of the 
study are made publicly available. 
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error. With this 
procedure, the primary endpoint (time to the first relapse) will be evaluated first. If the 
primary efficacy endpoint demonstrates statistical significance (2-sided, alpha=0.05) then 
inference will proceed to the major secondary efficacy endpoint, time to the first major relapse 
(2-sided, alpha = 0.05). If the result is statistically significant, superiority of belimumab on the 
time to the first major relapse will be established. If statistical significance is not met, p values 
may be reported and considered descriptive.
Analyses of all other efficacy endpoints other than the primary and major secondary efficacy 
endpoints will not be subject to any multiple testing procedure. All statistical tests will be 
2-sided and performed at an overall significance level of 0.05.
Change to:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject. All subjects and study site personnel will remain blinded to original treatment 
assignment until after the final database is locked and the results of the study are made 
publicly available. 
Analysis of primary and secondary endpoints will be exploratory in nature. Nominal p 
values may be reported and considered descriptive. Where appropriate point estimates and 
95% confidence intervals will be constructed.


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Section 8.2 Randomization Procedure and Assignment to Treatment Groups
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled 
study. Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  Day 0 (first administration of belimumab/placebo and azathioprine) 
must occur no more than 2 weeks after confirmation of remission.  
Change to:
This is a, multi-center, multinational, randomized, double-blind, placebo-controlled study. 
Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  
Section 8.5.2 Primary Efficacy Analysis
Change from:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less 5 in subjects using the oral or IV cyclophosphamide. For any subject 
who does not experience a relapse, the time to first relapse will be censored at the time of the 
subject’s last assessment. Subjects who discontinue study agent prior to relapse/flare 
(as defined in primary efficacy endpoint) are to be followed per protocol for inclusion in the 
primary efficacy analysis until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). The database will be locked and the primary efficacy analysis will be 
performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized.


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Change to:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using the oral or IV cyclophosphamide. If there are 
then still less than 5 patients with an event (relapse) in any of the levels of this or any 
other stratification factor then the stratification term may be removed from the model.
For any subject who does not experience a relapse, the time to first relapse will be censored at 
the time of the subject’s last assessment. Subjects who discontinue study agent prior to 
relapse/flare (as defined in primary efficacy endpoint) are to be followed per protocol for 
inclusion in the primary efficacy analysis until relapse/flare or the end of the double-blind 
treatment phase (whichever is earlier). The database will be locked and the primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the last 
subject.
Deleted:
Section 8.5.2.1 Subgroup Analysis
Subgroup analysis, of the primary efficacy endpoint only, will be performed in the following 
subgroups:

ANCA type (anti-PR3 vs. anti-MPO)

Disease type (WG vs. MPA)

Disease stage at induction (initial diagnosis vs. relapsing disease)

Induction regimen (rituximab vs. IV cyclophosphamide vs. oral cyclophosphamide)

Race (white, American Indian, Asian, and black)

Region (US/Canada, EU/Australia/Israel, Americas excluding US/Canada, and Asia)

Age (< 65 vs. ≥ 65)

Gender

Duration of IV corticosteroid pulse used for induction (1 day vs > 1 day)
Section 8.5.5 Major Secondary Endpoint analysis and Other Efficacy Analyses
Change from:
The analysis of the major secondary efficacy endpoint will be performed using the same 
method described for the primary efficacy endpoint, but censoring subjects who receive any 
prohibited medication (as defined in Section 5.5.1) prior to an observation of any major 
BVAS item. Any censoring will be applied on the date prohibited medications are received.


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Change to:
The exploratory analysis of the major secondary efficacy endpoint will be performed using 
the same method described for the primary efficacy endpoint, but censoring subjects who 
receive any prohibited medication (as defined in Section 5.5.1) prior to an observation of any 
major BVAS item. Any censoring will be applied on the date prohibited medications are 
received.
References
Added:
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.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Study Overview and 
Patient Population
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
A target of 300 to 400 subjects who are between 6 and 26 weeks from starting induction 
therapy, achieve a BVAS v.3 score of 0 (ie, are in remission), and are receiving ≤10 mg/day 
prednisone (or equivalent) on 2 consecutive measurements at least 14 days apart will be 
enrolled into the study.
Change to:
Approximately 100 subjects with ANCA-vasculitis who are between 6 and 26 weeks from 
starting induction therapy, who achieve a BVAS v.3 score of 0 (ie, are in remission), and are 
receiving ≤10 mg/day prednisone (or equivalent) on 2 consecutive measurements at least 14 
days apart will be enrolled into the study.


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Change from:
The database will be locked and the primary analysis will be performed after at least 66 
subjects have experienced a relapse and at least 12 months have elapsed after the last subject 
is randomized.
Change to:
The database will be locked and the primary analysis will be performed when 12 months have 
elapsed after the last subject is randomized.
Deleted:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety.
Deleted:
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Safety Considerations
Change from:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase and the open-label extension.
Change to:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase.


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Appendix 13 Algorithm for Liver Chemistry Stopping and Follow-up Criteria
Added:
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.2.1. 
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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Liver Monitoring Event Algorithm with Continued Therapy for ALT≥3xULN but 
<8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.2.1.


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Deleted:


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Protocol Amendment 03, 04 February 2014
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to provide flexibility in timing of initiation of azathioprine 
maintenance therapy i.e., option to initiate as soon as clinically indicated and prior to 
confirmation of remission.
2. The protocol has been modified to allow alternative unlicensed rituximab dose for 
induction (1 g every 2 weeks) in addition to the licensed dosing regimen (375 mg/m2/wk 
for 4 doses).
3. The protocol has been modified to provide flexibility in timing of baseline BVAS 
assessments – allowing 2 baseline assessments separated by at least 14 days (instead of 
strict 21-35 days separation).
4. The absolute requirement to randomize within 14 days of confirmation of remission has 
been removed and clarification has been added that subjects cannot be randomized until at 
least 6 weeks after initiation of induction therapy.
5. A study schematic diagram has been added to clarify the trial design.
6. Clarification has been added regarding ‘high dose corticosteroids’ for induction and text 
provides guidance but allows locally accepted practice. No subject should receive <10mg 
for induction.
7. The protocol has been modified to allow some flexibility to cyclophosphamide dosing 
regimens (allows adjustment for age, obesity, renal insufficiency, leukopenia, other 
toxicities) for induction.
8. The protocol has been modified to allow the option to use methotrexate from the outset, as 
an alternative to azathioprine, if patient is a priori known to be azathioprine intolerant or 
has low/absent thiopurine methyltransferase (TPMT) activity. Exclusion of subject with 
intolerance or contraindications to methotrexate (where this is being considered as an 
alternative to azathioprine). 
9. The protocol has been modified to allow equal to/less than 10 mg prednisone daily during 
maintenance (rather than strictly <10 mg prednisone daily); articulated option to taper as 
clinically appropriate.
10. Progressive multifocal leukoencephalopathy text has been updated based on new 
information. This addition is to ensure full awareness of PML risk in the trial population 
and to provide clarification on clinical assessment and actions.
11. In Appendices 1 and 2, “criteria” in the title and text has been changed to “definition”. 
The List of Appendices has been updated accordingly.
12. Appendix 5 has been updated to include a sample of the VDI case report form.
13. The Benefit and Risk Assessment section has been updated to reflect new and/or amended 
information in the protocol body.


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14. Minor administrative change was made for bulleted presentation in Benefit and Risk 
Assessment. These minor changes are not shown in the Modifications section below. 
15. The list of abbreviations has been updated to add abbreviations as a result of new and/or 
amended text and to correct previous errors.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment 02
Date: 25 April 2013
Modified to:
Protocol Amendment 03
Date: 04 February 2014
Revision Chronology for HGS1006-C1100 (BEL115466)
Added row:
Date
Document*
Global
DNG2013N167980_01
04 February 2014
Amendment No 03
Synopsis, Diagnosis & Inclusion Criteria
Section 4.1, Inclusion Criteria
Formerly:
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:

A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

cyclophosphamide 2 mg/kg/day orally plus HDCS OR

cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving < 10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements 21 to 
35 days apart, achieved no more than 26 weeks after the first dose of induction therapy (either 


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CYC or RTX, as defined in Section 3.1). Maintenance therapy (belimumab/placebo + 
azathioprine) must start no more than 2 weeks after confirmation of remission.
Modified to:
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:

A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a 
two-week interval, plus HDCS OR

cyclophosphamide 2 mg/kg/day orally plus HDCS OR

cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving 10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at least 
14 days apart, between 6 and 26 weeks after the first dose of induction therapy (either CYC 
or RTX, as defined in Section 3.1). A minimum 6 week period should elapse between 
initiation of induction therapy and randomization.
Synopsis, Exclusion Criteria and Section 4.2, Exclusion Criteria
Formerly:
2. Known intolerance to azathioprine (AZA) or in whom AZA is contraindicated.
Modified to:
2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance 
or contraindications to methotrexate where methotrexate is being considered as an 
alternative to AZA for maintenance therapy.
Synopsis, Section Study Design and Schedule
and Section 3.1 Basic Design 
Characteristics
Formerly:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:


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
A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Subjects who are within 26 weeks of starting induction therapy, achieve a BVAS v.3 score 
of 0 (Appendix 4), and are receiving < 10 mg/day prednisone (or equivalent) on 2 consecutive 
measurements 21 to 35 days apart may be enrolled into the study. Randomization will be 
performed on Day 0. Day 0 (first administration of belimumab/placebo) must occur no more 
than 2 weeks after confirmation of remission. Azathioprine must be initiated at any time 
following confirmation of remission up to and including Day 0. All subjects will be treated 
with oral azathioprine (AZA) at a dose of 2 mg/kg/day. Subjects who meet eligibility criteria 
will be randomized in a 1:1 ratio to receive study agent (belimumab [10 mg/kg] or placebo) 
administered intravenously (IV) over 1 hour. The randomization will be stratified according to 
ANCA type (anti-PR3 vs. anti-MPO), disease stage at induction (initial diagnosis vs. relapsing 
disease) and induction regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. 
rituximab). Belimumab or placebo will be supplied by the sponsor during this double-blind 
treatment phase. It is anticipated that no more than 25% of the patients would be newly 
diagnosed and anti-MPO positive, and as such enrollment of these patients may be capped if 
they exceed this proportion. Study agent (belimumab/placebo) will be administered at Day 0, 
14, 28, and every 28 days thereafter.  
Modified to:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:

A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.


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[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10 
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
Subjects who are between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3 
score of 0 (Appendix 4), and are receiving ≤ 10 mg/day prednisone (or equivalent) on 2 
consecutive measurements at least 14 days apart may be enrolled into the study. A minimum 
6 week period should elapse between initiation of induction therapy and randomization.
Randomization will be performed on Day 0. A schematic of the study design is shown 
below/in Figure 1.
All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 
2 mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than 
Day 0. Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to receive study 
agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.  


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Added:
Schematic of Study Design/Figure 1 Schematic of Study Design
Section List of Abbreviations
Formerly:
CRO
Contract Reseach Organization
WG
Wegener’s Granulmatosis
Modified to:
CRO
Contract Research Organization
WG
Wegener’s Granulmatosis (Granulomatosis with polyangiitis)
Added:
TPMT 
thiopurine methyltransferase


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Section 1.1 Disease Background, 2nd sentence
Formerly:
A subset of the primary small vessel vasculitides: Wegener’s granulomatosis; also known as 
granulomatosis with polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss 
syndrome (CSS), are characterized by the presence of anti-neutrophil cytoplasmic antibodies 
(ANCA) (Jennette and Falk, 1997).
Modified to:
A subset of the primary small vessel vasculitides: Wegener’s granulomatosis (also commonly
referred to as granulomatosis with polyangiitis [GPA]), microscopic polyangiitis and Churg-
Strauss syndrome (CSS), are characterized by the presence of anti-neutrophil cytoplasmic 
antibodies (ANCA) (Jennette and Falk, 1997).
Section 5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent) for > 1 week, or

IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 1 week, are only allowable within the first 2 months of the double-blind 
treatment period.
Modified to:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent), or

IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 1 week, are only allowable within the first 2 months of the double-blind 
treatment period.
Section 5.5.3 Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 


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1 week within the first 2 months of the double-blind treatment period. At other times, subjects 
are restricted to < 10 mg/day. Inhaled corticosteroids for asthma, or topical corticosteroids for 
atopic dermatitis are also permitted. Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 
days or an  IV corticosteroid pulse up to 125 mg prednisone (or equivalent) are permitted for 
reasons other than vasculitis (eg. acute allergic reaction), but a subject cannot receive more 
than 1 such corticosteroid regimen in any 365 day period (See also Section 5.5.1).
Modified to:
The use of stable baseline dose regimens of corticosteroids (≤ 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 1 
week within the first 2 months of the double-blind treatment period. At other times, subjects 
are restricted to ≤ 10 mg/day prednisone or equivalent. It is expected that this dose may be 
tapered as clinically appropriate. Inhaled corticosteroids for asthma, or topical 
corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or equivalent) > 
20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg prednisone (or equivalent) 
are permitted for reasons other than vasculitis (eg. acute allergic reaction), but a subject 
cannot receive more than 1 such corticosteroid regimen in any 365 day period (See also 
Section 5.5.1).
Section 5.5.3.1 Azathioprine and Methotrexate
Formerly:
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). Azathioprine must 
be initiated at any time following confirmation of remission up to and including Day 0 at a 
dose of 50 mg/day and increased by no more than 50 mg/day every week until the target dose 
is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
It is recommended that the appropriate local prescribing information (eg, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine or 
methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator. 


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Modified to:
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). For the 
maintenance of remission azathioprine may be initiated as soon as it is clinically indicated 
following administration of induction therapy. Azathioprine must not be initiated any 
later than Day 0. Azathioprine should be started at a dose of 50 mg/day and increased by 
no more than 50 mg/day every week until the target dose is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
For subjects previously identified as being intolerant to azathioprine, or for subjects 
identified as having undetectable or reduced activity of thiopurine methyltransferase 
(TPMT), it may be permissible for methotrexate to be used as an alternative to 
azathioprine for the maintenance of remission from the outset. This should be discussed 
with the medical monitor. Methotrexate would not be recommended for those subjects 
with significantly impaired renal function.
The appropriate local prescribing information (eg, dose adjustments, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine 
or methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator.
Section 6.2 Study Enrollment Procedures
Formerly:
Subjects who have undergone all screening procedures and have met the entry criteria will be 
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
Azathioprine must be initiated at any time following confirmation of remission up to and 
including Day 0. Female subjects who require pregnancy testing must have a negative urine 
pregnancy test done on Day 0, prior to randomization. Subjects will be randomized in a 
1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + AZA).
Modified to:


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Subjects who have undergone all screening procedures and have met the entry criteria will be 
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Azathioprine may be initiated as soon 
as it is clinically indicated following administration of induction therapy. Azathioprine 
must not be initiated any later than Day 0. Female subjects who require pregnancy testing 
must have a negative urine pregnancy test done on Day 0, prior to randomization. Subjects 
will be randomized in a 1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + 
AZA). 
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Footnotes
Formerly:
10. Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience 
the toxicities described above a switch to methotrexate at doses of up to 25 mg/week as an 
alternative to azathioprine will be permitted.
Modified to:
10. Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience 
the toxicities described above a switch to methotrexate at doses of up to 25 mg/week as an 
alternative to azathioprine will be permitted. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate 
to be used as an alternative to azathioprine for the maintenance of remission from the 
outset following discussion with the medical monitor.
Section 7.1 Definitions
Formerly:
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above. 
These should also usually be considered serious. (ICH guidelines, March 1995)


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Modified to:
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be
immediately life threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above (eg, 
possible drug-induced liver injury). These should also usually be considered serious. (ICH 
guidelines, March 1995)
Section7.5 Progressive Multifocal Leukoencephalopathy
Formerly:
There have been no reported cases of PML in subjects with SLE or RA treated with 
belimumab. However, patients with autoimmune diseases may be at increased risk for PML 
secondary to the diseases themselves, as well as the concurrent use of immunosuppressive 
drugs. The most common signs and symptoms of PML include visual disturbances, ocular 
movements, ataxia, and mental status changes such as disorientation or confusion. Clinical 
signs and symptoms of PML and vasculitis can be similar. The investigator must exercise best 
judgment in further workup and clinical intervention as appropriate. If PML is suspected, this 
should be promptly reported to the sponsor.
Modified to:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and 
symptoms. The subject should be referred to a neurologist or other appropriate 
specialist for evaluation. If PML is confirmed, study agent should be discontinued and 
consideration should be given to stopping immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.  The 
appropriateness of continuing study agent, while the case is being assessed, should be 
discussed.
Section 11 References
Added:
Jones,RB, Ferraro,AJ, Chaudhry,AN, et al. A multicenter survey of rituximab therapy 
for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis 
Rheum 2009; 60: 2156-68.


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Appendix 1 Chapel Hill Consensus Criteria for Wegener’s Granulomatosis
Formerly:
Appendix 1 Chapel Hill Consensus Criteria for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Criteria require:
Modified to:
Appendix 1 Chapel Hill Consensus Definition for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Definition requires:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis
Formerly:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis (MPA) (Jennette et 
al, 2013)
The CHCC criteria require:
Modified to:
Appendix 2 Chapel Hill Consensus Definition for Microscopic Polyangiitis (MPA) (Jennette 
et al, 2013)
The CHCC Definition requires:


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Appendix 5 Vasculitis Damage Index
Added:
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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


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Appendix 12 Protocol Addendum – Benefit and Risk Assessment, IV Belimumab
Added:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving 
immunosuppressant pharmacotherapy, including belimumab. Although the benefit-risk 
profile for belimumab remains unchanged following these events, the Sponsor considers 
that knowledge of these cases is important and has updated the clinical investigator’s 
brochure (IB) for belimumab and revised the informed consent form (ICF) to 
communicate that development of PML is a potential risk.  
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Belimumab in ANCA-
Associated Vasculitis, Study Overview and Patient Population
Formerly:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of CYC are given as targets but may be adjusted for renal insufficiency or white 
cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.


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A target of 300 to 400 subjects who are within 26 weeks of starting induction therapy, achieve 
a BVAS v.3 score of 0 (ie, are in remission), and are receiving less than 10 mg/day prednisone 
(or equivalent) on 2 consecutive measurements 21 to 35 days apart will be enrolled into the 
study. Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to receive 
study agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. 
Study agent (belimumab/placebo) will be administered at Day 0, 14, and every 28 days 
thereafter. Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. Azathioprine must be initiated at any time following 
confirmation of remission up to and including Day 0. Patients with known intolerance to 
azathioprine will be excluded from the trial. Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is
substituted for azathioprine will be included in the primary analysis.
Modified to:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.


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[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
A target of 300 to 400 subjects who are between 6 and 26 weeks from starting induction 
therapy, achieve a BVAS v.3 score of 0 (ie, are in remission), and are receiving ≤10 mg/day 
prednisone (or equivalent) on 2 consecutive measurements at least 14 days apart will be 
enrolled into the study. Subjects who meet the eligibility criteria will be randomized in a 1:1 
ratio to receive study agent (belimumab [10 mg/kg] or placebo) administered intravenously 
(IV) over 1 hour. Study agent (belimumab/placebo) will be administered at Day 0, 14, and 
every 28 days thereafter. Randomization will be performed on Day 0. 
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. For the maintenance of remission, azathioprine may be 
initiated as soon as it is clinically indicated following administration of induction 
therapy. Azathioprine must not be initiated any later than Day 0. For subjects 
previously identified as being intolerant to azathioprine, or for subjects identified as 
having undetectable or reduced activity of thiopurine methyltransferase (TPMT), it may 
be permissible for methotrexate to be used as an alternative to azathioprine for the 
maintenance of remission from the outset.  Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Dose and Schedule, 
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Formerly:
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 


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to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX regimen specified in this vasculitis study is the 
same as that approved by the FDA for this indication.
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.


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Once disease remission (defined as having, on 2 consecutive measurements 3 to 5 weeks 
apart: a BVAS v3 score of 0 and be receiving < 10 mg/day of oral prednisone [or equivalent], 
no more than 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2 
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol must occur within 2 
weeks of achieving a confirmed remission and the randomization will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. In this study, subjects who have a known 
intolerance to azathioprine will be excluded. Subjects naive to azathioprine and who 
experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or thrombocytopenia, AST 
or ALT 2 times ULN, or a several gastrointestinal hypersensitivity reaction characterized by 
severe nausea and vomiting), following initiation of azathioprine will be permitted to reduce 
the dose to no less than 1 mg/kg/day. If the subject continues to experience toxicities, a switch 
to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be 
permitted. As azathioprine is among the better tolerated immunomodulatory agents, it is not 
anticipated that many subjects will need to substitute methotrexate for azathioprine (Walters 
et al, 2010). Subjects for whom methotrexate is substituted for azathioprine will be included
in the primary analysis. The protocol instructs physicians to follow the appropriate local 
prescribing information for azathioprine or methotrexate (as applicable) prior to and during 
treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Modified to:
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR 

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

CYC 2mg/kg/day orally plus HDCS OR


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
CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX dosing regimen of 4 infusions of 375 mg/m2
each given 1 week apart reflects the dosing regimen that is approved by the FDA for this 
indication. An alternative RTX induction regimen (2 infusions of 1 gram each 
administered 2 weeks apart) is also offered in the protocol. Although the latter regimen 
is not licensed as an induction therapy for ANCA-vasculitis, it is very widely used in 
clinical practice and clinical evidence suggests that there is no difference between the 
two dosing regimens in terms of duration of B-cell depletion or therapeutic efficacy 
efficacy (Jones et al, 2009).
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 3 
weeks thereafter) plus prednisone has been the standard induction regimen for WG and MPA 
since the early 1970s when initial work by Fauci and Wolff at the National Institutes of Health 
showed that this regimen induced disease remission in 12/14 patients and subsequent work 
showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 


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with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements at least 14 days
apart: a BVAS v3 score of 0 and be receiving ≤ 10 mg/day of oral prednisone [or equivalent], 
between 6 and 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2 
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. For the maintenance of remission, 
azathioprine may be initiated as soon as it is clinically indicated following administration 
of induction therapy and no later than Day 0. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate 
to be used as an alternative to azathioprine for the maintenance of remission from the 
outset. Subjects naive to azathioprine and who experience azathioprine-related toxicity 
(Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT 2 times ULN, or a several 
gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting), 
following initiation of azathioprine will be permitted to reduce the dose to no less than 1 
mg/kg/day. If the subject continues to experience toxicities, a switch to methotrexate at doses 
of up to 25 mg/week as an alternative to azathioprine will be permitted. As azathioprine is 
among the better tolerated immunomodulatory agents, it is not anticipated that many subjects 
will need to substitute methotrexate for azathioprine (Walters et al, 2010). Subjects for whom 
methotrexate is substituted for azathioprine will be included in the primary analysis. The 
protocol instructs physicians to follow the appropriate local prescribing information for 
azathioprine or methotrexate (as applicable) prior to and during treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Safety Considerations
Added:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving


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immunosuppressant pharmacotherapy, including belimumab. Therefore, a diagnosis of 
PML should be considered in any subject presenting with new-onset or deteriorating 
neurological signs and symptoms. The protocol requires that subjects 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.


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Protocol Amendment 02, 25 April 2013
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to include testing at Screening for HIV antibody, to 
expand Hepatitis B serology testing, and to exclude patients who test positive according to 
the criteria specified. 
2. Because the RIBA antibody confirmation assay for hepatitis C is not available due to
non-availability of manufacturer’s reagents, an alternative test, HCV RNA-PCR assay, 
will be used to detect the presence of viral RNA, and hence confirm a current infection.
3. The protocol has been modified to exclude patients at baseline with abnormal liver 
function according to the criteria specified.
4. A new section has been added to clarify how patient care should be managed if a patient 
has a liver chemistry event during the study. The accompanying figure has been placed in 
an appendix (Appendix 13) and the List of Appendices has been updated accordingly.
5. Measurement of vital signs (temperature, sitting blood pressure [systolic and diastolic], 
and heart rate) have been added to the procedures for all scheduled study visits and a 
12-lead ECG has been added to the procedures for the Day 0 visit. These procedures have 
been added to provide increased understanding and to assist analyses of potential safety 
events should they occur.
6. A page with the protocol’s revision chronology has been added.
7. The Synopsis has been corrected to include study agent dosing on day 28.
8. Text has been added to clarify that study agents (belimumab or placebo) will be provided 
by the sponsor during the double-blind treatment phase and that belimumab will be 
provided by the sponsor during the open-label extension phase.
9. Within the definition of postmenopausal in Inclusion Criterion #7, “1 year without 
menses” has been changed to “12 consecutive months with no menses without an 
alternative medical cause.” Also, the sub-bullet formatting of the last 8 rows of Inclusion 
Criterion #7 has been corrected.
10. Steroid use for vasculitis has been modified to restrict the use of corticosteroids up to a 
maximum of 20 mg/day of prednisone (or equivalent) for a maximum of 1 week within 
the first 2 months of the double-blind treatment period, and at other times, to < 10 mg/day.
11. The Reference List has been updated to include references cited in text but not present in 
the list and to delete a reference included in error. Also, the in text citation for Posner et al 
has been corrected to Posner et al 2007 and the reference has been added to the list.
12. Cross-references have been added in Section 1 for references that were in the Reference 
List but which inadvertenly had not been cited in text.


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13. In Appendix 8, for the question at baseline/screening “Is the time the subject felt most 
suicidal (i.e. the lifetime rating) more than X month(s) ago?”, the “X” has been corrected 
to “2”, i.e, “more than 2 month(s) ago”.
14. The investigator evaluation of adverse events regarding causality has been modified from 
a multi-choice assessment (definitely related, probably related, etc.) to an assessment of 
“reasonable possibility”.  
15. Appendix 9 has been corrected to cite the reference and the publication has been added to 
the Reference List.
16. Two new appendices have been added to provide the questionnaires for the PSRHQ 
(Appendix 10) and the PSRQ (Appendix 11) and cross-references added in-text as 
appropriate. The List of Appendices has been updated accordingly.
17. The protocol has been modified to include a Benefit and Risk Assessment (Appendix 12). 
The List of Appendices has been updated accordingly.
18. Minor administrative change was made for presentation of cross-referencing sections and 
tables, e.g., “see Sections X.1 and X.2” was changed to “see Section X.1 and 
Section X.2”. These minor changes are not shown in the Modifications section below. 
19. The list of abbreviations has been updated to add abbreviations as a result of new and/or 
amended text and to correct previous errors.
20. The Chapel Hill Consensus Conference (CHCC) definitions for Wegener’s granulomatosis 
and microscopic polyangiitis in Appendices 1 and 2 of the protocol have been updated to 
reflect the most recent CHCC (2012) definitions. The reference for this (Jeannette et al 
2013) is cited in the text (Section 1.1) and in the reference list.


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Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 01
Date: 22 June 2012
Modified to:
Protocol Amendment 02
Date: 25 April 2013
Revision Chronology for HGS1006-C1100 (BEL115466)
Added:
Date
Document*
Global
07 March 2012
Original
Global
22 June 2012
Amendment No 01
Local
29 January 2013
Addendum 01 for Sweden
Local
DNG2013N160488_01
31 January 2013
Addendum 01 for Ireland
Global
DNG2013N167980_00
25 April 2013
Amendment No 02
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.


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Synopsis, Diagnosis & Inclusion Criteria
Section 4.1, Inclusion Criteria
Formerly:


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Modified to:
Synopsis, Exclusion Criteria and Section 4.2, Exclusion Criteria
Formerly:
12. Have a historically positive test or test positive at screening for hepatitis B surface antigen, 
or hepatitis C antibody or are known to be HIV-1 positive.
Modified to:
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:


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
Patients positive for HBsAg are excluded.

Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs 
antibody and with no history of Hepatitis B vaccination are excluded.

Patients negative for HBsAg but positive for both anti-HBc and anti-HBs 
antibodies are excluded.

Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc 
antibody are excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate.
Added:
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of 
normal (ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin 
> 1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
Synopsis, Section Study Design and Schedule
Formerly:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). It is anticipated that no more 
than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, and every 28 days thereafter.
Modified to:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.


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Formerly:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months.
Modified to:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Section List of Abbreviations
Formerly:
ALT
aspartate aminotransferase alanine
LDH
lactic dehydrogenase
Modified to:
ALT
alanine aminotransferase
LDH
lactate dehydrogenase
Added:
CPK
creatine phosphokinase
ECG
electrocardiogram
HB
hepatitis B
HBsAg
hepatitis B surface antigen
HBc
hepatitis B core
HCV
hepatitis C virus


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Section 1.1 Disease Background
Formerly:
Anti-PR3 antibodies are associated with increased morbidity and mortality compared to anti-
MPO. The most widely used classification criteria for diagnosing the 3 types of AAV are 
those published by the American College of Rheumatology (ACR) for WG and CSS (Leavitt 
et al, 1990 and Masi et al, 1990, respectively), and that published by the Chapel Hill 
Consensus Conference (CHCC) for MPA (Jennette et al, 1994).
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007).
In the US, the prevalence rates of WG range from 2.6-9/100000 (Mahr et al, 2006).
Modified to:
Anti-PR3 antibodies are associated with increased morbidity and mortality compared to anti-
MPO (Hogan et al, 1996; Franssen et al, 1998). The most widely used classification criteria 
for diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994; Jennette et al, 2013).
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007; 
Mahr, 2009).
In the US, the prevalence rates of WG range from 2.6 9/100000 (Zeft et al, 2005; Mahr et al, 
2006).
Section 1.3.1 Belimumab Administered Intravenously
Added:
A benefit-risk evaluation of belimumab in the context of the present study is provided in 
Appendix 12 of this protocol.


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Section 1.4 Rationale for the Study
Formerly:
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease.
Modified to:
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20 (Dass et al, 2008; Wang et al 2008), recently showed success in inducing 
remission in AAV (Stone et al, 2010) and was granted approval for the treatment of WG and 
MPA supports the rationale that belimumab, which down regulates B cells by targeting BLyS, 
may be useful in the treatment of this disease.
Section 3.1 Basic Design Characteristics
Formerly:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). It is anticipated that no more 
than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, and every 28 days thereafter.
Modified to:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.
Formerly:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 


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the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months.
Modified to:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Section 5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent), or

IV corticosteroid pulses at any dose;
Modified to:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent) for > 1 week, or

IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for 
vasculitis, for a maximum of 1 week, are only allowable within the first 2 months of 
the double-blind treatment period.
Section 5.5.3 Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or 
equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg prednisone 
(or equivalent) are permitted for reasons other than vasculitis (eg. acute allergic reaction), but 
a subject cannot receive more than 1 such corticosteroid regimen in any 365 day period (See 
also Section 5.5.1).


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Modified to:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a 
maximum of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a 
maximum of 1 week within the first 2 months of the double-blind treatment period. At 
other times, subjects are restricted to < 10 mg/day. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or 
equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg prednisone 
(or equivalent) are permitted for reasons other than vasculitis (eg. acute allergic reaction), but 
a subject cannot receive more than 1 such corticosteroid regimen in any 365 day period (See 
also Section 5.5.1).
Section 6.1 Screening Procedures (Day -60 to Day 0):
Formerly:

Blood samples for: (see Appendix 6 – Laboratory Tests)

Hepatitis B surface antigen, and Hepatitis C antibody testing
Modified to:

Blood samples for: (see Appendix 6 – Laboratory Tests)

HIV antibody testing, serologic investigations for Hepatitis B (HB) infection 
(HBsAg, anti-HBc, and anti-HBs), and Hepatitis C antibody testing ± confirmatory 
HCV RNA-PCR testing
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs15, 16 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.


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Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
12-lead ECG: Day 0 Visit
Formerly:
Not listed.
Modified to:
12-lead ECG16 is added to the study calendar under Clinical Assessments.
12-lead ECG is marked “X” as required at this visit.
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
HIV, Hepatitis B, C: Screening Visits
Formerly:
Hep B surface antigen & Hep C antibody
Modified to:
HIV, Hepatitis B, C17
HIV, Hepatitis B, C is marked “X” as required at this visit.
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Footnotes
Formerly:
1Complete physical examination, including height, weight and vital signs.
Modified to:
1Complete physical examination, including height and weight.
Added:
15Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
16Complete prior to dosing.
17HIV, Hepatitis B surface antigen, anti-HBc, anti-HBs and hepatitis C antibody (if hepatitis C 
antibody positive, HCV RNA-PCR assay will be performed on a subsequent blood sample to 
confirm the results).


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Table 6-2  Study Calendar, Double-blind Treatment Phase Additional Years
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs11, 12 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.
Table 6-2  Study Calendar, Double-blind Treatment Phase Additional Years
Footnotes
Added
11Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12Complete prior to dosing.
Table 6-3  Study Calendar, Open-Label Extension Phase
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs11, 12 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.
Table 6-3  Study Calendar, Open-Label Extension Phase
Footnotes
Added:
11Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12Complete prior to dosing.


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Section 6.6 Laboratory Tests
The following section has been added:
Section 6.6.2 Phase III-IV Liver Chemistry Stopping and Follow-up Criteria
The liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology.
Phase III-IV liver chemistry stopping criteria 1-5 are defined below:
1. ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and 
INR>1.5, if INR measured). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
from that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be 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.
2. ALT ≥ 8xULN.
3. ALT ≥ 5xULN but <8 xULN persists for ≥2 weeks.
4. ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice), or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT ≥ 5xULN but <8 xULN and cannot be monitored weekly for ≥2 weeks.
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) 
(or ALT ≥ 3xULN and INR>1.5, if INR measured); INR measurement is not required and 
the threshold value stated will not apply to patients receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
from that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be 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.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed


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
Perform liver event follow up assessments, and monitor the subject until liver chemistries 
resolve, stabilize, or return to baseline values as described below.

Withdraw the subject from the study (unless further safety follow up is required) after 
completion of the liver chemistry monitoring as described below.

Do not re-start investigational product.
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat 
liver chemistries, liver event follow up assessments (see below), and close monitoring

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hours for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should 
be monitored as frequently as possible
Subjects with ALT ≥5xULN and <8xULN which exhibit a decrease to ALT ≥3xULN, but 
<5xULN and bilirubin <2xULN without hepatitis symptoms or rash, 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

Can continue investigational product

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects 
twice monthly until liver chemistries normalize or return to within baseline values.
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

• Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);


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
Hepatitis C RNA;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);

Hepatitis E IgM antibody;

Blood sample for PK analysis, obtained within approximately 1 to 2 weeks after the liver 
event. Record the date/time of the PK blood sample draw and the date/time of the last dose 
of investigational product 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 Procedures Manual.

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 hepatitis or hypersensitivity, such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form

Record use of concomitant medications, paracetamol (acetaminophen), herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form.

Record alcohol use on the liver event alcohol intake case report form
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and 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]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease.
Section 7.6 Suicidality Assessment
Formerly:
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 


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Questionnaire (PSRHQ, only the first time this condition is met) eCRF and a Possible 
Suicidality Related Questionnaire (PSRQ) eCRF (at all times this condition is met).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2010).
Modified to:
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 
Questionnaire (PSRHQ, only the first time this condition is met; refer to Appendix 10 for 
the PSRHQ) eCRF and a Possible Suicidality Related Questionnaire (PSRQ) eCRF (at all 
times this condition is met; refer to Appendix 11 for the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2007).
Section7.6.1 Possible Suicidality Related Questionnaire (PSRQ)
Formerly:
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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.
Modified to:
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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. Refer to Appendix 11 for the PSRQ.
Section 7.8 Investigator Evaluation of Adverse Events
Formerly:
CAUSALITY
Definitely Related
- reasonable temporal relationship to study agent administration


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- follows a known response pattern (eg, study agent is known to cause 
this AE)
- there is no alternative etiology
Probably Related
- reasonable temporal relationship
- follows a suspected response pattern (eg, based on similar drugs)
- no evidence for a more likely alternative etiology 
Possibly Related
- reasonable temporal relationship 
- little evidence for a more likely alternative etiology
Probably Not Related - does not have a reasonable temporal relationship OR
- good evidence for a more likely alternative etiology
Not Related
- does not have a temporal relationship OR
- definitely due to alternative etiology 
The causality assessment must be made by the investigator based on information available at 
the time that the AE eCRF or SAE worksheet is completed. The initial causality assessment 
may be revised as new information becomes available.
Modified to:
CAUSALITY
It is a regulatory requirement for investigators to assess relationship between the 
investigational product(s) and the occurrence of each AE/SAE based on the information 
available. The assessment should be reviewed on receipt of any new information and 
amended if necessary. A “reasonable possibility” is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship. Facts/evidence or 
arguments that may support “a reasonable possibility” include, e.g., a temporal 
relationship, a pharmacologically-predicted event, or positive dechallenge or 
rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, 
or relevant medical history, should also be considered.
Section 11 References
Formerly:
Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham 
Vasculitis Activity Score (version 3). Ann Rheum Dis 2009; 68:1827-32.


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Modified to:
Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham 
Vasculitis Activity Score (version 3). Ann Rheum Dis 2009; 68:1827-32. doi: 
10.1136/ard.2008.101279. Epub 2008 Dec3.
Added:
Bachen EA, Chesney MA, Criswell LA. Prevalence of mood and anxiety disorders in 
women with systemic lupus erythematosus. Arthritis Rheum 2009;61:822-9.
Fauci AS, Wolff SM. Wegener's granulomatosis: studies in eighteen patients and a 
review of the literature. Medicine (Baltimore) 1973;52:535-61.
Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical 
and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983;98:76-
85.
Gorman C, Leandro M, Isenberg D. B cell depletion in autoimmune disease. Arthritis 
Res Ther 2003;5 (Suppl 4):S17-S21.
Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener's 
granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322-9.
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.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross 
WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CGM, Lamprecht P, 
Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, 
Rasmussen N, Rees AJ, Scott DGI, Specks U, Stone JH, Takahashi K and Watts RA. 
2012 Revised International Chapel Hill Consensus Conference Nomenclature of 
Vasculitides. Arthritis Rheum. 2013; 65(1):1-11.
Langford CA. Cyclophosphamide as induction therapy for Wegener's granulomatosis 
and microscopic polyangiitis. Clin Exp Immunol. 2011;164 (Suppl 1):31-4. doi: 
10.1111/j.1365-2249.2011.04364.x.
Monach PA, Merkel PA. Genetics of vasculitis. Curr Opin Rheumatol 2010;22:157-163.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 
2007;164:1035-43.


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Smith KGC, Jones RB, Burns SM, Jayne DR. Long-term comparison of rituximab 
treatment for refractory systemic lupus erythematosus and vasculitis: Remission, 
relapse, and re-treatment. Arthritis Rheum 2006;54:2970-82.
Stenager EN, Stenager E, Koch-Henriksen N, et al. Suicide and multiple sclerosis: an 
epidemiological investigation. J Neurology, Neurosurg Psychiatry 1992;55:542-5.
Timonen M, Viilo K, Hakko H, et al. Suicides in persons suffering from rheumatoid 
arthritis. Rheumatology 2003;42:287-91.
Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A 
systematic review.BMC Nephrol 2010;11:12. doi: 10.1186/1471-2369-11-12.
Deleted:
Szczeklik W, Jakieła B, Adamek D, et al. Cutting Edge Issues in the Churg-Strauss 
Syndrome. Clin Rev Allergy Immunol 2011;66:222-7.


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Appendix 1 Chapel Hill Consensus Criteria for Wegener’s Granulomatosis
Formerly:
The CHCC Criteria require:
Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis 
affecting small to medium-sized vessels (eg, capillaries, venules, arterioles, and arteries) for a 
diagnosis of Wegener’s.
Another symptoms that may be present in WG, but that are not required according the CHCC 
classification scheme, is necrotizing glomerulonephritis.
Modified to:
Appendix 1 Chapel Hill Consensus Criteria for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Criteria require:
Necrotizing granulomatous inflammation usually involving the upper and lower respiratory 
tract, and necrotizing vasculitis affecting predominantly small to medium-sized vessels (eg, 
capillaries, venules, arterioles, and arteries) for a diagnosis of Wegener’s.
Another feature that may be commonly present in GPA, but which is not required according 
to the CHCC definition, is necrotizing glomerulonephritis.
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis
Formerly:
The CHCC criteria require:
Necrotizing vasculitis with few or no immune deposits that affects small vessels (ie, 
capillaries, venules, or arterioles) for a diagnosis of MPA. 
Other symptoms that may be present in MPA, but that are not required according the CHCC 
classification scheme, are: necrotizing arteritis involving small- and medium-sized vessels; 
glomerulonephritis; and pulmonary capilliaritis.
Modified to:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis (MPA) (Jennette et 
al, 2013)
The CHCC criteria require:


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Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small 
vessels (ie, capillaries, venules, or arterioles) for a diagnosis of MPA. Granulomatous 
inflammation is absent.
Other features that may be present in MPA, but that are not required according to the CHCC 
definition, are: necrotizing arteritis involving small- and medium-sized arteries; commonly 
necrotizing glomerulonephritis; and often pulmonary capillaritis.
Appendix 6 Laboratory Tests
Formerly:
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
Hepatitis C antibody
Hepatitis B surface antigen
Estimated Creatinine Clearance/ GFR (Cockcroft-Gault)
Modified to:
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid


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Glucose
HIV-1/2 antibody
Hepatitis C antibody (± HCV RNA PCR for confirmation of positive antibody test)
Hepatitis B surface antigen
Hepatitis B surface and core antigen antibodies
Estimated Creatinine Clearance/ GFR (Cockcroft-Gault)
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal antibodies
Footnote added:
Appendix 6 Laboratory Tests1
1
Institution or country specific guidelines for blood sample volume limits must be followed in collection 
of the subsequent blood sample.
Appendix 8 Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline/Screening/Since 
Last Visit
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Modified to:
Appendix 9 Pharmacogenetic Research, Research Rationale
Formerly:
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations.
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach, 2010) for example the association of alpha 1-antitrypsin deficiency in 
WG.  
Modified to:
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for 
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations (Monach and Merkel, 2010).
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach and Merkel, 2010) for example the association of alpha 1-antitrypsin 
deficiency in WG. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Appendix 10 Possible Suicidality Related History Questionnaire (PSRHQ)
Added:


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Appendix 11 Possible Suicidality Related Questionnaire (PSRQ)
Added:


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Appendix 12 Protocol Addendum – Benefit and Risk Assessment
Added:
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis; also known as granulomatosis with 
polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to lifethreatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. 
Historically, ANCA have been classified on the basis of their staining patterns in 
immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear (P-ANCA). It is 
now recognized that in AAV, C-ANCA is usually directed against proteinase 3 (PR3), and P-
ANCA is generally directed against myeloperoxidase (MPO), both of which are enzymes that 
are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel et al, 1997). 
Anti-PR3 antibodies are generally associated with WG, while anti-MPO autoantibodies are 
more common in MPA and CSS. Anti-PR3 antibodies are associated with increased morbidity 
and mortality compared to anti-MPO. The most widely used classification criteria for 
diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994). Of note, none of these diagnostic criteria incorporate the measurement 
of ANCA.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007). 
In the case of MPA, in particular, epidemiological studies are confounded by its original 
inclusion as a form of polyarteritis nodosa (PAN). Utilizing the ACR or CHCC criteria, 
prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and 0.4-
1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes et al, 2008). AAV are extremely rare in childhood with peak age of onset in 
those aged 65 to 74 years (Ntatski et al, 2010), with other small vessel vasculitides being the 
major concern in childhood (Brogan et al, 2010).Current therapy is usually determined by 
severity of the disease, with more severe forms warranting more aggressive approaches. These 
usually involve an initial remission induction regimen of high dose corticosteroid 
administered with either cyclophosphamide (CYC) or rituximab (RTX) followed by a 
remission maintenance period usually with azathioprine (Stone et al, 2010; Bosch et al, 2007; 
Jayne et al, 2003). Minor manifestations are usually treated with low dose corticosteroid 


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administered with either azathioprine or methotrexate (Belmont, 2006). Even with recent 
treatment advances the morbidity and mortality of patients with AAV remains unacceptably 
high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG 
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2009). In its current form it is a list of 
56 items which are considered to be manifestations of vasculitis. A weighted numerical score
is attached to each item to reflect the importance of each manifestation. The items are grouped 
by organ systems, and each organ system has a maximum or ‘ceiling’ score to reflect the 
relative importance of the organ system (Mukhtyar et al, 2009). The tool also makes a 
distinction between new or worsening disease and persistent disease with new or worsening 
attracting higher scores.
IV Belimumab
Over 2,000 individuals with SLE have been treated with belimumab in clinical studies. In two 
global Phase 3 studies, belimumab 10 mg/kg met the primary efficacy endpoint (SRI at 
Week 52). Evidence of other possible benefits in these trials included reductions in risk of 
severe flare and corticosteroid use, and improvements in patient reported quality of life and 
fatigue. Serological activity was reduced as measured by reductions in autoantibodies and 
normalization of hypergammaglobulinemia and complement levels. B cells, including 
autoreactive B cells, were also reduced, but not severely depleted, consistent with what would 
be expected from inhibition of BLyS (reference belimumab IB, Section 5.3.1). These results 
supported the approval of belimumab in the EU, US, Canada and other countries.
In the United States belimumab is approved for the following indication:
BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, 
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard 
therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with 
severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA 
has not been studied in combination with other biologics or intravenous 
cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
In the EU, the approved indication focuses on patients with high disease activity (where 
belimumab offered the greatest benefit):
Benlysta 
is 
indicated 
as 
add-on 
therapy 
in 
adult 
patients 
with 
active, 
autoantibodypositive systemic lupus erythematosus (SLE) with a high degree of disease 
activity (e.g positive anti-dsDNA and low complement) despite standard therapy.
The EU SPC also includes special warnings and precautions for use similar to the US 
labeling, including that belimumab has not been studied in and is thus not recommended in 


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patients with severe active central nervous system lupus or severe active lupus nephritis. In 
addition, caution should be exercised if belimumab is co-administered with other B cell 
targeted therapy or cyclophosphamide. Reference Section 4.4 of the SPC for the complete list 
of specials warnings and precautions.
Treatment with belimumab plus standard therapy was generally well tolerated, with rates of 
AEs, severe AEs, SAEs, AEs leading to discontinuation, and serious/severe infections 
generally comparable to the rates observed in the placebo plus standard therapy group. The 
most commonly-reported adverse reactions, occurring in ≥ 3% of patients receiving 10 mg/kg 
belimumab IV in clinical trials (and at a ≥ 1% greater rate than placebo) were nausea, 
diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, 
migraine, pharyngitis, cystitis, leukopenia, and gastroenteritis viral. In clinical trials, 
hypersensitivity and infusion reactions were observed more frequently with belimumab, with 
anaphylaxis observed in ≤ 1% of subjects. Data from the post-marketing setting indicate that 
hypersensitivity reactions may be serious or result in death, that the onset of such reactions 
may be delayed, and that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. In addition, it is also known from clinical trials and 
the post-marketing setting that the vast majority of hypersensitivity reactions occur with the 
1st or 2nd infusion. The product labeling, belimumab IB, protocol, and informed consent forms 
have been updated to include this new information, as applicable.
Other risks that may be associated with belimumab based on its mechanism of action include 
serious infections and malignancy, although no increases in the rates of serious infections or 
malignancies have been observed. Psychiatric events including depression and suicide were 
observed more frequently with belimumab than with placebo, although it is unknown if 
belimumab treatment is associated with an increased risk for these events. Finally, mortality 
rates in the controlled clinical trials were low, although numerically higher in the belimumab 
groups (0.4% and 0.8% in the placebo and belimumab groups, respectively). Causes of death 
were as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as corticosteroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide.
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence of AEs or SAEs over time, including important events such 
as infections and malignancies. Long-term belimumab treatment appears to provide sustained 
improvement in SLE disease activity and reduction of flares.
Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Belimumab at a dose of 10 mg/kg in combination with standard SLE therapy demonstrated a 
statistically significant and clinically meaningful reduction in SLE disease activity versus 
placebo plus standard SLE therapy at Week 52 in two Phase 3 clinical studies in subjects with 
active, autoantibody-positive SLE.


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Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 18 
months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the most 
effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al, 2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels. Therefore, 
for the proposed study, subjects are required to have documented evidence of anti-PR3 or 
anti-MPO autoantibodies prior to randomization, as this population is considered the most 
likely to benefit from treatment with a B cell modulating agent like belimumab. This is 
consistent with the Phase 3 SLE results for belimumab where the subjects who benefitted 
from treatment were those who were antinuclear antibody (ANA/anti-dsDNA) autoantibody 
positive at baseline.
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval in the US for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease. Finally, limited data from the small (n = 111) subset of subjects in the Phase 3 
trials of SLE who had vasculitic symptoms as part of their SLE (as assessed by the SELENA 
SLEDAI) showed that more subjects in the belimumab plus standard of care treatment arms 
had resolution of their vasculitic symptoms at Week 52 compared with subjects receiving 
placebo plus standard of care. Specifically, 19/36 (52.8%) and 28/38 (73.7%) of subjects in 
the belimumab 1 mg/kg and 10 mg/kg dose groups, respectively, had resolution of vasculitic 
activity at Week 52 compared with 15/37 (40.5%) of placebo subjects. Taken together, these 
data support the evaluation of belimumab in AAV.
The safety of the proposed study is supported by data from the Phase 2 and 3 trials in SLE in 
which subjects who were receiving belimumab in combination with significant background 
therapies, including steroids and immunosuppressants, had an adverse event profile similar to 
that of subjects receiving placebo plus standard therapies.
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:


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
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of CYC are given as targets but may be adjusted for renal insufficiency or white 
cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
A target of 300 to 400 subjects who are within 26 weeks of starting induction therapy, achieve 
a BVAS v.3 score of 0 (ie, are in remission), and are receiving less than 10 mg/day prednisone 
(or equivalent) on 2 consecutive measurements 21 to 35 days apart will be enrolled into the 
study. Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to receive 
study agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. 
Study agent (belimumab/placebo) will be administered at Day 0, 14, and every 28 days 
thereafter. Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. Azathioprine must be initiated at any time following 
confirmation of remission up to and including Day 0. Patients with known intolerance to 
azathioprine will be excluded from the trial. Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease), and induction regimen (IV 
CYC vs. oral CYC vs. RTX). It is anticipated that no more than 25% of the patients would be 
newly diagnosed and anti-MPO positive, and as such enrollment of these patients may be 
capped if they exceed this proportion. Refer to Section 4 of Protocol HGS1006-C1100 for a 
complete list of inclusion and exclusion criteria.
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as at least 
1 major BVAS item or a minimum total BVAS score of 6 or receipt of prohibited medications 


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according to the protocol. Subjects will receive study agent (belimumab/placebo) plus AZA 
until the results from the primary efficacy analysis are available or until they experience a 
flare (relapse) as defined in the primary efficacy endpoint. The database will be locked and 
the primary analysis will be performed after at least 66 subjects have experienced a relapse 
and at least 12 months have elapsed after the last subject is randomized. Subjects who 
discontinue study agent prior to relapse/flare are to be followed per the double blind visit 
schedule until relapse/flare or the end of the double-blind treatment phase (whichever is 
earlier). In subjects who withdraw consent from the study prior to 1 year an attempt will be 
made to ascertain survival status at 12 months after the first dose of study agent.
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety. All subjects will return 
for an Exit visit approximately 4 weeks after their last dose of study agent as well as a follow-
up visit approximately 8 weeks after the last dose of study agent. These visits apply to 
subjects who have completed as well as those who have withdrawn early from the open-label 
extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Dose and Schedule
Investigational Study Agent (Belimumab or Placebo)
The dose and schedule of belimumab proposed for use in the ANCA-associated vasculitis 
study is the same dosage (10 mg/kg every 2 weeks for 3 doses and every 4 weeks thereafter) 
and route of administration (IV) as that approved for marketing. The belimumab BDS and 
FDP that will be used for this study is the same as that approved for marketing.
In the Phase 3 IV SLE studies, several clinical measures of improvement including the 
primary efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, there 
appeared to be a greater dose response in subjects with high disease and serological activity. 
There was no apparent dose-response in the safety profile of belimumab with both doses 
being generally well-tolerated. These data supported the selection of 10 mg/kg belimumab as 


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the marketed dose in general SLE, and also support its continued evaluation in combination 
with standard maintenance therapies in patients with WG or MPA.
The use of placebo in this trial is considered appropriate and does not put placebo patients at 
undue risk because all subjects in both the placebo group and the belimumab group will 
receive standard of care maintenance therapies for vasculitis (ie, azathioprine or methotrexate) 
and, if needed, subjects will receive appropriate rescue therapy in accordance with standard 
clinical practice as described above.
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX regimen specified in this vasculitis study is the 
same as that approved by the FDA for this indication.
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).


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A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements 3 to 5 weeks 
apart: a BVAS v3 score of 0 and be receiving < 10 mg/day of oral prednisone [or equivalent], 
achieved no more than 26 weeks after the first dose of induction therapy) has been achieved, 
subject randomization into this protocol occurs. In this maintenance of remission trial, 
subjects will be randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + 
placebo or AZA (2 mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol must 
occur within 2 weeks of achieving a confirmed remission and the randomization will be 
stratified by induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. In this study, subjects who have a known 
intolerance to azathioprine will be excluded. Subjects naive to azathioprine and who 
experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or thrombocytopenia, AST 
or ALT 2 times ULN, or a several gastrointestinal hypersensitivity reaction characterized by 
severe nausea and vomiting), following initiation of azathioprine will be permitted to reduce 
the dose to no less than 1 mg/kg/day. If the subject continues to experience toxicities, a switch 
to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be 
permitted. As azathioprine is among the better tolerated immunomodulatory agents, it is not 
anticipated that many subjects will need to substitute methotrexate for azathioprine (Walters 
et al, 2010). Subjects for whom methotrexate is substituted for azathioprine will be included 
in the primary analysis. The protocol instructs physicians to follow the appropriate local 
prescribing information for azathioprine or methotrexate (as applicable) prior to and during 
treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.


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Safety Considerations
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Belimumab has not yet been studied following use of 
IV cyclophosphamide (CYC) or rituximab (RTX); there is limited experience with the 
combination of belimumab and oral CYC. As an added safety precaution, initial 
randomization will be limited to 40 subjects per induction regimen (40 post-RTX induction 
and 40 post-CYC induction). The first DMC reviews will occur after the first 20 subjects per 
induction regimen (RTX or IV/oral CYC) have been randomized and have had a Week 8 visit. 
Once the first 20 subjects randomized following induction with RTX have had a Week 8 visit, 
safety data will be reviewed by the DMC, who will make a recommendation regarding 
whether to continue randomization. The same procedure would be applied for the first 
20 subjects randomized following induction with CYC. The DMC will review the data 
approximately every 6 months thereafter across both induction regimens. At all times the 
patients, study sites and sponsor will remain blinded to treatment allocation. Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting.
The DMC will be notified of:

• all unexpected causally-related SAEs that are life-threatening or result in death;

• other unexpected causally-related SAEs;

• all reports of serious infections and opportunistic infections, irrespective of relationship 
to study agent; and

• subjects experiencing IgG < 250 mg/dL; 
within protocol-specified timeframes. Based on these data, an ad hoc DMC meeting may be 
called at any time (see Section 8.3 of Protocol HGS1006-C1100 for additional detail 
regarding the DMC).
Based on the large body of safety data from SLE patients treated with belimumab and/or the 
mechanism of action of belimumab as a B cell immunosuppressant, anticipated potential risks 
of belimumab treatment in vasculitis patents include serious infusion and hypersensitivity 
reactions, infections, depression-related events, and malignancy. These risks are briefly 
reviewed here and are detailed more fully in the belimumab Investigator’s Brochure. Both 
investigators and subjects will be appropriately informed regarding these risks. It is noted that 
because of the older patient population affected by this disease, the average age of subjects 
anticipated to participate in this study will be older than the average age of the SLE 
population studied to date (mean age of ~53 years at the time of diagnosis in vasculitis (Stone 
et al, 2010) compared with an average age of ~38 years in controlled Phase 3 studies of 
belimumab in SLE). As such, patients with vasculitis may be at a greater risk for infection 
than the SLE patients; however, the increased monitoring for infections by both the DMC 
(described above) and recommended to investigators (see below) will help to ensure subject 
safety through timely detection, treatment and reporting of infections.


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The protocol states that all subjects should be monitored closely for infection and increased 
vigilance for infection is recommended in subjects who experience IgG levels < 250 mg/dL, 
especially for prolonged periods; clinical judgment should be applied with respect to the 
appropriateness of continuing study therapy in these subjects. The Medical Monitor must be 
consulted before administering subsequent doses of study agent in subjects with IgG levels 
< 250 mg/dL. Study agent will be discontinued in subjects with IgG levels < 250 mg/dL that 
are associated with a severe or serious infection. If a subject experiences a clinically 
significant, potentially life-threatening (Grade 4) AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo, then treatment with study agent 
will be discontinued. The subject will be followed at regularly scheduled study visits as 
specified by the protocol through the end of the double-blind period and also until resolution 
of the AE(s) (whichever is longer).
In order to ensure subject safety with respect to infusion and hypersensitivity reactions, the 
protocol excludes patients with known history of allergic reactions to human or murine 
proteins or monoclonal antibodies. There is currently insufficient evidence to determine 
whether premedication diminishes the frequency or severity of hypersensitivity reactions to 
belimumab. The protocol recommends that based on clinical judgment, premedication 
including an antihistamine, with or without an antipyretic, may be administered before the 
infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 
Belimumab/placebo will be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 
closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. Per protocol, 
subjects are to remain under clinical supervision for 3 hours after completion of the first 
2 infusions in the double-blind treatment phase and the open-label extension. Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment. This may include, but is not limited to, monitoring 
vital signs and observing for any untoward reactions. 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.
The protocol recommends that subjects with persistent or worsening disease should receive 
appropriate rescue therapy in accordance with standard clinical practice, but if exceeding what 
is allowed per protocol, treatment with study agent (ie, belimumab or placebo) will be 
discontinued and the subject will be considered as having relapsed for the primary analysis. 
The list of prohibited medications that results in the subjects being considered as relapsed for 
the primary endpoint (Protocol Section 5.5.2.1), was developed because the need for the use 
of these agents (eg, RTX or CYC) is indicative of treatment failure (ie, disease relapse).
Moreover, concomitant use of such medications (eg, high-dose steroids) can be associated 
both with potent disease-modifying activity and/or significant toxicity that may introduce


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bias and confound interpretation of results. As such, no subject will be denied appropriate 
medical care for their condition due to their participation in this clinical study.
In addition, the Sponsor notes that although this is a placebo controlled trial, the sponsor does 
not consider that placebo patients are at undue risk because all subjects in both the placebo 
group and the belimumab group will receive standard of care maintenance therapies for 
vasculitis (ie, azathioprine or methotrexate) and, if needed, subjects will receive appropriate 
rescue therapy in accordance with standard clinical practice as described above.
Risk:Benefit Conclusions
In summary, the proposed Phase 3 study is a superiority study evaluating the safety and 
efficacy of belimumab for the maintenance of disease remission in patients with a clinical 
diagnosis of Wegener’s granulomatosis or microscopic polyangiitis. The risk:benefit profile of 
10 mg/kg IV belimumab in patients with active, autoantibody-positive SLE was demonstrated 
to be positive in the two Phase 3 SLE studies, thereby supporting its approval in Canada, the 
US, and the EU. Belimumab has already been shown to be effective in treating patients with 
active, autoantibody-positive SLE, a B cell mediated autoimmune disease. Like SLE, WG and 
MPA are also B cell mediated autoimmune diseases in which autoantibodies (in this case, 
against neutrophil components), are considered to be pathogenic (Popa et al, 1999). In each of 
these diseases, the general purpose of the therapy is similar – reducing disease activity by 
down regulating B cells (including autoreactive B cells) and reducing the level autoantibodies 
produced by those autoreactive B cell clones. Down regulating B cell numbers may also 
reduce inflammatory processes because of the role of B cells in antigen presentation. A 
limited amount of data from the IV Phase 3 studies suggests that belimumab may reduce 
vasculitic symptoms.
There are potential risks associated with belimumab treatment including serious infusion and 
hypersensitivity reactions, infections, depression-related events, and malignancy; however, in 
view of the serious and potentially life threatening nature of disease flares in WG and MPA, it 
is believed that the overall risk:benefit analysis for belimumab in the maintenance of 
remission in WG and MPA is favorable, especially in view of the nature of the trial as a 
superiority trial over a current standard of care regimen.


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Protocol Amendment 01, 22 June 2012
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to further define allowable/prohibited doses of 
corticosteroids that can be given for vasculitis and for reasons other than vasculitis. It is 
now specified that IV corticosteroid pulses for vasculitis at any dose are prohibited and 
use of such will result in the subject being considered as relapsed for the primary 
endpoint; it is considered that subjects requiring IV corticosteroid pulses are having 
sufficient disease activity to qualify as having relapsed. In relation to this, it is now 
clarified that IV steroid pulses > 125 mg prednisone (or equivalent) are prohibited for 
reasons other than vasculitis and such use will also result in the subject being considered a 
treatment failure. Importantly, it is also now stated that use of high dose steroids (ie, 
average daily dose of > 20 mg/day prednisone or equivalent for ≤ 14 days or IV 
corticosteroid pulses ≤ 125 mg prednisone or equivalent) for non vasculitis reasons may 
only be given to a subject 1 time in any 365 day period without the subject being 
considered a treatment failure. These modifications to the protocol will prevent 
uncontrolled use of oral and IV pulse corticosteroids that could confound the 
interpretation of study results. 
2. A statement has been added to clarify that the protocol-defined induction regimens for 
cyclophosphamide are given as treatment targets but that they may be adjusted to account 
for renal insufficiency or reduced white blood cell counts as dictated by local standard of 
care practices.
3. A subgroup analysis by duration of IV corticosteroid pulse used for induction (1 day vs. 
> 1 day) has been added.
4. The language regarding the recommended HDCS tapering to reach the entry criteria of 
< 10 mg/day has been corrected from the previously written < 10 mg/kg.
5. The dose of methotrextate to be used in case of azathioprine toxicity has been clarified to 
be a target dose, to allow for flexibility in individual practice. A minimum dose of 
methotrexate (no less than 10 mg/week) is also specified, to ensure subjects are receiving 
a sufficient and relatively consistent therapy. This change also ensures the guidance given 
for methotrexate is consistent with that given for azathioprine.
6. Vital signs have been added to the listing of screening procedures to match the study 
calendar footnote.
7. The visit windows for the 8 and 12 week visits in Study Calendar 6-1 have been corrected 
to +/- 7 days rather than +/- 3 days.
8. Serum IgG has been added to the 8 Week Follow-up visits in Study Calendars 6-1 and 6-2.
This was omitted in error in amendment 00 of the protocol.
9. Footnote number 12 in Study Calendar 6-1 and footnote number 8 in Study Calendar 6-2 
have been revised to correspond with Section 7.2 of the protocol.


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10. Dysmorphic RBC analysis of Urine has been removed from the laboratory tests. This data 
will not be provided by the Central Lab contracted for this study.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 00
Date: 07 March 2012
Modified to:
Protocol Amendment 01
Date: 22 June 2012
Study Synopsis, Study Design and Schedule:
Section 3.1 Basic Design Characteristics:
Formerly:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Only subjects treated under the following induction regimens will be eligible 
for participation in the study:

A single course rituximab (RTX) administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HCDS) OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/kg.
Modified to:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:


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
A single course rituximab (RTX) administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Section 5.5.1  Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:
Subjects who start prohibited medication or therapies at any time during the double-blind 
phase will be considered as having relapsed as of the time of receipt of the prohibited 
medication, and treatment with study agent will be discontinued. However, the subject will 
continue to be followed for survival through at least 12 months after randomization. The 
following medications and therapies are prohibited during the study:

Other immunomodulatory investigational agents (biologic or non-biologic);

Rituximab;

Cyclophosphamide;

Other immunosuppressive agents (eg, cyclosporine) with the exception of methotrexate 
for AZA intolerance described in Section 5.5.3;

Corticosteroids for vasculitis at doses > 20 mg/day prednisone (or equivalent);

Corticosteroids at an average daily dose of > 20 mg/day prednisone (or equivalent) for 
> 14 days for any reason (average daily dose is the sum of the dose over 7 consecutive 
days divided by 7); 

IV corticosteroid pulses > 125 mg prednisone (or equivalent); and

Plasmapharesis.
Modified to:
Subjects who start prohibited medication or therapies at any time during the double-blind 
phase will be considered as having relapsed as of the time of receipt of the prohibited 
medication, and treatment with study agent will be discontinued. However, the subject will 
continue to be followed for survival through at least 12 months after randomization. The 
following medications and therapies are prohibited during the study:


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
Other immunomodulatory investigational agents (biologic or non-biologic);

Rituximab;

Cyclophosphamide;

Other immunosuppressive agents (eg, cyclosporine) with the exception of methotrexate 
for AZA intolerance described in Section 5.5.3;

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent), or

IV corticosteroid pulses at any dose;

Corticosteroids for reasons other than vasculitis:

at an average daily dose of > 20 mg/day prednisone (or equivalent) for > 14 days 
where the average daily dose is calculated as the sum of the dose over 7 consecutive 
days divided by 7, or

IV corticosteroid pulses > 125 mg prednisone (or equivalent)
Note: Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or IV 
corticosteroid pulses ≤ 125 mg prednisone (or equivalent) for reasons other than 
vasculitis cannot be given more than once in any 365 day period (See also Section 
5.5.3).

Plasmapharesis.
5.5.3  Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) are permitted over the course of the trial. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted.
Modified to:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or 
equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg 
prednisone (or equivalent) are permitted for reasons other than vasculitis (eg. acute 
allergic reaction), but a subject cannot receive more than 1 such corticosteroid regimen 
in any 365 day period (See also Section 5.5.3).
5.5.3.1  Azathioprine and Methotrexate, - Second paragraph
Formerly:
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times the ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 


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permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at doses of up to 
25mg/week as an alternative to azathioprine will be permitted. These subjects will be included 
in the primary analysis.
Modified to:
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times the ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of 
25mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be 
permitted. These subjects will be included in the primary analysis.
Study Procedures:
6.1   Screening Procedures; Fourth Bullet
Formerly:
Complete physical examination, including height, weight.
Modified to:
Complete physical examination, including height, weight and vital signs.
Table 6-1  Study Calendar:
Study Visit Window for Week 8 and Week 12
Formerly:
+ 3 days
Modified to:
+ 7 days


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Table 6-1 and Table 6-2  Study Calendars:
Serum IgG – 8 Week Follow-up Visit
Formerly:
Serum IgG was not assessed at this time point
Modified to:
Serum IgG is marked “X” as required at this visit.
Table 6-1; Footnote number 12
Table 6-2; Footnote number 8
Formerly:
In subjects who discontinue study agent prior to relapse/flare all AEs and SAEs will be 
reported on the AE eCRF through 8 weeks following administration of the last dose of study 
agent. After this time, all SAE, regardless of relationship to study drug, will be collected until 
relapse or the study is analyzed for the primary endpoint and study sites are informed that 
SAE data collection can cease, whichever occurs first.
Modified to:
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF 
through 8 weeks following administration of the last dose of study agent. After this time, all 
SAE, regardless of relationship to study drug, will be collected until relapse or the study is 
analyzed for the primary endpoint, whichever occurs first.
Subgroup Analysis:
8.5.2.1  Ninth Bullet added
Formerly:
Not listed.
Modified to:

Duration of IV corticosteroid pulse used for induction (1 day vs. > 1 day)


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Appendix 6 Laboratory Tests
Formerly:
Occult blood microscopic examination including Dysmorphic RBC;
Modified to:
[Text deleted]


PPD


CLINICAL PROTOCOL HGS1006-C1100
Protocol Amendment: 04
Date: 26 February 2015
EudraCT 2011-004569-33
Local Amendment 01 for Belgium, Date: 06 July 2015
TITLE OF STUDY:
A Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
STUDY SPONSOR:
Human Genome Sciences, Inc.
14200 Shady Grove Road
Rockville, Maryland 20850
Confidentiality
This document contains proprietary and confidential information of Human Genome 
Sciences, Inc. Acceptance of this document constitutes agreement by the recipient that 
no unpublished information contained herein will be published or disclosed without 
prior written approval from Human Genome Sciences, Inc., except that this document 
may be disclosed to study personnel under your supervision who need to know the 
contents 
for 
conducting 
the 
study 
and 
appropriate 
Institutional 
Review 
Boards/Independent Ethics Committees under the condition that they are requested to 
keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws however, Human Genome Sciences, Inc. must be 
promptly informed of any such disclosure.
Amend 01
22Jun12
Amend 02
25Apr13
Amend 03
04Feb14
Amend 04
26Feb15
Am01/Belgium
06Jul15


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Revision Chronology for HGS1006-C1100 (BEL115466)
Date
Document*
Global
07 March 2012
Original
Global
22 June 2012
Amendment No 01
Local 
29 January 2013
Addendum 01 for Sweden
Local
DNG2013N160488_01
31 January 2013
Addendum 01 for Ireland
Global
DNG2013N167980_00
25 April 2013
Amendment No 02
Global
DNG2013N167980_01
04 February 2014
Amendment No 03
Local
DNG2014N217970_01
01 October 2014
Local Amendment 01 for France
Local
DNG2014N217970_02
03 February 2015
Local Amendment 02 for France
Global
DNG2013N167980_02
26 February 2015
Amendment No 04
Local
2015N245521_00
06 July 2015
Local Amendment 01 for Belgium
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.
Amend 02
25Apr13


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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


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Study Synopsis
Study Number: HGS1006-C1100
Title of the Study: 
A Multi-Center, Multinational, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Clinical Development Phase: 3
Objectives: 
•
To evaluate the efficacy of belimumab in the maintenance of remission following a 
standard induction regimen in subjects with Wegener’s granulomatosis (WG) or 
microscopic polyangiitis (MPA).
•
To evaluate the safety of belimumab in subjects with WG or MPA.
Diagnosis & Inclusion Criteria: Subjects enrolled in the study must meet the following 
inclusion criteria:
1. Are at least 18 years of age.
2. Have a clinical diagnosis of Wegener’s granulomatosis (WG) or a diagnosis of 
microscopic polyangiitis (MPA) according to the Chapel Hill criteria (Appendix 1 and 
Appendix 2).
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:
A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks plus 
high dose corticosteroids (HDCS) OR
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
cyclophosphamide 2 mg/kg/day orally plus HDCS OR
cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
4. Have documented evidence of either anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase 
(anti-MPO) prior to Day 0.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving ≤10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at 
least 14 days apart, between 6 and 26 weeks after the first dose of induction therapy 
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(either CYC or RTX, as defined in Section 3.1). A minimum 6 week period should elapse 
between initiation of induction therapy and randomization.
6. Subjects receiving non-systemic corticosteroids for reasons other than vasculitis must be 
on a stable regimen prior to randomization.
7. A female subject is eligible to enter the study if she is:
Not pregnant or nursing;
Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal 
which is defined as 12 consecutive months with no menses without an alternative medical 
cause, have both ovaries surgically removed or have current documented tubal ligation or 
other permanent sterilization procedure); or
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are peri-menopausal or 
have just begun to menstruate. These women must have a negative serum pregnancy test 
at screening, and agree to 1 of the following:
o
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or
o
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 
16 weeks after the last dose of study agent:
o Implants of levonorgestrel or etonogestrel;
o Injectable progesterone;
o Transdermal contraceptive patch
o Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
o Oral contraceptives (either combined or progesterone only);
o Ethinyl estradiol/Etonogestrel vaginal ring
o Double barrier method: Condom and Occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; or
o Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject.
8. Have the ability to understand the requirements of the study and provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).
Exclusion Criteria: Subjects will be excluded from participating in the study if they meet 
any of the following exclusion criteria:
1. Co-existence of other multisystem autoimmune diseases.
2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance or 
contraindications to methotrexate where methotrexate is being considered as an alternative 
to AZA for maintenance therapy.
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3. Have received treatment with a B-cell directed therapy (other than rituximab), for example 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], anti-CD40L antibody [BG9588/ 
IDEC-131], BLyS-receptor fusion protein [BR3], LY2127399, TACI-Fc, or belimumab at 
any time.
4. Have required 3 or more courses of systemic corticosteroids for concomitant conditions 
not related to their vasculitis (eg, asthma, atopic dermatitis) within 364 days of Day 0.
(Topical or inhaled steroids are permitted.)
5. Have received a non-biologic or biologic investigational agent within 60 days or 
5 half-lives of the agent (whichever is longer) of Day 0.
6. Have received a live vaccine within 30 days of Day 0.
7. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to vasculitis (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious disease) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk.
8. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study.
9. 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.
10. Have required management of acute or chronic infections, as follows:
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, aspergillosis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (intravenous, subcutaneous or intramuscular) antibiotics, antibacterials, 
antivirals, anti-fungals, or anti-parasitic agents within 60 days of Day 0.
11. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to Day 0.
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:
Patients positive for HBsAg are excluded.
Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody 
and with no history of Hepatitis B vaccination are excluded.
Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are 
excluded.
Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are 
excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will 
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be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a 
positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the 
subsequent sample will not be eligible to participate.
15. Have an IgA deficiency (IgA level < 10 mg/dL).
16. Have a Grade 3 or greater laboratory abnormality based on the protocol DMID toxicity 
scale, unless considered by the investigator to be related to the underlying disease or 
induction therapy.
17. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies.
18. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS 
(Refer to Appendix 8 for C-SSRS) in the last 2 months or who in the investigator’s 
opinion, pose a significant suicide risk.
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of normal 
(ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin > 1.5ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%).
Study Design and Schedule:
This is a multi-center, multi-national, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:
•
A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
Cyclophosphamide 2mg/kg/day orally plus HDCS OR
•
Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
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For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Subjects who are between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3 
score of 0 (Appendix 4), and are receiving ≤10 mg/day prednisone (or equivalent) on 2
consecutive measurements at least 14 days apart may be enrolled into the study. A minimum 
6 week period should elapse between initiation of induction therapy and randomization. 
Randomization will be performed on Day 0. A schematic of the study design is shown below.
All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 
2 mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than Day 0. 
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to receive study agent 
(belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.  
Initial randomization will be limited to 40 subjects per induction regimen (40 post-RTX 
induction and 40 post-CYC induction). Once the first 20 patients randomized following 
induction with RTX have had a Week 8 visit, safety data will be reviewed by the independent 
data monitoring committee (DMC), who will make a recommendation regarding whether to 
continue randomization. The same procedure would be applied for the first 20 subjects 
randomized following induction with CYC. At all times the sites and sponsor will remain 
blinded to treatment allocation.
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The double-blind phase of the study will complete, the database will be 
locked and the primary analysis will be performed when 12 months have elapsed after the last 
subject is randomized.
In consultation with the investigating physician, subjects participating in the double-blind 
period of the trial will have the option to continue to receive treatment with belimumab in a 6-
month open label extension phase. The criteria for entry into the extension phase of the study 
are: (1) the safety profile of belimumab is considered to be acceptable, based on ongoing 
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IDMC data reviews of the safety data, and other relevant safety data sources; (2) the risk-
benefit profile for continuing treatment with belimumab must be favorable in the opinion of 
the investigator; (3) the subject will have completed the double-blind treatment period of the 
trial without having relapsed (as defined in the primary endpoint); (4) a favorable opinion has 
been obtained from the local ethics committee or IRB with respect to continuation of 
belimumab treatment. Subjects who enter the open-label extension phase will receive 
belimumab for up to an additional 6 months and this will be supplied by the sponsor.
Following completion of the study and, where applicable, completion of the 6-month open-
label extension phase, subjects will not receive any additional treatment supplied by the 
sponsor. The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition.
Subjects who discontinue study agent prior to relapse/flare (as defined below) are to be 
followed per the double blind visit schedule until relapse/flare or the end of the double-blind 
treatment phase (whichever is earlier). In subjects who withdraw consent from the study prior 
to 1 year an attempt will be made to ascertain survival status at 12 months after the first dose 
of study agent.  
Schematic of study design:
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Efficacy Endpoints and Analysis:
Primary Efficacy Endpoint:
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as:
•
At least 1 major BVAS item (Appendix 4) OR 
•
A minimum total BVAS score of 6 (Appendix 4) OR
•
Receipt of prohibited medications (as defined in Section 5.5.1).
Major Secondary Efficacy Endpoint:
•
Time from Day 0 to the first major relapse (defined as experiencing at least 1 major BVAS 
item, see Appendix 4).
Other efficacy endpoints are described in Section 8.5.4.
Sample Size Considerations:
Approximately 100 subjects will be randomized. The sample size has been determined based 
on the feasibility of enrolling patients into the study within a reasonable time-frame. The 
sample size was not based on statistical considerations and the analysis of primary and 
secondary endpoints will be exploratory in nature. The primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo group, a 
relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically significant 
(p<0.05) in a study of 100 subjects (50 per arm). 
Analysis of Primary Efficacy Endpoint:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazards model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage
at induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using oral cyclophosphamide
or IV 
cyclophosphamide. For any subject who does not experience a relapse, the time to first relapse 
will be censored at the time of the subject’s last assessment.
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after 12 months have elapsed following randomization of the last subject.
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Analysis of Major Secondary Efficacy Endpoints:
The analysis of the major secondary efficacy endpoint will be performed using the same 
method described for the primary efficacy analysis, but censoring subjects who receive any 
prohibited medication prior to an observation of any major BVAS item.
Safety Endpoints and Analysis:
Descriptive statistics will be used to summarize adverse events (AEs), changes in laboratory 
parameters and immunogenicity. The frequency and rate of laboratory abnormalities will be 
tabulated by treatment group. The frequency and rate of AEs will be tabulated by MedDRA 
system organ class (SOC) and preferred term and presented by treatment group.
Adverse events of special interest that will be analyzed in this protocol include: all-cause 
mortality; serious and/or severe infections; opportunistic infections; infusion reactions 
including hypersensitivity reactions; malignant neoplasms; selected serious psychiatric events; 
suicidality assessment (Appendix 8); and immunogenicity.
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed. The DMC will include at least 3 physicians and a 
statistician, none of whom are affiliated with the Sponsor. The first DMC reviews will occur 
after the first 20 subjects per induction regimen (RTX or IV/oral CYC) have been randomized 
and have had a Week 8 visit. Once the first 20 subjects randomized following induction with 
RTX have had a Week 8 visit, safety data will be reviewed by the DMC, who will make a 
recommendation regarding whether to continue randomization. The same procedure would be 
applied for the first 20 subjects randomized following induction with IV or oral CYC. The 
DMC will review the data approximately every 6 months thereafter across both induction 
regimens. At all times the sites and sponsor will remain blinded to treatment allocation.  The 
DMC will monitor this trial until the data are locked, unblinded, and analyzed for the primary 
efficacy outcome, after which time monitoring may be assumed by an internal Human 
Genome Sciences (HGS) committee. Investigators and IRBs/ECs will be notified of the 
outcome of each DMC meeting.
PK Endpoints and Analysis:
Serum samples will be collected from all randomized subjects who receive a dose of study 
agent during the study and analyzed to determine serum belimumab concentrations. Serum 
belimumab concentration data will be used in a population PK analysis, which will be 
reported separately.
Immunogenicity:
Serum samples for the measurement of anti-belimumab antibodies will be obtained from all 
subjects before administration of study agent on Day 0, Week 8, Week 24, Week 48 and
Exit/8-week Follow-up. Additionally, samples will be obtained from subjects at Weeks 24 and 
48 during additional years. For any subject who had a positive antibody response at the 
8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-week 
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follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or 
after completion and/or unblinding of the study, whichever is later. 
Biological Markers and Autoantibodies:
Pharmacogenetic sampling (in consenting subjects) will be taken once during the course of 
this study (see Appendix 9).  
Biological markers will be measured at baseline (Day 0) and at multiple time points 
thereafter:
•
Anti-neutrophil cytoplasmic antibody (ANCA: antiPR3, anti-MPO)
•
Serum complement (C3, C4)
•
Serum immunoglobulin isotypes (IgA, IgM, IgG)
•
C-reactive Protein (CRP)
•
Erythrocyte sedimentation rate (ESR)
•
Urinary protein: urinary creatinine ratio
•
BLyS protein (Day 0 only)
•
FACS of peripheral lymphocytes
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...................................................................................................................... 13
List of Tables............................................................................................................................ 16
List of Abbreviations................................................................................................................ 17
1
Background................................................................................................................... 20
1.1 Disease Background ..................................................................................................... 20
1.2 Study Agent Background.............................................................................................. 21
1.3 Clinical Experience....................................................................................................... 21
1.3.1
Belimumab Administered Intravenously...................................................... 21
1.4 Rationale for the Study................................................................................................. 22
2
Study Objectives........................................................................................................... 23
2.1 Primary Objective......................................................................................................... 23
3
Study Design................................................................................................................. 23
3.1 Basic Design Characteristics ........................................................................................ 23
4
Inclusion and Exclusion Criteria .................................................................................. 26
4.1 Inclusion Criteria.......................................................................................................... 26
4.2 Exclusion Criteria......................................................................................................... 27
5
Study Treatment Regimen............................................................................................ 29
5.1 Study Agent Name and Formulation............................................................................ 29
5.2 Packaging, Labeling, Preparation, and Storage............................................................ 29
5.3 Dose, Route of Administration, and Schedule ............................................................. 30
5.4 Alteration of Dose/Schedule Due to Toxicity .............................................................. 31
5.5 Concurrent Medications ............................................................................................... 32
5.5.1
Prohibited Medications and Therapies that Result in Treatment Failure ..... 32
5.5.2
Other Prohibited Medications and Therapies ............................................... 32
5.5.3
Allowable Medications................................................................................. 32
6
Study Procedures .......................................................................................................... 33
6.1 Screening Procedures (Day -60 to Day 0).................................................................... 34
6.2 Study Enrollment Procedures....................................................................................... 35
6.3 Double-Blind Treatment Phase .................................................................................... 35
6.4 Open-Label Extension Phase........................................................................................ 41
6.5 Unscheduled Visits....................................................................................................... 44
6.6 Laboratory Tests........................................................................................................... 44
6.6.1
Pharmacokinetics.......................................................................................... 44
6.6.2
Liver Chemistry Stopping and Follow-up Criteria....................................... 45


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6.6.3
Increased Monitoring Criteria with Continued Therapy .............................. 47
6.6.4
Study Treatment Restart ............................................................................... 48
6.6.5
Immunogenicity............................................................................................ 49
6.7 Exit Visit....................................................................................................................... 49
6.8 8-Week Follow-up Visit ............................................................................................... 49
6.9 Withdrawal of Subjects from Treatment ...................................................................... 50
6.10
Subject Unblinding................................................................................................. 50
7
Adverse Event Reporting.............................................................................................. 51
7.1 Definitions .................................................................................................................... 51
7.2 Reporting Adverse Events to the Sponsor.................................................................... 53
7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events) ....................... 53
7.4 Laboratory Abnormalities as Adverse Events.............................................................. 54
7.5 Progressive Multifocal Leukoencephalopathy ............................................................. 54
7.6 Suicidality Assessment................................................................................................. 54
7.6.1
Possible Suicidality Related Questionnaire (PSRQ) .................................... 55
7.7 Reporting a Pregnancy.................................................................................................. 55
7.8 Investigator Evaluation of Adverse Events .................................................................. 56
7.9 Follow-Up of Adverse Events...................................................................................... 57
7.10
Reporting Serious Adverse Events to Regulatory Authorities and Institutional 
Review Boards/Independent Ethics Committees ................................................... 57
8
Endpoints and Statistical Analysis ............................................................................... 58
8.1 General Statistical Considerations................................................................................ 58
8.2 Randomization Procedure and Assignment to Treatment Groups ............................... 58
8.3 Data Monitoring Committee (DMC)............................................................................ 58
8.4 Sample Size Rationale.................................................................................................. 59
8.5 Efficacy......................................................................................................................... 59
8.5.1
Primary Efficacy Endpoint........................................................................... 59
8.5.2
Primary Efficacy Analysis............................................................................ 59
8.5.3
Major Secondary Efficacy Endpoint ............................................................ 60
8.5.4
Other Efficacy Endpoints ............................................................................. 60
8.5.5
Major Secondary Endpoint analysis and Other Efficacy Analyses.............. 61
8.6 Safety............................................................................................................................ 61
8.6.1
Definition of Safety Variables...................................................................... 61
8.6.2
Analysis of Safety Variables ........................................................................ 61
8.7 Pharmacokinetics.......................................................................................................... 62
8.7.1
Definition of Pharmacokinetic Evaluation ................................................... 62
8.7.2
Analysis of Pharmacokinetics ...................................................................... 62


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9
Pharmacogenetics (PGx) .............................................................................................. 62
10
Study Administration.................................................................................................... 62
10.1
Informed Consent ................................................................................................... 62
10.2
Institutional Review Board Review/Independent Ethics Committee Review and 
Approval ................................................................................................................. 63
10.3
Protocol Compliance .............................................................................................. 63
10.4
Protocol Revisions.................................................................................................. 63
10.5
Data Collection and Management .......................................................................... 64
10.6
Study Monitoring.................................................................................................... 64
10.7
Drug Accountability ............................................................................................... 65
10.8
Retention of Records .............................................................................................. 65
10.9
Financial Disclosure ............................................................................................... 65
10.10 Publication Policy................................................................................................... 65
10.11 Study or Study Site Termination ............................................................................ 66
11
References .................................................................................................................... 67
List of Appendices.................................................................................................................... 71


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List of Tables
Table 6-1
Double-blind Treatment Phase Year One..................................................... 36
Table 6-2
Double-blind Treatment Phase Additional Years......................................... 39
Table 6-3
Open Label Extension Phase ........................................................................ 42
Table 6-4
PK visit days and sample times .................................................................... 45


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List of Abbreviations
AAV
ANCA-associated vasculitis
aCL
anticardiolipin
ACR
American College of Rheumatology
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody 
ANCA
anti-neutrophil cytoplasmic antibodies
Anti-dsDNA
anti-double-stranded DNA
Anti-MPO
anti- myeloperoxidase
Anti-PR3
anti-proteinase 3
Anti-RNP
anti-ribonucleoprotein
Anti-Sm
anti-Smith antibody (see Sm)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the serum drug concentration-time curve
AZA
azathioprine
BAFF
B Cell Activating Factor belonging to the TNF Ligand Family
BILAG
British Isles Lupus Assessment Group of SLE Clinics
BLyS
B lymphocyte Stimulator
BR3
BLyS-receptor fusion protein
BUN
blood urea nitrogen
BVAS
Birmingham Vasculitis Activity Score
ºC
degrees Celsius
C3
Complement Factor 3
C4
Complement Factor 4
C-ANCA
Cytoplasmic antineutrophil cytoplasmic antibodies
CHCC
Chapel Hill consensus Conference
Chem
chemistry
Clcr
creatinine clearance
Coag
Coagulation
CPK
creatine phosphokinase
CRF
case report form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSS
Churg-Strauss Syndrome
C-SSRS
Columbia-Suicide Severity Rating Scale
CYC
cyclophosphamide
dL
deciliter
DMC
Data Monitoring Committee
DMID
Division of Microbiology & Infectious Diseases
DNA
deoxyribonucleic acid
dsDNA
double stranded DNA
DSM
Diagnostic and Statistical Manual


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ECG
electrocardiogram
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme linked immunosorbent assay
ESR
erythrocyte sedimentation rate
EU
Europe
FACS
florescence activated cell sorting
Fc 
immunoglobulin constant region (fragment crystallizable)
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GPA
Granulomatosis with polyangiitis
HB
hepatitis B
HBsAg
hepatitis B surface antigen
HBc
hepatitis B core
HDCS
high dose corticosteroids
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGS
Human Genome Sciences, Inc.
HIV
human immunodeficiency virus
HLA
Human Leukocyte Antigen
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IM
intramuscular
INR
International Normalized Ratio
INN
international nonproprietary Name
IRB
Institutional Review Board
ITT
intention to treat
IUD
intrauterine device
IV
intravenous
IVIG
intravenous immunoglobulin
IWRS
Interactive Web Response System 
kDa
kilodalton
kg
kilogram
LDH
lactate dehydrogenase
m2
meters squared
MDD 
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MPA
microscopic polyangiitis
MPO
myeloperoxidase


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MTX
methotrexate
n
number
μg
microgram
mg
milligram
mL
milliliter
OD
optical density
PAN
polyarteritis nodosa
P-ANCA
perinuclear antineutrophil cytoplasmic antibodies
PGx
pharmacogenetics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PR3
proteinase 3
PSE
protocol specified events
PSRHQ
possible suicidality related history questionnaire
PSRQ
possible suicidality related questionnaire
PT
prothrombin time
PTT
partial thromboplastin time
RA
rheumatoid arthritis
RBC
red blood cell
RF
rheumatoid factor
RTX
rituximab
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SLE
Systemic lupus erythematosus
SOC
System Organ Class
SRI
SLE responder index
SWFI
sterile water for injection
t1/2,term
terminal half-life 
TACI
transmembrane activator and calcium-modulator and cyclophilin ligand 
interactor
TEN
toxic epidermal necrolysis
TNFSF13B
Tumor Necorsis Factor Superfamily Member 13 B
TPMT 
thiopurine methyltransferase
ULN
upper limits of normal
USA
United States of America
USAN
United States Adopted Name
VDI
Vasculitis Damage Index
WBC
white blood cell
WG
Wegener’s Granulmatosis (Granulomatosis with polyangiitis)


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1 Background
1.1
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis (also commonly referred to as granulomatosis 
with polyangiitis [GPA]), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to life-threatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. Historically, ANCA have been classified on the basis of their staining 
patterns in immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear 
(P-ANCA). It is now recognized that in AAV, C-ANCA is usually directed against proteinase 
3 (PR3), and P-ANCA is generally directed against myeloperoxidase (MPO), both of which 
are enzymes that are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel
et al, 1997). Anti-PR3 antibodies are generally associated with WG, while anti-MPO 
autoantibodies are more common in MPA and CSS.  Anti-PR3 antibodies are associated with 
increased morbidity and mortality compared to anti-MPO (Hogan et al, 1996; Franssen et al, 
1998). The most widely used classification criteria for diagnosing the 3 types of AAV are 
those published by the American College of Rheumatology (ACR) for WG and CSS (Leavitt
et al, 1990 and Masi et al, 1990, respectively), and that published by the Chapel Hill 
Consensus Conference (CHCC) for MPA (Jennette et al, 1994; Jennette et al, 2013). Of note, 
none of these diagnostic criteria incorporate the measurement of ANCA. The Chapel Hill 
criteria for WG can be found in Appendix 1 and for MPA in Appendix 2.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007; 
Mahr, 2009). In the case of MPA, in particular, epidemiological studies are confounded by its 
original inclusion as a form of polyarteritis nodosa (PAN). Utilising the ACR or CHCC 
criteria, prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and
0.4-1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes and Nossent, 2008). In the US, the prevalence rates of WG range from 
2.6-9/100000 (Zeft et al, 2005; Mahr et al, 2006). AAV are extremely rare in childhood with 
peak age of onset in those aged 65 to 74 years (Ntatsaki et al, 2010), with other small vessel 
vasculitides being the major concern in childhood (Brogan et al, 2010).
Current therapy is usually determined by severity of the disease, with more severe forms 
warranting more aggressive approaches. These usually involve an initial remission induction 
regimen of high dose corticosteroid administered with either cyclophosphamide or rituximab 
followed by a remission maintenance period usually with azathioprine (Stone et al, 2010; 
Bosch et al, 2007; Jayne et al, 2003). Minor manifestations are usually treated with low dose 
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corticosteroid administered with either azathioprine or methotrexate (Belmont, 2006). Even 
with recent treatment advances the morbidity and mortality of patients with AAV remains 
unacceptably high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2008, Appendix 3). In its current 
form it is a list of 56 items which are considered to be manifestations of vasculitis. A 
weighted numerical score is attached to each item to reflect the importance of each 
manifestation. The items are grouped by organ systems, and each organ system has a 
maximum or ‘ceiling’ score to reflect the relative importance of the organ system 
(Mukhtyar et al, 2008). The tool also makes a distinction between new or worsening disease 
and persistent disease with new or worsening attracting higher scores.
1.2
Study Agent Background
Belimumab (also known as LymphoStat-B; BENLYSTA™) is a B-lymphocyte stimulator 
(BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to 
its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, 
belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the 
differentiation of B cells into immunoglobulin-producing plasma cells.
Nonclinical pharmacologic, pharmacokinetic (PK), and toxicologic data generated with 
belimumab are provided in the Investigator’s Brochure (IB).
1.3
Clinical Experience
1.3.1 Belimumab Administered Intravenously
Belimumab administered as an intravenous (IV) infusion has been studied in SLE subjects in 
1 Phase 1 trial (LBSL01), 1 Phase 2 randomized, double-blind, placebo-controlled trial 
(LBSL02) and 2 Phase 3 randomized, double-blind, placebo-controlled trials [BLISS 52 
(HGS1006-C1057) and BLISS 76 (HGS1006-C1056)], and in RA subjects in a Phase 2 
double-blind, placebo-controlled trial (LBRA01).
Phase 3 studies of belimumab in SLE were completed in 2009 and 2010 and formed the basis 
of IV belimumab in the US, Canada and EU. The Phase 3 trials included 1,684 subjects where 
belimumab 10 mg/kg plus standard therapy demonstrated superiority over placebo plus 
standard therapy in reduction in disease activity as measured by the SLE responder index 
(SRI) with an acceptable safety profile. The primary safety population supporting approval 
also included data from a Phase 2 study in 449 subjects with SLE. Evidence of benefit in other 
clinical measures such as reductions in disease activity as measured by SELENA SLEDAI, 
severe flare, and reduced steroid use was also observed. Treatment with belimumab plus 
standard of care was generally well tolerated, with rates of adverse events (AEs), severe AEs, 
serious AEs, AEs leading to discontinuation and serious/severe infections generally 
comparable to the rates observed in the placebo plus standard of care group. Mortality rates in 


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the controlled clinical trials were low, although numerically higher in the belimumab groups: 
0.4% and 0.8% in the placebo and belimumab groups, respectively. Causes of death were as 
expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as steroids and immunosuppressants, and included infection, cardiovascular 
disease, and suicide. Serious infections were observed in 5.2% and 6.0% of subjects receiving 
placebo and belimumab, respectively. The rate of malignancy (excluding non-melanoma skin 
cancer) was the same between the placebo and belimumab groups at 0.4%; however as with 
other immunomodulating agents, the mechanism of action of belimumab could increase the 
risk for the development of malignancies. Hypersensitivity and infusion reactions were 
observed. Anaphylaxis was also observed, though rare (< 1%). Depression-related events, 
common in patients with SLE, were observed more frequently with belimumab than with 
placebo; it is unknown if belimumab treatment is associated with an increased risk for these 
events. The most commonly-reported adverse reactions, occurring in ≥5% of subjects in 
clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in 
extremity, depression, migraine, and pharyngitis.
Experience from open-label, long-term continuation trials of belimumab in SLE subjects 
suggests that prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence rate of AEs or serious adverse events (SAEs) over time, 
including important events such as infections and malignancies. The prevalence rate of AEs 
and SAEs has also remained relatively stable over time. Long term belimumab treatment 
through 6 years appears to provide sustained improvement in SLE disease activity.
Results of the clinical trials of belimumab administered IV are described in further detail in 
the Investigator’s Brochure.
A benefit-risk evaluation of belimumab in the context of the present study is provided in 
Appendix 12 of this protocol.
1.4
Rationale for the Study
Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 
18 months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the 
most effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al,
2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels.
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The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20 (Dass et al, 2008; Wang et al 2008), recently showed success in inducing 
remission in AAV (Stone et al, 2010) and was granted approval for the treatment of WG and 
MPA supports the rationale that belimumab, which down regulates B cells by targeting BLyS, 
may be useful in the treatment of this disease. Finally, limited data from the small (n = 111) 
subset of subjects in the Phase 3 trials of SLE who had vasculitic symptoms as part of their 
SLE (as assessed by the SELENA SLEDAI) showed that more subjects in the belimumab plus 
standard of care treatment arms had resolution of their vasculitic symptoms at Week 52 
compared with subjects receiving placebo plus standard of care. Specifically, 19/36 (52.8%) 
and 28/38 (73.7%) of subjects in the belimumab 1 mg/kg and 10 mg/kg dose groups, 
respectively, had resolution of vasculitic activity at Week 52 compared with 15/37 (40.5%) of 
placebo subjects. Taken together, these data support the evaluation of belimumab in AAV.
2 Study Objectives
2.1
Primary Objective
1. To evaluate the efficacy of belimumab in the maintenance of remission following a 
standard induction regimen in subjects with Wegener’s granulomatosis (WG) or 
microscopic polyangiitis (MPA).
2. To evaluate the safety of belimumab in subjects with WG or MPA.
3 Study Design
3.1
Basic Design Characteristics
This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen. Subjects enrolled into the trial must have had an 
initial or relapsing episode of moderate to severely active WG or MPA that was treated with 
corticosteroids and either cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 
6 months leading up to randomization.
Subjects treated under the following induction 
regimens will be eligible for participation in the study:
•
A single course rituximab (RTX) administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval plus HSCS OR
•
Cyclophosphamide 2mg/kg/day orally plus HDCS OR
•
Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
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[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Subjects who between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3
score of 0 (Appendix 4) and are receiving ≤10 mg/day oral prednisone (or equivalent) on 
2 consecutive visits at least 14 days apart may be enrolled into the study. A minimum 6 week 
period should elapse between initiation of induction therapy and randomization.
Randomization will be performed on Day 0. A schematic of the study design is shown in 
Figure 1.
Figure 1 Schematic of study design
All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 2 
mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than Day 0. 
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Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to also receive study 
agent (belimumab [10 mg/kg] or placebo) administered intravenously over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent will be 
administered at Day 0, 14, 28 and every 28 days thereafter.
Initial randomization will be limited to 40 subjects per induction regimen (40 post-RTX 
induction and 40 post-CYC induction). Once the first 20 patients randomized following 
induction with RTX have had a Week 8 visit, safety data will be reviewed by the independent 
data monitoring committee (DMC), who will make a recommendation regarding whether to 
continue randomization. The same procedure would be applied for the first 20 subjects
randomized following induction with CYC. At all times the sites and sponsor will remain 
blinded to treatment allocation.
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1). The double-blind phase of the study will complete, the database 
will be locked, and the primary analysis will be performed when 12 months have elapsed after 
the last subject is randomized.
In consultation with the investigating physician, subjects participating in the double-blind 
period of the trial will have the option to continue to receive treatment with belimumab in a 6-
month open label extension phase. The criteria for entry into the extension phase of the study 
are: (1) the safety profile of belimumab is considered to be acceptable, based on ongoing 
IDMC data reviews of the safety data, and other relevant safety data sources; (2) the risk-
benefit profile for continuing treatment with belimumab must be favorable in the opinion of 
the investigator; (3) the subject will have completed the double-blind treatment period of the 
trial without having relapsed (as defined in the primary endpoint); (4) a favorable opinion has 
been obtained from the local ethics committee or IRB with respect to continuation of 
belimumab treatment. Subjects who enter the open-label extension phase will receive 
belimumab for up to an additional 6 months and this will be supplied by the sponsor.
Following completion of the study and, where applicable, completion of the 6-month open-
label extension phase, subjects will not receive any additional treatment supplied by the 
sponsor. The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition.
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
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attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent.  
4 Inclusion and Exclusion Criteria
4.1
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Are at least 18 years of age.
2. Have a clinical diagnosis of Wegener’s granulomatosis or a diagnosis of microscopic 
polyangiitis (MPA) according to the Chapel Hill criteria (Appendix 1 and Appendix 2).
3. In the 26 weeks prior to Day 0, had an episode of moderate to severely active WG or MPA 
requiring treatment under one of the following induction regimens:
A single course of rituximab administered at  a dose of 375 mg /m2/week for 4 weeks plus 
high dose corticosteroids (HDCS) OR
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
cyclophosphamide 2 mg/kg/day orally plus HDCS OR
cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
4. Have documented evidence of either anti-PR3 or anti-MPO prior to Day 0.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving ≤10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at 
least 14 days apart, between 6 and 26 weeks after the first dose of induction therapy 
(either CYC or RTX, as defined in Section 3.1).  A minimum 6 week period should elapse 
between initiation of induction therapy and randomization.
6. Subjects receiving non-systemic corticosteroids for reasons other than vasculitis must be 
on a stable regimen prior to randomization.  
7. A female subject is eligible to enter the study if she is:
Not pregnant or nursing;
Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal 
which is defined as 12 consecutive months with no menses without an alternative medical 
cause, have both ovaries surgically removed or have current documented tubal ligation or 
other permanent sterilization procedure); or
Of childbearing potential (ie, women with functional ovaries and no documented 
impairment of oviductal or uterine function that would cause sterility). This category 
includes women with oligomenorrhoea [even severe], women who are perimenopausal or 
have just begun to menstruate. These women must have a negative serum pregnancy test 
at screening, and agree to 1 of the following:
o
Complete abstinence from intercourse from 2 weeks prior to administration of the 
1st dose of study agent until 16 weeks after the last dose of study agent; or
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o
Consistent and correct use of 1 of the following acceptable methods of birth 
control for 1 month prior to the start of the study agent, during the study, and 
16 weeks after the last dose of study agent:
o Implants of levonorgestrel or etonogestrel;
o Injectable progesterone;
o Transdermal contraceptive patch
o Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year;
o Oral contraceptives (either combined or progesterone only);
o Ethinyl estradiol/Etonogestrel vaginal ring;
o Double barrier method: Condom and Occlusive cap (diaphragm or 
cervical/vault caps) with spermidical foam/gel/film/cream/suppository; or
o Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for the female subject.
8. Have the ability to understand the requirements of the study and provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits).
4.2
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria:
1. Co-existence of other multisystem autoimmune diseases. 
2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance or 
contraindications to methotrexate where methotrexate is being considered as an alternative 
to AZA for maintenance therapy.
3. Have received treatment with a B-cell directed therapy (other than rituximab), for example 
anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], antiCD40L antibody [BG9588/ 
IDEC-131], BLyS-receptor fusion protein [BR3], LY2127399, TACI-Fc, or belimumab at 
any time.
4. Have required 3 or more courses of systemic corticosteroids for concomitant conditions 
not related to their vasculitis (eg, asthma, atopic dermatitis) within 364 days of Day 0.
(Topical or inhaled steroids are permitted.)
5. Have received a non-biologic or biologic investigational agent within 60 days or 
5 half-lives of the agent (whichever is the longer) of Day 0.
6. Have received a live vaccine within 30 days of Day 0.
7. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases 
not due to vasculitis (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy or infectious disease) which, in the opinion of the 
principal investigator, could confound the results of the study or put the subject at undue 
risk.
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8. Have a planned surgical procedure or a history of any other medical disease 
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, 
in the opinion of the principal investigator, makes the subject unsuitable for the study.
9. 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.
10. Have required management of acute or chronic infections, as follows:
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, aspergillosis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (IV, SC or IM) antibiotics, antibacterials, antivirals, anti-fungals, or anti-
parasitic agents within 60 days of Day 0.
11. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within 364 days prior to Day 0.
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:
Patients positive for HBsAg are excluded.
Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody 
and with no history of Hepatitis B vaccination are excluded.
Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are 
excluded.
Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are 
excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood
sample by RNA PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will 
be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a 
positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the 
subsequent sample will not be eligible to participate.
15. Have an IgA deficiency (IgA level < 10 mg/dL).
16. Have a Grade 3 or greater laboratory abnormality based on the protocol DMID toxicity 
scale, unless considered by the investigator to be related to the underlying disease or 
induction therapy.
17. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies.
18. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS 
(Refer to Appendix 8 for C-SSRS) in the last 2 months or who in the investigator’s 
judgment, pose a significant suicide risk.
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of normal 
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25Apr13
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(ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin > 1.5ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%).
5 Study Treatment Regimen
5.1
Study Agent Name and Formulation
The common name of the investigational product is BENLYSTA™. The generic (USAN/INN) 
name is belimumab.
Belimumab is a recombinant, human, IgG1monoclonal antibody specific for soluble human 
B lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a 
molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA 
technology in a mammalian cell expression system.
Belimumab drug product is provided as a sterile, lyophilized product in a 20 mL vial. Upon 
reconstitution with 4.8 mL sterile water for injection (SWFI), each vial will contain 80 mg/mL 
belimumab in 0.16 mg/mL citric acid, 2.7 mg/mL sodium citrate, 80 mg/mL sucrose, 
0.4 mg/mL polysorbate 80, pH 6.5. Each vial is single use.
The placebo control is prepared as a sterile, lyophilized product in a 20 mL vial. Placebo is
reconstituted with 4.8 mL SWFI. Upon reconstitution with 4.8 mL sterile water for injection 
(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 placebo 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;


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•
Storage conditions;
•
Investigational drug statement; and
•
Manufacturer’s name and address.
The calculated dose of study agent to be administered to the subject is determined in 
milligrams (mg) by the assigned treatment group and the subject's body weight in kilograms 
(kg).
The reconstituted study agent will be diluted in 250 mL normal saline for intravenous 
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 and to certain biomarkers and pharmacodynamic laboratory results. 
Separate monitors will be responsible for the clinical (blinded monitor) and study agent 
(unblinded monitor) aspects of the study.
Study agent inventory/accountability forms will be examined and reconciled by the Sponsor
or designee. At the end of the study, all used and unused study agent must be accounted for on 
a study agent accountability form.
Refer to the Pharmacy manual for more details regarding storage, handling, and drug 
accountability.
5.3
Dose, Route of Administration, and Schedule
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. The intent of this 
instruction is to prevent more rapid infusion of belimumab which may result in a higher 
incidence of infusion reactions. Infusion time need not be exactly one hour as it is often 
difficult to so precisely adjust infusion times and there may be clinical reasons for infusions
lasting longer than one hour. Therefore, the instruction should be interpreted as infusion over 
at least one hour. The target infusion time should still be approximately one hour assuming no 
other issues intervene. Once randomized, subjects will be dosed with study agent on Days 0, 
14, and 28 and every 28 days thereafter.
Premedication including an antihistamine, with or without an antipyretic, may be administered 
before the infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted.
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Belimumab/placebo should be administered by investigators/site personnel prepared to 
manage infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if 
the subject develops an infusion reaction. Investigators/site personnel should be aware of the 
risk of hypersensitivity reactions, which may present as infusion reaction, and monitor 
subjects closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. 
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase. 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. 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 IB.
5.4
Alteration of Dose/Schedule Due to Toxicity
The dose of belimumab/placebo administered may not be altered.  The rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reaction or infusion-
associated symptoms. At later visits, these subjects may continue to be infused over a longer 
infusion period at the investigator’s clinical discretion. 
If a subject experiences a clinically significant AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo and could potentially be 
exacerbated by the next dose, the investigator may delay the dose by up to 2 weeks or 
withhold 1 dose. If a similar concern is present after 2 weeks, the investigator should contact 
the medical monitor to determine whether treatment should be discontinued.
If a subject experiences a clinically significant, potentially life-threatening (Grade 4) AE that 
the 
investigator 
believes 
may 
be 
definitely, 
possibly 
or 
probably 
related 
to 
belimumab/placebo, then treatment with study agent will be discontinued. The subject will be 
followed at regularly scheduled study visits as specified by the protocol through the end of the 
double-blind period and also until resolution of the AE(s) (whichever is longer). All subjects 
should be monitored closely for infection. Increased vigilance for infection is recommended 
in subjects who experience IgG levels < 250 mg/dL, especially for prolonged periods; clinical 
judgment should be applied with respect to the appropriateness of continuing study therapy in 
these subjects. The Medical Monitor must be consulted before administering subsequent doses 
of study agent in subjects with IgG levels < 250 mg/dL.  Study agent will be discontinued in 
subjects with IgG levels < 250 mg/dL that are associated with a severe or serious infection.
Amend 04
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Belimumab
5.5
Concurrent Medications
5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Subjects who start prohibited medication or therapies at any time during the double-blind 
phase will be considered as having relapsed as of the time of receipt of the prohibited 
medication, and treatment with study agent will be discontinued. However, the subject will 
continue to be followed for survival through at least 12 months after randomization. The 
following medications and therapies are prohibited during the study:
•
Other immunomodulatory investigational agents (biologic or non-biologic);
•
Rituximab;
•
Cyclophosphamide;
•
Other immunosuppressive agents (eg, cyclosporine) with the exception of methotrexate 
for AZA intolerance described in Section 5.5.3;
•
Corticosteroids for vasculitis:
doses > 20 mg/day prednisone (or equivalent), or
IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 1 week, are only allowable within the first 2 months of the double-blind 
treatment period.
•
Corticosteroids for reasons other than vasculitis:
at an average daily dose of > 20 mg/day prednisone (or equivalent) for > 14 days where 
the average daily dose is calculated as the sum of the dose over 7 consecutive days divided 
by 7, or
IV corticosteroid pulses > 125 mg prednisone (or equivalent)
Note: Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or IV corticosteroid 
pulses ≤ 125 mg prednisone (or equivalent) for reasons other than vasculitis cannot be 
given more than once in any 365 day period (See also Section 5.5.3).
•
Plasmapharesis.
5.5.2 Other Prohibited Medications and Therapies
Due to the mechanism of action of belimumab, it is possible that response to vaccination may 
be impaired. Live vaccines should not be given for 30 days before or concurrently with 
belimumab/placebo infusions.
Other investigational agents are not permitted.
5.5.3 Allowable Medications
The use of stable baseline dose regimens of corticosteroids (≤10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
1 week within the first 2 months of the double-blind treatment period. At other times, subjects 
are restricted to ≤10 mg/day prednisone or equivalent. It is expected that this dose may be 
Amend 01
22Jun12
Amend 01
22Jun12
Amend 01
22Jun12
Amend 01
22Jun12
Amend 01
22Jun12
Amend 02
25Apr13
Amend 02
25Apr13
Amend 03
04Feb14
Amend 03
04Feb14


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Belimumab
tapered as clinically appropriate. Inhaled corticosteroids for asthma, or topical corticosteroids 
for atopic dermatitis are also permitted. Doses of prednisone (or equivalent) > 20mg/day for ≤ 
14 days or an IV corticosteroid pulse up to 125 mg prednisone (or equivalent) are permitted 
for reasons other than vasculitis (eg. acute allergic reaction), but a subject cannot receive more 
than 1 such corticosteroid regimen in any 365 day period (See also Section 5.5.1).
5.5.3.1
Azathioprine and Methotrexate
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). For the 
maintenance of remission azathioprine may be initiated as soon as it is clinically indicated 
following administration of induction therapy. Azathioprine must not be initiated any later 
than Day 0. Azathioprine should be started at a dose of 50 mg/day and increased by no more 
than 50 mg/day every week until the target dose is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
For subjects previously identified as being intolerant to azathioprine, or for subjects identified 
as having undetectable or reduced activity of thiopurine methyltransferase (TPMT), it may be
permissible for methotrexate to be used as an alternative to azathioprine for the maintenance 
of remission from the outset. This should be discussed with the medical monitor.
Methotrexate would not be recommended for those subjects with significantly impaired renal 
function.
The appropriate local prescribing information (eg, dose adjustments, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine 
or methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator. 
6 Study Procedures
The nature of potential risks and benefits associated with participation in the study will be 
explained to all potential study subjects. Written informed consent (including consent for the 
use and disclosure of research-related health information) must be obtained before the subject 
can begin any screening procedures that are not considered part of standard patient care. 
Subjects participating in the pharmacogenetics (PGx) research portion of the protocol 
(Appendix 9) must sign the PGx informed consent prior to any PGx samples being drawn 
from the subject.
Amend 01
22Jun12
Amend 03
04Feb14
Amend 03
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Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3), Study Procedures Manual, 
and Central Laboratory Manual for additional information.
6.1
Screening Procedures (Day -60 to Day 0)
The following assessments are required at screening and must be within 60 days prior to or on 
Day 0:
•
Demographics.
•
Medical history.
•
Lifetime cyclophosphamide exposure.
•
Complete physical examination, including height, weight and vital signs.
•
Document induction regimen and confirm successful induction of remission for WG or 
MPA vasculitis.
•
Document positive history for either anti-PR3 or anti-MPO.
•
Obtain historical biopsy information for documentation of vasculitis diagnosis as 
available.
•
Confirm subject meets study entry criteria. 
•
Blood samples for: (see Appendix 6 – Laboratory Tests)
-
Hematology
-
Modified Chem20 (non-fasting)
-
Serum pregnancy test – for all women with an intact uterus, unless exempted from 
pregnancy testing (ie, of non-childbearing potential – women who had a hysterectomy, 
are post-menopausal which is defined as 1 year without menses, have both ovaries 
surgically removed or have current documented tubal ligation or other permanent 
sterilization procedure)
-
HIV antibody testing, serologic investigations for Hepatitis B (HB) infection (HBsAg, 
anti-HBc, and anti-HBs), and Hepatitis C antibody testing ± confirmatory HCV RNA-
PCR testing
-
Biological markers (Complement C3, C4) 
-
Serum Immunoglobulin isotypes (IgG, IgM, IgA)
-
C-reactive Protein (CRP)
-
Erythrocyte sedimentation rate (ESR)
-
Autoantibodies (ANCA: anti-PR3, anti-MPO)
•
Urine Sample for:
-
Routine urinalysis
-
Spot urine for Urinary protein: urinary creatinine 
•
Suicidality Assessment using the Columbia Suicidality-Severity Rating Scale (C-SSRS) 
Screening assessment form (see Appendix 8).
Amend 01
22Jun12
Amend 02
25Apr13
Am01/Belgium
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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 Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Azathioprine may be initiated as soon as 
it is clinically indicated following administration of induction therapy. Azathioprine must not 
be initiated any later than Day 0. Female subjects who require pregnancy testing must have a 
negative urine pregnancy test done on Day 0, prior to randomization. Subjects will be 
randomized in a 1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + AZA).
6.3
Double-Blind Treatment Phase
Subjects will be evaluated during the scheduled study visits as outlined in the Study Calendar 
(Table 6-1 and Table 6-2). Time windows are provided for each study visit to allow flexibility 
in site and subject scheduling. All study visits should occur within the visit window of the 
scheduled study visit.
At baseline (Day 0), the subject will be randomized and receive the first dose of study agent. 
Visits to the study site will occur on Day 14, Day 28, and approximately every 28 days 
(calculated from the Day 0 dose) thereafter. All efforts should be made to retain subjects on 
schedule, based on the date of their Day 0 dose. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The double-blind phase of the study will complete and the primary 
efficacy analysis will be performed when 12 months have elapsed following randomization of 
the last subject.
In consultation with the investigating physician, subjects participating in the double-blind 
period of the trial will have the option to continue to receive treatment with belimumab in a 6-
month open label extension phase. The criteria for entry into the extension phase of the study 
are: (1) the safety profile of belimumab is considered to be acceptable, based on ongoing 
IDMC data reviews of the safety data, and other relevant safety data sources; (2) the risk-
benefit profile for continuing treatment with belimumab must be favorable in the opinion of 
the investigator; (3) the subject will have completed the double-blind treatment period of the 
trial without having relapsed (as defined in the primary endpoint); (4) a favorable opinion has 
been obtained from the local ethics committee or IRB with respect to continuation of 
belimumab treatment. Subjects who enter the open-label extension phase will receive 
belimumab for up to an additional 6 months and this will be supplied by the sponsor.
Subjects who do not enter the open-label extension will return for an Exit visit (approximately 
4 weeks after the last dose of study agent), and a follow-up visit (approximately 8 weeks after 
the last dose of study agent).
Amend 03
04Feb14
Amend 04
26Feb15
Am01/Belgium
06Jul15
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06Jul15
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Table 6-1
Double-blind Treatment Phase Year One
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7
days
Week 
12
± 7
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Written Informed 
Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Eligibility Criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Document Successful 
Induction Regimen
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Obtain Historical Biopsy 
Report (if available)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Randomization
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Clinical Assessments
Complete Physical 
Exam1
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Symptom Driven 
Physical Exam
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs15, 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
12-lead ECG16
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CSSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events3
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X12
X
X
BVAS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-
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22Jun12
Amend 02
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Belimumab
Table 6-1
Double-blind Treatment Phase Year One
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7
days
Week 
12
± 7
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Laboratory 
Assessments
Serum Beta hCG
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HIV, Hepatitis B, C17
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology & Modified 
Chem-20 (non fasting)4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
Coagulation – PT/aPTT 
and INR
X
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test5
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and 
creatinine clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X14
Pharmacokinetic 
Sampling (pre/post 
Belimumab dose)
-
X
Pre
X
Post
(0-4
hrs)
-
X
Pre
-
-
-
X
Post
(0-4
hrs)
-
-
-
-
-
X 
Pre
X
X
-
Pharmacogenetic 
Sampling6
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Immunogenicity (anti-
belimumab antibodies)7
-
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
X
-
BLyS Protein 
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
T cells/B cell subset 
-
X
-
X
X
X
-
-
X
-
-
X
-
-
X
X
X
-
C3/C4 and ANCA
X
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum IgG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgA  & IgM
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
CRP & ESR
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
Protocol Treatments
Study agent 
(Belimumab/Placebo)8, 9,
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration10
X
X
←Throughout the Study →
-
-
-
Footnotes on next page:
Amend 01
22Jun12
Amend 01
22Jun12
Amend 02
25Apr13


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Belimumab
Table 6-1 Footnotes:
1.
Complete physical examination, including height and weight.  
2.
Any SAEs occurring prior to the start of study agent administration and assessed as related to study participation (eg, protocol-mandated procedures, invasive tests) will be recorded on the SAE worksheet and 
reported as described in Section 7.2 from the time a subject consents to participate in the study.
3.
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent should 
be recorded on the Adverse Event Case Report Form (AE eCRF).  SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, possibly or probably related to study agent 
must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
4.
Refer to Appendix 6 for laboratory assessments to be completed.
5.
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for definition of those exempted from pregnancy testing.
6.
In consenting subjects only (Appendix 9).
7.
Immunogenicity samples are collected pre-dose at all time points.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-
week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion 
and/or unblinding of the study, whichever is later. 
8.
Subjects who discontinue treatment with study agent (belimumab/placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1.
9.
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.
10.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by severe nausea and 
vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described above a switch to methotrexate at doses of 
up to 25 mg/week as an alternative to azathioprine will be permitted. For subjects previously identified as being intolerant to azathioprine, or for subjects identified as having undetectable or reduced activity of 
thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be used as an alternative to azathioprine for the maintenance of remission from the outset following discussion with the medical 
monitor.
11.
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 4 weeks after the last dose of study agent). The Exit Visit should only be completed for subjects who discontinue the double 
blind treatment phase early or for subjects that have successfully completed the double-blind treatment phase and do not wish to participate in the open label extension phase. Subjects who discontinue treatment 
but have not relapsed will remain on the double blind study visit schedule. For subjects who complete the double blind phase and enter the open label phase, refer to Table 6-3 for visit details.
12.
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent.  After this time, all SAEs, regardless of 
relationship to study drug, will be collected until relapse or the study is analysed for the primary endpoint, whichever occurs first.
13.
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent.
14.
Hematology and Modified Chem 20, Urinary protein, urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be clinically indicated by 
the Principal Investigator.  
15.
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
16.
Complete prior to dosing.
17.
HIV, Hepatitis B surface antigen, anti-HBc, anti-HBs and hepatitis C antibody (if hepatitis C antibody positive, HCV RNA-PCR assay will be performed on a subsequent blood sample to confirm the results).
Amend 01
22Jun12
Amend 02
22Apr13
Amend 02
25Apr13
Amend 03
04Feb14
Amend 04
26Feb15
Am01/Belgium
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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab
Table 6-2
Double-blind Treatment Phase Additional Years
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events1
X
X
X
X
X
X
X
X
X
X
X
X
X8
X
X
BVAS
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-
Laboratory Assessments
Hematology & Modified Chem- 20 
(non fasting)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X10
Coagulation – PT/aPTT and INR
-
-
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and creatinine 
clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X10
Pharmacokinetic Sampling (pre 
or post Belimumab dose)
-
-
-
-
-
X 
Pre
-
-
-
-
-
X 
Pre
X
X
-
Immunogenicity (anti- belimumab 
antibodies)4
-
-
-
-
-
X
-
-
-
-
-
X
X
X
-
T cells/B cells 
X
-
-
-
-
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgG
-
-
X
-
-
X
-
-
X
-
-
X
X
X
-
Serum IgA & IgM
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-
CRP & ESR
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-
Amend 01
22Jun12
Amend 02
25Apr13


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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab
Table 6-2
Double-blind Treatment Phase Additional Years
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Protocol Treatments
Study Agent 
(Belimumab/Placebo)5
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
-
-
-
Table 6-2 Footnotes:
1
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent should 
be recorded on the Adverse Event Case Report Form (AE eCRF).    SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, possibly or probably related to study agent 
must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
2
Refer to Appendix 6 for laboratory assessments to be completed.
3
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for definition of those exempted from pregnancy testing.
4
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-
week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion 
and/or unblinding of the study, whichever is later.
5
Subjects who discontinue treatment with study agent (belimumab/Placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1.
6
Subjects naïve to  azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by severe nausea and 
vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described above a switch to methotrexate at doses of 
up to 25 mg/week as an alternative to azathioprine will be permitted.
7
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 1-4 weeks after the last dose of study agent). The Exit Visit should only be completed for subjects who discontinue the 
double blind treatment phase early or when subjects have successfully completed the double-blind treatment phase and do not wish to participate in the open label extension phase. For subjects who complete the 
double blind phase and enter the open label phase, refer to Table 6-3 for visit details.
8
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent. After this time, all SAEs, regardless of 
relationship to study drug, will be collected until relapse or the study is analysed for the primary endpoint, whichever occurs first.
9
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent.
10
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be clinically indicated  by the 
Principal Investigator.
11
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12
Complete prior to dosing.
Amend 01
22Jun12
Amend 02
25Apr13
Amend 04
26Feb15
Am01/Belgium
06Jul15


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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab
6.4
Open-Label Extension Phase
In the 6-month open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the last dose). The 
first dose on the open-label extension will be given 4 weeks after completion of the 
double-blind period. Day 0 is the first visit in the extension phase of the trial and represents 
the first belimumab administration for placebo subjects. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-3). 
During the 6-month open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications 
during this phase are live vaccines, biological therapies and other investigational agents. 
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.
Following completion of the 6-month open-label extension phase, subjects will not receive 
any additional treatment supplied by the sponsor. The investigator is responsible for ensuring 
that consideration has been given to the post-study care of the subject’s medical condition.
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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab
Table 6-3
Open Label Extension Phase
Study Visit
Day 07
Week 4
± 7 days
Week 8
± 7 days
Week 12
± 7 days
Week 16
± 7 days
Week 20
± 7 days
Week 24
± 7 days
Week 28/ 
Exit8
8 Week 
Follow Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
-
-
Weight
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
Assess/Record Adverse Events1
X
X
X
X
X
X
X
X
X
X
BVAS
X
-
-
-
-
-
X
X
-
-
VDI
X
-
-
-
-
-
X
X
-
-
Laboratory Assessments
Labs: Hematology & Modified Chem-
20 (non fasting)2
X
-
-
-
-
-
X
X
X
X10
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
-
-
Urinary protein: urinary creatinine  
and  creatinine clearance
X
-
-
-
-
-
X
X
-
X10
Immunogenicity (anti- belimumab 
antibodies)4
X
-
-
-
-
-
X
X
X
-
T cells/B cell subset 
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
-
-
-
-
-
X
X
X
-
Serum IgG
-
-
X
-
-
-
X
X
-
-
Serum IgA & IgM
-
-
-
-
-
-
X
X
-
-
CRP & ESR
X
-
-
-
-
-
X
X
X
-
Protocol Treatments
Study agent (belimumab)5
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
X
-
-
Footnotes on next page:
Am01/Belgium
06Jul15


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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab
Table 6-3 Footnotes:
1
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of study agent should 
be recorded on the Adverse Event Case Report Form (AE eCRF).
2
Refer to Appendix 6 for laboratory assessments to be completed.
3
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for definition of those exempted from pregnancy testing.
4
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-
week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion 
and/or unblinding of the study, whichever is later.
5
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 infusions. Should symptoms of acute hypersensitivity occur, an extended period of monitoring may be appropriate, based 
on clinical judgment.
6
AZA/MTX continued at the discretion of the investigator.
7
Day 0 is first visit in the extension phase of the trial and represents the first belimumab administration for placebo subjects.  
8
Any visit in which the subject discontinues treatment becomes the Exit visit (ie generally 1-4 weeks after the last dose of study agent).
9
The 8 week follow-up visit is not required for subjects who participate in the separate continuation protocol.  
10
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be clinically indicated by the 
Principal Investigator.
11
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12
Complete prior to dosing.


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Belimumab
6.5
Unscheduled Visits
Unscheduled visits may be necessary during the course of the study to capture a subject’s 
status between regularly scheduled visits. Examples include, but are not limited to, a 
worsening of disease symptoms (eg, flare), AE reporting, or follow-up to a previously 
reported AE.
6.6
Laboratory Tests
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Due to the potential for unblinding, the following lab results will not be provided to study 
sites after baseline (Day 0): serum immunoglobulin isotypes IgM/IgA and the results from the 
FACS analysis listed below.  
In geographies where feasible, the following biological markers will be measured (using 
FACS analysis):
•
T cell subsets: CD3+/CD4+, CD3+/CD8+
•
B lymphocytes: (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived 
plasma, CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, 
CD138+/CD20+ plasmacytoid, CD27−/IgD+/CD10+ transitional)
6.6.1 Pharmacokinetics
All randomized subjects who receive a dose of study agent will be sampled for the assessment 
of serum belimumab levels. A blood sample for pharmacokinetic analysis will be drawn 
according to the time schedule below.


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Table 6-4
PK visit days and sample times
Week
Time (Related to Dosing of Study 
Agent)
0
Prior to the start of infusion
2
0-4 hours after the end of infusion
8
Prior to the start of infusion
24
0-4 hours after the end of infusion
48
Prior to the start of infusion 
24 (of each additional year)
Prior to the start of infusion 
48 (of each additional year)
Prior to the start of infusion 
Exit visit
Any time during visit
8-week follow-up
Any time during visit
Detailed instructions regarding the collection, processing, storage and shipment of blood 
samples are available in the Study Procedures Manual that is provided to all study sites.
6.6.2
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity
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).
Amend 02
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Amend 04
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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
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6.6.2.1
Required Actions and Follow up Assessments following ANY Liver 
Stopping Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the event 
also meets the criteria for an SAE (All events of ALT 3xULN and bilirubin 
2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 13).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24-72 hours
Monitor subjects weekly until liver chemistries resolve, stabilize or return to within baseline
FOLLOW UP ASSESSMENTS

Viral hepatitis serology (includes: Hepatitis A IgM antibody; Hepatitis B surface 
antigen and Hepatitis B Core Antibody (IgM); 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)


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Clinical Protocol HGS1006-C1100 Amend 04 (Local 01 Belgium)
Belimumab

Blood sample for pharmacokinetic (PK) analysis, obtained within approximately one 
to two weeks after last dose (PK sample may not be required for subjects known to 
be receiving placebo or non-GSK comparator treatments.) Record the date/time of 
the PK blood sample draw and the date/time of the last dose of study treatment prior 
to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report form 
including acetaminophen, herbal remedies, other over the counter medications

Record alcohol use on the liver event alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]). 
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.
6.6.3
Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 
weeks OR

ALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 
weeks


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6.6.3.1
Required Actions and Follow Up Assessments for Increased 
Monitoring with Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following ANY 
Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline.
6.6.4
Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, 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 
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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
6.6.5 Immunogenicity
Serum samples for the measurement of anti-belimumab antibodies will be obtained from all 
subjects before administration of study agent on Day 0, Week 8, Week 24, Week 48 and 
Exit/8-week Follow-up. Additionally, samples will be obtained from subjects at Weeks 24 and 
48 during additional years. For any subject who had a positive antibody response at the 
8-week follow-up visit (or last study visit at which immunogenicity was assessed if 8-week 
follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or 
after completion and/or unblinding of the study, whichever is later. 
6.7
Exit Visit
Subjects who relapse/flare and do not complete the study must return for an Exit visit 4 weeks 
after the final dose of study agent. 
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent.
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
6.8
8-Week Follow-up Visit
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (see Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.
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6.9
Withdrawal of Subjects from Treatment
Subjects will be free to withdraw from treatment or from the study at any time, for any reason, 
or they may be withdrawn/removed, if necessary, to protect their health (see reasons for 
withdrawal below). It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of subjects should be 
avoided.
Subjects may be withdrawn from treatment with study agent for any of the following reasons:
•
Unacceptable toxicity (see Section 5.4)
•
Prohibited concurrent medication or therapy (see Section 5.5.1 and Section 5.5.2)
•
Withdrawal of consent (including use and disclosure of research-related health 
information)
•
Pregnancy
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). In subjects who withdraw consent from the study prior to 1 year an 
attempt will be made to ascertain survival status 12 months after the first dose of study agent.  
Any subject that withdraws consent for use and disclosure of research-related health 
information will be considered withdrawn from the study and not followed. 
6.10
Subject Unblinding
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will be 
employed. The study agent will be reconstituted and diluted by the unblinded site pharmacist 
or designee, independent of the study (person responsible for receiving and dispensing study 
agent). Except for a limited number of safety oversight personnel, all study site personnel, the 
subject, the sponsor and the Contract Research Organization (CRO) remain blinded to the 
study agent received and to the results of certain biomarker and pharmacodynamic laboratory 
results. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study.
If a medical emergency occurs and a decision regarding the subject’s condition requires 
knowledge of the treatment assignment, the study blind may be broken for the specific 
subject. Whenever possible, the investigator should consult with the medical monitor prior to 
unblinding any subject. Any broken blind will be clearly justified and explained by a 
comment in the eCRF. The investigator must notify the Medical Monitor of any broken blind, 
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7 Adverse Event Reporting
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1
Definitions
ADVERSE EVENT 
Any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the
use of a medicinal product. For marketed medicinal products, this also includes failure to
produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported
as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from
lack of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen
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
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 hospitalization or prolongation of an existing hospitalization
NOTE: In general, hospitalisation signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-
patient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be 
considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in disability / incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly / birth defect
f. Medical or scientific judgment should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. Examples 
of such events are invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalisation, or development of drug dependency or drug abuse.


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g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT ≥ 
3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥3xULN and INR>1.5, if INR 
measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold 
value stated will not apply to patients receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin
elevations and suggesting liver injury. If testing is unavailable and a subject meets the
criterion of total bilirubin ≥2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.
7.2
Reporting Adverse Events to the Sponsor
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start 
of study agent administration (Day 0) through 8 weeks following administration of the last 
dose of study agent will be recorded on the Adverse Event Case Report Form (AE eCRF). All 
data fields on the AE eCRF should be completed.
For subjects who discontinue treatment with study agent during the double-blind period (for 
reasons other than withdrawal of consent), all adverse events will be collected through 
8 weeks following the administration of the last dose of study agent. After this time, all SAEs, 
regardless of relationship to study drug, will be collected until relapse or the study is analysed 
for the primary endpoint and study sites are informed that SAE data collection can cease, 
whichever occurs first.
Serious Adverse Events (SAEs) must ALSO 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 eCRF 
within 24 hours of site personnel becoming aware of the event as described in the Study 
Procedure Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol-mandated procedures, invasive tests) will be reported as an SAE 
from the time a subject consents to participate in the study.  
SAEs that occur off study, after the follow-up period that are assessed by the investigator as
definitely, possibly or probably related to study agent must be reported to the sponsor as 
outlined in the Study Procedures Manual.
7.3
Other Events Requiring Rapid Reporting (Protocol Specified 
Events)
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (See Section 7.1). PSEs are 
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recorded on the PSE page of the eCRF within 24 hours of site personnel becoming aware of 
the event. 
IgG < 250 mg/dL (Grade 4) is a protocol specified event for this protocol. 
7.4
Laboratory Abnormalities as Adverse Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator are to be recorded as AEs or SAEs. However, any clinically 
significant safety assessments that are associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s condition, are not to be 
reported as AEs or SAEs. 
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg,
elevated creatinine, urine RBC increased). In addition, an IgG abnormality < 250 mg/dL 
(Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 mg/dL should 
also be reported as an SAE if it meets one or more of the SAE criteria in Section 7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in the Appendix, the lab test should be graded 
mild, moderate or severe as specified in Section 7.8.
7.5
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
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 all immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.  The 
appropriateness of continuing study agent, while the case is being assessed, should be 
discussed.
7.6
Suicidality Assessment
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation 
(Bachen et al, 2009, Timonen et al, 2003, Stenager et al, 1992). In order to objectively assess 
suicidality in belimumab clinical programs the C-SSRS will be utilized to collect information 
on suicidal behavior and ideation. Since major depressive disorder may increase the risk of 
suicidal ideation or behavior before or during clinical studies, subjects participating in this 
study will be assessed at every visit for suicidality.
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Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 
Questionnaire (PSRHQ, only the first time this condition is met; refer to Appendix 10 for the 
PSRHQ) eCRF and a Possible Suicidality Related Questionnaire (PSRQ) eCRF (at all times 
this condition is met; refer to Appendix 11 for the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2007). The C-SSRS is administered 
by a qualified clinician and is designed to address the need for a summary measure to track 
change in the severity/density of suicidality across both clinical settings and treatment trials. It 
assesses intensity of ideation (a potentially important marker of severity) by specifically 
asking about frequency, duration, intrusiveness, controllability, and deterrents. In addition, it 
captures both the modal and most severe forms of ideation. The C-SSRS is to be completed by 
the investigator or his/her qualified designee at every visit during the double-blind portion of 
the study. 
Although assessment of suicidality using the C-SSRS will take place only during the blinded 
portion of the study, investigators are reminded of the importance to clinically assess for 
suicidality at every visit given that study patients are at increased risk of suicidal behavior 
and/or ideation.
7.6.1 Possible Suicidality Related Questionnaire (PSRQ)
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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. Refer to Appendix 11 for the PSRQ. 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 the SAE.
7.7
Reporting a Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form. To ensure subject safety, each pregnancy must be reported to the Sponsor 
within 2 weeks of learning of its occurrence. All pregnancies that are identified from the start 
of study agent through 16 weeks following the last dose of study agent should be reported. 
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child. Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an 
SAE.
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Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to the Sponsor.
7.8
Investigator Evaluation of Adverse Events
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to study 
agent). The investigator will make an assessment of intensity based on the Division of 
Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading Tables (see 
Appendix 7) where possible:
SEVERITY
Mild
An event that is easily tolerated by the subject, causing minimal  
discomfort and not interfering with everyday activities (Grade 1
DMID).
Moderate
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).
Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID). 
Not applicable
Those event(s) where intensity is meaningless or impossible to
determine (i.e., blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.  
An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE.
CAUSALITY
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated. The investigator will also consult the Investigator Brochure (IB) 
and/or Product Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
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There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool 
accordingly. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
7.9
Follow-Up of Adverse Events
Serious and non-serious adverse events that occur from the start of study medication 
administration through 8 weeks after the date of last administration of study agent are 
reported.
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAEs and non-serious AEs of special interest (see Section 
8.6.2) will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the subject is lost to follow-up. This applies to all subjects, 
including those withdrawn prematurely. 
PSEs (see Section 7.3) that occur after the Screening visit through 8 weeks after the date of 
last administration of study agent are reported and followed as described above for 
AEs/SAEs.
7.10
Reporting Serious Adverse Events to Regulatory Authorities and
Institutional Review Boards/Independent Ethics Committees
All SAEs that are considered by the sponsor to be unexpected and related to belimumab will 
be reported by the sponsor or designee as expedited (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 regulatory requirements related to the reporting of SAEs to the IRBs/IECs 
responsible for reviewing the study at their site, as well as the regulatory authority(ies) (if 
applicable).
All serious adverse events, including serious disease-related events (discussed below), will 
be monitored by treatment group by an independent DMC. Investigators and IRBs/IECs will 
be notified of the outcome of each DMC meeting, and any recommendations made.
The conditions listed in Appendix 3 are disease related events that can occur in the study 
population regardless of belimumab exposure. When these conditions are considered SAEs, 
they must be reported to the Sponsor within 24 hours of site personnel becoming aware as 
described in Section 7.2. Where these are clearly related to the underlying vasculitis, the 
Sponsor may not submit them as expedited reports to regulatory authorities or participating 
investigators.
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8 Endpoints and Statistical Analysis
8.1
General Statistical Considerations
Unless otherwise specified, all analyses will be performed on the intent to treat (ITT) 
population defined as all subjects who are randomized and received at least 1 dose of study 
agent (belimumab or placebo). The ITT analysis will be performed according to the treatment 
that a subject was randomized to receive, regardless of the actual treatment received.
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject. All subjects and study site personnel will remain blinded to original treatment 
assignment until after the final database is locked and the results of the study are made 
publicly available. 
Analysis of primary and secondary endpoints will be exploratory in nature. Nominal p values
may be reported and considered descriptive. Where appropriate point estimates and 95% 
confidence intervals will be constructed.
8.2
Randomization Procedure and Assignment to Treatment Groups
This is a multi-center, multinational, randomized, double-blind, placebo-controlled study. 
Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs.
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  
8.3
Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Initial randomization will be limited to 40 subjects 
per induction regimen (40 post-RTX induction and 40 post-CYC induction). The first DMC 
reviews will occur after the first 20 subjects per induction regimen (RTX or IV/oral CYC) 
have been randomized and have had a Week 8 visit. Once the first 20 subjects randomized 
following induction with RTX have had a Week 8 visit, safety data will be reviewed by the 
DMC, who will make a recommendation regarding whether to continue randomization. The 
same procedure would be applied for the first 20 subjects randomized following induction 
with CYC. The DMC will review the data approximately every 6 months thereafter across 
both induction regimens. At all times the sites and sponsor will remain blinded to treatment 
allocation.  Investigators and IRBs/IECs will be notified of the outcome of each DMC 
meeting.
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The DMC will receive information within 72 hours of the sponsor or designee receiving 
notification of any IgG < 250 mg/dL and all unexpected causally-related SAEs that are life 
threatening or result in death. Other unexpected, causally-related SAEs will be provided to the 
DMC within 15 calendar days.  In addition, the DMC will receive information on all serious 
infections and all opportunistic infections, irrespective of relationship to study agent, within 
15 calendar days.
8.4
Sample Size Rationale
Approximately 100 subjects will be randomized. The sample size has been determined based 
on the feasibility of enrolling patients into the study within a reasonable time-frame. The 
sample size was not based on statistical considerations and the analysis of primary and 
secondary endpoints will be exploratory in nature. The primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo group, a 
relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically significant 
(p<0.05) in a study of 100 subjects (50 per arm). 
8.5
Efficacy
8.5.1 Primary Efficacy Endpoint
The primary endpoint is time from Day 0 to the first relapse, defined as 
•
at least 1 major BVAS item (Appendix 4) OR 
•
a minimum total BVAS score of 6 (Appendix 4) OR
•
receipt of prohibited medications (as defined in Section 5.5.1).
8.5.2 Primary Efficacy Analysis
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using the oral or IV cyclophosphamide. If there are 
then still less than 5 patients with an event (relapse) in any of the levels of this or any other 
stratification factor then the stratification term may be removed from the model. For any 
subject who does not experience a relapse, the time to first relapse will be censored at the time 
of the subject’s last assessment. Subjects who discontinue study agent prior to relapse/flare 
(as defined in primary efficacy endpoint) are to be followed per protocol for inclusion in the 
primary efficacy analysis until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). The database will be locked and the primary efficacy analysis will be 
performed after 12 months have elapsed following randomization of the last subject.
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8.5.3 Major Secondary Efficacy Endpoint
1. Time from Day 0 to the first major relapse (defined as experiencing at least 1 major 
BVAS item).
8.5.4 Other Efficacy Endpoints
1. Time from Day 0 to first minor or major relapse (defined as experiencing at least 1 minor 
BVAS item and/or using a dose of rescue medication).
2. Absolute change in Vasculitis Damage Index (VDI) at double-blind Week 48 of Year 1 
and double-blind Week 28 of Year 2 and by visit;
3. Proportion of subjects with any increase in VDI at double-blind Week 48 of Year 1 and 
double-blind Week 28 of Year 2 and by visit;
4. Absolute change in BVAS at double-blind Week 48 of Year 1 and double-blind Week 28 
of Year 2 and by visit; 
5. Proportion of subjects with any increase in BVAS at double-blind Week 48 of Year 1 and 
double-blind Week 28 of Year 2 and by visit; and 
6. Proportion of subjects with any increase in BVAS organ domains at double-blind Week 48
of Year 1 and double-blind Week 28 of Year 2 and by visit and by domain.
7. Proportion of patients in remission (defined as BVAS=0 and corticosteroid dose 
< 10 mg/day) at double-blind Week 48 of Year 1, double-blind Week 28 of Year 2 and by 
visit.
8. Proportion of patients with no relapse at double-blind Week 48 of Year 1, double-blind 
Week 28 of Year 2 and by visit.
Biological Markers and Autoantibodies:
Pharmacogenetic sampling (in consenting subjects) will be taken once during the course of 
this study (see Appendix 9).  
Biological markers will be measured at baseline (Day 0) and at multiple time points 
thereafter:
•
Anti-neutrophil cytoplasmic antibody (ANCA – anti-PR3, anti-MPO)
•
Serum complement (C3, C4)
•
Serum immunoglobulin isotypes (IgA, IgM, IgG)
•
C-reactive Protein (CRP)
•
Erythrocyte sedimentation rate (ESR)
•
Urinary protein: urinary creatinine ratio
•
BLyS protein (Day 0 only)


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•
FACS of peripheral lymphocytes:
B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived 
plasma, CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, 
CD138+/CD20+ plasmacytoid,  CD27−/IgD+/CD10+ transitional)
T cell subsets: CD3+/CD4+, CD3+/CD8+
8.5.5 Major Secondary Endpoint analysis and Other Efficacy Analyses
The exploratory analysis of the major secondary efficacy endpoint will be performed using the
same method described for the primary efficacy endpoint, but censoring subjects who receive 
any prohibited medication (as defined in Section 5.5.1) prior to an observation of any major 
BVAS item. Any censoring will be applied on the date prohibited medications are received.
The analysis of other efficacy endpoints, biomarkers, and auto-antibodies measurements will 
be described in the statistical analysis plan.
8.6
Safety
8.6.1 Definition of Safety Variables
Safety will be evaluated by adverse events, changes in laboratory parameters, suicidality 
assessment (Appendix 8), and immunogenicity.
8.6.2 Analysis of Safety Variables
AEs will be graded for severity by the investigator using Adverse Event Severity Grading 
Tables (Appendix 7) or as described in Section 7.8, as appropriate. The frequency and rate of 
AEs will be tabulated by MedDRA system organ class (SOC) and preferred term. Additional 
analyses may be performed based on event rates adjusting for subject-years on study agent if 
the time on study agent is imbalanced across treatment groups. Serious and severe (Grade 3 
and Grade 4) AEs will also be summarized by MedDRA SOC and preferred term. 
Discontinuations due to AEs will be summarized. 
The frequency of laboratory abnormalities will be tabulated by treatment group. Laboratory 
values will be assessed for changes from baseline. Laboratory toxicity will be graded using 
Adverse Event Severity Grading Tables when possible. Shift tables will be used to determine 
if subjects move from normal to abnormal during the course of the study. Shifts of ≥ 2 grades 
and Grade 3 or 4 laboratory abnormalities will be summarized.
Safety Endpoints of Special Interest
•
All cause mortality
•
Serious and/or severe infections
•
Opportunistic infections
•
Malignant neoplasms
•
Selected serious psychiatric events
•
Suicidality assessment (see Appendix 8)
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•
Infusion reactions including hypersensitivity reactions
•
Immunogenicity
The analyses of these safety endpoints will be described in the statistical analysis plan.
8.7
Pharmacokinetics
8.7.1 Definition of Pharmacokinetic Evaluation
All randomized subjects who receive a dose of study agent will be sampled for the assessment 
of serum belimumab levels. Assessment of belimumab concentrations will be performed at the 
timepoints indicated in Section 6.6.1.
8.7.2 Analysis of Pharmacokinetics
Serum belimumab concentration will be determined by an electrochemiluminescence (ECL) -
based assay. Results for this study will be presented using appropriate graphic and tabular 
summaries. Serum belimumab concentration data obtained from this study will be used in a 
population PK analysis, which will be reported separately. Potential effects of demographic 
characteristics, concurrent medications, renal function or disease state on belimumab PK will 
be evaluated.
9 Pharmacogenetics (PGx)
In consenting subjects, a blood sample for PGx research will be drawn at baseline (Day 0) to 
better characterize genetic variability (eg, HLA typing) that may affect efficacy or safety 
endpoints. Information regarding PGx research is included in Appendix 9.
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 9). In 
some cases, approval of the PGx assessments can occur after approval is obtained for the rest 
of the study. If so, then the written approval will clearly indicate that approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments are not approved, then approval for the rest of the study will clearly 
indicate this and that PGx assessments will not be conducted.
10 Study Administration
Belimumab is under joint development by Human Genome Sciences, Inc and 
GlaxoSmithKline Pharmaceuticals. Human Genome Sciences, Inc. is the sponsor of the study.
10.1
Informed Consent
A copy of the proposed informed consent document must be submitted to the Sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 


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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.
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 using
an Electronic Data Capture (EDC) system provided and approved by the Sponsor. Refer to the 
Study Procedures Manual for additional information regarding CRFs that will be used as 
source documentation. Sites must complete the eCRFs in a timely manner and the investigator 
must promptly review the completed eCRFs for each subject. As the person ultimately 
responsible for the accuracy of all eCRF data, the investigator must sign the Investigator's 
Statement in each subject's eCRF.
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system, so as to ensure accuracy, quality, consistency, and completeness of 
the database. Manual queries resulting from review by monitors, medical coders, and other 
Data Management staff are also generated from within the EDC system, where they are 
tracked. Sites resolve the queries and correct the entered data when necessary. Every change 
to data is captured in the EDC system audit trail. Upon completion of the study, or after 
reaching a pre-specified point in the study, Data Management will lock the database and 
generate the SAS datasets necessary for data analysis and reporting. Upon completion of the 
study, each site will be provided with a compact disk containing the eCRFs for each of their 
subjects.
10.6
Study Monitoring
The study Sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the Sponsor will visit study sites routinely throughout the trial. The 
Sponsor will review CRFs and compare them with source documents to verify accurate and 
complete collection of data and confirm that the study is being conducted according to the 
protocol. Auditors representing the Sponsor may also similarly evaluate the study and its 
monitors. For these purposes, the investigator will make CRFs and source documents 
available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
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10.7
Drug Accountability
Upon receipt, the investigator is responsible for taking an inventory of the study agent, 
including any buffers or diluents. A record of this inventory must be kept and usage must be 
documented on study agent inventory forms provided by the Sponsor.
Study agent inventory forms will be examined and reconciled by a Sponsor’s unblinded 
monitor, or designee. At the end of the study, all used and unused study agent must be 
accounted for on a study agent accountability form.
10.8
Retention of Records
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the Sponsor at the time the study is completed, terminated, or 
discontinued.
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the Sponsor.
10.9
Financial Disclosure
The investigator and all sub-investigators will provide HGS sufficient and accurate 
information on financial interests (proprietary or equity interests, payments exclusive of 
clinical trial costs) to allow complete disclosure to regulatory authorities. The investigator 
shall promptly update this information if any relevant changes occur during the course of the 
investigation and for a period of 1 year following study completion.
10.10 Publication Policy
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and Sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the Sponsor
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites.
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 


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Sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by Sponsor to be confidential information has been removed. If 
requested in writing by the Sponsor, the investigator shall withhold material from submission 
for publication or presentation for an additional 60 days to allow for the filing of a patent 
application or the taking of other measures to establish and preserve the Sponsor’s proprietary 
rights.
10.11 Study or Study Site Termination
If HGS, the investigator, IRB/IEC, or a regulatory authority discovers conditions arising 
during the study that indicate that the study should be halted or that the study center should be 
terminated, this action may be taken after appropriate consultation between HGS and the 
investigator. Conditions that may warrant termination of the study include, but are not limited 
to, the following:
•
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study.
•
A decision on the part of HGS to suspend or discontinue testing, evaluation, or 
development of the product for WG or MPA.
The study site may warrant termination under the following conditions:
•
Failure of the investigator to enroll subjects into the study at an acceptable rate.
•
Failure of the investigator to comply with pertinent regulatory authority regulations.
•
Submission of knowingly false information from the research facility to HGS, study 
monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.


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List of Appendices
Appendix 1
Chapel Hill Consensus Definition for Granulomatosis with polyangiitis 
(GPA) (Wegener’s Granulomatosis) (Jennette et al, 2013).......................... 72
Appendix 2
Chapel Hill Consensus Definition for Microscopic Polyangiitis (MPA) 
(Jennette et al, 2013)..................................................................................... 73
Appendix 3
BVAS Activity Assessment Form ................................................................ 74
Appendix 4
BVAS Item Scoring...................................................................................... 75
Appendix 5
Vasculitis Damage Index.............................................................................. 78
Appendix 6
Laboratory Tests1.......................................................................................... 85
Appendix 7
Adverse Event Severity Grading Tables....................................................... 86
Appendix 8
Columbia- Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening/Since Last Visit............................................................. 94
Appendix 9
Pharmacogenetic Research ......................................................................... 114
Appendix 10
Possible Suicidality Related History Questionnaire (PSRHQ)................... 119
Appendix 11
Possible Suicidality Related Questionnaire (PSRQ)................................... 121
Appendix 12
Protocol Addendum – Benefit and Risk Assessment ................................. 123
Appendix 13
Algorithm for Liver Chemistry Stopping and Follow-up Criteria.............. 135


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Appendix 1
Chapel Hill Consensus Definition for Granulomatosis 
with polyangiitis (GPA) (Wegener’s Granulomatosis)
(Jennette et al, 2013)
The CHCC Definition requires:
Necrotizing granulomatous inflammation usually involving the upper and lower respiratory 
tract, and necrotizing vasculitis affecting predominantly small to medium-sized vessels (eg,
capillaries, venules, arterioles, and arteries) for a diagnosis of Wegener’s.
Another feature that may be commonly present in GPA, but which is not required according 
to the CHCC definition, is necrotizing glomerulonephritis.
Amend 02
25Apr13
Amend 03
04Feb14


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Appendix 2
Chapel Hill Consensus Definition for Microscopic 
Polyangiitis (MPA) (Jennette et al, 2013)
The CHCC definition requires:
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels 
(ie, capillaries, venules, or arterioles) for a diagnosis of MPA. Granulomatous inflammation is 
absent.
Other features that may be present in MPA, but that are not required according to the CHCC 
definition, are: necrotizing arteritis involving small- and medium-sized arteries; commonly 
necrotizing glomerulonephritis; and often pulmonary capillaritis.
Amend 02
25Apr13
Amend 03
04Feb14


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Appendix 3
BVAS Activity Assessment Form
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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Appendix 4
BVAS Item Scoring
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws and therefore have been excluded.


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


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Amend 03
04Feb14
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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by third party copyright laws and therefore have been excluded.


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Appendix 6
Laboratory Tests1
Hematology
Urinalysis
Modified Chem-20
Total white blood cell count 
Differential:
Absolute Neutrophils
Segmented Neutrophils
Band Neutrophils
Myelocytes
Metamylocytes
Promyelocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Red blood cell (RBC) count
Platelet count
Prothrombin time (PT)
Partial thromboplastin time (PTT)
INR
Serum Pregnancy 
Protein
Glucose
Ketones
Occult blood
Microscopic examination 
including:
WBC per hpf
RBC per hpf
Casts (specified by 
type eg, RBC, WBC)
Spot Urine (protein : creatinine 
ratio)
Urine Pregnancy
Electrolytes:
Sodium
Potassium
Magnesium
Chloride
Carbon dioxide
Calcium adjusted for Albumin
Inorganic Phosphate
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
HIV-1/2 antibody
Hepatitis C antibody (± HCV RNA 
PCR for confirmation of positive antibody 
test)
Hepatitis B surface antigen
Hepatitis B surface and core antigen 
antibodies
Estimated Creatinine Clearance/ GFR 
(Cockcroft-Gault)
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM 
antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal 
antibodies
Biological Markers
FACS of peripheral lymphocytes: 
T cell subsets: CD3+/CD4+, CD3+/CD8+
B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, 
CD27hi/CD20- short-lived plasma, CD27+/CD20+ memory, CD27-
/CD20+ naïve, CD138+/CD20- 138 plasma cells, CD138+/CD20+ 
plasmacytoid, CD27−/IgD+/CD10+ transitional)
BLyS protein
Serum complement (C3 and C4) 
C-Reactive Protein (CRP)
Erythrocyte sedimentation rate (ESR)
Immunoglobulins
Serum immunoglobulin isotypes: IgG, IgM, IgA
PK and Immunogenicity
Autoantibodies
ANCA (anti-PR3; anti-MPO)
1Institution or country specific guidelines for blood sample volume limits must be followed in collection of the 
subsequent blood sample.
Amend 01
22Jun12
Amend 02
25Apr13
Amend 02
25Apr13
Amend 02
25Apr13
Amend 02
25Apr13


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Appendix 7
Adverse Event Severity Grading Tables
HEMATOLOGY
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY LIFE-THREATENING
Hemoglobin
9.5-11.0 g/dL
> 8.0-9.5 g/dL
6.5-8.0 g/dL
6.5 g/dL
Leukocytes
3000-3999/mm3
2000-2999/mm3
1000-1999/mm3
< 1000/mm3
Absolute Neutrophil Count
1500-1999/mm3
1000-1499/mm3
500-999/mm3
< 500/mm3
Platelets
75,000-99,999/mm3
50,000–74,999/mm3
25,000-49,999/mm3
< 25,000/mm3
Prothrombin Time (PT)
> 1.0-1.25 x ULN*
> 1.25-1.5 x ULN
> 1.5-3.0 x ULN
> 3.0 x ULN
Partial Thromboplastin Time (PTT)
> 1.0-1.66 x ULN
> 1.66-2.33 x ULN
> 2.33-3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0-10.0 %
10.1-15.0 %
15.1-20.0 %
> 20%
*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
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
*(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
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
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
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
Modified from DMID Adult Toxicity Tables, 2001


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


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COLUMBIA SUICIDE-SEVERITY 
RATING SCALE (C-SSRS)
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copyright laws and therefore have been excluded.


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Appendix 9
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
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for 
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations (Monach and Merkel, 2010).
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach and Merkel, 2010) for example the association of alpha 1-antitrypsin 
deficiency in WG. 
Blood samples for pharmacogenetics will be drawn as described in Section 9. Insights into the 
genetic pathways underlying AAV may help identify subgroups of patients that may have 
additional benefit from therapies from specific therapies. Fc Receptor polymorphism analysis 
may further define the interaction between underlying genetic heterogeneity and the 
therapeutic endpoints utilized in this trial.  
Collection of whole blood samples may enable PGx analyses to be conducted if there are any 
unexplained or unexpected results. 
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.
Amend 02
25Apr13
Amend 02
25Apr13


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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.
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 using a DNA tube. 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 
will be drawn on Day 0 (baseline) visit provided informed consent for PGx research has been 
obtained from the subject, but 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 may 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 ie, no questions are raised about how people respond to belimumab. 
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) 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.


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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. Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by the sponsor and maintain the documentation in 
the site study records. In either case, the sponsor will only use study information 
collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the clinical study, then the 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.
Pharmacogenetics Analyses
Specific sections of DNA may be selected from areas of the genome (ie, candidate genes)
known to encode the drug target, drug metabolizing enzymes, areas associated with 
mechanisms underlying adverse events, and those linked to study disease and, thus, linked to 
drug response. 
Generally, two approaches will be utilized to explore genetic variation in drug response.
The candidate genes that may be selected and investigated in this study are the following: 
•
HLA alleles
•
Alpha-1 anti-trypsin (A1AT)
•
Fc receptors
•
Cytokines, immune receptors and chemokines related to immune cell function
In addition, 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.
By evaluating large numbers of polymorphic markers (eg, single nucleotide polymorphisms or 
SNPs) throughout the genome, sets of markers may be identified that correspond to 
differential drug response. These will include:


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
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 
genotype (or haplotype) and selected parameters (eg, pharmacokinetics, SLE disease 
activity and safety). Where such genotypic tests are inappropriate (eg, where the number 
of marker genotypes is too large and/or the frequency of individual genotypes too small), 
allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker 
allele is the same in responders and non-responders.

Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the 
selected parameters, the possibility of a treatment group by genotype (haplotype or allele) 
interaction will also be explored. If appropriate, the joint effects of multiple markers 
(gene-gene interactions) may also be evaluated.

Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the 2 sites are correlated 
(linkage disequilibrium) may also be evaluated. If the genotypes at 2 polymorphic sites 
within a gene are shown to be statistically associated with a response to investigational 
product, the degree of linkage disequilibrium will aid interpretation in that it will indicate 
the extent to which the 2 sites are exerting independent effects.

Multiple Comparisons and Multiplicity
Adjustment to observed p-values may be made to limit erroneous conclusions due to 
multiple tests when multiple markers are evaluated (especially in the case of a genome 
scan for association). 

Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site 
depends on the total number of subjects genotyped and the frequency distribution of the 
different genotypes. Consequently, genotyping analyses are plausible for those 
polymorphic sites where the number of subjects comprising the genotypic groups is 
sufficiently large; however, these frequencies will not be known until sufficient samples 
have been collected and genotyping is complete. 


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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. 
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 10
Possible Suicidality Related History Questionnaire 
(PSRHQ)
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Appendix 11
Possible Suicidality Related Questionnaire (PSRQ)
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Appendix 12
Protocol Addendum – Benefit and Risk Assessment
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis; also known as granulomatosis with 
polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to lifethreatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. 
Historically, ANCA have been classified on the basis of their staining patterns in 
immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear (P-ANCA). It is 
now recognized that in AAV, C-ANCA is usually directed against proteinase 3 (PR3), and P-
ANCA is generally directed against myeloperoxidase (MPO), both of which are enzymes that 
are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel et al, 1997). 
Anti-PR3 antibodies are generally associated with WG, while anti-MPO autoantibodies are 
more common in MPA and CSS. Anti-PR3 antibodies are associated with increased morbidity 
and mortality compared to anti-MPO. The most widely used classification criteria for 
diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994). Of note, none of these diagnostic criteria incorporate the measurement 
of ANCA.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007). 
In the case of MPA, in particular, epidemiological studies are confounded by its original 
inclusion as a form of polyarteritis nodosa (PAN). Utilizing the ACR or CHCC criteria, 
prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and 0.4-
1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes et al, 2008). AAV are extremely rare in childhood with peak age of onset in 
those aged 65 to 74 years (Ntatsaki et al, 2010), with other small vessel vasculitides being the 
major concern in childhood (Brogan et al, 2010).Current therapy is usually determined by 
severity of the disease, with more severe forms warranting more aggressive approaches. These 
usually involve an initial remission induction regimen of high dose corticosteroid 
administered with either cyclophosphamide (CYC) or rituximab (RTX) followed by a 
remission maintenance period usually with azathioprine (Stone et al, 2010; Bosch et al, 2007; 
Jayne et al, 2003). Minor manifestations are usually treated with low dose corticosteroid 
administered with either azathioprine or methotrexate (Belmont, 2006). Even with recent 
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treatment advances the morbidity and mortality of patients with AAV remains unacceptably 
high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG 
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2009). In its current form it is a list of 
56 items which are considered to be manifestations of vasculitis. A weighted numerical score 
is attached to each item to reflect the importance of each manifestation. The items are grouped 
by organ systems, and each organ system has a maximum or ‘ceiling’ score to reflect the 
relative importance of the organ system (Mukhtyar et al, 2009). The tool also makes a 
distinction between new or worsening disease and persistent disease with new or worsening 
attracting higher scores.
IV Belimumab
Over 2,000 individuals with SLE have been treated with belimumab in clinical studies. In two 
global Phase 3 studies, belimumab 10 mg/kg met the primary efficacy endpoint (SRI at 
Week 52). Evidence of other possible benefits in these trials included reductions in risk of 
severe flare and corticosteroid use, and improvements in patient reported quality of life and 
fatigue. Serological activity was reduced as measured by reductions in autoantibodies and 
normalization of hypergammaglobulinemia and complement levels. B cells, including 
autoreactive B cells, were also reduced, but not severely depleted, consistent with what would 
be expected from inhibition of BLyS (reference belimumab IB, Section 5.3.1). These results 
supported the approval of belimumab in the EU, US, Canada and other countries.
In the United States belimumab is approved for the following indication:
BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, 
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard 
therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with 
severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA 
has not been studied in combination with other biologics or intravenous 
cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
In the EU, the approved indication focuses on patients with high disease activity (where 
belimumab offered the greatest benefit):
Benlysta 
is 
indicated 
as 
add-on 
therapy 
in 
adult 
patients 
with 
active, 
autoantibodypositive systemic lupus erythematosus (SLE) with a high degree of disease 
activity (e.g positive anti-dsDNA and low complement) despite standard therapy.
The EU SPC also includes special warnings and precautions for use similar to the US 
labeling, including that belimumab has not been studied in and is thus not recommended in 


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patients with severe active central nervous system lupus or severe active lupus nephritis. In 
addition, caution should be exercised if belimumab is co-administered with other B cell 
targeted therapy or cyclophosphamide. Reference Section 4.4 of the SPC for the complete list 
of specials warnings and precautions.
Treatment with belimumab plus standard therapy was generally well tolerated, with rates of 
AEs, severe AEs, SAEs, AEs leading to discontinuation, and serious/severe infections 
generally comparable to the rates observed in the placebo plus standard therapy group. The 
most commonly-reported adverse reactions, occurring in ≥ 3% of patients receiving 10 mg/kg 
belimumab IV in clinical trials (and at a ≥ 1% greater rate than placebo) were nausea, 
diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, 
migraine, pharyngitis, cystitis, leukopenia, and gastroenteritis viral. In clinical trials, 
hypersensitivity and infusion reactions were observed more frequently with belimumab, with 
anaphylaxis observed in ≤ 1% of subjects. Data from the post-marketing setting indicate that 
hypersensitivity reactions may be serious or result in death, that the onset of such reactions 
may be delayed, and that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. In addition, it is also known from clinical trials and 
the post-marketing setting that the vast majority of hypersensitivity reactions occur with the 
1st or 2nd infusion. The product labeling, belimumab IB, protocol, and informed consent forms 
have been updated to include this new information, as applicable.
Other risks that may be associated with belimumab based on its mechanism of action include 
serious infections and malignancy, although no increases in the rates of serious infections or 
malignancies have been observed. Psychiatric events including depression and suicide were 
observed more frequently with belimumab than with placebo, although it is unknown if 
belimumab treatment is associated with an increased risk for these events. Finally, mortality 
rates in the controlled clinical trials were low, although numerically higher in the belimumab 
groups (0.4% and 0.8% in the placebo and belimumab groups, respectively). Causes of death 
were as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as corticosteroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide.
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving immunosuppressant 
pharmacotherapy, including belimumab. Although the benefit-risk profile for belimumab 
remains unchanged following these events, the Sponsor considers that knowledge of these 
cases is important and has updated the clinical investigator’s brochure (IB) for belimumab and 
revised the informed consent form (ICF) to communicate that development of PML is a 
potential risk.  
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence of AEs or SAEs over time, including important events such 
as infections and malignancies. Long-term belimumab treatment appears to provide sustained 
improvement in SLE disease activity and reduction of flares.
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Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Belimumab at a dose of 10 mg/kg in combination with standard SLE therapy demonstrated a 
statistically significant and clinically meaningful reduction in SLE disease activity versus 
placebo plus standard SLE therapy at Week 52 in two Phase 3 clinical studies in subjects with 
active, autoantibody-positive SLE.
Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 18 
months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the most 
effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al, 2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels. Therefore, 
for the proposed study, subjects are required to have documented evidence of anti-PR3 or 
anti-MPO autoantibodies prior to randomization, as this population is considered the most 
likely to benefit from treatment with a B cell modulating agent like belimumab. This is 
consistent with the Phase 3 SLE results for belimumab where the subjects who benefitted 
from treatment were those who were antinuclear antibody (ANA/anti-dsDNA) autoantibody 
positive at baseline.
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval in the US for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease. Finally, limited data from the small (n = 111) subset of subjects in the Phase 3 
trials of SLE who had vasculitic symptoms as part of their SLE (as assessed by the SELENA 
SLEDAI) showed that more subjects in the belimumab plus standard of care treatment arms 
had resolution of their vasculitic symptoms at Week 52 compared with subjects receiving 
placebo plus standard of care. Specifically, 19/36 (52.8%) and 28/38 (73.7%) of subjects in 
the belimumab 1 mg/kg and 10 mg/kg dose groups, respectively, had resolution of vasculitic 
activity at Week 52 compared with 15/37 (40.5%) of placebo subjects. Taken together, these 
data support the evaluation of belimumab in AAV.
The safety of the proposed study is supported by data from the Phase 2 and 3 trials in SLE in 
which subjects who were receiving belimumab in combination with significant background 
therapies, including steroids and immunosuppressants, had an adverse event profile similar to 
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This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen. Subjects enrolled into the study must have a clinical 
diagnosis of WG or MPA according to the Chapel Hill criteria and must have had an initial or 
relapsing episode of moderate to severely active WG or MPA that was treated with 
corticosteroids and either CYC or RTX in the 6 months leading up to randomization. Subjects 
treated with 1 of the following induction regimens will be eligible for participation in the 
study:
•
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
CYC 2 mg/kg/day orally plus HDCS OR
•
CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Approximately 100 subjects with ANCA-vasculitis who are between 6 and 26 weeks from 
starting induction therapy, who achieve a BVAS v.3 score of 0 (ie, are in remission), and are 
receiving ≤10 mg/day prednisone (or equivalent) on 2 consecutive measurements at least 14 
days apart will be enrolled into the study. Subjects who meet the eligibility criteria will be 
randomized in a 1:1 ratio to receive study agent (belimumab [10 mg/kg] or placebo) 
administered intravenously (IV) over 1 hour. Study agent (belimumab/placebo) will be 
administered at Day 0, 14, and every 28 days thereafter. Randomization will be performed on 
Day 0. 
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. For the maintenance of remission, azathioprine may be 
initiated as soon as it is clinically indicated following administration of induction therapy. 
Azathioprine must not be initiated any later than Day 0. For subjects previously identified as 
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being intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be 
used as an alternative to azathioprine for the maintenance of remission from the outset. 
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above, a switch to methotrexate at a target dose of 25 
mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. As 
azathioprine is among the better tolerated immunomodulatory agents, it is not anticipated that 
many subjects will need to substitute methotrexate for azathioprine (Walters et al, 2010). 
Subjects for whom methotrexate is substituted for azathioprine will be included in the primary 
analysis.
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease), and induction regimen (IV 
CYC vs. oral CYC vs. RTX). It is anticipated that no more than 25% of the patients would be 
newly diagnosed and anti-MPO positive, and as such enrollment of these patients may be 
capped if they exceed this proportion. Refer to Section 4 of Protocol HGS1006-C1100 for a 
complete list of inclusion and exclusion criteria.
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as at least 
1 major BVAS item or a minimum total BVAS score of 6 or receipt of prohibited medications 
according to the protocol. Subjects will receive study agent (belimumab/placebo) plus AZA 
until the results from the primary efficacy analysis are available or until they experience a 
flare (relapse) as defined in the primary efficacy endpoint. The database will be locked and 
the primary analysis will be performed when 12 months have elapsed after the last subject is 
randomized. Subjects who discontinue study agent prior to relapse/flare are to be followed per 
the double blind visit schedule until relapse/flare or the end of the double-blind treatment 
phase (whichever is earlier). In subjects who withdraw consent from the study prior to 1 year 
an attempt will be made to ascertain survival status at 12 months after the first dose of study 
agent.
In consultation with the investigating physician, subjects participating in the double-blind 
period of the trial will have the option to continue to receive treatment with belimumab in a 6-
month open label extension phase. The criteria for entry into the extension phase of the study 
are: (1) the safety profile of belimumab is considered to be acceptable, based on ongoing 
IDMC data reviews of the safety data, and other relevant safety data sources; (2) the risk-
benefit profile for continuing treatment with belimumab must be favorable in the opinion of 
the investigator; (3) the subject will have completed the double-blind treatment period of the 
trial without having relapsed (as defined in the primary endpoint); (4) a favorable opinion has 
been obtained from the local ethics committee or IRB with respect to continuation of 
belimumab treatment. Subjects who enter the open-label extension phase will receive 
belimumab for up to an additional 6 months and this will be supplied by the sponsor. Subjects 
participating in the open-label extension will continue to be monitored for efficacy and safety.
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Following completion of the study and, where applicable, completion of the 6-month open-
label extension phase, subjects will not receive any additional treatment supplied by the 
sponsor. The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition.
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
Dose and Schedule
Investigational Study Agent (Belimumab or Placebo)
The dose and schedule of belimumab proposed for use in the ANCA-associated vasculitis 
study is the same dosage (10 mg/kg every 2 weeks for 3 doses and every 4 weeks thereafter) 
and route of administration (IV) as that approved for marketing. The belimumab BDS and 
FDP that will be used for this study is the same as that approved for marketing.
In the Phase 3 IV SLE studies, several clinical measures of improvement including the 
primary efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, there 
appeared to be a greater dose response in subjects with high disease and serological activity. 
There was no apparent dose-response in the safety profile of belimumab with both doses 
being generally well-tolerated. These data supported the selection of 10 mg/kg belimumab as 
the marketed dose in general SLE, and also support its continued evaluation in combination 
with standard maintenance therapies in patients with WG or MPA.
The use of placebo in this trial is considered appropriate and does not put placebo patients at 
undue risk because all subjects in both the placebo group and the belimumab group will 
receive standard of care maintenance therapies for vasculitis (ie, azathioprine or methotrexate) 
and, if needed, subjects will receive appropriate rescue therapy in accordance with standard 
clinical practice as described above.
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:
•
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR
•
A single course of rituximab comprising two doses, 1g IV each, separated by a two-week 
interval, plus HDCS OR
•
CYC 2mg/kg/day orally plus HDCS OR
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•
CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach 
≤10 mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous steroid 
pulses are not part of standard of care on site. However, all subjects must be receiving more 
than 10 mg of prednisone/day or equivalent for induction.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX dosing regimen of 4 infusions of 375 mg/m2 each 
given 1 week apart reflects the dosing regimen that is approved by the FDA for this indication.
An alternative RTX induction regimen (2 infusions of 1 gram each administered 2 weeks 
apart) is also offered in the protocol. Although the latter regimen is not licensed as an 
induction therapy for ANCA-vasculitis, it is very widely used in clinical practice and clinical 
evidence suggests that there is no difference between the two dosing regimens in terms of 
duration of B-cell depletion or therapeutic efficacy efficacy (Jones et al, 2009).
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection,
cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
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with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements at least 14 days
apart: a BVAS v3 score of 0 and be receiving ≤10 mg/day of oral prednisone [or equivalent], 
between 6 and 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2 
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. For the maintenance of remission, 
azathioprine may be initiated as soon as it is clinically indicated following administration of 
induction therapy and no later than Day 0. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced activity 
of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be used as 
an alternative to azathioprine for the maintenance of remission from the outset. Subjects naive 
to azathioprine and who experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or 
thrombocytopenia, AST or ALT 2 times ULN, or a several gastrointestinal hypersensitivity 
reaction characterized by severe nausea and vomiting), following initiation of azathioprine 
will be permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience toxicities, a switch to methotrexate at doses of up to 25 mg/week as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis. The protocol instructs 
physicians to follow the appropriate local prescribing information for azathioprine or 
methotrexate (as applicable) prior to and during treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Amend 03
04Feb14
Amend 03
04Feb14


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Safety Considerations
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Belimumab has not yet been studied following use of 
IV cyclophosphamide (CYC) or rituximab (RTX); there is limited experience with the 
combination of belimumab and oral CYC. As an added safety precaution, initial 
randomization will be limited to 40 subjects per induction regimen (40 post-RTX induction 
and 40 post-CYC induction). The first DMC reviews will occur after the first 20 subjects per 
induction regimen (RTX or IV/oral CYC) have been randomized and have had a Week 8 visit. 
Once the first 20 subjects randomized following induction with RTX have had a Week 8 visit, 
safety data will be reviewed by the DMC, who will make a recommendation regarding 
whether to continue randomization. The same procedure would be applied for the first 
20 subjects randomized following induction with CYC. The DMC will review the data 
approximately every 6 months thereafter across both induction regimens. At all times the 
patients, study sites and sponsor will remain blinded to treatment allocation. Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting.
The DMC will be notified of:
•
all unexpected causally-related SAEs that are life-threatening or result in death;
•
other unexpected causally-related SAEs;
•
all reports of serious infections and opportunistic infections, irrespective of relationship to 
study agent; and
•
subjects experiencing IgG < 250 mg/dL; 
within protocol-specified timeframes. Based on these data, an ad hoc DMC meeting may be 
called at any time (see Section 8.3 of Protocol HGS1006-C1100 for additional detail 
regarding the DMC).
Based on the large body of safety data from SLE patients treated with belimumab and/or the 
mechanism of action of belimumab as a B cell immunosuppressant, anticipated potential risks 
of belimumab treatment in vasculitis patents include serious infusion and hypersensitivity 
reactions, infections, depression-related events, and malignancy. These risks are briefly 
reviewed here and are detailed more fully in the belimumab Investigator’s Brochure. Both 
investigators and subjects will be appropriately informed regarding these risks. It is noted that 
because of the older patient population affected by this disease, the average age of subjects 
anticipated to participate in this study will be older than the average age of the SLE 
population studied to date (mean age of ~53 years at the time of diagnosis in vasculitis (Stone
et al, 2010) compared with an average age of ~38 years in controlled Phase 3 studies of 
belimumab in SLE). As such, patients with vasculitis may be at a greater risk for infection 
than the SLE patients; however, the increased monitoring for infections by both the DMC 
(described above) and recommended to investigators (see below) will help to ensure subject 
safety through timely detection, treatment and reporting of infections.


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The protocol states that all subjects should be monitored closely for infection and increased 
vigilance for infection is recommended in subjects who experience IgG levels < 250 mg/dL, 
especially for prolonged periods; clinical judgment should be applied with respect to the 
appropriateness of continuing study therapy in these subjects. The Medical Monitor must be 
consulted before administering subsequent doses of study agent in subjects with IgG levels 
< 250 mg/dL. Study agent will be discontinued in subjects with IgG levels < 250 mg/dL that 
are associated with a severe or serious infection. If a subject experiences a clinically 
significant, potentially life-threatening (Grade 4) AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo, then treatment with study agent 
will be discontinued. The subject will be followed at regularly scheduled study visits as 
specified by the protocol through the end of the double-blind period and also until resolution 
of the AE(s) (whichever is longer).
In order to ensure subject safety with respect to infusion and hypersensitivity reactions, the 
protocol excludes patients with known history of allergic reactions to human or murine 
proteins or monoclonal antibodies. There is currently insufficient evidence to determine 
whether premedication diminishes the frequency or severity of hypersensitivity reactions to 
belimumab. The protocol recommends that based on clinical judgment, premedication 
including an antihistamine, with or without an antipyretic, may be administered before the 
infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 
Belimumab/placebo will be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 
closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. Per protocol, 
subjects are to remain under clinical supervision for 3 hours after completion of the first 
2 infusions in the double-blind treatment phase. 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. 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.
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving immunosuppressant 
pharmacotherapy, including belimumab. Therefore, a diagnosis of PML should be considered 
in any subject presenting with new-onset or deteriorating neurological signs and symptoms. 
The protocol requires that subjects 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.
Amend 03
04Feb14
Amend 04
26Feb15


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The protocol recommends that subjects with persistent or worsening disease should receive 
appropriate rescue therapy in accordance with standard clinical practice, but if exceeding what 
is allowed per protocol, treatment with study agent (ie, belimumab or placebo) will be 
discontinued and the subject will be considered as having relapsed for the primary analysis. 
The list of prohibited medications that results in the subjects being considered as relapsed for 
the primary endpoint (Protocol Section 5.5.2.1), was developed because the need for the use 
of these agents (eg, RTX or CYC) is indicative of treatment failure (ie, disease relapse).
Moreover, concomitant use of such medications (eg, high-dose steroids) can be associated 
both with potent disease-modifying activity and/or significant toxicity that may introduce bias 
and confound interpretation of results. As such, no subject will be denied appropriate medical 
care for their condition due to their participation in this clinical study.
In addition, the Sponsor notes that although this is a placebo controlled trial, the sponsor does 
not consider that placebo patients are at undue risk because all subjects in both the placebo 
group and the belimumab group will receive standard of care maintenance therapies for 
vasculitis (ie, azathioprine or methotrexate) and, if needed, subjects will receive appropriate 
rescue therapy in accordance with standard clinical practice as described above.
Risk:Benefit Conclusions
In summary, the proposed Phase 3 study is a superiority study evaluating the safety and 
efficacy of belimumab for the maintenance of disease remission in patients with a clinical 
diagnosis of Wegener’s granulomatosis or microscopic polyangiitis. The risk:benefit profile of 
10 mg/kg IV belimumab in patients with active, autoantibody-positive SLE was demonstrated 
to be positive in the two Phase 3 SLE studies, thereby supporting its approval in Canada, the 
US, and the EU. Belimumab has already been shown to be effective in treating patients with 
active, autoantibody-positive SLE, a B cell mediated autoimmune disease. Like SLE, WG and 
MPA are also B cell mediated autoimmune diseases in which autoantibodies (in this case, 
against neutrophil components), are considered to be pathogenic (Popa et al, 1999). In each of 
these diseases, the general purpose of the therapy is similar – reducing disease activity by 
down regulating B cells (including autoreactive B cells) and reducing the level autoantibodies 
produced by those autoreactive B cell clones. Down regulating B cell numbers may also 
reduce inflammatory processes because of the role of B cells in antigen presentation. A 
limited amount of data from the IV Phase 3 studies suggests that belimumab may reduce 
vasculitic symptoms.
There are potential risks associated with belimumab treatment including serious infusion and 
hypersensitivity reactions, infections, depression-related events, and malignancy; however, in 
view of the serious and potentially life threatening nature of disease flares in WG and MPA, it 
is believed that the overall risk:benefit analysis for belimumab in the maintenance of 
remission in WG and MPA is favorable, especially in view of the nature of the trial as a 
superiority trial over a current standard of care regimen.


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Appendix 13
Algorithm for Liver Chemistry Stopping and Follow-up 
Criteria
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 6.6.2.1. 
Amend 02
25Apr13
Amend 04
26Feb15


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Liver Monitoring Event Algorithm with Continued Therapy for ALT≥3xULN but 
<8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 6.6.2.1.
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the attractive 
hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver injury 
following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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Protocol HGS1006-C1100 Amendment 04 (with Local Amendment 01 for Belgium)
Belimumab
Summary of Modifications
Protocol Amendment 04 With Local Amendment 01 for Belgium, 06 July 2015
Protocol Number: HGS1006-C1100
Protocol Title: A Multi-Center, Multinational, Randomized, Double-Blind, Study to 
Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination with 
Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. For Belgium, the protocol (Amendment 04) has been modified at the request of the 
coordinating investigator in Leuven and the ethics committee to re-instate a 6-month open 
label extension phase to the study in order to maintain consistency with earlier versions of 
the protocol and ‘fairness’ to patients.
2. It should be noted that all previous versions of the protocol (including Amendments 01, 02 
and 03) had incorporated a 6-month open label extension phase, which would allow 
participating subjects, who had completed the double-blind phase of the trial, the 
opportunity to subsequently receive open-label belimumab, supplied by the sponsor, for a 
further 6 months.
Although the 6-month open-label extension phase had previously been removed from the 
trial as part of a global protocol amendment 04 [an amendment which fundamentally 
changed the status of the trial from Phase 3 to ‘exploratory’], ethical objections were
subsequently raised in Belgium, because subjects currently enrolled onto the trial had 
previously been informed that there would be an opportunity to receive a 6-month 
extended supply of belimumab in a 6-month open-label phase. It was felt that the change 
to the protocol was unfair to patients in Belgium where treatment options for ANCA-
vasculitis are considered to be limited.
3. Having considered the ethical objections raised in Belgium, the sponsor agrees to re-
instate the 6-month open-label phase of the study for this country. The conditions for
entry into the open-label phase of the study are: (i) the safety profile of belimumab is
considered to be acceptable, based on ongoing IDMC reviews and other relevant safety
data sources, (ii) the risk-benefit profile for continuing treatment with belimumab is 
considered to be favorable in the opinion of the investigating physician, (iii) the subject 
will have completed the double-blind treatment phase without having a disease relapse, 
and (iv) a favorable opinion has been obtained from the local ethics committee in Belgium 
with respect to extended belimumab treatment for 6 months.
At the end of the 6-months open label extension phase, the sponsor will no longer supply 
belimumab to Belgium investigators. The investigators will then be responsible for 
ensuring that consideration has been given to the post-study care of the patient’s 
condition.
4. To reflect these changes, Protocol Amendment 04 has been amended locally for Belgium. 
The changes to the various sections are detailed below and include a Time and Events 
Table (Table 6.3) which details the schedule for the various safety and efficacy 
assessments.  


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Summary of Modifications
5. The date of Local Amendment 01 for Belgium has been added to the cover page for 
clarity.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 04
Date: 26 February 2014
EudraCT 2011-004569-33
Modified to:
Protocol Amendment 04
Date: 26 February 2014
EudraCT 2011-004569-33
Local Amendment 01 for Belgium, Date: 06 July 2015
Revision Chronology for HGS1006-C1100 (BEL115466)
Added row:
Date
Document*
Local
2015N245521_00
06 July 2015
Local Amendment 01 for Belgium
Study Synopsis
Study Design and Schedule:
Paragraph 8:
Formerly:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The study will complete, the database will be locked and the primary 
analysis will be performed when 12 months have elapsed after the last subject is randomized.


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Summary of Modifications
Modified to:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The double-blind phase of the study will complete, the database will 
be locked and the primary analysis will be performed when 12 months have elapsed after the 
last subject is randomized.
Added:
In consultation with the investigating physician, subjects participating in the double-
blind period of the trial will have the option to continue to receive treatment with 
belimumab in a 6-month open label extension phase. The criteria for entry into the 
extension phase of the study are: (1) the safety profile of belimumab is considered to be 
acceptable, based on ongoing IDMC data reviews of the safety data, and other relevant 
safety data sources; (2) the risk-benefit profile for continuing treatment with belimumab 
must be favorable in the opinion of the investigator; (3) the subject will have completed 
the double-blind treatment period of the trial without having relapsed (as defined in the 
primary endpoint); (4) a favorable opinion has been obtained from the local ethics
committee or IRB with respect to continuation of belimumab treatment. Subjects who 
enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Following completion of the study and, where applicable, completion of the 6-month 
open-label extension phase, subjects will not receive any additional treatment supplied 
by the sponsor. The investigator is responsible for ensuring that consideration has been 
given to the post-study care of the subject’s medical condition.
Section 3, Study Design
Section 3.1 Basic Design Characteristics:
Paragraph 7:
Formerly:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1). The study will complete, the database will be locked, and the 
primary analysis will be performed when 12 months have elapsed after the last subject is 
randomized.


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Summary of Modifications
Modified to:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1). The double-blind phase of the study will complete, the 
database will be locked, and the primary analysis will be performed when 12 months have 
elapsed after the last subject is randomized.
Added:
In consultation with the investigating physician, subjects participating in the double-
blind period of the trial will have the option to continue to receive treatment with 
belimumab in a 6-month open label extension phase. The criteria for entry into the 
extension phase of the study are: (1) the safety profile of belimumab is considered to be 
acceptable, based on ongoing IDMC data reviews of the safety data, and other relevant 
safety data sources; (2) the risk-benefit profile for continuing treatment with belimumab 
must be favorable in the opinion of the investigator; (3) the subject will have completed 
the double-blind treatment period of the trial without having relapsed (as defined in the 
primary endpoint); (4) a favorable opinion has been obtained from the local ethics 
committee or IRB with respect to continuation of belimumab treatment. Subjects who 
enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Following completion of the study and, where applicable, completion of the 6-month 
open-label extension phase, subjects will not receive any additional treatment supplied 
by the sponsor. The investigator is responsible for ensuring that consideration has been 
given to the post-study care of the subject’s medical condition.
Section 6 Study Procedures
Paragraph 3:
Formerly:
Refer to the Study Calendar (Table 6-1, Table 6-2), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
Modified to:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3), Study Procedures Manual, 
and Central Laboratory Manual for additional information.


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Summary of Modifications
Section 6.3 Double-Blind Treatment Phase
Paragraph 3:
Formerly:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The study will complete and the primary efficacy analysis will be 
performed when 12 months have elapsed following randomization of the last subject.
Modified to:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The double-blind phase of the study will complete and the primary 
efficacy analysis will be performed when 12 months have elapsed following randomization of 
the last subject.
Added:
In consultation with the investigating physician, subjects participating in the double-
blind period of the trial will have the option to continue to receive treatment with 
belimumab in a 6-month open label extension phase. The criteria for entry into the 
extension phase of the study are: (1) the safety profile of belimumab is considered to be 
acceptable, based on ongoing IDMC data reviews of the safety data, and other relevant 
safety data sources; (2) the risk-benefit profile for continuing treatment with belimumab 
must be favorable in the opinion of the investigator; (3) the subject will have completed 
the double-blind treatment period of the trial without having relapsed (as defined in the 
primary endpoint); (4) a favorable opinion has been obtained from the local ethics 
committee or IRB with respect to continuation of belimumab treatment. Subjects who 
enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Paragraph 4:
Formerly:
Subjects will return for an Exit visit (approximately 4 weeks after the last dose of study 
agent), and a follow-up visit (approximately 8 weeks after the last dose of study agent).
Modified to:
Subjects who do not enter the open-label extension will return for an Exit visit 
(approximately 4 weeks after the last dose of study agent), and a follow-up visit 
(approximately 8 weeks after the last dose of study agent).


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Summary of Modifications
Table 6.1 Double-blind Treatment Phase Year One
Footnote 11:
Formerly:
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 4 weeks after 
the last dose of study agent). The Exit Visit should be completed for subjects who discontinue the 
double blind treatment phase early or when subjects have completed the double-blind treatment 
phase. Subjects who discontinue treatment but have not relapsed will remain on the double blind study 
visit schedule.  
Modified to:
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 4 weeks after 
the last dose of study agent). The Exit Visit should only be completed for subjects who discontinue the 
double blind treatment phase early or for subjects that have successfully completed the double-
blind treatment phase and do not wish to participate in the open label extension phase. Subjects 
who discontinue treatment but have not relapsed will remain on the double blind study visit schedule.  
For subjects who complete the double blind phase and enter the open label phase, refer to 
Table 6-3 for visit details.
Table 6.2 Double-blind Treatment Phase Additional Years
Footnote 7:
Formerly:
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 1-4 weeks 
after the last dose of study agent). The Exit Visit should be completed for subjects who discontinue the 
double blind treatment phase early or when subjects have completed the double-blind treatment 
phase. 
Modified to:
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 1-4 weeks 
after the last dose of study agent). The Exit Visit should only be completed for subjects who 
discontinue the double blind treatment phase early or when subjects have successfully completed the 
double-blind treatment phase and do not wish to participate in the open label extension phase. 
For subjects who complete the double blind phase and enter the open label phase, refer to 
Table 6-3 for visit details.
Added:
6.4 Open-Label Extension Phase
In the 6-month open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the last dose). 
The first dose on the open-label extension will be given 4 weeks after completion of the 


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Summary of Modifications
double-blind period. Day 0 is the first visit in the extension phase of the trial and 
represents the first belimumab administration for placebo subjects. Subjects should 
remain under clinical supervision for 3 hours after completion of the first 2 infusions.  
Should symptoms of acute hypersensitivity occur, an extended period of monitoring may 
be appropriate, based on clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-3). 
During the 6-month open-label extension, the investigator may adjust concurrent 
medications (add, eliminate, change dose level/frequency) as clinically appropriate. 
Prohibited medications during this phase are live vaccines, biological therapies and 
other investigational agents. 
All subjects will return for an Exit visit approximately 4 weeks after their last dose of 
study agent as well as a follow-up visit approximately 8 weeks after the last dose of study 
agent. These visits apply to subjects who have completed as well as those who have 
withdrawn early from the open-label extension.
Following completion of the 6-month open-label extension phase, subjects will not 
receive any additional treatment supplied by the sponsor. The investigator is responsible 
for ensuring that consideration has been given to the post-study care of the subject’s 
medical condition.
Added:
Table 6.3 Open-Label Extension Phase:


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Summary of Modifications
Table 6-3 Open Label Extension Phase
Study Visit
Day 07
Week 4
± 7 days
Week 8
± 7 days
Week 12
± 7 days
Week 16
± 7 days
Week 20
± 7 days
Week 24
± 7 days
Week 28/ 
Exit8
8 Week 
Follow Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
-
-
Weight
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
Assess/Record Adverse Events1
X
X
X
X
X
X
X
X
X
X
BVAS
X
-
-
-
-
-
X
X
-
-
VDI
X
-
-
-
-
-
X
X
-
-
Laboratory Assessments
Labs: Hematology & Modified Chem-
20 (non fasting)2
X
-
-
-
-
-
X
X
X
X10
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
-
-
Urinary protein: urinary creatinine  
and  creatinine clearance
X
-
-
-
-
-
X
X
-
X10
Immunogenicity (anti- belimumab 
antibodies)4
X
-
-
-
-
-
X
X
X
-
T cells/B cell subset 
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
-
-
-
-
-
X
X
X
-
Serum IgG
-
-
X
-
-
-
X
X
-
-
Serum IgA & IgM
-
-
-
-
-
-
X
X
-
-
CRP & ESR
X
-
-
-
-
-
X
X
X
-
Protocol Treatments
Study agent (belimumab)5
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
X
-
-
Footnotes on next page:


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Table 6-3 Footnotes:
1
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks 
following administration of the last dose of study agent should be recorded on the Adverse Event Case Report Form (AE eCRF).
2
Refer to Appendix 6 for laboratory assessments to be completed.
3
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) for 
definition of those exempted from pregnancy testing.
4
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit 
(or last study visit at which immunogenicity was assessed if 8-week follow-up immunogenicity sample is not available), an attempt will be made to 
obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose of study agent or after completion and/or unblinding of the 
study, whichever is later.
5
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 infusions. Should symptoms of acute hypersensitivity 
occur, an extended period of monitoring may be appropriate, based on clinical judgment.
6
AZA/MTX continued at the discretion of the investigator.
7
Day 0 is first visit in the extension phase of the trial and represents the first belimumab administration for placebo subjects.  
8
Any visit in which the subject discontinues treatment becomes the Exit visit (ie generally 1-4 weeks after the last dose of study agent).
9
The 8 week follow-up visit is not required for subjects who participate in the separate continuation protocol.  
10
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be 
obtained only when determined to be clinically indicated by the Principal Investigator.
11
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12
Complete prior to dosing.


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6.6Laboratory Tests
Formerly:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2).
Modified to:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2, and Table 6-3).
Section 6.7 8-Week Follow-up Visit
Formerly:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (see Table 6-1, Table 6-2) for a list of procedures required at this 
visit.
Modified to:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (see Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment
Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Added:
In consultation with the investigating physician, subjects participating in the double-
blind period of the trial will have the option to continue to receive treatment with 
belimumab in a 6-month open label extension phase. The criteria for entry into the 
extension phase of the study are: (1) the safety profile of belimumab is considered to be 
acceptable, based on ongoing IDMC data reviews of the safety data, and other relevant 
safety data sources; (2) the risk-benefit profile for continuing treatment with belimumab 


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must be favorable in the opinion of the investigator; (3) the subject will have completed 
the double-blind treatment period of the trial without having relapsed (as defined in the 
primary endpoint); (4) a favorable opinion has been obtained from the local ethics 
committee or IRB with respect to continuation of belimumab treatment. Subjects who 
enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety.
Following completion of the study and, where applicable, completion of the 6-month 
open-label extension phase, subjects will not receive any additional treatment supplied 
by the sponsor. The investigator is responsible for ensuring that consideration has been 
given to the post-study care of the subject’s medical condition.


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Protocol Amendment 04 With Local Amendments 01, 02 for France, 06 April 2015
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The proposed modifications to the protocol reflect a change by the sponsor to the strategic 
objectives for the evaluation of belimumab in ANCA-associated vasculitis (AAV). It is 
proposed that the trial should be changed from a Phase 3 study to allow for an exploratory 
evaluation of belimumab in AAV only. There is no longer the intention to seek a licensed 
indication for belimumab as an adjunctive maintenance therapy in AAV on the basis of 
the data emerging from this study. The term “Phase 3” has been removed from the study 
title.
Enrolment of subjects onto the current trial has progressed at a much slower than expected 
rate. Based on current enrolment projections, data outputs from the current trial would 
unlikely be available for review until mid-2018.
Having reviewed the timing of the study in the context of the evolving therapy area for 
ANCA-associated vasculitis, the sponsor feels that the current format and design of the 
BREVAS trial, if driven to completion as a Phase 3 investigation, would no longer 
provide significant and timely new information for the vasculitis community. On the basis 
of the BREVAS trial data alone, even in the event of a successful outcome, it is not felt 
that belimumab can be sufficiently well differentiated as a concomitant therapy for 
remission maintenance in AAV to fulfill a significant unmet need for patients where other 
therapeutic options are now available (e.g., rituximab). 
As such, GSK is proposing to modify the strategic objective of the trial such that it will be 
conducted as an exploratory study, in which global enrolment would be restricted to 
approximately 100 patients (compared to the original target of approximately 300). It is 
planned that the data will be published in descriptive format with exploratory analyses on 
efficacy endpoints undertaken as appropriate. It is expected that the safety data emerging 
from the smaller cohort of patients in BREVAS will contribute to our understanding of 
belimumab safety. 
2. The study design and schedule has been modified throughout the protocol to clarify that 
the study will no longer be driven by the requirement to achieve at least 66 relapse events. 
The study will complete and the primary analysis will be undertaken once 12 months have 
elapsed following enrolment of the last subject.
3. The protocol has been modified throughout such that subjects completing the study will no 
longer have the option to participate in a 6-month open-label extension following 
completion of the double-blind treatment phase. The section entitled “open label extension 
phase” (6.4) and the related time and events table (Table 6-3) has been removed.


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4. The study design schematics have been modified in the protocol by removal of the 
expected number of enrolled subjects; ‘N=300-400’ has been removed from the 
schematic.
5. In the statistical sections of the protocol, the sample size considerations have been 
modified to reflect the fact that approximately 100 patients will be recruited. The sample 
size is based largely on the feasibility of recruitment within a reasonable time-frame. 
Sample size calculations based on expected relapse rates have been removed from the 
protocol. The minimum detectable effect for a sample size of N=100 subjects has been 
determined. 
For the purposes of reporting the data, analysis of primary and secondary endpoints will 
be exploratory in nature. Nominal ‘p’ values may be reported and considered descriptive. 
Where appropriate point estimates and 95% confidence intervals will be constructed.
The section on “Subgroup analyses” (8.5.2.1) has been removed as this is no longer 
considered relevant in the context of the smaller expected total sample size of 
approximately 100 subjects.
In the section “Primary Efficacy Analysis” (8.5.2), we have clarified how stratification 
terms may be handled in the analysis if there are fewer than 5 events (relapses) in any of 
the stratification levels.
6. In the section “Dose, route of administration and schedule”, we have clarified that the 
administration of belimumab/placebo should be over approximately one hour, but not less 
than one hour for reasons of safety.
7. The section on liver chemistry stopping and follow-up criteria, which describes how 
patient care should be managed if a liver event occurs during the study, has been updated 
with the most recent GSK-specified protocol for managing these events. The section also 
defines the circumstances and criteria that may allow a study treatment restart following a 
liver event. The section also includes the criteria for more intensive monitoring with 
continued therapy following a liver event. Accompanying figures have been placed in 
Appendix 13.
8. The adverse event reporting section (Section 7) has been modified throughout for 
consistency with AE, SAE or PSE data collection procedures and forms.
9. The text on progressive multifocal leukoencephalopathy (PML) has been updated to 
provide further guidance on the management of suspected cases.
10. The section “Reporting a pregnancy” has been modified to provide scope for following up 
the outcomes of a pregnancy (including premature termination) as well as the status of 
mother and child.
11. The reference list has been updated in the protocol.
13. Appendix 12 (Benefit-Risk assessment) has been updated to reflect the change in study 
status to an exploratory trial and to reflect the changes in the main protocol as outlined 
above.


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Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment 03
Date: 04 February 2014
EudraCT 2011-004569-33
Local Amendment 02 for France, Date: 02 February 2015
Local Amendment 01 for France, Date: 01 October 2014
Modified to:
Protocol Amendment 04
Date: 06 April 2015
EudraCT 2011-004569-33
Local Amendment 02 for France, Date: 02 February 2015
Local Amendment 01 for France, Date: 01 October 2014
Title of Study, Cover Page and Synopsis
Change from:
A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Change to:
A Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy 
and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance 
of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Revision Chronology for HGS1006-C1100 (BEL115466)
Added rows:
Date
Document*
Global
DNG2013N167980_02
26 February 2015
Amendment No 04


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Local
DNG2014N217970_02
06 April 2015
Amendment No 04 with Local Am01, 
Am02 for France
Study Design and Schedule, Synopsis and Section 3.1, Basic Design Characteristics
Change from:
This is a Phase 3, multi-center, multi-national, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multi-national, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
Subjects will receive study agent (belimumab/placebo) plus AZA until the results from the 
primary efficacy analysis are available or until they experience a flare (relapse) as defined in 
the primary efficacy endpoint (see below). The database will be locked and the primary 
analysis will be performed after at least 66 subjects have experienced a relapse and at least
when 12 months have elapsed after the last subject is randomized.
Change to:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The study will complete, the database will be locked and the primary 
analysis will be performed when 12 months have elapsed after the last subject is randomized.
Study Design and Schedule, Synopsis
Deleted:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 


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the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 6 
months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 
protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8-week follow-up visit is not required for subjects entering the continuation protocol.
Schematic of study design, Synopsis and Section 3.1, Basic Design Characteristics
Change from:


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Change to (removed number of subjects randomized from graphic):
Sample Size Considerations, Synopsis and Section 8.4, Sample Size Rationale
Deleted:
The relapse rate in the study is anticipated to be approximately 20% in the control group. 
However, there is some uncertainty around this relapse event rate which could be 30% or 
higher. This study is designed to target at least 66 subjects experiencing a relapse (as defined 
in the primary endpoint), which will provide 85% power to detect a reduction in relapse rates 
of 20 vs. 10% (hazard ratio = 0.472). With this same hazard ratio and a 30% event rate, a 
study with 66 subjects experiencing a relapse will provide 85% power to detect a reduction in 
the relapse rate from 30% to 15.5%. A target of 300 to 400 subjects will be randomized to 
achieve the required number of events.
After approximately 300 subjects have been randomized, the relapse rate in the overall 
population will be evaluated in a blinded manner internally by HGS while the enrollment 
continues. If the relapse rate is consistent with the 20% control rate assumption, enrollment 
will continue to 400 subjects to ensure timely accrual of the 66 events. However, if there is 
evidence that the relapse rate is higher than 20% control rate assumption, enrollment may be 
stopped at approximately 300 subjects. The primary efficacy analysis will be performed after 
at least 66 subjects have experienced a relapse and at least 12 months have elapsed after the 
last subject is randomized.
Added:
Approximately 100 subjects will be randomized. The sample size has been determined 
based on the feasibility of enrolling patients into the study within a reasonable time-
frame. The sample size was not based on statistical considerations and the analysis of 


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primary and secondary endpoints will be exploratory in nature. The primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the 
last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo 
group, a relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically 
significant (p<0.05) in a study of 100 subjects (50 per arm). 
Analysis of Primary Efficacy Endpoint, Synopsis
Change from:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized.
Change to:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after 12 months have elapsed following randomization of the last subject.
Analysis of Major Secondary Efficacy Endpoints, Synopsis
Deleted:
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error (Section 8.1).
Section 3.1, Basic Design Characteristics
Deleted:
If the result on the primary efficacy endpoint from the double blind portion of this trial shows 
that belimumab is superior to placebo, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 


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6 months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 
protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8 week follow-up visit is not required for subjects entering the continuation protocol. 
Section 5.3 Dose, Route of Administration, and Schedule
Change from:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. Once randomized, 
subjects will be dosed with study agent on Days 0, 14, and 28 and every 28 days thereafter. 
Following the final double-blind visit, eligible subjects (see Section 6.4) will have the option 
to continue in the 6-month open-label extension period.
Change to:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. The intent of this 
instruction is to prevent more rapid infusion of belimumab which may result in a higher 
incidence of infusion reactions. Infusion time need not be exactly one hour as it is often 
difficult to so precisely adjust infusion times and there may be clinical reasons for 
infusions lasting longer than one hour. Therefore, the instruction should be interpreted 
as infusion over at least one hour. The target infusion time should still be approximately 
one hour assuming no other issues intervene. Once randomized, subjects will be dosed with 
study agent on Days 0, 14, and 28 and every 28 days thereafter.
Change from:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase and the open-label 
extension.
Change to:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase.


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Section 6 Study Procedures
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3), Study Procedures Manual, 
and Central Laboratory Manual for additional information.
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
Section 6.3 Double-Blind Treatment Phase
Change from:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until top 
line data from the primary analysis are available. If top line data from the double blind portion 
of this trial show that belimumab is superior to placebo on the primary efficacy endpoint, and 
the safety profile of belimumab is acceptable, subjects who received treatment with study 
agent until completion of the double-blind treatment period and have not relapsed (as defined 
by the primary endpoint) will be given the option to receive treatment with belimumab in the 
6-month open-label extension phase.
Subjects who do not enter the open-label extension, will return for an Exit visit 
(approximately 4 weeks after the last dose of study agent), and a follow-up visit 
(approximately 8 weeks after the last dose of study agent).
Change to:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The study will complete and the primary efficacy analysis will be 
performed when 12 months have elapsed following randomization of the last subject.
Subjects will return for an Exit visit (approximately 4 weeks after the last dose of study 
agent), and a follow-up visit (approximately 8 weeks after the last dose of study agent).


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Table 6-1 Footnotes:
Change from:
11.  Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase. Subjects who discontinue treatment but have not relapsed 
will remain on the double blind study visit schedule. For subjects who complete the 
double blind phase and enter the open label phase, refer to Table 6-3 for visit details.
Change to:
11. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should be completed for subjects 
who discontinue the double blind treatment phase early or when subjects have completed 
the double-blind treatment phase. Subjects who discontinue treatment but have not 
relapsed will remain on the double blind study visit schedule.  
Change from:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 
month open-label extension phase.
Change to:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent. 
Table 6-2 Footnotes
Change from:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase.  For subjects who complete the double blind phase and 
enter the open label phase, refer to Table 6-3 for visit details.


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Change to:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should be completed for 
subjects who discontinue the double blind treatment phase early or when subjects have 
completed the double-blind treatment phase. 
Change from:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 month 
open-label extension phase.
Change to:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent.
Deleted: Section 6.4 “Open-Label Extension Phase” has been deleted and all subsequent 
sections have been renumbered accordingly.
6.4 Open-Label Extension Phase
In the 6-month open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the last dose). The 
first dose on the open-label extension will be given 4 weeks after completion of the 
double-blind period. Day 0 is the first visit in the extension phase of the trial and represents 
the first belimumab administration for placebo subjects. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-3). 
During the 6-month open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications 
during this phase are live vaccines, biological therapies and other investigational agents. 
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.


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After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
need to be provided for the continuation protocol. The 8 week follow-up visit is not required 
for subjects entering the continuation protocol.
Deleted:
Table 6-3 Open Label Extension Phase and all associated footnotes have been deleted
and the subsequent table has been renumbered accordingly.
Section 6.5 Laboratory Tests
Change from:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Change to:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2).
Section 6.6.2 Phase III-IV Liver Chemistry Stopping and Follow-up Criteria
The section “Phase III-IV Liver Chemistry Stopping and Follow-up Criteria” has been 
deleted. The deleted text is not shown here. The section has been replaced by the following 
sections (6.5.2-6.5.3) and text:
6.5.2 Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks


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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
1) Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury. 
2) All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants.
3) New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).
6.5.2.1 Required Actions and Follow up Assessments following ANY Liver Stopping 
Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the event 
also meets the criteria for an SAE (All events of ALT 3xULN and bilirubin 
2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to subjects receiving
anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 13).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is recommended


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


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6.5.3 Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 
weeks OR

ALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 
weeks
6.5.3.1 Required Actions and Follow Up Assessments for Increased Monitoring with 
Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following ANY 
Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline.
Added:
6.5.4 Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, 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 


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marker associated with liver injury (e.g., lapatinib, abacavir, amoxicillin/clavulanate) are 
reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart must 
be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries have 
been demonstrated and then laboratory monitoring may resume as per protocol. 

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
Section 6.6 Exit Visit
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
Section 6.7 8-Week Follow-up Visit
Change from:


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All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent, unless entering the long-term continuation protocol. 
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
Section 7 Adverse Event Reporting
Added:
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Section 7.1 Definitions
Change from:
ADVERSE EVENT (EXPERIENCE): Any unfavorable or unintended sign, symptom, or 
disease that is temporally associated with the use of a study agent but is not necessarily caused 
by the study agent. This includes worsening (eg, increase in frequency or severity) of 
preexisting conditions.
SERIOUS ADVERSE EVENT: An adverse event resulting in any of the following 
outcomes:

death

is life-threatening (ie, an immediate threat to life)

inpatient hospitalization*

prolongation of an existing hospitalization

persistent or significant disability/incapacity

congenital anomaly/birth defect

is medically important+


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*An inpatient hospitalization is defined as an admission for any length of time. A 
hospitalization for administration of study agent, for routine or planned clinical procedures, or 
for “social” reasons (not the result of any adverse change in the subject’s condition) should 
not be considered an adverse event and should not be reported as a serious adverse event. If 
the subject experiences any adverse change in condition during hospitalization, the condition 
must be reported as an adverse event or serious adverse event according to the above 
definitions. 
+Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above (eg, 
possible drug-induced liver injury). These should also usually be considered serious. (ICH 
guidelines, March 1995)
UNEXPECTED ADVERSE EVENT: An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means the event has previously been observed with the study 
agent and is identified and/or described in the applicable product information. It does not 
mean that the event is expected with the underlying disease(s) or concomitant medications.
Change to:
ADVERSE EVENT
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (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 


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


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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 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.   
Section 7.2 Reporting Adverse Events to the Sponsor
Change from:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
the HGS Drug Safety designee within 24 hours of site personnel becoming aware of the SAE, 
regardless of expectedness. All pages of the SAE Worksheet should be completed, but the 
SAE Worksheet should not be held until all information is available. Additional information 
and corrections should be provided on subsequent SAE Worksheets as described in the Study 
Procedures Manual. SAE Worksheets should be sent either via the EDC system, if SAE EDC 
functionality is available or by facsimile to the HGS Drug Safety designee using the fax 
number listed on the SAE Worksheet.


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In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be recorded on the SAE 
worksheet and reported as described  above from the time a subject consents to participate in 
the study. Pre-treatment SAEs will not be documented on the AE eCRF.
SAEs that occur off study, after the follow-up period, that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the Drug Safety 
designee on the SAE worksheet. Post study SAEs will not be documented on the AE eCRF.
Change to:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE eCRF within 24 hours 
of site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
eCRF within 24 hours of site personnel becoming aware of the event as described in the 
Study Procedures Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an SAE 
from the time a subject consents to participate in the study.
SAEs that occur off study, after the follow-up period that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the sponsor as 
outlined in the Study Procedures Manual.
Section 7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events)
Change from:
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (see Section 7.1). PSEs are 
recorded on SAE Worksheets and sent to the Drug Safety designee within 24 hours of site 
personnel becoming aware of the event. 
Change to:
Protocol Specified Events (PSEs) are additional events that must be reported in an expedited 
manner. A PSE may or may not be an SAE. PSEs are considered SAEs if they meet 1 or more 
of the criteria for an SAE (see Section 7.1). PSEs are recorded on the PSE page of the eCRF
within 24 hours of site personnel becoming aware of the event.


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Section 7.4 Laboratory Abnormalities as Adverse Events
Change from:
A laboratory abnormality should be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, or concomitant therapy. In addition, any medically important laboratory 
abnormality may be reported as an adverse event at the discretion of the investigator. This 
includes laboratory abnormalities for which there is no intervention but the abnormal value(s) 
suggests a disease or organ toxicity. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC increased). In 
addition, an IgG abnormality < 250 mg/dL (Grade 4) should be recorded as an adverse event 
(and SAE if meeting the criteria in Section 7.1).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, severe, or life-threatening as specified in Section 7.8.
Change to:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, 
elevated creatinine, urine RBC increased). In addition, an IgG abnormality < 250 mg/dL 
(Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 mg/dL
should also be reported as an SAE if it meets one or more of the SAE criteria in Section
7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, or severe as specified in Section 7.8.


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Section 7.5 Progressive Multifocal Leukoencephalopathy
Change from:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping immunosuppressant therapy.
Change to:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping all immunosuppressant therapy.
Section 7.7 Reporting a Pregnancy
Change from:
Pregnancies must be reported to the HGS Drug Safety designee within 24 hours of the site
becoming aware of a pregnancy in a study subject. All pregnancies that are identified from the 
start of study agent through 16 weeks following the last dose of study agent should be 
reported. All pregnancies are tracked up to term or delivery following the last study agent 
treatment. When pregnancy is reported, HGS Drug Safety sends an acknowledgement 
memorandum to the principal investigator along with a Pregnancy Assessment Form. A 
Pregnancy Assessment Form must be completed every three months until live birth, elective 
termination of the pregnancy, or miscarriage. The site is responsible for following the 
subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 7.1 and 
Section 7.2.
Change to:
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor within 2 weeks of learning of its occurrence. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE 
or SAE. Spontaneous abortions must be reported as an SAE.


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Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the Sponsor.
Section 7.8 Investigator Evaluation of Adverse Events
Change from:
The investigator will evaluate all adverse events with respect to seriousness, severity 
(intensity or grade), and causality (relationship to study agent). The criteria for serious are 
listed in Section 7.1. The severity of an AE is to be evaluated according to the Adverse Event 
Severity Grading Tables in Appendix 7. If an AE does not have Adverse Event Severity 
Grading in Appendix 7, the following severity classifications will be used:
SEVERITY:
Grade 1- Mild
     - causing no limitation of usual activities.
Grade 2- Moderate 
     - causing some limitation of usual activities.
Grade 3- Severe
    - causing inability to carry out usual activities.
Grade 4- Life-threatening*
  - potentially life-threatening or disabling; significant medical 
intervention is required.
*Note – a severity assessment of Life-threatening is not necessarily the same as the 
seriousness criterion of Life-threatening (see “serious” criteria Section 7.1). The former means 
that the event is a potential threat. The latter means that the event is an immediate threat to 
life.
CAUSALITY:
It is a regulatory requirement for investigators to assess relationship between the 
investigational product(s) and the occurrence of each AE/SAE based on the information 
available. The assessment should be reviewed on receipt of any new information and amended 
if necessary. A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship. Facts/evidence or arguments that may support a 
“reasonable possibility” include, e.g., a temporal relationship, a pharmacologically-predicted 
event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant 
medication, a concurrent illness, or relevant medical history, should also be considered.
Change to:
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to study 
agent). The investigator will make an assessment of intensity based on the Division of 


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Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading Tables (see
Appendix 7) where possible:
SEVERITY:

Mild
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities (Grade 1 
DMID).

Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).

Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID).

Not applicable
Those event(s) where intensity is meaningless or impossible to 
determine (i.e., blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. The investigator will also consult the 
Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK. The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.


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Section 7.9 Follow-up of Adverse Events
Change from:
Adverse events that occur from the start of study medication through 8 weeks after the date of 
last administration of study agent are followed until final outcome is known or until the end of 
the 8-week study follow-up period. Adverse events that have not resolved at the end of the 8-
week study follow-up visit are recorded on the adverse event case report form (AE eCRF) as 
ONGOING. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for an SAE (eg, the subject is lost to follow-up), the reason a final outcome 
could not be obtained will be documented by the investigator. 
Change to:
Serious and non-serious adverse events that occur from the start of study medication 
administration through 8 weeks after the date of last administration of study agent are 
reported. 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up. This applies to all 
subjects, including those withdrawn prematurely. 
PSEs (see Section 7.3) that occur after the Screening visit through 8 weeks after the date 
of last administration of study agent are reported and followed as described above for 
AEs/SAEs.
Section 8.1 General Statistical Considerations
Change from:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject or when 66 events (relapse as defined for the primary efficacy endpoint) have 
been observed, whichever is later. All subjects and study site personnel will remain blinded to 
original treatment assignment until after the final database is locked and the results of the 
study are made publicly available. 
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error. With this 


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procedure, the primary endpoint (time to the first relapse) will be evaluated first. If the 
primary efficacy endpoint demonstrates statistical significance (2-sided, alpha=0.05) then 
inference will proceed to the major secondary efficacy endpoint, time to the first major relapse 
(2-sided, alpha = 0.05). If the result is statistically significant, superiority of belimumab on the 
time to the first major relapse will be established. If statistical significance is not met, p values
may be reported and considered descriptive.
Analyses of all other efficacy endpoints other than the primary and major secondary efficacy 
endpoints will not be subject to any multiple testing procedure. All statistical tests will be 
2-sided and performed at an overall significance level of 0.05.
Change to:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject. All subjects and study site personnel will remain blinded to original treatment 
assignment until after the final database is locked and the results of the study are made 
publicly available. 
Analysis of primary and secondary endpoints will be exploratory in nature. Nominal p
values may be reported and considered descriptive. Where appropriate point estimates and 
95% confidence intervals will be constructed.
Section 8.2 Randomization Procedure and Assignment to Treatment Groups
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled 
study. 
Change to:
This is a, multi-center, multinational, randomized, double-blind, placebo-controlled study. 
Section 8.5.2 Primary Efficacy Analysis
Change from:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 


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regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less 5 in subjects using the oral or IV cyclophosphamide. For any subject 
who does not experience a relapse, the time to first relapse will be censored at the time of the 
subject’s last assessment. Subjects who discontinue study agent prior to relapse/flare 
(as defined in primary efficacy endpoint) are to be followed per protocol for inclusion in the 
primary efficacy analysis until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). The database will be locked and the primary efficacy analysis will be 
performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized.
Change to:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using the oral or IV cyclophosphamide. If there are 
then still less than 5 patients with an event (relapse) in any of the levels of this or any 
other stratification factor then the stratification term may be removed from the model.
For any subject who does not experience a relapse, the time to first relapse will be censored at 
the time of the subject’s last assessment. Subjects who discontinue study agent prior to 
relapse/flare (as defined in primary efficacy endpoint) are to be followed per protocol for 
inclusion in the primary efficacy analysis until relapse/flare or the end of the double-blind 
treatment phase (whichever is earlier). The database will be locked and the primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the last 
subject.
Deleted:
Section 8.5.2.1 Subgroup Analysis
Subgroup analysis, of the primary efficacy endpoint only, will be performed in the following 
subgroups:

ANCA type (anti-PR3 vs. anti-MPO)

Disease type (WG vs. MPA)

Disease stage at induction (initial diagnosis vs. relapsing disease)

Induction regimen (rituximab vs. IV cyclophosphamide vs. oral cyclophosphamide)

Race (white, American Indian, Asian, and black)

Region (US/Canada, EU/Australia/Israel, Americas excluding US/Canada, and Asia)

Age (< 65 vs. ≥ 65)


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
Gender

Duration of IV corticosteroid pulse used for induction (1 day vs > 1 day)
Section 8.5.5 Major Secondary Endpoint analysis and Other Efficacy Analyses
Change from:
The analysis of the major secondary efficacy endpoint will be performed using the same 
method described for the primary efficacy endpoint, but censoring subjects who receive any 
prohibited medication (as defined in Section 5.5.1) prior to an observation of any major 
BVAS item. Any censoring will be applied on the date prohibited medications are received.
Change to:
The exploratory analysis of the major secondary efficacy endpoint will be performed using 
the same method described for the primary efficacy endpoint, but censoring subjects who 
receive any prohibited medication (as defined in Section 5.5.1) prior to an observation of any 
major BVAS item. Any censoring will be applied on the date prohibited medications are 
received.
References
Added:
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.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Study Overview and 
Patient Population
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 


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subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
A target of 300 to 400 subjects who are between 6 and 26 weeks from starting induction 
therapy, achieve a BVAS v.3 score of 0 (ie, are in remission), and are receiving ≤10 mg/day 
prednisone (or equivalent) on 2 consecutive measurements at least 14 days apart will be 
enrolled into the study.
Change to:
Approximately 100 subjects with ANCA-vasculitis who are between 6 and 26 weeks from 
starting induction therapy, who achieve a BVAS v.3 score of 0 (ie, are in remission), and are 
receiving ≤10 mg/day prednisone (or equivalent) on 2 consecutive measurements at least 14 
days apart will be enrolled into the study.
Change from:
The database will be locked and the primary analysis will be performed after at least 66 
subjects have experienced a relapse and at least 12 months have elapsed after the last subject 
is randomized.
Change to:
The database will be locked and the primary analysis will be performed when 12 months have 
elapsed after the last subject is randomized.
Deleted:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety.
Deleted:
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 


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commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Safety Considerations
Change from:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase and the open-label extension.
Change to:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase.
Appendix 13 Algorithm for Liver Chemistry Stopping and Follow-up Criteria
Added:
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.2.1. 


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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. 
Liver Monitoring Event Algorithm with Continued Therapy for ALT≥3xULN but 
<8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.3.1.


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Deleted:


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Belimumab
Local Amendment 02 for France, 02 February 2015
Protocol Number: HGS1006-C1100-03
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified, at the request of the French National Agency for 
Medicines and Health Products Safety (ANSM), to limit the duration of treatment with 
belimumab to 3 years. Further dosing after 3 years might be possible, but only following 
additional approval from ANSM and re-visiting of risk-benefit at that time.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 03
Date: 04 February 2014
Modified to:
Protocol Amendment: 03
Date: 04 February 2014
Local Amendment 02 for France, Date: 02 February 2015
Local Amendment 01 for France, Date: 01 October 2014
Section 3.1 Basic Design Characteristics
Section 8.4 Sample Size Rationale
Added:
The maximum duration of treatment with study agent (belimumab/placebo) for patients 
enrolled onto this trial in France should not exceed 3 years in the first instance. If it is 
anticipated that some patient(s) would be likely to require extended treatment beyond 
3 years, this will be subject to approval by the Agence nationale de sécurité du 
médicament et des produits de santé (ANSM), following timely submission of an 
application with due consideration of the risk/benefit ratio of the treatment beyond 
3 years. The trial sponsor will be monitoring the duration of treatment for enrolled 
subjects and will advise investigators and ANSM accordingly.


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Belimumab
Local Amendment 01 for France, 01 October 2014
Protocol Number: HGS1006-C1100-03
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified, at the request of the French National Security Agency for 
Medicines and Health Products (ANSM), to include guidance for French investigators to 
evaluate suspected cases of Progressive multifocal leukoencephalopathy (PML) using 
brain imaging and polymerase chain reaction (PCR) on cerebrospinal fluid for JC virus 
(JCV).
2. During Amendment 03, the absolute requirement to randomize within 2 weeks of 
confirmation of remission was removed, but a statement to this effect was inadvertently 
left in Section 8.2 Randomization Procedure and Assignment to Treatment Groups. The 
statement has now been deleted from Section 8.2.
3. In the Revision Chronology, Local Addendum 02 for Ireland was inadvertently not listed. 
This information has now been added. This change is not shown in the Modifications 
section below.
4. In Appendix 12, the cross-reference to Protocol Section “5.5.2.1” should have been to 
Protocol Section “5.5.1". The typographical error has now been corrected. This change is 
not shown in the Modifications section below.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 03
Date: 04 February 2014
Modified to:
Protocol Amendment: 03
Date: 04 February 2014
Local Amendment 01 for France, Date: 01 October 2014


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Belimumab
List of Abbreviations
Added:
JCV
JC virus
Section 7.5 Progressive Multifocal Leukoencephalopathy
Formerly:
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.
Modified to:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in any 
subject presenting with new-onset or deteriorating neurological signs and symptoms. The 
subject should be referred to a neurologist or other appropriate specialist for evaluation. 
Evaluation of suspected PML may include the following: 1. Magnetic resonance imaging 
of the brain, with and without contrast enhancement; 2. Cerebrospinal fluid analysis for 
JCV DNA by polymerase chain reaction; 3. If these tests are negative or inconclusive, 
they may need to be repeated, or a brain biopsy from a region of the brain that is 
associated with clinical symptoms may be needed. 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.


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Belimumab
Section 8.2  Randomization Procedure and Assignment to Treatment Groups
Formerly:
This is a Phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled 
study. Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  Day 0 (first administration of belimumab/placebo and azathioprine) 
must occur no more than 2 weeks after confirmation of remission.  
Modified to:
This is a Phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled 
study. Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  


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Summary of Modifications
Protocol Amendment 04 With Local Addenda 01, 02 for Ireland, 06 April 2015
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The proposed modifications to the protocol reflect a change by the sponsor to the strategic 
objectives for the evaluation of belimumab in ANCA-associated vasculitis (AAV). It is 
proposed that the trial should be changed from a Phase 3 study to allow for an exploratory 
evaluation of belimumab in AAV only. There is no longer the intention to seek a licensed 
indication for belimumab as an adjunctive maintenance therapy in AAV on the basis of 
the data emerging from this study. The term “Phase 3” has been removed from the study 
title.
Enrolment of subjects onto the current trial has progressed at a much slower than expected 
rate. Based on current enrolment projections, data outputs from the current trial would 
unlikely be available for review until mid-2018.
Having reviewed the timing of the study in the context of the evolving therapy area for 
ANCA-associated vasculitis, the sponsor feels that the current format and design of the 
BREVAS trial, if driven to completion as a Phase 3 investigation, would no longer 
provide significant and timely new information for the vasculitis community. On the basis 
of the BREVAS trial data alone, even in the event of a successful outcome, it is not felt 
that belimumab can be sufficiently well differentiated as a concomitant therapy for 
remission maintenance in AAV to fulfill a significant unmet need for patients where other 
therapeutic options are now available (e.g., rituximab). 
As such, GSK is proposing to modify the strategic objective of the trial such that it will be 
conducted as an exploratory study, in which global enrolment would be restricted to 
approximately 100 patients (compared to the original target of approximately 300). It is 
planned that the data will be published in descriptive format with exploratory analyses on 
efficacy endpoints undertaken as appropriate. It is expected that the safety data emerging 
from the smaller cohort of patients in BREVAS will contribute to our understanding of 
belimumab safety. 
2. The study design and schedule has been modified throughout the protocol to clarify that 
the study will no longer be driven by the requirement to achieve at least 66 relapse events. 
The study will complete and the primary analysis will be undertaken once 12 months have 
elapsed following enrolment of the last subject.
3. The protocol has been modified throughout such that subjects completing the study will no 
longer have the option to participate in a 6-month open-label extension following 
completion of the double-blind treatment phase. The section entitled “open label extension 
phase” (6.4) and the related time and events table (Table 6-3) has been removed.


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Summary of Modifications
4. The study design schematics have been modified in the protocol by removal of the 
expected number of enrolled subjects; ‘N=300-400’ has been removed from the 
schematic.
5. In the statistical sections of the protocol, the sample size considerations have been 
modified to reflect the fact that approximately 100 patients will be recruited. The sample 
size is based largely on the feasibility of recruitment within a reasonable time-frame. 
Sample size calculations based on expected relapse rates have been removed from the
protocol. The minimum detectable effect for a sample size of N=100 subjects has been 
determined. 
For the purposes of reporting the data, analysis of primary and secondary endpoints will 
be exploratory in nature. Nominal ‘p’ values may be reported and considered descriptive. 
Where appropriate point estimates and 95% confidence intervals will be constructed.
The section on “Subgroup analyses” (8.5.2.1) has been removed as this is no longer 
considered relevant in the context of the smaller expected total sample size of 
approximately 100 subjects.
In the section “Primary Efficacy Analysis” (8.5.2), we have clarified how stratification 
terms may be handled in the analysis if there are fewer than 5 events (relapses) in any of 
the stratification levels.
6. In the section “Dose, route of administration and schedule”, we have clarified that the 
administration of belimumab/placebo should be over approximately one hour, but not less 
than one hour for reasons of safety.
7. The section on liver chemistry stopping and follow-up criteria, which describes how 
patient care should be managed if a liver event occurs during the study, has been updated 
with the most recent GSK-specified protocol for managing these events. The section also 
defines the circumstances and criteria that may allow a study treatment restart following a 
liver event. The section also includes the criteria for more intensive monitoring with 
continued therapy following a liver event. Accompanying figures have been placed in 
Appendix 13.
8. The adverse event reporting section (Section 7) has been modified throughout for 
consistency with AE, SAE or PSE data collection procedures and forms.
9. The text on progressive multifocal leukoencephalopathy (PML) has been updated to 
provide further guidance on the management of suspected cases.
10. The section “Reporting a pregnancy” has been modified to provide scope for following up 
the outcomes of a pregnancy (including premature termination) as well as the status of 
mother and child.
11. The section “Randomization procedure and assignment to treatment requirements” has 
been modified to remove the requirement for subjects to be randomised within 2 weeks of 
achieving remission. This corrects an error in the protocol and ensures consistency with 
wording across other sections of the protocol.
12. The reference list has been updated in the protocol.
13. Appendix 12 (Benefit-Risk assessment) has been updated to reflect the change in study 
status to an exploratory trial and to reflect the changes in the main protocol as outlined 
above.


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Summary of Modifications
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment 03
Date: 25 February 2014
EudraCT 2011-004569-33
Local Addendum 01 for Ireland, Date: 31 January 2013
Local Addendum 02 for Ireland, Date: 07 August 2013
Modified to:
Protocol Amendment 04
Date: 06 April 2015
EudraCT 2011-004569-33
Local Addendum 01 for Ireland, Date: 31 January 2013
Local Addendum 02 for Ireland, Date: 07 August 2013
Title of Study, Cover Page and Synopsis
Change from:
A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Change to:
A Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy 
and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance 
of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis
Revision Chronology for HGS1006-C1100 (BEL115466)
Added rows:
Date
Document*
Local
DNG2014N217970_01
01 October 2014
Local Amendment 01 for France


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Local
DNG2014N217970_02
03 February 2015
Local Amendment 02for France
Global
DNG2013N167980_02
26 February 2015
Amendment No 04
Local
DNG2013N160488_04
06 April 2015
Amendment No 04 with Addendum 
01, 02 for Ireland
Study Design and Schedule, Synopsis and Section 3.1, Basic Design Characteristics
Change from:
This is a Phase 3, multi-center, multi-national, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multi-national, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
Subjects will receive study agent (belimumab/placebo) plus AZA until the results from the 
primary efficacy analysis are available or until they experience a flare (relapse) as defined in 
the primary efficacy endpoint (see below). The database will be locked and the primary 
analysis will be performed after at least 66 subjects have experienced a relapse and at least
when 12 months have elapsed after the last subject is randomized.
Change to:
Subjects will receive study agent (belimumab/placebo) plus AZA until the study has 
completed or until they experience a flare (relapse) as defined in the primary efficacy 
endpoint (see below). The study will complete, the database will be locked and the primary 
analysis will be performed when 12 months have elapsed after the last subject is randomized.


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Study Design and Schedule, Synopsis
Deleted:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 6 
months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 
protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8-week follow-up visit is not required for subjects entering the continuation protocol.
Schematic of study design, Synopsis and Section 3.1, Basic Design Characteristics
Change from:


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Change to (removed number of subjects randomized from graphic):
Sample Size Considerations, Synopsis and Section 8.4, Sample Size Rationale
Deleted:
The relapse rate in the study is anticipated to be approximately 20% in the control group. 
However, there is some uncertainty around this relapse event rate which could be 30% or 
higher. This study is designed to target at least 66 subjects experiencing a relapse (as defined 
in the primary endpoint), which will provide 85% power to detect a reduction in relapse rates 
of 20 vs. 10% (hazard ratio = 0.472). With this same hazard ratio and a 30% event rate, a 
study with 66 subjects experiencing a relapse will provide 85% power to detect a reduction in 
the relapse rate from 30% to 15.5%. A target of 300 to 400 subjects will be randomized to 
achieve the required number of events.
After approximately 300 subjects have been randomized, the relapse rate in the overall 
population will be evaluated in a blinded manner internally by HGS while the enrollment 
continues. If the relapse rate is consistent with the 20% control rate assumption, enrollment 
will continue to 400 subjects to ensure timely accrual of the 66 events. However, if there is 
evidence that the relapse rate is higher than 20% control rate assumption, enrollment may be 
stopped at approximately 300 subjects. The primary efficacy analysis will be performed after 
at least 66 subjects have experienced a relapse and at least 12 months have elapsed after the 
last subject is randomized.
Added:
Approximately 100 subjects will be randomized. The sample size has been determined 
based on the feasibility of enrolling patients into the study within a reasonable time-
frame. The sample size was not based on statistical considerations and the analysis of 


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primary and secondary endpoints will be exploratory in nature. The primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the 
last subject.
Although the sample size is based on feasibility, the minimal detectable effect has been 
determined. Assuming an observed relapse rate at 18 months of 20% in the placebo 
group, a relapse rate of ≤7.0% on belimumab (hazard ratio ≤0.32) would be statistically 
significant (p<0.05) in a study of 100 subjects (50 per arm). 
Analysis of Primary Efficacy Endpoint, Synopsis
Change from:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized.
Change to:
Subjects who discontinue study agent prior to relapse/flare are to be followed per the double 
blind visit schedule for inclusion in the primary efficacy analysis until relapse/flare or the end 
of the double-blind treatment phase (whichever is earlier). The primary efficacy analysis will 
be performed after 12 months have elapsed following randomization of the last subject.
Analysis of Major Secondary Efficacy Endpoints, Synopsis
Deleted:
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error (Section 8.1).
Section 3.1, Basic Design Characteristics
Deleted:
If the result on the primary efficacy endpoint from the double blind portion of this trial shows 
that belimumab is superior to placebo, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 


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6 months and this will be supplied by the sponsor. After the 6-month open-label extension 
phase, subjects who wish to continue treatment may do so by being prescribed commercially 
available belimumab. If belimumab is not commercially available in a subject’s country of 
participation, the subject may continue to receive belimumab under a separate continuation 
protocol. A separate informed consent will need to be provided for the continuation protocol. 
The 8 week follow-up visit is not required for subjects entering the continuation protocol. 
Section 5.3 Dose, Route of Administration, and Schedule
Change from:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. Once randomized, 
subjects will be dosed with study agent on Days 0, 14, and 28 and every 28 days thereafter. 
Following the final double-blind visit, eligible subjects (see Section 6.4) will have the option 
to continue in the 6-month open-label extension period.
Change to:
The treatment groups include one active treatment arm of 10 mg/kg belimumab and a placebo 
arm, with all treatment groups receiving azathioprine (as described in Section 5.5.3). 
Belimumab/placebo will be administered intravenously over 1 hour. The intent of this 
instruction is to prevent more rapid infusion of belimumab which may result in a higher 
incidence of infusion reactions. Infusion time need not be exactly one hour as it is often 
difficult to so precisely adjust infusion times and there may be clinical reasons for 
infusions lasting longer than one hour. Therefore, the instruction should be interpreted 
as infusion over at least one hour. The target infusion time should still be approximately 
one hour assuming no other issues intervene. Once randomized, subjects will be dosed with 
study agent on Days 0, 14, and 28 and every 28 days thereafter.
Change from:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase and the open-label 
extension.
Change to:
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions 
has been observed. Subjects should remain under clinical supervision for 3 hours after 
completion of the first 2 infusions in the double-blind treatment phase.


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Section 6 Study Procedures
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3), Study Procedures Manual, 
and Central Laboratory Manual for additional information.
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2), Study Procedures Manual, and Central 
Laboratory Manual for additional information.
Section 6.3 Double-Blind Treatment Phase
Change from:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until top 
line data from the primary analysis are available. If top line data from the double blind portion 
of this trial show that belimumab is superior to placebo on the primary efficacy endpoint, and 
the safety profile of belimumab is acceptable, subjects who received treatment with study 
agent until completion of the double-blind treatment period and have not relapsed (as defined 
by the primary endpoint) will be given the option to receive treatment with belimumab in the 
6-month open-label extension phase.
Subjects who do not enter the open-label extension, will return for an Exit visit 
(approximately 4 weeks after the last dose of study agent), and a follow-up visit 
(approximately 8 weeks after the last dose of study agent).
Change to:
Subjects who have not experienced a flare (relapse) as defined in the primary efficacy 
endpoint (see Section 8.5.1) will remain on double-blind treatment with study agent until the 
study has completed. The study will complete and the primary efficacy analysis will be 
performed when 12 months have elapsed following randomization of the last subject.
Subjects will return for an Exit visit (approximately 4 weeks after the last dose of study 
agent), and a follow-up visit (approximately 8 weeks after the last dose of study agent).


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Table 6-1 Footnotes:
Change from:
11.  Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase. Subjects who discontinue treatment but have not relapsed 
will remain on the double blind study visit schedule. For subjects who complete the 
double blind phase and enter the open label phase, refer to Table 6-3 for visit details.
Change to:
11. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
4 weeks after the last dose of study agent). The Exit Visit should be completed for subjects 
who discontinue the double blind treatment phase early or when subjects have completed 
the double-blind treatment phase. Subjects who discontinue treatment but have not 
relapsed will remain on the double blind study visit schedule.  
Change from:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 
month open-label extension phase.
Change to:
13. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent. 
Table 6-2 Footnotes
Change from:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should only be completed for 
subjects who discontinue the double blind treatment phase early or for subjects that have 
successfully completed the double-blind treatment phase and do not wish to participate in 
the open label extension phase.  For subjects who complete the double blind phase and 
enter the open label phase, refer to Table 6-3 for visit details.


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Change to:
7. Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 
1-4 weeks after the last dose of study agent). The Exit Visit should be completed for 
subjects who discontinue the double blind treatment phase early or when subjects have 
completed the double-blind treatment phase. 
Change from:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent for subjects withdrawing early and those subjects who do not continue in the 6 month 
open-label extension phase.
Change to:
9. The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study 
agent.
Deleted: Section 6.4 “Open-Label Extension Phase” has been deleted and all subsequent 
sections have been renumbered accordingly.
6.4 Open-Label Extension Phase
In the 6-month open-label extension, all subjects will receive 10 mg/kg belimumab every 
28 days until Week 24, with a final evaluation at Week 28 (4 weeks after the last dose). The 
first dose on the open-label extension will be given 4 weeks after completion of the 
double-blind period. Day 0 is the first visit in the extension phase of the trial and represents 
the first belimumab administration for placebo subjects. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on 
clinical judgment.
All subjects participating in the open-label extension will continue to be monitored for 
efficacy and safety as per the study calendar (see Table 6-3). 
During the 6-month open-label extension, the investigator may adjust concurrent medications 
(add, eliminate, change dose level/frequency) as clinically appropriate. Prohibited medications 
during this phase are live vaccines, biological therapies and other investigational agents. 
All subjects will return for an Exit visit approximately 4 weeks after their last dose of study 
agent as well as a follow-up visit approximately 8 weeks after the last dose of study agent. 
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.


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After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
need to be provided for the continuation protocol. The 8 week follow-up visit is not required 
for subjects entering the continuation protocol.
Deleted:
Table 6-3 Open Label Extension Phase and all associated footnotes have been deleted
and the subsequent table has been renumbered accordingly.
Section 6.5 Laboratory Tests
Change from:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar 
(see Table 6-1, Table 6-2, and Table 6-3).
Change to:
Non-fasting clinical laboratory tests will be performed as outlined in the Study Calendar (see 
Table 6-1, Table 6-2).
Section 6.6.2 Phase III-IV Liver Chemistry Stopping and Follow-up Criteria
The section “Phase III-IV Liver Chemistry Stopping and Follow-up Criteria” has been 
deleted. The deleted text is not shown here. The section has been replaced by the following 
sections (6.5.2-6.5.3) and text:
6.5.2 Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance [James, 2009; Le Gal, 2005].
Liver Chemistry Stopping Criteria- Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks


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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
1) Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury. 
2) All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants.
3) New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).
6.5.2.1 Required Actions and Follow up Assessments following ANY Liver Stopping 
Event
ACTIONS:

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete SAE data collection tool if the event 
also meets the criteria for an SAE (All events of ALT 3xULN and bilirubin 
2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR measured 
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants)

Perform liver event follow up assessments

Monitor the subject until liver chemistries resolve , stabilize, or return to within 
baseline (see MONITORING below)
Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted (refer to Appendix 13).
MONITORING
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments within 24 hours

Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is recommended


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


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6.5.3 Increased Monitoring Criteria with Continued Therapy
If met see required actions below:

If ALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 
weeks OR

ALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to 
be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 
weeks
6.5.3.1 Required Actions and Follow Up Assessments for Increased Monitoring with 
Continued Therapy

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or return to within baseline 

If at any time subject meets the liver chemistry stopping criteria, proceed as 
described above for Required Actions and Follow up Assessments following ANY 
Liver Stopping Event

If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, 
continue to monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline.
Added:
6.5.4 Study Treatment Restart
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, 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 


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marker associated with liver injury (e.g., lapatinib, abacavir, amoxicillin/clavulanate) are 
reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart must 
be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries have 
been demonstrated and then laboratory monitoring may resume as per protocol. 

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
Section 6.6 Exit Visit
Change from:
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
Section 6.7 8-Week Follow-up Visit
Change from:


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All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent, unless entering the long-term continuation protocol. 
Refer to the Study Calendar (Table 6-1, Table 6-2 and Table 6-3) for a list of procedures 
required at this visit.  
Change to:
All subjects must return for a follow-up visit approximately 8 weeks after the last dose of 
study agent. 
Refer to the Study Calendar (Table 6-1, Table 6-2) for a list of procedures required at this 
visit.  
Section 7 Adverse Event Reporting
Added:
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Section 7.1 Definitions
Change from:
ADVERSE EVENT (EXPERIENCE): Any unfavorable or unintended sign, symptom, or 
disease that is temporally associated with the use of a study agent but is not necessarily caused 
by the study agent. This includes worsening (eg, increase in frequency or severity) of 
preexisting conditions.
SERIOUS ADVERSE EVENT: An adverse event resulting in any of the following 
outcomes:

death

is life-threatening (ie, an immediate threat to life)

inpatient hospitalization*

prolongation of an existing hospitalization

persistent or significant disability/incapacity

congenital anomaly/birth defect

is medically important+


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*An inpatient hospitalization is defined as an admission for any length of time. A 
hospitalization for administration of study agent, for routine or planned clinical procedures, or 
for “social” reasons (not the result of any adverse change in the subject’s condition) should 
not be considered an adverse event and should not be reported as a serious adverse event. If 
the subject experiences any adverse change in condition during hospitalization, the condition 
must be reported as an adverse event or serious adverse event according to the above 
definitions. 
+Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above (eg, 
possible drug-induced liver injury). These should also usually be considered serious. (ICH 
guidelines, March 1995)
UNEXPECTED ADVERSE EVENT: An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means the event has previously been observed with the study 
agent and is identified and/or described in the applicable product information. It does not 
mean that the event is expected with the underlying disease(s) or concomitant medications.
Change to:
ADVERSE EVENT
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (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 


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


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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 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.   
Section 7.2 Reporting Adverse Events to the Sponsor
Change from:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
the HGS Drug Safety designee within 24 hours of site personnel becoming aware of the SAE, 
regardless of expectedness. All pages of the SAE Worksheet should be completed, but the 
SAE Worksheet should not be held until all information is available. Additional information 
and corrections should be provided on subsequent SAE Worksheets as described in the Study 
Procedures Manual. SAE Worksheets should be sent either via the EDC system, if SAE EDC 
functionality is available or by facsimile to the HGS Drug Safety designee using the fax 
number listed on the SAE Worksheet.


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In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be recorded on the SAE 
worksheet and reported as described  above from the time a subject consents to participate in 
the study. Pre-treatment SAEs will not be documented on the AE eCRF.
SAEs that occur off study, after the follow-up period, that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the Drug Safety 
designee on the SAE worksheet. Post study SAEs will not be documented on the AE eCRF.
Change to:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE eCRF within 24 hours 
of site personnel becoming aware of the SAE, regardless of expectedness. All fields of the 
SAE eCRF should be completed, but completion of the report should not be held until all 
information is available. Follow-up information and corrections should be added to the 
eCRF within 24 hours of site personnel becoming aware of the event as described in the 
Study Procedures Manual. 
In addition, prior to study drug administration, any SAE assessed as related to study 
participation (eg, protocol mandated procedures, invasive tests) will be reported as an SAE 
from the time a subject consents to participate in the study.
SAEs that occur off study, after the follow-up period that are assessed by the investigator as 
definitely, possibly or probably related to study agent must be reported to the sponsor as 
outlined in the Study Procedures Manual.
Section 7.3 Other Events Requiring Rapid Reporting (Protocol Specified Events)
Change from:
Protocol Specified Events (PSEs) are additional events that must be reported to the Drug 
Safety designee in an expedited manner. A PSE may or may not be an SAE. PSEs are 
considered SAEs if they meet 1 or more of the criteria for an SAE (see Section 7.1). PSEs are 
recorded on SAE Worksheets and sent to the Drug Safety designee within 24 hours of site 
personnel becoming aware of the event. 
Change to:
Protocol Specified Events (PSEs) are additional events that must be reported in an expedited 
manner. A PSE may or may not be an SAE. PSEs are considered SAEs if they meet 1 or more 
of the criteria for an SAE (see Section 7.1). PSEs are recorded on the PSE page of the eCRF
within 24 hours of site personnel becoming aware of the event.


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Section 7.4 Laboratory Abnormalities as Adverse Events
Change from:
A laboratory abnormality should be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, or concomitant therapy. In addition, any medically important laboratory 
abnormality may be reported as an adverse event at the discretion of the investigator. This 
includes laboratory abnormalities for which there is no intervention but the abnormal value(s) 
suggests a disease or organ toxicity. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC increased). In 
addition, an IgG abnormality < 250 mg/dL (Grade 4) should be recorded as an adverse event 
(and SAE if meeting the criteria in Section 7.1).
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, severe, or life-threatening as specified in Section 7.8.
Change to:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, 
elevated creatinine, urine RBC increased). In addition, an IgG abnormality < 250 mg/dL 
(Grade 4) should always be recorded on the PSE page of the eCRF. IgG < 250 mg/dL
should also be reported as an SAE if it meets one or more of the SAE criteria in Section
7.1.
Laboratory tests are graded according to the Adverse Event Severity Grading Tables in 
Appendix 7. If a particular lab test is not listed in Appendix 7, the lab test should be graded as 
mild, moderate, or severe as specified in Section 7.8.


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Section 7.5 Progressive Multifocal Leukoencephalopathy
Change from:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping immunosuppressant therapy.
Change to:
If PML is confirmed, study agent should be discontinued and consideration should be given to 
stopping all immunosuppressant therapy.
Section 7.7 Reporting a Pregnancy
Change from:
Pregnancies must be reported to the HGS Drug Safety designee within 24 hours of the site
becoming aware of a pregnancy in a study subject. All pregnancies that are identified from the 
start of study agent through 16 weeks following the last dose of study agent should be 
reported. All pregnancies are tracked up to term or delivery following the last study agent 
treatment. When pregnancy is reported, HGS Drug Safety sends an acknowledgement 
memorandum to the principal investigator along with a Pregnancy Assessment Form. A 
Pregnancy Assessment Form must be completed every three months until live birth, elective 
termination of the pregnancy, or miscarriage. The site is responsible for following the 
subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 7.1 and 
Section 7.2.
Change to:
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the 
Sponsor within 2 weeks of learning of its occurrence. All pregnancies that are identified 
from the start of study agent through 16 weeks following the last dose of study agent 
should be reported. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE 
or SAE. Spontaneous abortions must be reported as an SAE.


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Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the Sponsor.
Section 7.8 Investigator Evaluation of Adverse Events
Change from:
The investigator will evaluate all adverse events with respect to seriousness, severity 
(intensity or grade), and causality (relationship to study agent). The criteria for serious are 
listed in Section 7.1. The severity of an AE is to be evaluated according to the Adverse Event 
Severity Grading Tables in Appendix 7. If an AE does not have Adverse Event Severity 
Grading in Appendix 7, the following severity classifications will be used:
SEVERITY:
Grade 1- Mild
     - causing no limitation of usual activities.
Grade 2- Moderate 
     - causing some limitation of usual activities.
Grade 3- Severe
    - causing inability to carry out usual activities.
Grade 4- Life-threatening*
  - potentially life-threatening or disabling; significant medical 
intervention is required.
*Note – a severity assessment of Life-threatening is not necessarily the same as the 
seriousness criterion of Life-threatening (see “serious” criteria Section 7.1). The former means 
that the event is a potential threat. The latter means that the event is an immediate threat to 
life.
CAUSALITY:
It is a regulatory requirement for investigators to assess relationship between the 
investigational product(s) and the occurrence of each AE/SAE based on the information 
available. The assessment should be reviewed on receipt of any new information and amended 
if necessary. A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship. Facts/evidence or arguments that may support a 
“reasonable possibility” include, e.g., a temporal relationship, a pharmacologically-predicted 
event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant 
medication, a concurrent illness, or relevant medical history, should also be considered.
Change to:
The investigator will evaluate all adverse events with respect to seriousness (criteria for 
seriousness are listed in Section 7.1), severity (intensity), and causality (relationship to study 
agent). The investigator will make an assessment of intensity based on the Division of 


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Microbiology and Infectious Diseases (DMID) Adverse Event Severity Grading Tables (see
Appendix 7) where possible:
SEVERITY:

Mild
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities (Grade 1 
DMID).

Moderate 
An event that is sufficiently discomforting to interfere with 
everyday activities (Grade 2 DMID).

Severe
An event that prevents normal everyday activities (Grade 3 or 4 
DMID).

Not applicable
Those event(s) where intensity is meaningless or impossible to 
determine (i.e., blindness and coma).
An AE that is assessed as severe will not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
CAUSALITY:
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. The investigator will also consult the 
Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK. The investigator may change his/her 
opinion of causality in light of follow-up information, amending the SAE data collection 
tool accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.


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Section 7.9 Follow-up of Adverse Events
Change from:
Adverse events that occur from the start of study medication through 8 weeks after the date of 
last administration of study agent are followed until final outcome is known or until the end of 
the 8-week study follow-up period. Adverse events that have not resolved at the end of the 8-
week study follow-up visit are recorded on the adverse event case report form (AE eCRF) as 
ONGOING. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for an SAE (eg, the subject is lost to follow-up), the reason a final outcome 
could not be obtained will be documented by the investigator. 
Change to:
Serious and non-serious adverse events that occur from the start of study medication 
administration through 8 weeks after the date of last administration of study agent are 
reported. 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(see Section 8.6.2) will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up. This applies to all 
subjects, including those withdrawn prematurely. 
PSEs (see Section 7.3) that occur after the Screening visit through 8 weeks after the date 
of last administration of study agent are reported and followed as described above for 
AEs/SAEs.
Section 8.1 General Statistical Considerations
Change from:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject or when 66 events (relapse as defined for the primary efficacy endpoint) have 
been observed, whichever is later. All subjects and study site personnel will remain blinded to 
original treatment assignment until after the final database is locked and the results of the 
study are made publicly available. 
For the analysis of the primary and the major secondary efficacy endpoint, a step-down 
sequential testing procedure will be used to control the overall type 1 error. With this 


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procedure, the primary endpoint (time to the first relapse) will be evaluated first. If the 
primary efficacy endpoint demonstrates statistical significance (2-sided, alpha=0.05) then 
inference will proceed to the major secondary efficacy endpoint, time to the first major relapse 
(2-sided, alpha = 0.05). If the result is statistically significant, superiority of belimumab on the 
time to the first major relapse will be established. If statistical significance is not met, p values
may be reported and considered descriptive.
Analyses of all other efficacy endpoints other than the primary and major secondary efficacy 
endpoints will not be subject to any multiple testing procedure. All statistical tests will be 
2-sided and performed at an overall significance level of 0.05.
Change to:
The database will be locked for the primary analysis after all data have been collected, 
verified and validated for all subjects through 12 months after the randomization of the 
last subject. All subjects and study site personnel will remain blinded to original treatment 
assignment until after the final database is locked and the results of the study are made 
publicly available. 
Analysis of primary and secondary endpoints will be exploratory in nature. Nominal p
values may be reported and considered descriptive. Where appropriate point estimates and 
95% confidence intervals will be constructed.
Section 8.2 Randomization Procedure and Assignment to Treatment Groups
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled 
study. Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 
1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  Day 0 (first administration of belimumab/placebo and azathioprine) 
must occur no more than 2 weeks after confirmation of remission.  
Change to:
This is a, multi-center, multinational, randomized, double-blind, placebo-controlled study. 
Once subjects have consented, have undergone all screening procedures and have been 
determined to be eligible for the study, they will be randomly assigned (via an interactive web 
response system [IWRS]) to 1 of 2 treatment groups (belimumab [10 mg/kg] or placebo) in a 


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1:1 ratio. At randomization, subjects will be stratified according to ANCA type (anti-PR3 vs. 
anti-MPO), disease stage at induction (initial diagnosis vs. relapsing disease), and induction 
regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. RTX). Randomization will be 
performed on Day 0.  
Section 8.5.2 Primary Efficacy Analysis
Change from:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less 5 in subjects using the oral or IV cyclophosphamide. For any subject 
who does not experience a relapse, the time to first relapse will be censored at the time of the 
subject’s last assessment. Subjects who discontinue study agent prior to relapse/flare 
(as defined in primary efficacy endpoint) are to be followed per protocol for inclusion in the 
primary efficacy analysis until relapse/flare or the end of the double-blind treatment phase 
(whichever is earlier). The database will be locked and the primary efficacy analysis will be 
performed after at least 66 subjects have experienced a relapse and at least 12 months have 
elapsed after the last subject is randomized.
Change to:
The primary efficacy analysis will compare the time to first relapse from Day 0 between the 
placebo/azathioprine group and the belimumab/azathioprine combination group using a Cox 
proportional hazard model, adjusted for ANCA type (anti-PR3 vs. anti-MPO), disease stage at 
induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide). However, the adjustment of induction 
regimen will be changed to rituximab vs. IV and/or oral cyclophosphamide if the number of 
events (relapse) is less than 5 in subjects using the oral or IV cyclophosphamide. If there are 
then still less than 5 patients with an event (relapse) in any of the levels of this or any 
other stratification factor then the stratification term may be removed from the model.
For any subject who does not experience a relapse, the time to first relapse will be censored at 
the time of the subject’s last assessment. Subjects who discontinue study agent prior to 
relapse/flare (as defined in primary efficacy endpoint) are to be followed per protocol for 
inclusion in the primary efficacy analysis until relapse/flare or the end of the double-blind 
treatment phase (whichever is earlier). The database will be locked and the primary efficacy 
analysis will be performed after 12 months have elapsed following randomization of the last 
subject.


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Deleted:
Section 8.5.2.1 Subgroup Analysis
Subgroup analysis, of the primary efficacy endpoint only, will be performed in the following 
subgroups:

ANCA type (anti-PR3 vs. anti-MPO)

Disease type (WG vs. MPA)

Disease stage at induction (initial diagnosis vs. relapsing disease)

Induction regimen (rituximab vs. IV cyclophosphamide vs. oral cyclophosphamide)

Race (white, American Indian, Asian, and black)

Region (US/Canada, EU/Australia/Israel, Americas excluding US/Canada, and Asia)

Age (< 65 vs. ≥ 65)

Gender

Duration of IV corticosteroid pulse used for induction (1 day vs > 1 day)
Section 8.5.5 Major Secondary Endpoint analysis and Other Efficacy Analyses
Change from:
The analysis of the major secondary efficacy endpoint will be performed using the same 
method described for the primary efficacy endpoint, but censoring subjects who receive any 
prohibited medication (as defined in Section 5.5.1) prior to an observation of any major 
BVAS item. Any censoring will be applied on the date prohibited medications are received.
Change to:
The exploratory analysis of the major secondary efficacy endpoint will be performed using 
the same method described for the primary efficacy endpoint, but censoring subjects who 
receive any prohibited medication (as defined in Section 5.5.1) prior to an observation of any 
major BVAS item. Any censoring will be applied on the date prohibited medications are 
received.
References
Added:
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 12 Protocol Addendum – Benefit and Risk Assessment, Study Overview and 
Patient Population
Change from:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen.
Change to:
This is a multi-center, multinational, randomized, double-blind study to evaluate the efficacy 
and safety of belimumab in combination with azathioprine for the maintenance of remission in 
subjects with systemic Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA) 
following a standard induction regimen.
Change from:
A target of 300 to 400 subjects who are between 6 and 26 weeks from starting induction 
therapy, achieve a BVAS v.3 score of 0 (ie, are in remission), and are receiving ≤10 mg/day 
prednisone (or equivalent) on 2 consecutive measurements at least 14 days apart will be 
enrolled into the study.
Change to:
Approximately 100 subjects with ANCA-vasculitis who are between 6 and 26 weeks from 
starting induction therapy, who achieve a BVAS v.3 score of 0 (ie, are in remission), and are 
receiving ≤10 mg/day prednisone (or equivalent) on 2 consecutive measurements at least 14 
days apart will be enrolled into the study.
Change from:
The database will be locked and the primary analysis will be performed after at least 66 
subjects have experienced a relapse and at least 12 months have elapsed after the last subject 
is randomized.
Change to:
The database will be locked and the primary analysis will be performed when 12 months have 
elapsed after the last subject is randomized.
Deleted:


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If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety.
Deleted:
These visits apply to subjects who have completed as well as those who have withdrawn early 
from the open-label extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Safety Considerations
Change from:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase and the open-label extension.
Change to:
Per protocol, subjects are to remain under clinical supervision for 3 hours after completion of 
the first 2 infusions in the double-blind treatment phase.


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Appendix 13 Algorithm for Liver Chemistry Stopping and Follow-up Criteria
Added:
Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.2.1. 
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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Liver Monitoring Event Algorithm with Continued Therapy for ALT≥3xULN but 
<8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 
6.5.2.1.


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Deleted:


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Protocol Amendment 03 With Local Addenda 01, 02 for Ireland, 25 February 2014
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to provide flexibility in timing of initiation of azathioprine 
maintenance therapy i.e., option to initiate as soon as clinically indicated and prior to 
confirmation of remission.
2. The protocol has been modified to allow alternative unlicensed rituximab dose for 
induction (1 g every 2 weeks) in addition to the licensed dosing regimen (375 mg/m2/wk 
for 4 doses).
3. The protocol has been modified to provide flexibility in timing of baseline BVAS 
assessments – allowing 2 baseline assessments separated by at least 14 days (instead of 
strict 21-35 days separation).
4. The absolute requirement to randomize within 14 days of confirmation of remission has 
been removed and clarification has been added that subjects cannot be randomized until at 
least 6 weeks after initiation of induction therapy.
5. A study schematic diagram has been added to clarify the trial design.
6. Clarification has been added regarding ‘high dose corticosteroids’ for induction and text 
provides guidance but allows locally accepted practice. No subject should receive <10mg 
for induction.
7. The protocol has been modified to allow some flexibility to cyclophosphamide dosing 
regimens (allows adjustment for age, obesity, renal insufficiency, leukopenia, other 
toxicities) for induction.
8. The protocol has been modified to allow the option to use methotrexate from the outset, as 
an alternative to azathioprine, if patient is a priori known to be azathioprine intolerant or 
has low/absent thiopurine methyltransferase (TPMT) activity. Exclusion of subject with 
intolerance or contraindications to methotrexate (where this is being considered as an 
alternative to azathioprine). 
9. The protocol has been modified to allow equal to/less than 10 mg prednisone daily during 
maintenance (rather than strictly <10 mg prednisone daily); articulated option to taper as 
clinically appropriate.
10. Progressive multifocal leukoencephalopathy text has been updated based on new 
information. This addition is to ensure full awareness of PML risk in the trial population 
and to provide clarification on clinical assessment and actions.
11. In Appendices 1 and 2, “criteria” in the title and text has been changed to “definition”. 
The List of Appendices has been updated accordingly.
12. Appendix 5 has been updated to include a sample of the VDI case report form.


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13. The Benefit and Risk Assessment section has been updated to reflect new and/or amended 
information in the protocol body.
14. Minor administrative change was made for bulleted presentation in Benefit and Risk 
Assessment and to correct a protocol section cross-reference. These minor changes are not 
shown in the Modifications section below. 
15. The list of abbreviations has been updated to add abbreviations as a result of new and/or 
amended text and to correct previous errors.
16. The date of Local Addendum 01 for Ireland has been added to the cover page for clarity.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 02
Date: 27 May 2013
EudraCT 2011-004569-33
Local Addendum 02 for Ireland, Date: 07 August 2013
Modified to:
Protocol Amendment 03
Date: 25 February 2014
EudraCT 2011-004569-33
Local Addendum 01 for Ireland, Date: 31 January 2013
Local Addendum 02 for Ireland, Date: 07 August 2013
Revision Chronology for HGS1006-C1100 (BEL115466)
Added row:
Date
Document*
Global
DNG2013N167980_01
04 February 2014
Amendment No 03
Local
DNG2013N160488_03
25 February 2014
Amendment No 03 with Local 
Addenda 01, 02 for Ireland


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Synopsis, Diagnosis & Inclusion Criteria
Section 4.1, Inclusion Criteria
Formerly:
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:

A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

cyclophosphamide 2 mg/kg/day orally plus HDCS OR

cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving < 10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements 21 to 
35 days apart, achieved no more than 26 weeks after the first dose of induction therapy (either 
CYC or RTX, as defined in Section 3.1). Maintenance therapy (belimumab/placebo + 
azathioprine) must start no more than 2 weeks after confirmation of remission.
Modified to:
3. In the 26 weeks prior to randomization (Day 0), had an episode of moderately to severely 
active WG or MPA requiring treatment under one of the following induction regimens:

A single course of rituximab administered at a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a 
two-week interval, plus HDCS OR

cyclophosphamide 2 mg/kg/day orally plus HDCS OR

cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
5. Have a Birmingham Vasculitis Activity Score (BVAS v.3 [Appendix 3]) of 0 and be 
receiving 10 mg/day oral prednisone (or equivalent) on 2 consecutive measurements at least 
14 days apart, between 6 and 26 weeks after the first dose of induction therapy (either CYC 
or RTX, as defined in Section 3.1). A minimum 6 week period should elapse between 
initiation of induction therapy and randomization.


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Synopsis, Exclusion Criteria and Section 4.2, Exclusion Criteria
Formerly:
2. Known intolerance to azathioprine (AZA) or in whom AZA is contraindicated.
Modified to:
2. Known intolerance or contraindications to azathioprine (AZA); and known intolerance 
or contraindications to methotrexate where methotrexate is being considered as an 
alternative to AZA for maintenance therapy.
Synopsis, Section Study Design and Schedule
and Section 3.1 Basic Design 
Characteristics
Formerly:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:

A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Subjects who are within 26 weeks of starting induction therapy, achieve a BVAS v.3 score 
of 0 (Appendix 4), and are receiving < 10 mg/day prednisone (or equivalent) on 2 consecutive 
measurements 21 to 35 days apart may be enrolled into the study. Randomization will be 
performed on Day 0. Day 0 (first administration of belimumab/placebo) must occur no more 
than 2 weeks after confirmation of remission. Azathioprine must be initiated at any time 
following confirmation of remission up to and including Day 0. All subjects will be treated 


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with oral azathioprine (AZA) at a dose of 2 mg/kg/day. Subjects who meet eligibility criteria 
will be randomized in a 1:1 ratio to receive study agent (belimumab [10 mg/kg] or placebo) 
administered intravenously (IV) over 1 hour. The randomization will be stratified according to 
ANCA type (anti-PR3 vs. anti-MPO), disease stage at induction (initial diagnosis vs. relapsing 
disease) and induction regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. 
rituximab). Belimumab or placebo will be supplied by the sponsor during this double-blind 
treatment phase. It is anticipated that no more than 25% of the patients would be newly 
diagnosed and anti-MPO positive, and as such enrollment of these patients may be capped if 
they exceed this proportion. Study agent (belimumab/placebo) will be administered at Day 0, 
14, 28, and every 28 days thereafter.  
Modified to:
Subjects enrolled into the trial must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (ie, induction therapy) in the 6 months leading up to 
randomization. Subjects treated under the following induction regimens will be eligible for 
participation in the study:

A single course rituximab (RTX) administered at  a dose of 375 mg /m2/week for 4 weeks 
plus high dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

Cyclophosphamide 2mg/kg/day orally plus HDCS OR

Cyclophosphamide 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 
15 mg/kg every 3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10 
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
Subjects who are between 6 and 26 weeks of starting induction therapy, achieve a BVAS v.3 
score of 0 (Appendix 4), and are receiving ≤ 10 mg/day prednisone (or equivalent) on 2 
consecutive measurements at least 14 days apart may be enrolled into the study. A minimum 
6 week period should elapse between initiation of induction therapy and randomization.
Randomization will be performed on Day 0. A schematic of the study design is shown 
below/in Figure 1.


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All randomized subjects should be treated with oral azathioprine (AZA) at a dose of 
2 mg/kg/day. Azathioprine may be initiated as soon as it is clinically indicated following 
administration of induction therapy. Azathioprine should not be initiated any later than 
Day 0. Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to receive study 
agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. The 
randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), disease 
stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.  
Added:
Schematic of Study Design/Figure 1 Schematic of Study Design
Section List of Abbreviations
Formerly:
CRO
Contract Reseach Organization
WG
Wegener’s Granulmatosis


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Modified to:
CRO
Contract Research Organization
WG
Wegener’s Granulmatosis (Granulomatosis with polyangiitis)
Added:
TPMT 
thiopurine methyltransferase
Section 1.1 Disease Background, 2nd sentence
Formerly:
A subset of the primary small vessel vasculitides: Wegener’s granulomatosis; also known as 
granulomatosis with polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss 
syndrome (CSS), are characterized by the presence of anti-neutrophil cytoplasmic antibodies 
(ANCA) (Jennette and Falk, 1997).
Modified to:
A subset of the primary small vessel vasculitides: Wegener’s granulomatosis (also commonly
referred to as granulomatosis with polyangiitis [GPA]), microscopic polyangiitis and Churg-
Strauss syndrome (CSS), are characterized by the presence of anti-neutrophil cytoplasmic 
antibodies (ANCA) (Jennette and Falk, 1997).
Section 5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent) at any time during the study, or

IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 7 days (consecutive or non consecutive), are only allowable within the 
first 2 months of the double-blind treatment period.
Modified to:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent) at any time during the study, or

IV corticosteroid pulses at any dose;


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Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 7 days (consecutive or non consecutive), are only allowable within the 
first 2 months of the double-blind treatment period.
Section 5.5.3 Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
7 days (consecutive or non consecutive) within the first 2 months of the double-blind 
treatment period. At other times, subjects are restricted to < 10 mg/day. Inhaled 
corticosteroids for asthma, or topical corticosteroids for atopic dermatitis are also permitted. 
Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse 
up to 125 mg prednisone (or equivalent) are permitted for reasons other than vasculitis (eg. 
acute allergic reaction), but a subject cannot receive more than 1 such corticosteroid regimen 
in any 365 day period (See also Section 5.5.1).
Modified to:
The use of stable baseline dose regimens of corticosteroids (≤ 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
7 days (consecutive or non consecutive) within the first 2 months of the double-blind 
treatment period. At other times, subjects are restricted to ≤ 10 mg/day prednisone or 
equivalent. It is expected that this dose may be tapered as clinically appropriate. Inhaled 
corticosteroids for asthma, or topical corticosteroids for atopic dermatitis are also permitted. 
Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse 
up to 125 mg prednisone (or equivalent) are permitted for reasons other than vasculitis (eg. 
acute allergic reaction), but a subject cannot receive more than 1 such corticosteroid regimen 
in any 365 day period (See also Section 5.5.1).


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Section 5.5.3.1 Azathioprine and Methotrexate
Formerly:
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). Azathioprine must 
be initiated at any time following confirmation of remission up to and including Day 0 at a 
dose of 50 mg/day and increased by no more than 50 mg/day every week until the target dose 
is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
It is recommended that the appropriate local prescribing information (eg, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine or 
methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued
based on the discretion of the investigator. 
Modified to:
The target dose of azathioprine is 2 mg/kg/day (not to exceed 200 mg/day). For the 
maintenance of remission azathioprine may be initiated as soon as it is clinically indicated 
following administration of induction therapy. Azathioprine must not be initiated any 
later than Day 0. Azathioprine should be started at a dose of 50 mg/day and increased by 
no more than 50 mg/day every week until the target dose is achieved.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1 mg/kg/day. If the subject continues to 
experience the toxicities described above a switch to methotrexate at a target dose of  
25 mg/week (and no less than 10 mg/week) as an alternative to azathioprine will be permitted. 
These subjects will be included in the primary analysis. 
For subjects previously identified as being intolerant to azathioprine, or for subjects 
identified as having undetectable or reduced activity of thiopurine methyltransferase 
(TPMT), it may be permissible for methotrexate to be used as an alternative to 
azathioprine for the maintenance of remission from the outset. This should be discussed 


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with the medical monitor. Methotrexate would not be recommended for those subjects 
with significantly impaired renal function.
The appropriate local prescribing information (eg, dose adjustments, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine 
or methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
As per the Summary of Product Characteristics (SmPC) for azathioprine, it is suggested that 
during the first 8 weeks of therapy, complete blood counts, including platelets, should be 
performed weekly or more frequently if high dosage is used or if severe renal and/or hepatic 
disorder is present. The blood count frequency may be reduced later in therapy, but it is 
suggested that complete blood counts are repeated monthly, or at least at intervals of not 
longer than 3 months.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator.
Section 6.2 Study Enrollment Procedures
Formerly:
Subjects who have undergone all screening procedures and have met the entry criteria will be
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
Azathioprine must be initiated at any time following confirmation of remission up to and 
including Day 0. Female subjects who require pregnancy testing must have a negative urine 
pregnancy test done on Day 0, prior to randomization. Subjects will be randomized in a 
1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + AZA).
Modified to:
Subjects who have undergone all screening procedures and have met the entry criteria will be 
enrolled into the study and assigned to treatment by Interactive Web Response System 
(IWRS). Randomization will be performed on Day 0. Azathioprine may be initiated as soon 
as it is clinically indicated following administration of induction therapy. Azathioprine 
must not be initiated any later than Day 0. Female subjects who require pregnancy testing 
must have a negative urine pregnancy test done on Day 0, prior to randomization. Subjects 
will be randomized in a 1:1 ratio to 1 of 2 treatment groups (belimumab + AZA or placebo + 
AZA). 


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Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Footnotes
Formerly:
10. Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience 
the toxicities described above a switch to methotrexate at doses of up to 25 mg/week as an 
alternative to azathioprine will be permitted.
Modified to:
10. Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, 
AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, 
characterized by severe nausea and vomiting, following initiation of azathioprine will be 
permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience 
the toxicities described above a switch to methotrexate at doses of up to 25 mg/week as an 
alternative to azathioprine will be permitted. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate 
to be used as an alternative to azathioprine for the maintenance of remission from the 
outset following discussion with the medical monitor.
Section 7.1 Definitions
Formerly:
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above. 
These should also usually be considered serious. (ICH guidelines, March 1995)
Modified to:
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be
immediately life threatening or result in death or result in hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed above (eg, 
possible drug-induced liver injury). These should also usually be considered serious. (ICH 
guidelines, March 1995)


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Section7.5 Progressive Multifocal Leukoencephalopathy
Formerly:
There have been no reported cases of PML in subjects with SLE or RA treated with 
belimumab. However, patients with autoimmune diseases may be at increased risk for PML 
secondary to the diseases themselves, as well as the concurrent use of immunosuppressive 
drugs. The most common signs and symptoms of PML include visual disturbances, ocular 
movements, ataxia, and mental status changes such as disorientation or confusion. Clinical 
signs and symptoms of PML and vasculitis can be similar. The investigator must exercise best 
judgment in further workup and clinical intervention as appropriate. If PML is suspected, this 
should be promptly reported to the sponsor.
Modified to:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and 
symptoms. The subject should be referred to a neurologist or other appropriate 
specialist for evaluation. If PML is confirmed, study agent should be discontinued and 
consideration should be given to stopping immunosuppressant therapy. 
If PML is suspected, this should be immediately reported to the Medical Monitor.  The 
appropriateness of continuing study agent, while the case is being assessed, should be 
discussed.
Section 11 References
Added:
Jones,RB, Ferraro,AJ, Chaudhry,AN, et al. A multicenter survey of rituximab therapy 
for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis 
Rheum 2009; 60: 2156-68.
Appendix 1 Chapel Hill Consensus Criteria for Wegener’s Granulomatosis
Formerly:
Appendix 1 Chapel Hill Consensus Criteria for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Criteria require:


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Modified to:
Appendix 1 Chapel Hill Consensus Definition for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Definition requires:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis
Formerly:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis (MPA) (Jennette et 
al, 2013)
The CHCC criteria require:
Modified to:
Appendix 2 Chapel Hill Consensus Definition for Microscopic Polyangiitis (MPA) (Jennette 
et al, 2013)
The CHCC Definition requires:
Appendix 5 Vasculitis Damage Index
Added:
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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


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Appendix 12 Protocol Addendum – Benefit and Risk Assessment, IV Belimumab
Added:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases,
has been reported in patients with SLE receiving 
immunosuppressant pharmacotherapy, including belimumab. Although the benefit-risk 
profile for belimumab remains unchanged following these events, the Sponsor considers 
that knowledge of these cases is important and has updated the clinical investigator’s 
brochure (IB) for belimumab and revised the informed consent form (ICF) to 
communicate that development of PML is a potential risk.  
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Belimumab in ANCA-
Associated Vasculitis, Study Overview and Patient Population
Formerly:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of CYC are given as targets but may be adjusted for renal insufficiency or white 
cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.


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A target of 300 to 400 subjects who are within 26 weeks of starting induction therapy, achieve 
a BVAS v.3 score of 0 (ie, are in remission), and are receiving less than 10 mg/day prednisone 
(or equivalent) on 2 consecutive measurements 21 to 35 days apart will be enrolled into the 
study. Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to receive 
study agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. 
Study agent (belimumab/placebo) will be administered at Day 0, 14, and every 28 days 
thereafter. Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. Azathioprine must be initiated at any time following 
confirmation of remission up to and including Day 0. Patients with known intolerance to 
azathioprine will be excluded from the trial. Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.
Modified to:
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.


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[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
A target of 300 to 400 subjects who are between 6 and 26 weeks from starting induction 
therapy, achieve a BVAS v.3 score of 0 (ie, are in remission), and are receiving ≤10 mg/day 
prednisone (or equivalent) on 2 consecutive measurements at least 14 days apart will be 
enrolled into the study. Subjects who meet the eligibility criteria will be randomized in a 1:1 
ratio to receive study agent (belimumab [10 mg/kg] or placebo) administered intravenously 
(IV) over 1 hour. Study agent (belimumab/placebo) will be administered at Day 0, 14, and 
every 28 days thereafter. Randomization will be performed on Day 0. 
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. For the maintenance of remission, azathioprine may be 
initiated as soon as it is clinically indicated following administration of induction 
therapy. Azathioprine must not be initiated any later than Day 0. For subjects 
previously identified as being intolerant to azathioprine, or for subjects identified as 
having undetectable or reduced activity of thiopurine methyltransferase (TPMT), it may 
be permissible for methotrexate to be used as an alternative to azathioprine for the 
maintenance of remission from the outset.  Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.


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Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Dose and Schedule, 
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Formerly:
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX regimen specified in this vasculitis study is the 
same as that approved by the FDA for this indication.
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992;
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 


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Summary of Modifications
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements 3 to 5 weeks 
apart: a BVAS v3 score of 0 and be receiving < 10 mg/day of oral prednisone [or equivalent], 
no more than 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol must occur within 2 
weeks of achieving a confirmed remission and the randomization will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. In this study, subjects who have a known 
intolerance to azathioprine will be excluded. Subjects naive to azathioprine and who 
experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or thrombocytopenia, AST 
or ALT 2 times ULN, or a several gastrointestinal hypersensitivity reaction characterized by 
severe nausea and vomiting), following initiation of azathioprine will be permitted to reduce 
the dose to no less than 1 mg/kg/day. If the subject continues to experience toxicities, a switch 
to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be 
permitted. As azathioprine is among the better tolerated immunomodulatory agents, it is not 
anticipated that many subjects will need to substitute methotrexate for azathioprine (Walters 
et al, 2010). Subjects for whom methotrexate is substituted for azathioprine will be included 
in the primary analysis. The protocol instructs physicians to follow the appropriate local 
prescribing information for azathioprine or methotrexate (as applicable) prior to and during 
treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Modified to:
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:


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Belimumab
Summary of Modifications

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR 

A single course of rituximab comprising two doses, 1g IV each, separated by a two-
week interval, plus HDCS OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
[The cyclophosphamide dosing regimens are provided as targets but may be adjusted for 
older age, obesity, renal insufficiency, leukopenia, or other toxicities as dictated by local 
practice.]
For guidance purposes, the recommended HDCS regimen with any of the above induction 
therapies is: methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 
0.5-1 mg/kg/day not to exceed 80 mg/day and tapered as clinically appropriate to reach ≤ 10
mg/day. As doses for HDCS pulses per the protocol are recommended doses, local 
standard of care for the steroid dosing regimen would be acceptable if intravenous 
steroid pulses are not part of standard of care on site. However, all subjects must be 
receiving more than 10 mg of prednisone/day or equivalent for induction.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX dosing regimen of 4 infusions of 375 mg/m2
each given 1 week apart reflects the dosing regimen that is approved by the FDA for this 
indication. An alternative RTX induction regimen (2 infusions of 1 gram each 
administered 2 weeks apart) is also offered in the protocol. Although the latter regimen 
is not licensed as an induction therapy for ANCA-vasculitis, it is very widely used in 
clinical practice and clinical evidence suggests that there is no difference between the 
two dosing regimens in terms of duration of B-cell depletion or therapeutic efficacy 
efficacy (Jones et al, 2009).
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 3 
weeks thereafter) plus prednisone has been the standard induction regimen for WG and MPA 
since the early 1970s when initial work by Fauci and Wolff at the National Institutes of Health 
showed that this regimen induced disease remission in 12/14 patients and subsequent work 
showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).


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Summary of Modifications
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements at least 14 days
apart: a BVAS v3 score of 0 and be receiving ≤ 10 mg/day of oral prednisone [or equivalent], 
between 6 and 26 weeks after the first dose of induction therapy) has been achieved, subject 
randomization into this protocol occurs. In this maintenance of remission trial, subjects will be 
randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + placebo or AZA (2 
mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol will be stratified by 
induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. For the maintenance of remission, 
azathioprine may be initiated as soon as it is clinically indicated following administration 
of induction therapy and no later than Day 0. For subjects previously identified as being 
intolerant to azathioprine, or for subjects identified as having undetectable or reduced 
activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate 
to be used as an alternative to azathioprine for the maintenance of remission from the 
outset. Subjects naive to azathioprine and who experience azathioprine-related toxicity 
(Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT 2 times ULN, or a several 
gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting), 
following initiation of azathioprine will be permitted to reduce the dose to no less than 1 
mg/kg/day. If the subject continues to experience toxicities, a switch to methotrexate at doses 
of up to 25 mg/week as an alternative to azathioprine will be permitted. As azathioprine is 
among the better tolerated immunomodulatory agents, it is not anticipated that many subjects 
will need to substitute methotrexate for azathioprine (Walters et al, 2010). Subjects for whom 
methotrexate is substituted for azathioprine will be included in the primary analysis. The 
protocol instructs physicians to follow the appropriate local prescribing information for 
azathioprine or methotrexate (as applicable) prior to and during treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 


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Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Appendix 12 Protocol Addendum – Benefit and Risk Assessment, Safety Considerations
Added:
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in patients with SLE receiving
immunosuppressant pharmacotherapy, including belimumab. Therefore, a diagnosis of 
PML should be considered in any subject presenting with new-onset or deteriorating 
neurological signs and symptoms. The protocol requires that subjects 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.


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Protocol HGS1006-C1100-02 Addendum 02 (Ireland) Summary of Modifications
Belimumab
Protocol Amendment 02 with Local Addendum 02 for Ireland, 07 August 2013
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified, at the request of the Irish Medicines Board, to further 
clarify the timing of restrictions regarding steroid use for vasculitis.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 02
Date: 27 May 2013
Local Addendum 01 for Ireland, Date: 31 January 2013
Modified to:
Protocol Amendment: 02
Date: 27 May 2013
Local Addendum 02 for Ireland, Date: 07 August 2013
Section 5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:

Corticosteroids for vasculitis:
doses > 20 mg/day prednisone (or equivalent) for > 1 week, or
IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 1 week, are only allowable within the first 2 months of the double-blind 
treatment period.


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Modified to:

Corticosteroids for vasculitis:
doses > 20 mg/day prednisone (or equivalent) at any time during the study, or
IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for vasculitis, 
for a maximum of 7 days (consecutive or non consecutive), are only allowable within the 
first 2 months of the double-blind treatment period.
Section 5.5.3 Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
1 week within the first 2 months of the double-blind treatment period. At other times, subjects 
are restricted to < 10 mg/day. Inhaled corticosteroids for asthma, or topical corticosteroids for 
atopic dermatitis are also permitted. Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 
days or an  IV corticosteroid pulse up to 125 mg prednisone (or equivalent) are permitted for 
reasons other than vasculitis (eg. acute allergic reaction), but a subject cannot receive more 
than 1 such corticosteroid regimen in any 365 day period (See also Section 5.5.1).
Modified to:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a maximum 
of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a maximum of 
7 days (consecutive or non consecutive) within the first 2 months of the double-blind 
treatment period. At other times, subjects are restricted to < 10 mg/day. Inhaled 
corticosteroids for asthma, or topical corticosteroids for atopic dermatitis are also permitted. 
Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse 
up to 125 mg prednisone (or equivalent) are permitted for reasons other than vasculitis (eg. 
acute allergic reaction), but a subject cannot receive more than 1 such corticosteroid regimen 
in any 365 day period (See also Section 5.5.1).


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Protocol HGS1006-C1100-02 Addendum 01 (Ireland) Summary of Modifications
Belimumab
Protocol Amendment 02 with Local Addendum 01 for Ireland, 27 May 2013
Protocol Number: HGS1006-C1100
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to include testing at Screening for HIV antibody, to 
expand Hepatitis B serology testing, and to exclude patients who test positive according to 
the criteria specified. 
2. Because the RIBA antibody confirmation assay for hepatitis C is not available due to 
non-availability of manufacturer’s reagents, an alternative test, HCV RNA-PCR assay, 
will be used to detect the presence of viral RNA, and hence confirm a current infection.
3. The protocol has been modified to exclude patients at baseline with abnormal liver 
function according to the criteria specified.
4. A new section has been added to clarify how patient care should be managed if a patient 
has a liver chemistry event during the study. The accompanying figure has been placed in 
an appendix (Appendix 13) and the List of Appendices has been updated accordingly.
5. Measurement of vital signs (temperature, sitting blood pressure [systolic and diastolic], 
and heart rate) have been added to the procedures for all scheduled study visits and a 
12-lead ECG has been added to the procedures for the Day 0 visit. These procedures have 
been added to provide increased understanding and to assist analyses of potential safety 
events should they occur.
6. A page with the protocol’s revision chronology has been added.
7. The Synopsis has been corrected to include study agent dosing on day 28.
8. Text has been added to clarify that study agents (belimumab or placebo) will be provided 
by the sponsor during the double-blind treatment phase and that belimumab will be 
provided by the sponsor during the open-label extension phase.
9. Within the definition of postmenopausal in Inclusion Criterion #7, “1 year without 
menses” has been changed to “12 consecutive months with no menses without an 
alternative medical cause.” Also, the sub-bullet formatting of the last 8 rows of Inclusion 
Criterion #7 has been corrected.
10. Steroid use for vasculitis has been modified to restrict the use of corticosteroids up to a 
maximum of 20 mg/day of prednisone (or equivalent) for a maximum of 1 week within 
the first 2 months of the double-blind treatment period, and at other times, to < 10 mg/day.
11. The Reference List has been updated to include references cited in text but not present in 
the list and to delete a reference included in error. Also, the in text citation for Posner et al 
has been corrected to Posner et al 2007 and the reference has been added to the list.
12. Cross-references have been added in Section 1 for references that were in the Reference 
List but which inadvertenly had not been cited in text.


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13. In Appendix 8, for the question at baseline/screening “Is the time the subject felt most 
suicidal (i.e. the lifetime rating) more than X month(s) ago?”, the “X” has been corrected 
to “2”, i.e, “more than 2 month(s) ago”.
14. The investigator evaluation of adverse events regarding causality has been modified from 
a multi-choice assessment (definitely related, probably related, etc.) to an assessment of 
“reasonable possibility”.  
15. Appendix 9 has been corrected to cite the reference and the publication has been added to 
the Reference List.
16. Two new appendices have been added to provide the questionnaires for the PSRHQ 
(Appendix 10) and the PSRQ (Appendix 11) and cross-references added in-text as 
appropriate. The List of Appendices has been updated accordingly.
17. The protocol has been modified to include a Benefit and Risk Assessment (Appendix 12). 
The List of Appendices has been updated accordingly.
18. Minor administrative change was made for presentation of cross-referencing sections and 
tables, e.g., “see Sections X.1 and X.2” was changed to “see Section X.1 and 
Section X.2”. These minor changes are not shown in the Modifications section below. 
19. The list of abbreviations has been updated to add abbreviations as a result of new and/or 
amended text and to correct previous errors.
20. The Chapel Hill Consensus Conference (CHCC) definitions for Wegener’s granulomatosis 
and microscopic polyangiitis in Appendices 1 and 2 of the protocol have been updated to 
reflect the most recent CHCC (2012) definitions. The reference for this (Jeannette et al 
2013) is cited in the text (Section 1.1) and in the reference list.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 01
Date: 22 June 2012
Local Addendum 01 for Ireland, Date: 31 January 2013
Modified to:
Protocol Amendment: 02
Date: 27 May 2013
Local Addendum 01 for Ireland, Date: 31 January 2013


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Revision Chronology for HGS1006-C1100 (BEL115466)
Added:
Date
Document*
Global
07 March 2012
Original
Global
22 June 2012
Amendment No 01
Local
29 January 2013
Addendum 01 for Sweden
Local
DNG2013N160488_00
31 January 2013
Addendum 01 for Ireland
Global
DNG2013N167980_00
25 April 2013
Amendment No 02
Local
DNG2013N160488_01
27 May 2013
Amendment No 02 with Addendum 01 
for Ireland
*A Summary of Modifications document which provides a detailed list of changes for the 
amendment/addendum is available upon request.


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Synopsis, Diagnosis & Inclusion Criteria
Section 4.1, Inclusion Criteria
Formerly:


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Modified to:
Synopsis, Exclusion Criteria and Section 4.2, Exclusion Criteria
Formerly:
12. Have a historically positive test or test positive at screening for hepatitis B surface antigen, 
or hepatitis C antibody or are known to be HIV-1 positive.
Modified to:
12. Have a historically positive HIV test or test positive at screening for HIV.
13. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of 
testing for HBsAg, anti-HBc and anti-HBs as follows:


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
Patients positive for HBsAg are excluded.

Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs 
antibody and with no history of Hepatitis B vaccination are excluded.

Patients negative for HBsAg but positive for both anti-HBc and anti-HBs 
antibodies are excluded.

Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc 
antibody are excluded.
14. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood 
sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and 
negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample 
will be eligible to participate. Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate.
Added:
19. Subjects who have abnormal liver function tests defined as follows: aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≥2x upper limit of 
normal (ULN); alkaline phosphatase and bilirubin > 1.5xULN (isolated bilirubin 
> 1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
Synopsis, Section Study Design and Schedule
Formerly:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). It is anticipated that no more 
than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, and every 28 days thereafter.
Modified to:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.


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Formerly:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months.
Modified to:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Section List of Abbreviations
Formerly:
ALT
aspartate aminotransferase alanine
LDH
lactic dehydrogenase
Modified to:
ALT
alanine aminotransferase
LDH
lactate dehydrogenase
Added:
CPK
creatine phosphokinase
ECG
electrocardiogram
HB
hepatitis B
HBsAg
hepatitis B surface antigen
HBc
hepatitis B core
HCV
hepatitis C virus


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Section 1.1 Disease Background
Formerly:
Anti-PR3 antibodies are associated with increased morbidity and mortality compared to anti-
MPO. The most widely used classification criteria for diagnosing the 3 types of AAV are 
those published by the American College of Rheumatology (ACR) for WG and CSS (Leavitt 
et al, 1990 and Masi et al, 1990, respectively), and that published by the Chapel Hill 
Consensus Conference (CHCC) for MPA (Jennette et al, 1994).
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007).
In the US, the prevalence rates of WG range from 2.6-9/100000 (Mahr et al, 2006).
Modified to:
Anti-PR3 antibodies are associated with increased morbidity and mortality compared to anti-
MPO (Hogan et al, 1996; Franssen et al, 1998). The most widely used classification criteria 
for diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994; Jennette et al, 2013).
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007; 
Mahr, 2009).
In the US, the prevalence rates of WG range from 2.6 9/100000 (Zeft et al, 2005; Mahr et al, 
2006).
Section 1.3.1 Belimumab Administered Intravenously
Added:
A benefit-risk evaluation of belimumab in the context of the present study is provided in 
Appendix 12 of this protocol.


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Section 1.4 Rationale for the Study
Formerly:
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease.
Modified to:
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20 (Dass et al, 2008; Wang et al 2008), recently showed success in inducing 
remission in AAV (Stone et al, 2010) and was granted approval for the treatment of WG and 
MPA supports the rationale that belimumab, which down regulates B cells by targeting BLyS, 
may be useful in the treatment of this disease.
Section 3.1 Basic Design Characteristics
Formerly:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). It is anticipated that no more 
than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, and every 28 days thereafter.
Modified to:
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease) and induction regimen (IV 
cyclophosphamide vs. oral cyclophosphamide vs. rituximab). Belimumab or placebo will be 
supplied by the sponsor during this double-blind treatment phase. It is anticipated that no 
more than 25% of the patients would be newly diagnosed and anti-MPO positive, and as such 
enrollment of these patients may be capped if they exceed this proportion. Study agent 
(belimumab/placebo) will be administered at Day 0, 14, 28, and every 28 days thereafter.
Formerly:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 


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the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months.
Modified to:
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in the open-label extension phase. Subjects 
who enter the open-label extension phase will receive belimumab for up to an additional 
6 months and this will be supplied by the sponsor.
Section 5.5.1 Prohibited Medications and Therapies that Result in Treatment Failure
Formerly:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent), or

IV corticosteroid pulses at any dose;
Modified to:

Corticosteroids for vasculitis:

doses > 20 mg/day prednisone (or equivalent) for > 1 week, or

IV corticosteroid pulses at any dose;
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for 
vasculitis, for a maximum of 1 week, are only allowable within the first 2 months of 
the double-blind treatment period.
Section 5.5.3 Allowable Medications
Formerly:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or 
equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg prednisone 
(or equivalent) are permitted for reasons other than vasculitis (eg. acute allergic reaction), but 
a subject cannot receive more than 1 such corticosteroid regimen in any 365 day period (See 
also Section 5.5.1).


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Modified to:
The use of stable baseline dose regimens of corticosteroids (< 10 mg/day prednisone or 
equivalent) is permitted over the course of the trial. Doses of corticosteroid up to a 
maximum of 20 mg/day of prednisone (or equivalent), for vasculitis, are permitted for a 
maximum of 1 week within the first 2 months of the double-blind treatment period. At 
other times, subjects are restricted to < 10 mg/day. Inhaled corticosteroids for asthma, or 
topical corticosteroids for atopic dermatitis are also permitted. Doses of prednisone (or 
equivalent) > 20mg/day for ≤ 14 days or an  IV corticosteroid pulse up to 125 mg prednisone 
(or equivalent) are permitted for reasons other than vasculitis (eg. acute allergic reaction), but 
a subject cannot receive more than 1 such corticosteroid regimen in any 365 day period (See 
also Section 5.5.1).
Section 6.1 Screening Procedures (Day -60 to Day 0):
Formerly:

Blood samples for: (see Appendix 6 – Laboratory Tests)

Hepatitis B surface antigen, and Hepatitis C antibody testing
Modified to:

Blood samples for: (see Appendix 6 – Laboratory Tests)

HIV antibody testing, serologic investigations for Hepatitis B (HB) infection 
(HBsAg, anti-HBc, and anti-HBs), and Hepatitis C antibody testing ± confirmatory 
HCV RNA-PCR testing
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs18, 19 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.


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Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
12-lead ECG: Day 0 Visit
Formerly:
Not listed.
Modified to:
12-lead ECG19 is added to the study calendar under Clinical Assessments.
12-lead ECG is marked “X” as required at this visit.
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
HIV, Hepatitis B, C: Screening Visits
Formerly:
Hep B surface antigen & Hep C antibody
Modified to:
HIV, Hepatitis B, C20
HIV, Hepatitis B, C is marked “X” as required at this visit.
Table 6-1 Study Calendar, Double-blind Treatment Phase Year One
Footnotes
Formerly:
1Complete physical examination, including height, weight and vital signs.
Modified to:
1Complete physical examination, including height and weight.
Added:
18Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
19Complete prior to dosing.
20HIV, Hepatitis B surface antigen, anti-HBc, anti-HBs and hepatitis C antibody (if hepatitis C 
antibody positive, HCV RNA-PCR assay will be performed on a subsequent blood sample to 
confirm the results).


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Table 6-2  Study Calendar, Double-blind Treatment Phase Additional Years
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs11, 12 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.
Table 6-2  Study Calendar, Double-blind Treatment Phase Additional Years
Footnotes
Added
11Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12Complete prior to dosing.
Table 6-3  Study Calendar, Open-Label Extension Phase
Vital signs: All scheduled visits
Formerly:
Not listed.
Modified to:
Vital signs12, 13 is added to the study calendar under Clinical Assessments.
Vital signs is marked “X” as required at all scheduled visits.
Table 6-3  Study Calendar, Open-Label Extension Phase
Footnotes
Added:
12Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
13Complete prior to dosing.


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Section 6.6 Laboratory Tests
The following section has been added:
Section 6.6.2 Phase III-IV Liver Chemistry Stopping and Follow-up Criteria
The liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology.
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and presented in a figure 
in Appendix 13:
1. ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and 
INR>1.5, if INR measured). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
from that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be 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.
2. ALT ≥ 8xULN.
3. ALT ≥ 5xULN but <8 xULN persists for ≥2 weeks.
4. ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice), or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT ≥ 5xULN but <8 xULN and cannot be monitored weekly for ≥2 weeks.
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) 
(or ALT ≥ 3xULN and INR>1.5, if INR measured); INR measurement is not required and 
the threshold value stated will not apply to patients receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
from that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be 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.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed


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
Perform liver event follow up assessments, and monitor the subject until liver chemistries 
resolve, stabilize, or return to baseline values as described below.

Withdraw the subject from the study (unless further safety follow up is required) after 
completion of the liver chemistry monitoring as described below.

Do not re-start investigational product.
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat 
liver chemistries, liver event follow up assessments (see below), and close monitoring

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hours for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should 
be monitored as frequently as possible
Subjects with ALT ≥5xULN and <8xULN which exhibit a decrease to ALT ≥3xULN, but 
<5xULN and bilirubin <2xULN without hepatitis symptoms or rash, 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

Can continue investigational product

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects 
twice monthly until liver chemistries normalize or return to within baseline values.
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

• Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);


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
Hepatitis C RNA;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);

Hepatitis E IgM antibody;

Blood sample for PK analysis, obtained within approximately 1 to 2 weeks after the liver 
event. Record the date/time of the PK blood sample draw and the date/time of the last dose 
of investigational product 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 Procedures Manual.

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 hepatitis or hypersensitivity, such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form

Record use of concomitant medications, paracetamol (acetaminophen), herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form.

Record alcohol use on the liver event alcohol intake case report form
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and 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]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease.
Section 7.6 Suicidality Assessment
Formerly:
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 


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Questionnaire (PSRHQ, only the first time this condition is met) eCRF and a Possible 
Suicidality Related Questionnaire (PSRQ) eCRF (at all times this condition is met).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2010).
Modified to:
Subjects who answer “yes” to any suicidal behavior or “yes” to suicidal ideation questions 4 
or 5 on the C-SSRS should be referred to appropriate psychiatric care and prompts the 
completion of an SAE worksheet. The medical monitor should be notified when these events 
occur. In addition, a “yes” to any suicidal behavior or “yes” to suicidal ideation question 3, 4 
or 5 on the C-SSRS prompts the completion of the Possible Suicidality Related History 
Questionnaire (PSRHQ, only the first time this condition is met; refer to Appendix 10 for 
the PSRHQ) eCRF and a Possible Suicidality Related Questionnaire (PSRQ) eCRF (at all 
times this condition is met; refer to Appendix 11 for the PSRQ).  
Baseline/Screening and during treatment assessment of suicidality will be performed during 
the blinded portion of this study using C-SSRS (Refer to Appendix 8 for C-SSRS). 
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality 
by integrating both behaviour and ideation (Posner et al, 2007).
Section7.6.1 Possible Suicidality Related Questionnaire (PSRQ)
Formerly:
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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.
Modified to:
The investigator will be prompted to complete the PSRQ (in addition to the AE or SAE pages, 
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. Refer to Appendix 11 for the PSRQ.
Section 7.8 Investigator Evaluation of Adverse Events
Formerly:
CAUSALITY
Definitely Related
- reasonable temporal relationship to study agent administration


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- follows a known response pattern (eg, study agent is known to cause 
this AE)
- there is no alternative etiology
Probably Related
- reasonable temporal relationship
- follows a suspected response pattern (eg, based on similar drugs)
- no evidence for a more likely alternative etiology 
Possibly Related
- reasonable temporal relationship 
- little evidence for a more likely alternative etiology
Probably Not Related - does not have a reasonable temporal relationship OR
- good evidence for a more likely alternative etiology
Not Related
- does not have a temporal relationship OR
- definitely due to alternative etiology 
The causality assessment must be made by the investigator based on information available at 
the time that the AE eCRF or SAE worksheet is completed. The initial causality assessment 
may be revised as new information becomes available.
Modified to:
CAUSALITY
It is a regulatory requirement for investigators to assess relationship between the 
investigational product(s) and the occurrence of each AE/SAE based on the information 
available. The assessment should be reviewed on receipt of any new information and 
amended if necessary. A “reasonable possibility” is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship. Facts/evidence or 
arguments that may support “a reasonable possibility” include, e.g., a temporal 
relationship, a pharmacologically-predicted event, or positive dechallenge or 
rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, 
or relevant medical history, should also be considered.
Section 11 References
Formerly:
Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham 
Vasculitis Activity Score (version 3). Ann Rheum Dis 2009; 68:1827-32.


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Modified to:
Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham 
Vasculitis Activity Score (version 3). Ann Rheum Dis 2009; 68:1827-32. doi: 
10.1136/ard.2008.101279. Epub 2008 Dec3.
Added:
Bachen EA, Chesney MA, Criswell LA. Prevalence of mood and anxiety disorders in 
women with systemic lupus erythematosus. Arthritis Rheum 2009;61:822-9.
Fauci AS, Wolff SM. Wegener's granulomatosis: studies in eighteen patients and a 
review of the literature. Medicine (Baltimore) 1973;52:535-61.
Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical 
and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983;98:76-
85.
Gorman C, Leandro M, Isenberg D. B cell depletion in autoimmune disease. Arthritis 
Res Ther 2003;5 (Suppl 4):S17-S21.
Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener's 
granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322-9.
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.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross 
WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CGM, Lamprecht P, 
Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, 
Rasmussen N, Rees AJ, Scott DGI, Specks U, Stone JH, Takahashi K and Watts RA. 
2012 Revised International Chapel Hill Consensus Conference Nomenclature of 
Vasculitides. Arthritis Rheum. 2013; 65(1):1-11.
Langford CA. Cyclophosphamide as induction therapy for Wegener's granulomatosis 
and microscopic polyangiitis. Clin Exp Immunol. 2011;164 (Suppl 1):31-4. doi: 
10.1111/j.1365-2249.2011.04364.x.
Monach PA, Merkel PA. Genetics of vasculitis. Curr Opin Rheumatol 2010;22:157-163.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 
2007;164:1035-43.


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Smith KGC, Jones RB, Burns SM, Jayne DR. Long-term comparison of rituximab 
treatment for refractory systemic lupus erythematosus and vasculitis: Remission, 
relapse, and re-treatment. Arthritis Rheum 2006;54:2970-82.
Stenager EN, Stenager E, Koch-Henriksen N, et al. Suicide and multiple sclerosis: an 
epidemiological investigation. J Neurology, Neurosurg Psychiatry 1992;55:542-5.
Timonen M, Viilo K, Hakko H, et al. Suicides in persons suffering from rheumatoid 
arthritis. Rheumatology 2003;42:287-91.
Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A 
systematic review.BMC Nephrol 2010;11:12. doi: 10.1186/1471-2369-11-12.
Deleted:
Szczeklik W, Jakieła B, Adamek D, et al. Cutting Edge Issues in the Churg-Strauss 
Syndrome. Clin Rev Allergy Immunol 2011;66:222-7.


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Appendix 1 Chapel Hill Consensus Criteria for Wegener’s Granulomatosis
Formerly:
The CHCC Criteria require:
Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis 
affecting small to medium-sized vessels (eg, capillaries, venules, arterioles, and arteries) for a 
diagnosis of Wegener’s.
Another symptoms that may be present in WG, but that are not required according the CHCC 
classification scheme, is necrotizing glomerulonephritis.
Modified to:
Appendix 1 Chapel Hill Consensus Criteria for Granulomatosis with polyangiitis (GPA) 
(Wegener’s Granulomatosis) (Jennette et al, 2013)
The CHCC Criteria require:
Necrotizing granulomatous inflammation usually involving the upper and lower respiratory 
tract, and necrotizing vasculitis affecting predominantly small to medium-sized vessels (eg, 
capillaries, venules, arterioles, and arteries) for a diagnosis of Wegener’s.
Another feature that may be commonly present in GPA, but which is not required according 
to the CHCC definition, is necrotizing glomerulonephritis.
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis
Formerly:
The CHCC criteria require:
Necrotizing vasculitis with few or no immune deposits that affects small vessels (ie, 
capillaries, venules, or arterioles) for a diagnosis of MPA. 
Other symptoms that may be present in MPA, but that are not required according the CHCC 
classification scheme, are: necrotizing arteritis involving small- and medium-sized vessels; 
glomerulonephritis; and pulmonary capilliaritis.
Modified to:
Appendix 2 Chapel Hill Consensus Criteria for Microscopic Polyangiitis (MPA) (Jennette et 
al, 2013)
The CHCC criteria require:


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Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small 
vessels (ie, capillaries, venules, or arterioles) for a diagnosis of MPA. Granulomatous 
inflammation is absent.
Other features that may be present in MPA, but that are not required according to the CHCC 
definition, are: necrotizing arteritis involving small- and medium-sized arteries; commonly 
necrotizing glomerulonephritis; and often pulmonary capillaritis.
Appendix 6 Laboratory Tests
Formerly:
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactic dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid
Glucose
Hepatitis C antibody
Hepatitis B surface antigen
Estimated Creatinine Clearance/ GFR (Cockcroft-Gault)
Modified to:
Enzymes:
SGOT (AST)
SGPT (ALT)
Alkaline Phosphatase
Gamma glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Other:
Creatinine
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Bilirubin, total
Protein, total
Albumin
Uric acid


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Glucose
HIV-1/2 antibody
Hepatitis C antibody (± HCV RNA PCR for confirmation of positive antibody test)
Hepatitis B surface antigen
Hepatitis B surface and core antigen antibodies
Estimated Creatinine Clearance/ GFR (Cockcroft-Gault)
Liver event follow-up assessments:
Hepatitis A IgM antibody
HBsAg and HB Core antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody
Hepatitis E IgM antibody
CPK
Anti-smooth muscle antibody
Type 1 anti-liver kidney microsomal antibodies
Footnote added:
Appendix 6 Laboratory Tests1
1
Institution or country specific guidelines for blood sample volume limits must be followed in collection 
of the subsequent blood sample.
Appendix 8 Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline/Screening/Since 
Last Visit
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright 
laws and therefore have been excluded.


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Modified to:
Appendix 9 Pharmacogenetic Research, Research Rationale
Formerly:
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations.
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach, 2010) for example the association of alpha 1-antitrypsin deficiency in 
WG.  
Modified to:
Systemic vasculitides encompass a range of diseases affecting different sizes of blood vessels 
with a variety of etiologies but little is known regarding the genetic contribution to risk for 
developing different forms of vasculitis.  Recent gene studies in vasculitis are identifying both 
common polymorphisms associated with other autoimmune but also completely different 
associations (Monach and Merkel, 2010).
There is growing evidence for a genetic contribution to the risk of developing different forms 
of vasculitis (Monach and Merkel, 2010) for example the association of alpha 1-antitrypsin 
deficiency in WG. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Appendix 10 Possible Suicidality Related History Questionnaire (PSRHQ)
Added:


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Appendix 11 Possible Suicidality Related Questionnaire (PSRQ)
Added:


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Appendix 12 Protocol Addendum – Benefit and Risk Assessment
Added:
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis; also known as granulomatosis with 
polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to lifethreatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. 
Historically, ANCA have been classified on the basis of their staining patterns in 
immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear (P-ANCA). It is 
now recognized that in AAV, C-ANCA is usually directed against proteinase 3 (PR3), and P-
ANCA is generally directed against myeloperoxidase (MPO), both of which are enzymes that 
are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel et al, 1997). 
Anti-PR3 antibodies are generally associated with WG, while anti-MPO autoantibodies are 
more common in MPA and CSS. Anti-PR3 antibodies are associated with increased morbidity 
and mortality compared to anti-MPO. The most widely used classification criteria for 
diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994). Of note, none of these diagnostic criteria incorporate the measurement 
of ANCA.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007). 
In the case of MPA, in particular, epidemiological studies are confounded by its original 
inclusion as a form of polyarteritis nodosa (PAN). Utilizing the ACR or CHCC criteria, 
prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and 0.4-
1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes et al, 2008). AAV are extremely rare in childhood with peak age of onset in 
those aged 65 to 74 years (Ntatski et al, 2010), with other small vessel vasculitides being the 
major concern in childhood (Brogan et al, 2010).Current therapy is usually determined by 
severity of the disease, with more severe forms warranting more aggressive approaches. These 
usually involve an initial remission induction regimen of high dose corticosteroid 
administered with either cyclophosphamide (CYC) or rituximab (RTX) followed by a 
remission maintenance period usually with azathioprine (Stone et al, 2010; Bosch et al, 2007; 
Jayne et al, 2003). Minor manifestations are usually treated with low dose corticosteroid 


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administered with either azathioprine or methotrexate (Belmont, 2006). Even with recent 
treatment advances the morbidity and mortality of patients with AAV remains unacceptably 
high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG 
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2009). In its current form it is a list of 
56 items which are considered to be manifestations of vasculitis. A weighted numerical score
is attached to each item to reflect the importance of each manifestation. The items are grouped 
by organ systems, and each organ system has a maximum or ‘ceiling’ score to reflect the 
relative importance of the organ system (Mukhtyar et al, 2009). The tool also makes a 
distinction between new or worsening disease and persistent disease with new or worsening 
attracting higher scores.
IV Belimumab
Over 2,000 individuals with SLE have been treated with belimumab in clinical studies. In two 
global Phase 3 studies, belimumab 10 mg/kg met the primary efficacy endpoint (SRI at 
Week 52). Evidence of other possible benefits in these trials included reductions in risk of 
severe flare and corticosteroid use, and improvements in patient reported quality of life and 
fatigue. Serological activity was reduced as measured by reductions in autoantibodies and 
normalization of hypergammaglobulinemia and complement levels. B cells, including 
autoreactive B cells, were also reduced, but not severely depleted, consistent with what would 
be expected from inhibition of BLyS (reference belimumab IB, Section 5.3.1). These results 
supported the approval of belimumab in the EU, US, Canada and other countries.
In the United States belimumab is approved for the following indication:
BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, 
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard 
therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with 
severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA 
has not been studied in combination with other biologics or intravenous 
cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
In the EU, the approved indication focuses on patients with high disease activity (where 
belimumab offered the greatest benefit):
Benlysta 
is 
indicated 
as 
add-on 
therapy 
in 
adult 
patients 
with 
active, 
autoantibodypositive systemic lupus erythematosus (SLE) with a high degree of disease 
activity (e.g positive anti-dsDNA and low complement) despite standard therapy.
The EU SPC also includes special warnings and precautions for use similar to the US 
labeling, including that belimumab has not been studied in and is thus not recommended in 


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patients with severe active central nervous system lupus or severe active lupus nephritis. In 
addition, caution should be exercised if belimumab is co-administered with other B cell 
targeted therapy or cyclophosphamide. Reference Section 4.4 of the SPC for the complete list 
of specials warnings and precautions.
Treatment with belimumab plus standard therapy was generally well tolerated, with rates of 
AEs, severe AEs, SAEs, AEs leading to discontinuation, and serious/severe infections 
generally comparable to the rates observed in the placebo plus standard therapy group. The 
most commonly-reported adverse reactions, occurring in ≥ 3% of patients receiving 10 mg/kg 
belimumab IV in clinical trials (and at a ≥ 1% greater rate than placebo) were nausea, 
diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, 
migraine, pharyngitis, cystitis, leukopenia, and gastroenteritis viral. In clinical trials, 
hypersensitivity and infusion reactions were observed more frequently with belimumab, with 
anaphylaxis observed in ≤ 1% of subjects. Data from the post-marketing setting indicate that 
hypersensitivity reactions may be serious or result in death, that the onset of such reactions 
may be delayed, and that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. In addition, it is also known from clinical trials and 
the post-marketing setting that the vast majority of hypersensitivity reactions occur with the 
1st or 2nd infusion. The product labeling, belimumab IB, protocol, and informed consent forms 
have been updated to include this new information, as applicable.
Other risks that may be associated with belimumab based on its mechanism of action include 
serious infections and malignancy, although no increases in the rates of serious infections or 
malignancies have been observed. Psychiatric events including depression and suicide were 
observed more frequently with belimumab than with placebo, although it is unknown if 
belimumab treatment is associated with an increased risk for these events. Finally, mortality 
rates in the controlled clinical trials were low, although numerically higher in the belimumab 
groups (0.4% and 0.8% in the placebo and belimumab groups, respectively). Causes of death 
were as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as corticosteroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide.
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence of AEs or SAEs over time, including important events such 
as infections and malignancies. Long-term belimumab treatment appears to provide sustained 
improvement in SLE disease activity and reduction of flares.
Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Belimumab at a dose of 10 mg/kg in combination with standard SLE therapy demonstrated a 
statistically significant and clinically meaningful reduction in SLE disease activity versus 
placebo plus standard SLE therapy at Week 52 in two Phase 3 clinical studies in subjects with 
active, autoantibody-positive SLE.


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Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 18 
months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the most 
effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al, 2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels. Therefore, 
for the proposed study, subjects are required to have documented evidence of anti-PR3 or 
anti-MPO autoantibodies prior to randomization, as this population is considered the most 
likely to benefit from treatment with a B cell modulating agent like belimumab. This is 
consistent with the Phase 3 SLE results for belimumab where the subjects who benefitted 
from treatment were those who were antinuclear antibody (ANA/anti-dsDNA) autoantibody 
positive at baseline.
The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval in the US for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease. Finally, limited data from the small (n = 111) subset of subjects in the Phase 3 
trials of SLE who had vasculitic symptoms as part of their SLE (as assessed by the SELENA 
SLEDAI) showed that more subjects in the belimumab plus standard of care treatment arms 
had resolution of their vasculitic symptoms at Week 52 compared with subjects receiving 
placebo plus standard of care. Specifically, 19/36 (52.8%) and 28/38 (73.7%) of subjects in 
the belimumab 1 mg/kg and 10 mg/kg dose groups, respectively, had resolution of vasculitic 
activity at Week 52 compared with 15/37 (40.5%) of placebo subjects. Taken together, these 
data support the evaluation of belimumab in AAV.
The safety of the proposed study is supported by data from the Phase 2 and 3 trials in SLE in 
which subjects who were receiving belimumab in combination with significant background 
therapies, including steroids and immunosuppressants, had an adverse event profile similar to 
that of subjects receiving placebo plus standard therapies.
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:


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
A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of CYC are given as targets but may be adjusted for renal insufficiency or white 
cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
A target of 300 to 400 subjects who are within 26 weeks of starting induction therapy, achieve 
a BVAS v.3 score of 0 (ie, are in remission), and are receiving less than 10 mg/day prednisone 
(or equivalent) on 2 consecutive measurements 21 to 35 days apart will be enrolled into the 
study. Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to receive 
study agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. 
Study agent (belimumab/placebo) will be administered at Day 0, 14, and every 28 days 
thereafter. Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. Azathioprine must be initiated at any time following 
confirmation of remission up to and including Day 0. Patients with known intolerance to 
azathioprine will be excluded from the trial. Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated 
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease), and induction regimen (IV 
CYC vs. oral CYC vs. RTX). It is anticipated that no more than 25% of the patients would be 
newly diagnosed and anti-MPO positive, and as such enrollment of these patients may be 
capped if they exceed this proportion. Refer to Section 4 of Protocol HGS1006-C1100 for a 
complete list of inclusion and exclusion criteria.
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as at least 
1 major BVAS item or a minimum total BVAS score of 6 or receipt of prohibited medications 


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according to the protocol. Subjects will receive study agent (belimumab/placebo) plus AZA 
until the results from the primary efficacy analysis are available or until they experience a 
flare (relapse) as defined in the primary efficacy endpoint. The database will be locked and 
the primary analysis will be performed after at least 66 subjects have experienced a relapse 
and at least 12 months have elapsed after the last subject is randomized. Subjects who 
discontinue study agent prior to relapse/flare are to be followed per the double blind visit 
schedule until relapse/flare or the end of the double-blind treatment phase (whichever is 
earlier). In subjects who withdraw consent from the study prior to 1 year an attempt will be 
made to ascertain survival status at 12 months after the first dose of study agent.
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety. All subjects will return 
for an Exit visit approximately 4 weeks after their last dose of study agent as well as a follow-
up visit approximately 8 weeks after the last dose of study agent. These visits apply to 
subjects who have completed as well as those who have withdrawn early from the open-label 
extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Dose and Schedule
Investigational Study Agent (Belimumab or Placebo)
The dose and schedule of belimumab proposed for use in the ANCA-associated vasculitis 
study is the same dosage (10 mg/kg every 2 weeks for 3 doses and every 4 weeks thereafter) 
and route of administration (IV) as that approved for marketing. The belimumab BDS and 
FDP that will be used for this study is the same as that approved for marketing.
In the Phase 3 IV SLE studies, several clinical measures of improvement including the 
primary efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, there 
appeared to be a greater dose response in subjects with high disease and serological activity. 
There was no apparent dose-response in the safety profile of belimumab with both doses 
being generally well-tolerated. These data supported the selection of 10 mg/kg belimumab as 


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the marketed dose in general SLE, and also support its continued evaluation in combination 
with standard maintenance therapies in patients with WG or MPA.
The use of placebo in this trial is considered appropriate and does not put placebo patients at 
undue risk because all subjects in both the placebo group and the belimumab group will 
receive standard of care maintenance therapies for vasculitis (ie, azathioprine or methotrexate) 
and, if needed, subjects will receive appropriate rescue therapy in accordance with standard 
clinical practice as described above.
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX regimen specified in this vasculitis study is the 
same as that approved by the FDA for this indication.
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).


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A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements 3 to 5 weeks 
apart: a BVAS v3 score of 0 and be receiving < 10 mg/day of oral prednisone [or equivalent], 
achieved no more than 26 weeks after the first dose of induction therapy) has been achieved, 
subject randomization into this protocol occurs. In this maintenance of remission trial, 
subjects will be randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + 
placebo or AZA (2 mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol must 
occur within 2 weeks of achieving a confirmed remission and the randomization will be 
stratified by induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. In this study, subjects who have a known 
intolerance to azathioprine will be excluded. Subjects naive to azathioprine and who 
experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or thrombocytopenia, AST 
or ALT 2 times ULN, or a several gastrointestinal hypersensitivity reaction characterized by 
severe nausea and vomiting), following initiation of azathioprine will be permitted to reduce 
the dose to no less than 1 mg/kg/day. If the subject continues to experience toxicities, a switch 
to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be 
permitted. As azathioprine is among the better tolerated immunomodulatory agents, it is not 
anticipated that many subjects will need to substitute methotrexate for azathioprine (Walters 
et al, 2010). Subjects for whom methotrexate is substituted for azathioprine will be included 
in the primary analysis. The protocol instructs physicians to follow the appropriate local 
prescribing information for azathioprine or methotrexate (as applicable) prior to and during 
treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the European Vasculitis Society (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC), and consensus was reached that these 
regimens are appropriate for this international trial. 
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.


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Safety Considerations
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Belimumab has not yet been studied following use of 
IV cyclophosphamide (CYC) or rituximab (RTX); there is limited experience with the 
combination of belimumab and oral CYC. As an added safety precaution, initial 
randomization will be limited to 40 subjects per induction regimen (40 post-RTX induction 
and 40 post-CYC induction). The first DMC reviews will occur after the first 20 subjects per 
induction regimen (RTX or IV/oral CYC) have been randomized and have had a Week 8 visit. 
Once the first 20 subjects randomized following induction with RTX have had a Week 8 visit, 
safety data will be reviewed by the DMC, who will make a recommendation regarding 
whether to continue randomization. The same procedure would be applied for the first 
20 subjects randomized following induction with CYC. The DMC will review the data 
approximately every 6 months thereafter across both induction regimens. At all times the 
patients, study sites and sponsor will remain blinded to treatment allocation. Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting.
The DMC will be notified of:

• all unexpected causally-related SAEs that are life-threatening or result in death;

• other unexpected causally-related SAEs;

• all reports of serious infections and opportunistic infections, irrespective of relationship 
to study agent; and

• subjects experiencing IgG < 250 mg/dL; 
within protocol-specified timeframes. Based on these data, an ad hoc DMC meeting may be 
called at any time (see Section 8.3 of Protocol HGS1006-C1100 for additional detail 
regarding the DMC).
Based on the large body of safety data from SLE patients treated with belimumab and/or the 
mechanism of action of belimumab as a B cell immunosuppressant, anticipated potential risks 
of belimumab treatment in vasculitis patents include serious infusion and hypersensitivity 
reactions, infections, depression-related events, and malignancy. These risks are briefly 
reviewed here and are detailed more fully in the belimumab Investigator’s Brochure. Both 
investigators and subjects will be appropriately informed regarding these risks. It is noted that 
because of the older patient population affected by this disease, the average age of subjects 
anticipated to participate in this study will be older than the average age of the SLE 
population studied to date (mean age of ~53 years at the time of diagnosis in vasculitis (Stone 
et al, 2010) compared with an average age of ~38 years in controlled Phase 3 studies of 
belimumab in SLE). As such, patients with vasculitis may be at a greater risk for infection 
than the SLE patients; however, the increased monitoring for infections by both the DMC 
(described above) and recommended to investigators (see below) will help to ensure subject 
safety through timely detection, treatment and reporting of infections.


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The protocol states that all subjects should be monitored closely for infection and increased 
vigilance for infection is recommended in subjects who experience IgG levels < 250 mg/dL, 
especially for prolonged periods; clinical judgment should be applied with respect to the 
appropriateness of continuing study therapy in these subjects. The Medical Monitor must be 
consulted before administering subsequent doses of study agent in subjects with IgG levels 
< 250 mg/dL. Study agent will be discontinued in subjects with IgG levels < 250 mg/dL that 
are associated with a severe or serious infection. If a subject experiences a clinically 
significant, potentially life-threatening (Grade 4) AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo, then treatment with study agent 
will be discontinued. The subject will be followed at regularly scheduled study visits as 
specified by the protocol through the end of the double-blind period and also until resolution 
of the AE(s) (whichever is longer).
In order to ensure subject safety with respect to infusion and hypersensitivity reactions, the 
protocol excludes patients with known history of allergic reactions to human or murine 
proteins or monoclonal antibodies. There is currently insufficient evidence to determine 
whether premedication diminishes the frequency or severity of hypersensitivity reactions to 
belimumab. The protocol recommends that based on clinical judgment, premedication 
including an antihistamine, with or without an antipyretic, may be administered before the 
infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 
Belimumab/placebo will be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 
closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. Per protocol, 
subjects are to remain under clinical supervision for 3 hours after completion of the first 
2 infusions in the double-blind treatment phase and the open-label extension. Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment. This may include, but is not limited to, monitoring 
vital signs and observing for any untoward reactions. 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.
The protocol recommends that subjects with persistent or worsening disease should receive 
appropriate rescue therapy in accordance with standard clinical practice, but if exceeding what 
is allowed per protocol, treatment with study agent (ie, belimumab or placebo) will be 
discontinued and the subject will be considered as having relapsed for the primary analysis. 
The list of prohibited medications that results in the subjects being considered as relapsed for 
the primary endpoint (Protocol Section 5.5.2.1), was developed because the need for the use 
of these agents (eg, RTX or CYC) is indicative of treatment failure (ie, disease relapse).
Moreover, concomitant use of such medications (eg, high-dose steroids) can be associated 
both with potent disease-modifying activity and/or significant toxicity that may introduce


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bias and confound interpretation of results. As such, no subject will be denied appropriate 
medical care for their condition due to their participation in this clinical study.
In addition, the Sponsor notes that although this is a placebo controlled trial, the sponsor does 
not consider that placebo patients are at undue risk because all subjects in both the placebo 
group and the belimumab group will receive standard of care maintenance therapies for 
vasculitis (ie, azathioprine or methotrexate) and, if needed, subjects will receive appropriate 
rescue therapy in accordance with standard clinical practice as described above.
Risk:Benefit Conclusions
In summary, the proposed Phase 3 study is a superiority study evaluating the safety and 
efficacy of belimumab for the maintenance of disease remission in patients with a clinical 
diagnosis of Wegener’s granulomatosis or microscopic polyangiitis. The risk:benefit profile of 
10 mg/kg IV belimumab in patients with active, autoantibody-positive SLE was demonstrated 
to be positive in the two Phase 3 SLE studies, thereby supporting its approval in Canada, the 
US, and the EU. Belimumab has already been shown to be effective in treating patients with 
active, autoantibody-positive SLE, a B cell mediated autoimmune disease. Like SLE, WG and 
MPA are also B cell mediated autoimmune diseases in which autoantibodies (in this case, 
against neutrophil components), are considered to be pathogenic (Popa et al, 1999). In each of 
these diseases, the general purpose of the therapy is similar – reducing disease activity by 
down regulating B cells (including autoreactive B cells) and reducing the level autoantibodies 
produced by those autoreactive B cell clones. Down regulating B cell numbers may also 
reduce inflammatory processes because of the role of B cells in antigen presentation. A 
limited amount of data from the IV Phase 3 studies suggests that belimumab may reduce 
vasculitic symptoms.
There are potential risks associated with belimumab treatment including serious infusion and 
hypersensitivity reactions, infections, depression-related events, and malignancy; however, in 
view of the serious and potentially life threatening nature of disease flares in WG and MPA, it 
is believed that the overall risk:benefit analysis for belimumab in the maintenance of 
remission in WG and MPA is favorable, especially in view of the nature of the trial as a 
superiority trial over a current standard of care regimen.


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Local Addendum 01 for Ireland, 31 January 2013
Protocol Number: HGS1006-C1100-01
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified, at the request of the Irish Medicines Board, to ensure 
consistency with the current Summary of Product Characteristics for azathioprine with 
respect to recommendations for the frequency of monitoring complete blood count.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 01
Date: 22 June 2012
Modified to:
Protocol Amendment: 01
Date: 22 June 2012
Local Addendum 01 for Ireland, Date: 31 January 2013
List of Abbreviations
Added:
SmPC
Summary of Product Characteristics
Section 5.5.3.1 Azathioprine and Methotrexate
Formerly:
It is recommended that the appropriate local prescribing information (eg, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine or 
methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator.


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Modified to:
It is recommended that the appropriate local prescribing information (eg, contraindications, 
hematological and biochemical monitoring, pregnancy, contraception, etc.) for azathioprine or 
methotrexate (MTX) (as applicable), should be followed prior to and during treatment.
As per the Summary of Product Characteristics (SmPC) for azathioprine, it is suggested 
that during the first 8 weeks of therapy, complete blood counts, including platelets, 
should be performed weekly or more frequently if high dosage is used or if severe renal 
and/or hepatic disorder is present. The blood count frequency may be reduced later in 
therapy, but it is suggested that complete blood counts are repeated monthly, or at least 
at intervals of not longer than 3 months.
In the extension phase of the trial, the dose of AZA/MTX can be decreased or discontinued 
based on the discretion of the investigator.
Table 6-1 Double-blind Treatment Year One
Hematology & Modified Chem-20 (non-fasting)
Day 0Visit
Formerly:
“X”
Modified to:
“X15”
Table 6-1 Double-blind Treatment Year One
Hematology & Modified Chem-20 (non-fasting)
Week 2 Visit
Formerly:
“X”
Modified to:
“X16”


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Table 6-1 Double-blind Treatment Year One
Hematology & Modified Chem-20 (non-fasting)
Week 4 Visit
Formerly:
“X”
Modified to:
“X17”
Table 6-1 Double-blind Treatment Year One
Footnotes
Added:
15. In addition, at Week 1, a complete blood count including hemoglobin, hematocrit, RBC, 
platelet count, total white blood cell count, and differential white blood cell count should be 
performed.
16. In addition, at Week 3, a complete blood count including hemoglobin, hematocrit, RBC, 
platelet count, total white blood cell count, and differential white blood cell count should be 
performed.
17. In addition, at Weeks 5, 6 and 7, a complete blood count including hemoglobin, 
hematocrit, RBC, platelet count, total white blood cell count, and differential white blood cell 
count should be performed.
Table 6-3 Open-Label Extension Phase
Row, Hematology & Modified Chem-20 (non-fasting)
Week 12Visit
Formerly:
“X”
Modified to:
“X11”


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Table 6-3 Open-Label Extension Phase
Footnotes
Added:
11 A complete blood count including hemoglobin, hematocrit, RBC, platelet count, total 
white blood cell count, and differential white blood cell count should be performed.


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Local Addendum 01 for Sweden, 29 January 2013
Protocol Number: HGS1006-C1100-01
Protocol Title: A Phase 3, Multi-Center, Multinational, Randomized, Double-Blind, 
Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Combination 
with Azathioprine for the Maintenance of Remission in Wegener’s Granulomatosis and 
Microscopic Polyangiitis
Summary of Modifications and Rationale:
1. The protocol has been modified to include a Benefit and Risk Assessment (Appendix 10) 
at the request of the Swedish Regulatory Authority. The List of Appendices has been 
updated accordingly.
Associated Protocol Modifications: 
Protocol Cover Page
Formerly:
Protocol Amendment: 01
Date: 22 June 2012
Modified to:
Protocol Amendment: 01
Date: 22 June 2012
Local Addendum 01 for Sweden, Date: 29 Jan 2013
Appendix 10 Protocol Addendum – Benefit and Risk Assessment
Added:
Disease Background
The systemic vasculitides encompass a range of diseases affecting different sizes of blood 
vessels with a variety of etiologies including infective and drug-induced causes and can be 
either primary or secondary to other diseases such as SLE. A subset of the primary small 
vessel vasculitides: Wegener’s granulomatosis; also known as granulomatosis with 
polyangiitis (GPA), microscopic polyangiitis and Churg-Strauss syndrome (CSS), are 
characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Jennette and 
Falk, 1997). ANCA-associated vasculitides (AAV) are multisystem diseases with a broad 
range of manifestations from cutaneous ulcers, scleritis, pericarditis to lifethreatening 
manifestations such as lung hemorrhage and renal failure. All 3 forms of AAV share the 
characteristic of systemic necrotizing vasculitis; WG and CSS are further characterized by 
granuloma formation. 


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Historically, ANCA have been classified on the basis of their staining patterns in 
immunofluoresence assays as either cytoplasmic (C-ANCA) or perinuclear (P-ANCA). It is 
now recognized that in AAV, C-ANCA is usually directed against proteinase 3 (PR3), and P-
ANCA is generally directed against myeloperoxidase (MPO), both of which are enzymes that 
are abundant in the granules of neutrophils (Jennette and Falk, 1997; Merkel et al, 1997). 
Anti-PR3 antibodies are generally associated with WG, while anti-MPO autoantibodies are 
more common in MPA and CSS. Anti-PR3 antibodies are associated with increased morbidity 
and mortality compared to anti-MPO. The most widely used classification criteria for 
diagnosing the 3 types of AAV are those published by the American College of 
Rheumatology (ACR) for WG and CSS (Leavitt et al, 1990 and Masi et al, 1990, 
respectively), and that published by the Chapel Hill Consensus Conference (CHCC) for MPA 
(Jennette et al, 1994). Of note, none of these diagnostic criteria incorporate the measurement 
of ANCA.
The precise epidemiology of these diseases is uncertain as early studies did not utilize the 
same classification criteria as later ones (Koldingsnes and Nossent, 2008; Watts et al, 2007). 
In the case of MPA, in particular, epidemiological studies are confounded by its original 
inclusion as a form of polyarteritis nodosa (PAN). Utilizing the ACR or CHCC criteria, 
prevalence rates range from 5-16/100000 for WG, 2.5-9.4/100000 for MPA, and 0.4-
1.4/100000 for CSS making the latter the least prevalent of the three by some margin 
(Koldingsnes et al, 2008). AAV are extremely rare in childhood with peak age of onset in 
those aged 65 to 74 years (Ntatski et al, 2010), with other small vessel vasculitides being the 
major concern in childhood (Brogan et al, 2010).Current therapy is usually determined by 
severity of the disease, with more severe forms warranting more aggressive approaches. These 
usually involve an initial remission induction regimen of high dose corticosteroid 
administered with either cyclophosphamide (CYC) or rituximab (RTX) followed by a 
remission maintenance period usually with azathioprine (Stone et al, 2010; Bosch et al, 2007; 
Jayne et al, 2003). Minor manifestations are usually treated with low dose corticosteroid 
administered with either azathioprine or methotrexate (Belmont, 2006). Even with recent 
treatment advances the morbidity and mortality of patients with AAV remains unacceptably 
high (Drooger et al, 2009).
The Birmingham Vasculitis Activity Score (BVAS) was developed and validated as a tool to 
measure disease activity (Luqmani et al, 1994). It has been modified to form the BVAS/WG 
(Stone et al, 2001) and updated most recently with the validation of version 3 of the 
instrument, also known as BVAS 2003 (Mukhtyar et al, 2009). In its current form it is a list of 
56 items which are considered to be manifestations of vasculitis. A weighted numerical score 
is attached to each item to reflect the importance of each manifestation. The items are grouped 
by organ systems, and each organ system has a maximum or ‘ceiling’ score to reflect the 
relative importance of the organ system (Mukhtyar et al, 2009). The tool also makes a 
distinction between new or worsening disease and persistent disease with new or worsening 
attracting higher scores.
IV Belimumab
Over 2,000 individuals with SLE have been treated with belimumab in clinical studies. In two 
global Phase 3 studies, belimumab 10 mg/kg met the primary efficacy endpoint (SRI at 


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Week 52). Evidence of other possible benefits in these trials included reductions in risk of 
severe flare and corticosteroid use, and improvements in patient reported quality of life and 
fatigue. Serological activity was reduced as measured by reductions in autoantibodies and 
normalization of hypergammaglobulinemia and complement levels. B cells, including 
autoreactive B cells, were also reduced, but not severely depleted, consistent with what would 
be expected from inhibition of BLyS (reference belimumab IB, Section 5.3.1). These results 
supported the approval of belimumab in the EU, US, Canada and other countries.
In the United States belimumab is approved for the following indication:
BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, 
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard 
therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with 
severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA 
has not been studied in combination with other biologics or intravenous 
cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
In the EU, the approved indication focuses on patients with high disease activity (where 
belimumab offered the greatest benefit):
Benlysta 
is 
indicated 
as 
add-on 
therapy 
in 
adult 
patients 
with 
active, 
autoantibodypositive systemic lupus erythematosus (SLE) with a high degree of disease 
activity (e.g positive anti-dsDNA and low complement) despite standard therapy.
The EU SPC also includes special warnings and precautions for use similar to the US 
labeling, including that belimumab has not been studied in and is thus not recommended in 
patients with severe active central nervous system lupus or severe active lupus nephritis. In 
addition, caution should be exercised if belimumab is co-administered with other B cell 
targeted therapy or cyclophosphamide. Reference Section 4.4 of the SPC for the complete list 
of specials warnings and precautions.
Treatment with belimumab plus standard therapy was generally well tolerated, with rates of 
AEs, severe AEs, SAEs, AEs leading to discontinuation, and serious/severe infections 
generally comparable to the rates observed in the placebo plus standard therapy group. The 
most commonly-reported adverse reactions, occurring in ≥ 3% of patients receiving 10 mg/kg 
belimumab IV in clinical trials (and at a ≥ 1% greater rate than placebo) were nausea, 
diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, 
migraine, pharyngitis, cystitis, leukopenia, and gastroenteritis viral. In clinical trials, 
hypersensitivity and infusion reactions were observed more frequently with belimumab, with 
anaphylaxis observed in ≤ 1% of subjects. Data from the post-marketing setting indicate that 
hypersensitivity reactions may be serious or result in death, that the onset of such reactions 
may be delayed, and that patients with a history of multiple drug allergies or significant 
hypersensitivity may be at increased risk. In addition, it is also known from clinical trials and 
the post-marketing setting that the vast majority of hypersensitivity reactions occur with the 


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1st or 2nd infusion. The product labeling, belimumab IB, protocol, and informed consent forms 
have been updated to include this new information, as applicable.
Other risks that may be associated with belimumab based on its mechanism of action include 
serious infections and malignancy, although no increases in the rates of serious infections or 
malignancies have been observed. Psychiatric events including depression and suicide were 
observed more frequently with belimumab than with placebo, although it is unknown if 
belimumab treatment is associated with an increased risk for these events. Finally, mortality 
rates in the controlled clinical trials were low, although numerically higher in the belimumab 
groups (0.4% and 0.8% in the placebo and belimumab groups, respectively). Causes of death 
were as expected in an SLE population with active disease receiving a wide range of standard 
therapies, such as corticosteroids and immunosuppressants, and included infection, 
cardiovascular disease, and suicide.
Experience from open-label, long-term continuation trials of belimumab in SLE patients 
suggests prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence of AEs or SAEs over time, including important events such 
as infections and malignancies. Long-term belimumab treatment appears to provide sustained 
improvement in SLE disease activity and reduction of flares.
Belimumab in ANCA-Associated Vasculitis
Study Overview and Patient Population
Belimumab at a dose of 10 mg/kg in combination with standard SLE therapy demonstrated a 
statistically significant and clinically meaningful reduction in SLE disease activity versus 
placebo plus standard SLE therapy at Week 52 in two Phase 3 clinical studies in subjects with 
active, autoantibody-positive SLE.
Studies in subjects with WG and MPA have shown the need for more effective treatment for 
the maintenance of remission, with relapse rates with these 2 diseases ranging from 15% at 18 
months (Jayne et al, 2003) to 38% at 3 years (Hiemstra et al, 2010) on azathioprine – the most 
effective of current therapies (Jayne et al, 2003; Pagnoux et al, 2008; Hiemstra et al, 2010).
The presence of ANCA autoantibodies in AAV implicates B cells in the pathogenesis of 
AAV. Further supporting a role for B cells is the fact that activated B cells are present in 
greater numbers in GPA subjects compared with healthy persons (Popa et al, 1999). 
Additionally, elevated levels of BLyS, a B cell survival factor, are found in subjects with 
AAV (Krumbholz et al, 2005; Nagai et al, 2011; Schneeweis et al, 2010). Together, these 
provide a strong pharmacologic rationale for the use of belimumab to treat AAV, since 
belimumab has been shown in SLE to reduce both B cells and autoantibody levels. Therefore, 
for the proposed study, subjects are required to have documented evidence of anti-PR3 or 
anti-MPO autoantibodies prior to randomization, as this population is considered the mostly 
likely to benefit from treatment with a B cell modulating agent like belimumab. This is 
consistent with the Phase 3 SLE results for belimumab where the subjects who benefitted 
from treatment were those who were antinuclear antibody (ANA/anti-dsDNA) autoantibody 
positive at baseline.


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The fact that rituximab, a biologic therapy that targets B cells by binding to the B cell surface 
antigen CD20, recently showed success in inducing remission in AAV (Stone et al, 2010) and 
was granted approval in the US for the treatment of WG and MPA supports the rationale that 
belimumab, which down regulates B cells by targeting BLyS, may be useful in the treatment 
of this disease. Finally, limited data from the small (n = 111) subset of subjects in the Phase 3 
trials of SLE who had vasculitic symptoms as part of their SLE (as assessed by the SELENA 
SLEDAI) showed that more subjects in the belimumab plus standard of care treatment arms 
had resolution of their vasculitic symptoms at Week 52 compared with subjects receiving 
placebo plus standard of care. Specifically, 19/36 (52.8%) and 28/38 (73.7%) of subjects in 
the belimumab 1 mg/kg and 10 mg/kg dose groups, respectively, had resolution of vasculitic 
activity at Week 52 compared with 15/37 (40.5%) of placebo subjects. Taken together, these 
data support the evaluation of belimumab in AAV.
The safety of the proposed study is supported by data from the Phase 2 and 3 trials in SLE in 
which subjects who were receiving belimumab in combination with significant background 
therapies, including steroids and immunosuppressants, had an adverse event profile similar to 
that of subjects receiving placebo plus standard therapies.
This is a Phase 3, multi-center, multinational, randomized, double-blind study to evaluate the 
efficacy and safety of belimumab in combination with azathioprine for the maintenance of 
remission in subjects with systemic Wegener’s granulomatosis (WG) or microscopic 
polyangiitis (MPA) following a standard induction regimen. Subjects enrolled into the study 
must have a clinical diagnosis of WG or MPA according to the Chapel Hill criteria and must 
have had an initial or relapsing episode of moderate to severely active WG or MPA that was 
treated with corticosteroids and either CYC or RTX in the 6 months leading up to 
randomization. Subjects treated with 1 of the following induction regimens will be eligible for 
participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2 mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.
The doses of CYC are given as targets but may be adjusted for renal insufficiency or white 
cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
A target of 300 to 400 subjects who are within 26 weeks of starting induction therapy, achieve 
a BVAS v.3 score of 0 (ie, are in remission), and are receiving less than 10 mg/day prednisone 
(or equivalent) on 2 consecutive measurements 21 to 35 days apart will be enrolled into the 
study. Subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to receive 
study agent (belimumab [10 mg/kg] or placebo) administered intravenously (IV) over 1 hour. 


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Study agent (belimumab/placebo) will be administered at Day 0, 14, and every 28 days 
thereafter. Randomization will be performed on Day 0. Day 0 (first administration of 
belimumab/placebo) must occur no more than 2 weeks after confirmation of remission.
All subjects (in both the belimumab and placebo groups) will be treated with oral azathioprine 
(AZA) at a dose of 2 mg/kg/day. Azathioprine must be initiated at any time following 
confirmation of remission up to and including Day 0. Patients with known intolerance to 
azathioprine will be excluded from the trial. Subjects naïve to azathioprine who develop 
Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe 
gastrointestinal hypersensitivity reaction, characterized by severe nausea and vomiting, 
following initiation of azathioprine will be permitted to reduce the dose to no less than 
1 mg/kg/day. If the subject continues to experience the toxicities described above, a switch to 
methotrexate at a target dose of 25 mg/week (and no less than 10 mg/week) as an alternative 
to azathioprine will be permitted. As azathioprine is among the better tolerated
immunomodulatory agents, it is not anticipated that many subjects will need to substitute 
methotrexate for azathioprine (Walters et al, 2010). Subjects for whom methotrexate is 
substituted for azathioprine will be included in the primary analysis.
The randomization will be stratified according to ANCA type (anti-PR3 vs. anti-MPO), 
disease stage at induction (initial diagnosis vs. relapsing disease), and induction regimen (IV 
CYC vs. oral CYC vs. RTX). It is anticipated that no more than 25% of the patients would be 
newly diagnosed and anti-MPO positive, and as such enrollment of these patients may be 
capped if they exceed this proportion. Refer to Section 4 of Protocol HGS1006-C1100 for a 
complete list of inclusion and exclusion criteria.
The primary efficacy endpoint is time from Day 0 to the first relapse, defined as at least 
1 major BVAS item or a minimum total BVAS score of 6 or receipt of prohibited medications 
according to the protocol. Subjects will receive study agent (belimumab/placebo) plus AZA 
until the results from the primary efficacy analysis are available or until they experience a 
flare (relapse) as defined in the primary efficacy endpoint. The database will be locked and 
the primary analysis will be performed after at least 66 subjects have experienced a relapse 
and at least 12 months have elapsed after the last subject is randomized. Subjects who 
discontinue study agent prior to relapse/flare are to be followed per the double blind visit 
schedule until relapse/flare or the end of the double-blind treatment phase (whichever is 
earlier). In subjects who withdraw consent from the study prior to 1 year an attempt will be 
made to ascertain survival status at 12 months after the first dose of study agent.
If top line data from the double blind portion of this trial show that belimumab is superior to 
placebo on the primary efficacy endpoint, and the safety profile of belimumab is acceptable, 
subjects who receive treatment with study agent until the completion of the double-blind 
period of the study and have not relapsed (as defined by the primary endpoint) will be given 
the option to receive treatment with belimumab in a 6-month open-label extension period, in 
which all subjects will receive 10 mg/kg belimumab IV. Subjects participating in the open-
label extension will continue to be monitored for efficacy and safety. All subjects will return 
for an Exit visit approximately 4 weeks after their last dose of study agent as well as a follow-
up visit approximately 8 weeks after the last dose of study agent. These visits apply to 


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subjects who have completed as well as those who have withdrawn early from the open-label 
extension.
After the 6-month open-label extension phase, subjects who wish to continue treatment may 
do so by being prescribed commercially available belimumab. If belimumab is not 
commercially available in a subject’s country of participation, the subject may continue to 
receive belimumab under a separate continuation protocol. A separate informed consent will 
be provided for the continuation protocol. The 8 week follow-up visit is not required for 
subjects entering the continuation protocol.
Dose and Schedule
Investigational Study Agent (Belimumab or Placebo)
The dose and schedule of belimumab proposed for use in the ANCA-associated vasculitis 
study is the same dosage (10 mg/kg every 2 weeks for 3 doses and every 4 weeks thereafter) 
and route of administration (IV) as that approved for marketing. The belimumab BDS and 
FDP that will be used for this study is the same as that approved for marketing.
In the Phase 3 IV SLE studies, several clinical measures of improvement including the 
primary efficacy endpoint at Week 52 (SRI), SELENA SLEDAI reductions, severe flare risk 
reduction, and complement normalization generally favored the 10 mg/kg dose. Trends 
toward clinically significant steroid reduction were present for both doses. Additionally, there 
appeared to be a greater dose response in subjects with high disease and serological activity. 
There was no apparent dose-response in the safety profile of belimumab with both doses 
being generally well-tolerated. These data supported the selection of 10 mg/kg belimumab as 
the marketed dose in general SLE, and also support its continued evaluation in combination 
with standard maintenance therapies in patients with WG or MPA.
The use of placebo in this trial is considered appropriate and does not put placebo patients at 
undue risk because all subjects in both the placebo group and the belimumab group will 
receive standard of care maintenance therapies for vasculitis (ie, azathioprine or methotrexate) 
and, if needed, subjects will receive appropriate rescue therapy in accordance with standard 
clinical practice as described above.
Induction and Maintenance Regimens for ANCA-Associated Vasculitis
Subjects participating in this trial will have had a moderate to severe episode of WG or MPA 
that was treated with high-dose corticosteroids (HDCS) and either RTX or CYC (IV or oral) 
to induce the remission of the disease. Subjects treated under the following induction 
regimens will be eligible for participation in the study:

A single course of RTX administered at a dose of 375 mg /m2/week for 4 weeks plus high 
dose corticosteroids (HDCS) OR

CYC 2mg/kg/day orally plus HDCS OR

CYC 3 IV pulses of 15 mg/kg given 2 weeks apart followed by pulses of 15 mg/kg every 
3 weeks plus HDCS.


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The doses of cyclophosphamide are given as targets but may be adjusted for renal 
insufficiency or white cell counts as dictated by local practice.
The recommended HDCS regimen with any of the above induction therapies is: 
methylprednisolone pulses of up to 1000 mg IV each for 1-3 days, followed by 1 mg/kg/day 
not to exceed 80 mg/day and tapered as clinically appropriate to reach < 10 mg/day.
Rituximab was approved in April 2011 by the FDA for the treatment of WG and MPA. It has 
been used in induction of remission in AAV for a number of years, (Gorman et al, 2003, 
Smith et al, 2006) and 2 recent trials published in 2010 (Stone et al, 2010), demonstrated non-
inferiority to induction with cyclophosphamide, the latter of these trials being used as the 
basis for the recent US approval. The RTX regimen specified in this vasculitis study is the 
same as that approved by the FDA for this indication.
Cyclophosphamide (2 mg/kg/day orally or IV 15 mg every 2 weeks for 3 doses and every 
3 weeks thereafter) plus prednisone has been the standard induction regimen for WG and 
MPA since the early 1970s when initial work by Fauci and Wolff at the National Institutes of 
Health showed that this regimen induced disease remission in 12/14 patients and subsequent 
work showed that survival rates increased 80% using this regimen in what was previously an 
uniformly fatal disease (Fauci and Wolff, 1973; Fauci et al, 1983; Hoffman et al, 1992; 
Langford, 2011). Long term continued cyclophosphamide use, however, has been associated 
with significant toxicities (including infection, cystitis, cytopenias, and long term 
complications such as myelodysplasia and bladder cancer) and mortality (Langford, 2011).
A more recent study conducted by the European Vasculitis Group (Jayne et al, 2003) showed 
that after initial disease remission with cyclophosphamide and steroids, subjects could be 
switched to azathioprine (2 mg/kg/day) without having an increased risk of relapse compared 
to subjects whose remission was maintained using continued cyclophosphamide treatment. An 
induction regimen of CYC + prednisone followed by maintenance treatment with azathioprine 
is now considered the standard of care, given that administration of cyclophosphamide for 
longer durations does not offer an advantage from an efficacy standpoint and is associated 
with a greater potential for toxicity (Langford, 2011). The cyclophosphamide regimens 
described above are the same as those allowed in the inclusion criteria for this vasculitis 
study.
Once disease remission (defined as having, on 2 consecutive measurements 3 to 5 weeks 
apart: a BVAS v3 score of 0 and be receiving < 10 mg/day of oral prednisone [or equivalent], 
achieved no more than 26 weeks after the first dose of induction therapy) has been achieved, 
subject randomization into this protocol occurs. In this maintenance of remission trial, 
subjects will be randomized to receive a maintenance regimen of AZA (2 mg/kg/day) + 
placebo or AZA (2 mg/kg/day) + belimumab (10 mg/kg). Randomization in this protocol must 
occur within 2 weeks of achieving a confirmed remission and the randomization will be 
stratified by induction regimen.
The primary safety population for the SLE indication, including 473 subjects who were taking 
azathioprine as a concomitant medication at baseline, provides a substantial amount of safety 
data to support the conduct of the proposed trial. In this study, subjects who have a known 


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intolerance to azathioprine will be excluded. Subjects naive to azathioprine and who 
experience azathioprine-related toxicity (Grade 3 or 4 leukopenia or thrombocytopenia, AST 
or ALT 2 times ULN, or a several gastrointestinal hypersensitivity reaction characterized by 
severe nausea and vomiting), following initiation of azathioprine will be permitted to reduce 
the dose to no less than 1 mg/kg/day. If the subject continues to experience toxicities, a switch 
to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be 
permitted. As azathioprine is among the better tolerated immunomodulatory agents, it is not 
anticipated that many subjects will need to substitute methotrexate for azathioprine (Walters 
et al, 2010). Subjects for whom methotrexate is substituted for azathioprine will be included 
in the primary analysis. The protocol instructs physicians to follow the appropriate local 
prescribing information for azathioprine or methotrexate (as applicable) prior to and during 
treatment.
Input on selection of these standard of care regimens was obtained from international experts 
in vasculitis, including members of the EUVAS and VCRC consortiums, including Dr 
 
 and Dr 
 and consensus was reached that these regimens are appropriate for 
this international trial. Please also refer to Sub-Appendix 1 which includes a signed letter from 
Dr 
 confirming that the induction regimen and maintenance regimen proposed for 
Study HGS1006-C1100 are currently used as standard of care in clinical practice for the 
treatment of ANCA-associated vasculitis in Europe.
Complete details regarding the use of concurrent medications can be found in Section 5.5 of 
Protocol HGS1006-C1100.
Safety Considerations
An independent Data Monitoring Committee (DMC) will review safety data on an ongoing 
basis until the data are locked and analyzed (after which monitoring may be assumed by an 
internal HGS committee). The DMC will include at least 3 physicians and a statistician, none 
of whom are affiliated with the Sponsor. Belimumab has not yet been studied following use of 
IV cyclophosphamide (CYC) or rituximab (RTX); there is limited experience with the 
combination of belimumab and oral CYC. As an added safety precaution, initial 
randomization will be limited to 40 subjects per induction regimen (40 post-RTX induction 
and 40 post-CYC induction). The first DMC reviews will occur after the first 20 subjects per 
induction regimen (RTX or IV/oral CYC) have been randomized and have had a Week 8 visit. 
Once the first 20 subjects randomized following induction with RTX have had a Week 8 visit, 
safety data will be reviewed by the DMC, who will make a recommendation regarding 
whether to continue randomization. The same procedure would be applied for the first 
20 subjects randomized following induction with CYC. The DMC will review the data 
approximately every 6 months thereafter across both induction regimens. At all times the 
patients, study sites and sponsor will remain blinded to treatment allocation. Investigators and 
IRBs/IECs will be notified of the outcome of each DMC meeting.
The DMC will be notified of:

• all unexpected causally-related SAEs that are life-threatening or result in death;

• other unexpected causally-related SAEs;
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
• all reports of serious infections and opportunistic infections, irrespective of relationship 
to study agent; and

• subjects experiencing IgG < 250 mg/dL; 
within protocol-specified timeframes. Based on these data, an ad hoc DMC meeting may be 
called at any time (see Section 8.3 of Protocol HGS1006-C1100 for additional detail 
regarding the DMC).
Based on the large body of safety data from SLE patients treated with belimumab and/or the 
mechanism of action of belimumab as a B cell immunosuppressant, anticipated potential risks 
of belimumab treatment in vasculitis patents include serious infusion and hypersensitivity 
reactions, infections, depression-related events, and malignancy. These risks are briefly 
reviewed here and are detailed more fully in the belimumab Investigator’s Brochure. Both 
investigators and subjects will be appropriately informed regarding these risks. It is noted that 
because of the older patient population affected by this disease, the average age of subjects 
anticipated to participate in this study will be older than the average age of the SLE 
population studied to date (mean age of ~53 years at the time of diagnosis in vasculitis (Stone 
et al, 2010) compared with an average age of ~38 years in controlled Phase 3 studies of 
belimumab in SLE). As such, patients with vasculitis may be at a greater risk for infection 
than the SLE patients; however, the increased monitoring for infections by both the DMC 
(described above) and recommended to investigators (see below) will help to ensure subject 
safety through timely detection, treatment and reporting of infections.
The protocol states that all subjects should be monitored closely for infection and increased 
vigilance for infection is recommended in subjects who experience IgG levels < 250 mg/dL, 
especially for prolonged periods; clinical judgment should be applied with respect to the 
appropriateness of continuing study therapy in these subjects. The Medical Monitor must be 
consulted before administering subsequent doses of study agent in subjects with IgG levels 
< 250 mg/dL. Study agent will be discontinued in subjects with IgG levels < 250 mg/dL that 
are associated with a severe or serious infection. If a subject experiences a clinically 
significant, potentially life-threatening (Grade 4) AE that the investigator believes may be 
definitely, possibly or probably related to belimumab/placebo, then treatment with study agent 
will be discontinued. The subject will be followed at regularly scheduled study visits as 
specified by the protocol through the end of the double-blind period and also until resolution 
of the AE(s) (whichever is longer).
In order to ensure subject safety with respect to infusion and hypersensitivity reactions, the 
protocol excludes patients with known history of allergic reactions to human or murine 
proteins or monoclonal antibodies. There is currently insufficient evidence to determine 
whether premedication diminishes the frequency or severity of hypersensitivity reactions to 
belimumab. The protocol recommends that based on clinical judgment, premedication 
including an antihistamine, with or without an antipyretic, may be administered before the 
infusion. Antihistamine H2-receptor antagonists (eg, ranitidine) are also permitted. 
Belimumab/placebo will be administered by investigators/site personnel prepared to manage 
infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. Investigators/site personnel should be aware of the risk 
of hypersensitivity reactions, which may present as infusion reaction, and monitor subjects 


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closely. In the event of a serious reaction, belimumab/placebo administration must be 
discontinued immediately and the appropriate medical therapy administered. Per protocol, 
subjects are to remain under clinical supervision for 3 hours after completion of the first 
2 infusions in the double-blind treatment phase and the open-label extension. Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment. This may include, but is not limited to, monitoring 
vital signs and observing for any untoward reactions. 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.
The protocol recommends that subjects with persistent or worsening disease should receive 
appropriate rescue therapy in accordance with standard clinical practice, but if exceeding what 
is allowed per protocol, treatment with study agent (ie, belimumab or placebo) will be 
discontinued and the subject will be considered as having relapsed for the primary analysis. 
The list of prohibited medications that results in the subjects being considered as relapsed for 
the primary endpoint (Protocol Section 5.5.2.1), was developed because the need for the use 
of these agents (eg, RTX or CYC) is indicative of treatment failure (ie, disease relapse).
Moreover, concomitant use of such medications (eg, high-dose steroids) can be associated 
both with potent disease-modifying activity and/or significant toxicity that may introduce
bias and confound interpretation of results. As such, no subject will be denied appropriate 
medical care for their condition due to their participation in this clinical study.
In addition, the Sponsor notes that although this is a placebo controlled trial, the sponsor does 
not consider that placebo patients are at undue risk because all subjects in both the placebo 
group and the belimumab group will receive standard of care maintenance therapies for 
vasculitis (ie, azathioprine or methotrexate) and, if needed, subjects will receive appropriate 
rescue therapy in accordance with standard clinical practice as described above.
Risk:Benefit Conclusions
In summary, the proposed Phase 3 study is a superiority study evaluating the safety and 
efficacy of belimumab for the maintenance of disease remission in patients with a clinical 
diagnosis of Wegener’s granulomatosis or microscopic polyangiitis. The risk:benefit profile of 
10 mg/kg IV belimumab in patients with active, autoantibody-positive SLE was demonstrated 
to be positive in the two Phase 3 SLE studies, thereby supporting its approval in Canada, the 
US, and the EU. Belimumab has already been shown to be effective in treating patients with 
active, autoantibody-positive SLE, a B cell mediated autoimmune disease. Like SLE, WG and 
MPA are also B cell mediated autoimmune diseases in which autoantibodies (in this case, 
against neutrophil components), are considered to be pathogenic (Popa et al, 1999). In each of 
these diseases, the general purpose of the therapy is similar – reducing disease activity by 
down regulating B cells (including autoreactive B cells) and reducing the level autoantibodies 
produced by those autoreactive B cell clones. Down regulating B cell numbers may also
reduce inflammatory processes because of the role of B cells in antigen presentation. A 


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limited amount of data from the IV Phase 3 studies suggests that belimumab may reduce 
vasculitic symptoms.
There are potential risks associated with belimumab treatment including serious infusion and 
hypersensitivity reactions, infections, depression-related events, and malignancy; however, in 
view of the serious and potentially life threatening nature of disease flares in WG and MPA, it 
is believed that the overall risk:benefit analysis for belimumab in the maintenance of 
remission in WG and MPA is favorable, especially in view of the nature of the trial as a 
superiority trial over a current standard of care regimen.


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Sub-Appendix 1
ANCA-Associated Vasculitis Standard of Care Letter from 
Key Opinion Leader


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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
BEL115466
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Multi-Center, 
Multinational, Randomized, Double-Blind Study to Evaluate 
the Efficacy and Safety of Belimumab (HGS1006) in 
Combination with Azathioprine for the Maintenance of 
Remission in Wegener’s Granulomatosis and Microscopic 
Polyangiitis
Compound Number 
:
GSK1550188
Effective Date 
:
06-MAR-2017
Description :

The purpose of this RAP is to describe the planned analyses and outputs to be 
included in the Clinical Study Report of the double-blind and open-label phases for
Protocol HGS1006-C1100 (BEL115466).

This RAP is intended to describe the planned efficacy, safety, pharmacokinetics and 
biomarker analyses required for the double-blind and open-label phases of the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable for the study.
Author’s Name and Functional Area: 
06-MAR-2017
Statistician (Clinical Statistics)
Approved (via email) by: 
06-MAR-2017
Director (Clinical Statistics)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL
BEL115466
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objectives and Endpoints .................................................................11
2.2.1.
Study Objectives..........................................................................11
2.2.2.
Study Endpoints...........................................................................11
2.2.2.1.
Efficacy.......................................................................11
2.2.2.2.
Safety.........................................................................12
2.3.
Study Design ..............................................................................................13
2.4.
Statistical Hypotheses.................................................................................14
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Primary and End of Study Analyses............................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
5.1.
General Data Considerations......................................................................17
5.2.
Examination of Covariates, Subgroups & Other Strata................................18
5.2.1.
Examination of Strata and Covariates..........................................18
5.2.2.
Examination of Subgroups...........................................................18
5.3.
Rules for Relapse/Treatment Failure due to Receipt of Prohibited 
Medication ..................................................................................................19
5.3.1.
Overview of Treatment Failure Rules as specified in the 
Protocol .......................................................................................19
5.3.2.
Additional Detail for Treatment Failure Rules...............................20
6.
STUDY POPULATION ANALYSES .......................................................................21
6.1.
Overview of Planned Study Population Analyses........................................21
6.1.1.
Supplementary Information for Other Baseline 
Characteristics and Stratification Factors.....................................22
7.
PRIMARY STATISTICAL ANALYSES....................................................................24
7.1.
Efficacy Analyses........................................................................................24
7.1.1.
Overview of Planned Efficacy Analysis ........................................24
7.1.2.
Planned Efficacy Statistical Analyses...........................................26
8.
SECONDARY STATISTICAL ANALYSES .............................................................28
8.1.
Efficacy Analyses........................................................................................28
8.1.1.
Major Secondary Endpoint...........................................................28
8.1.2.
Other Efficacy Endpoints .............................................................28
8.1.2.1.
Overview of Planned Efficacy Analyses......................28
8.1.2.2.
Time to Event Endpoint ..............................................29
8.1.2.3.
Continuous Endpoints ................................................30
8.1.2.4.
Binary Endpoints ........................................................30


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BEL115466
3
8.1.3.
Biomarkers ..................................................................................31
8.1.3.1.
Overview of Planned Biomarker Analyses..................31
8.1.3.2.
Absolute and Percent Change (Observed) .................32
8.1.3.3.
B and T cell Subsets...................................................32
8.2.
Safety Analyses..........................................................................................36
8.2.1.
Overview of Planned Adverse Events Analyses...........................36
8.2.1.1.
Adverse Events ..........................................................38
8.2.1.2.
Adverse Event Summaries .........................................38
8.2.2.
Overview of Planned Adverse Event of Special Interest 
Analyses......................................................................................40
8.2.3.
Adverse Events of Special Interest Summaries ...........................42
8.2.4.
Overview of Planned Columbia-Suicide Severity Rating 
Scale (C-SSRS) Analyses ...........................................................44
8.2.4.1.
C-SSRS Suicidal Ideation...........................................44
8.2.4.2.
C-SSRS Suicidal Ideation or Behavior during 
Treatment...................................................................45
8.2.4.3.
C-SSRS Suicidal Ideation or Behavior Relative 
to Pre-treatment .........................................................45
8.2.4.4.
C-SSRS Shift Changes in Categories from Pre-
treatment to On-treatment ..........................................45
8.2.5.
Overview of Planned Laboratory & Immunogenicity 
Analyses......................................................................................46
8.2.5.1.
Clinical Laboratory Evaluations ..................................47
8.2.5.2.
Laboratory Summaries by Study Year ........................47
8.2.5.3.
Worst laboratory toxicity grade post-baseline .............47
8.2.5.4.
Laboratory toxicity ≥ 2 grade shift post-baseline.........47
8.2.5.5.
Laboratory reference range shifts from 
baseline by visit..........................................................48
8.2.5.6.
Immunoglobulin reference range shifts from 
baseline by visit..........................................................48
8.2.5.7.
Immunoglobulin below LLN by visit.............................48
8.2.5.8.
Immunogenicity ..........................................................48
8.3.
Pharmacokinetic Analyses..........................................................................49
9.
REFERENCES.......................................................................................................50
10. APPENDICES........................................................................................................51
10.1.
Appendix 1: Time & Events.........................................................................52
10.1.1.
Protocol Defined Time & Events ..................................................52
10.2.
Appendix 2: Treatment States and Phases.................................................59
10.2.1.
Treatment Phases .......................................................................59
10.2.2.
Treatment States .........................................................................59
10.2.2.1.
Treatment States for Adverse Events .........................59
10.3.
Appendix 3: Data Display Standards & Handling Conventions....................61
10.3.1.
Study Treatment & Subgroup Display Descriptors .......................61
10.3.2.
Baseline Definition & Derivations .................................................61
10.3.2.1.
Baseline Definitions....................................................61
10.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................61
10.3.3.
Reporting Process & Standards...................................................62
10.4.
Appendix 4: Derived and Transformed Data ...............................................64
10.4.1.
General........................................................................................64


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10.4.2.
Study Population..........................................................................66
10.4.3.
Safety ..........................................................................................67
10.4.4.
Efficacy........................................................................................70
10.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............72
10.5.1.
Premature Withdrawals................................................................72
10.5.2.
Handling of Missing Data.............................................................72
10.5.2.1.
Handling of Missing Dates..........................................72
10.5.2.2.
Handling of Partial Dates............................................73
10.6.
Appendix 6: B Cell and T Cell Subsets .......................................................74
10.7.
Appendix 7: BVAS Activity Assessment Form.............................................75
10.8.
Appendix 8: BVAS Item Scoring .................................................................76
10.9.
Appendix 9: Vasculitis Damage Index (VDI)................................................79
10.10. Appendix 10: Laboratory Parameters & Adverse Events Grading...............80
10.10.1. Laboratory Parameters ................................................................80
10.10.2. Adverse Events Grading..............................................................81
10.11. Appendix 11: Abbreviations & Trade Marks ................................................84
10.11.1. Abbreviations...............................................................................84
10.11.2. Trademarks .................................................................................85
10.12. Appendix 12: List of Data Displays..............................................................86
10.12.1. Data Display Numbering..............................................................86
10.12.2. Mock Example Shell Referencing ................................................86
10.12.3. Deliverable...................................................................................86
10.12.4. Study Population Tables..............................................................87
10.12.5. Efficacy Tables ............................................................................91
10.12.6. Efficacy Figures ...........................................................................94
10.12.7. Safety Tables...............................................................................96
10.12.8. Safety Figures ...........................................................................107
10.12.9. Pharmacokinetic Tables.............................................................108
10.12.10.Pharmacokinetic Figures ...........................................................108
10.12.11.Pharmacokinetic Listings ...........................................................109
10.12.12.Biomarker Tables.......................................................................109
10.12.13.Biomarker Figures .....................................................................111
10.12.14.ICH Listings ...............................................................................113
10.12.15.Non-ICH Listings........................................................................117
10.13. Appendix 13: Example Mock Shells for Data Displays ..............................119


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP details all planned analyses and outputs required for the final Clinical Study 
Report (CSR) of study BEL115466 (HGS1006-C1100).
Protocol

This RAP is based on protocol amendment 04 (Dated: 26/FEB/2015) and local 
amendment 01 of protocol amendment 04 (Dated: 06/JUL/2015) of study BEL115466
(HGS1006-C1100; GSK Document No. : 2013N167980_02 and GSK Document No. : 
2015N245521_00, respectively), and electronic case report form (eCRF) Version 7.0 
(Dated: 05/JUL/2016).
Primary 
Objective

To evaluate the efficacy of belimumab the maintenance of remission following a 
standard induction regimen in subjects with Wegener’s Granulomatosis (WG) or 
Microscopic Polyangiitis (MPA).

To evaluate the safety of belimumab in subjects with WG or MPA.
Primary 
Endpoint
Time from Day 0 to the first relapse, defined as 

at least 1 major BVAS item (Appendix 8)  OR

a minimum total BVAS score of 6 (Appendix 8) OR

receipt of prohibited medications (as defined in Section 5.3)
Major 
Secondary 
Endpoint

Time from Day 0 to the first major relapse (defined as experiencing at least 1 major
BVAS item).
Study 
Design

Multi-center, multi-national, randomized, double-blind study to evaluate the efficacy and 
safety of belimumab in combination with azathioprine for the maintenance of remission 
in subjects with systemic Wegener’s Granulomatosis (WG) or Microscopic Polyangiitis
(MPA) following a standard induction regimen.

The initial double-blind phase will be followed by a 6 month open-label extension in 
Belgium as detailed in local amendment 01 of protocol amendment 04. Subjects 
randomized to 10 mg/kg belimumab + oral 2 mg/kg/day azathioprine (AZA) in the 
double-blind phase will remain on this treatment and subjects randomized to placebo + 
2 mg/kg/day AZA will begin to receive belimumab at 10 mg/kg + AZA 4 weeks after their 
final dose of placebo.

The sample size has been determined based on the feasibility of enrolling patients into 
the study within a reasonable time-frame. The sample size is not based on statistical 
considerations and the analysis of primary and secondary endpoints will be exploratory 
in nature.  The primary efficacy analysis will be performed upon completion of the open 
label phase of the study.

Parallel-group study in approximately 100 subjects with two treatment groups 
comprising of one active and one placebo arm. Subjects will be randomized in a 1:1 
ratio to receive placebo + AZA or belimumab 10 mg/kg + AZA.
Planned 
Analyses

No interim analysis is planned for this study.

All decisions regarding final analysis, as defined in this RAP document, will be made 
prior to final Database Freeze (unblinding) of the study data.

Five subjects will continue to the open-label phase of the study and therefore data on 
these subjects for the open-label phase will be listed alongside the double-blind data
only.
Analysis 
Populations

The Screened population is defined as all subjects who were screened in the study, 
irrespective of whether or not they received study agent.

The Randomized population is defined as all subjects who were randomized in the 


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Overview
Key Elements of the RAP
study, irrespective of whether or not they received study agent.

The Intent-to-Treat (ITT) population is defined as all subjects who are randomized and 
received at least 1 dose of study agent.

The Per-Protocol population is defined as all randomized subjects who receive at least 
one dose of study agent and who do not incur any protocol deviations that could affect 
the primary efficacy endpoint.  

The Pharmacokinetic (PK) population is defined as all subjects randomized to 
belimumab treatment who receive at least one dose of study agent and from whom a 
pharmacokinetic sample is obtained and analyzed. 
Hypothesis

As the study is exploratory in nature, no formal hypothesis has been specified. 
However, the study will evaluate the superiority of belimumab versus placebo with 
respect to the time to first relapse.
Primary
Efficacy 
Analyses

The primary efficacy analysis will compare the time to first relapse from Day 0 between 
the placebo/AZA group and the belimumab/AZA combination group using a Cox 
proportional hazards model, adjusted for anti-neutrophil cytoplasmic antibody (ANCA)
type (anti-proteinase 3 [anti-PR3] vs. anti- myeloperoxidase [anti-MPO]), disease stage 
at induction (initial diagnosis vs. relapsing disease), and induction regimen (rituximab
vs. intravenous (IV) cyclophosphamide vs. oral cyclophosphamide).

Adjustment for covariates will be based on the eCRF categorization as oppose to the 
randomization strata.

The hazard ratio and corresponding 95% confidence interval and Wald chi-squared p-
value will be presented for the adjusted difference in risk between the two treatment 
groups.
Secondary 
Analyses
Efficacy - Major Secondary Endpoint

The major secondary endpoint will be listed only due to limited events occurring. 
Efficacy Other - Time to Event

Descriptive statistics for time to first event will be presented in tabular format and 
graphically by treatment group and visit.
Efficacy Other - Continuous Endpoints

Descriptive statistics for continuous endpoints will be presented in tabular format by 
treatment group and visit.
Efficacy Other - Binary Endpoints

Descriptive statistics for binary endpoints will be presented in tabular format and 
graphically by treatment group and visit.
Efficacy - Biomarkers and Autoantibodies

Biomarkers and autoantibodies will be summarized using the absolute change from 
baseline by treatment group and visit with the exception of B lymphocyte Stimulator
(BLyS) protein which is only collected at baseline and will be summarized as such. 
Descriptive statistics will be presented in tabular format and graphically.
Safety

Safety data will be presented in tabular format and summarized descriptively according 
to GSK’s Integrated Data Standards Library (IDSL) standards.
Pharmacokinetic

Serum belimumab concentration data will be summarized descriptively and presented 
graphically. 
Terminology

The name of Wegener’s Granulomatosis (WG) was officially changed in 2011 to


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Overview
Key Elements of the RAP
Granulomatosis with Polyangiitis (GPA). These terms are equivalent and both may be 
used throughout the RAP. GPA will be presented in displays.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
This study was originally intended to support regulatory filings for an ANCA vasculitis
treatment indication.  That is no longer the intent, and the originally intended enrolment 
of ~300 subjects has been significantly reduced to ~100 subjects (Protocol HGS1006-
C1100 Amend 04 Summary of Modifications; GSK Document No.: 2013N167980_02).
A 6 month open-label extension was originally planned, which would allow participants 
that completed the double-blind phase the opportunity to subsequently receive open-label 
belimumab supplied by the sponsor. This was removed from the protocol as part of
amendment 04, due to the change in scope of the study. However, ethical objections were 
raised in Belgium and therefore the open-label extension was reinstated in Belgium only.
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Synopsis: PK Endpoints and 
Analysis: Serum samples will be 
collected from all randomized
subjects who receive a dose of study 
agent during the study and analyzed
to determine serum belimumab 
concentrations. Serum belimumab 
concentration data will be used in a 
population PK analysis, which will be 
reported separately.
Results for this study will be 
presented using appropriate 
graphic and tabular summaries.
This study was originally 
intended to support regulatory 
filings for an ANCA vasculitis 
treatment indication. That is no 
longer the intent, and the 
originally intended enrolment 
has been significantly reduced.  
Therefore, a full population PK 
analysis is not required for this 
study.
Section 8.7.2 Analysis of 
Pharmacokinetics: Serum belimumab 
concentration will be determined by 
an electrochemiluminescence (ECL) -
based assay. Results for this study 
will be presented using appropriate 
graphic and tabular summaries. 
Serum belimumab concentration data 
obtained from this study will be used 
in a population PK analysis, which 
will be reported separately. Potential 
effects of demographic 
characteristics, concurrent 
medications, renal function or 
disease stage on belimumab PK will 
be evaluated.
Results for this study will be 
presented using appropriate 
graphic and tabular summaries 
and no population PK analyses 
will be conducted.
As above.
Section 8.5.4 Other Efficacy 
Endpoints

Absolute change in 
Vasculitis Damage Index 
VDI is not assessed at Week 28 
of Year 2; hence the midpoint of 


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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Absolute change in Vasculitis 
Damage Index (VDI) at double-blind 
Week 48 of Year 1
and double-blind Week 28 of Year 2 
and by visit;
Proportion of subjects with any 
increase in VDI at double-blind Week 
48 of Year 1 and
double-blind Week 28 of Year 2 and 
by visit;
(VDI) will be analyzed at 
double-blind Week 48 of 
Year 1 and double-blind 
Week 24 of Year 2 and by 
visit;

Proportion of subjects with 
any increase in VDI will be 
analyzed at double-blind 
Week 48 of Year 1 and 
double-blind Week 24 of 
Year 2 and by visit;
the study calendar year will be 
used for analysis.
Study Synopsis: Biological markers 
will be measured at baseline (Day 0) 
and at multiple time points thereafter:

Anti-neutrophil cytoplasmic 
antibody (ANCA: anti-PR3, 
anti-MPO)
ANCA type will be tabulated for 
time points at which 
immunogenicity samples are 
available.
ANCA type was not evaluated 
by an immunoassay throughout 
the study, as specified in the 
protocol. Instead, only immune-
fluorescence assay was 
performed on the collected 
samples. However, some 
remaining immunogenicity 
samples were available to 
evaluate ANCA type by 
immunoassay. Therefore, ANCA 
(anti-MPO and anti-PR3) will be 
summarized at the time points 
where immunogenicity samples 
are available. These are Day 0, 
year 1 week 8, year 1 week 24, 
then every 24 weeks, exit visit 
and follow-up visit. . 
If there are then still less than 5 
patients with an event (relapse) in 
any of the levels of this or any other 
stratification factor then the 
stratification term may be removed 
from the model.
If factors fail to converge they 
will be removed from the model
More general wording allows 
removal of factors based on 
assessment of model fit.
The exploratory analysis of the major 
secondary efficacy endpoint will be 
performed using the same method 
described for the primary efficacy 
endpoint, but censoring subjects who 
receive any prohibited medication (as 
defined in Section 5.5.1) prior to an 
observation of any major BVAS item. 
Any censoring will be applied on the 
date prohibited medications are 
received.
The major secondary endpoint 
will be listed only.
Due to a limited number of 
events occurring during the 
study, major relapses will be 
listed only.
Section 8.5.4 Other Efficacy 
Proportion of patients in 
The protocol was modified to 


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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Endpoints: Proportion of patients in 
remission (defined as BVAS=0 and 
corticosteroid dose < 10 mg/day) at 
double-blind Week 48 of Year 1, 
double-blind Week 28 of Year 2 and 
by visit.
remission (defined as BVAS=0 
and corticosteroid dose ≤10 
mg/day) at double-blind Week 
48 of Year 1, double-blind Week 
28 of Year 2 and by visit.
allow doses of prednisone less 
than or equal to 10mg/day for 
maintenance at protocol 
amendment 3 (Protocol 
HGS1006-C1100 Amend 03 
Summary of Modifications; GSK 
Document No.: 
2013N167980_01). Section 
8.5.4 should have been updated 
to be consistent with the 
protocol but was not. A note to 
file documenting this was 
produced.
Section 8.5.4 Other Efficacy 
Endpoints: CD27-/IgD+/CD10+ 
transitional
CD19+/CD24b+/CD38b+/CD27-
/IgD+/CD10+ transitional.
CD19+/CD24b+/CD38b+/CD27-
/IgD+/CD10+ transitional
provides a more thorough 
definition of CD10+ transitional 
B cells and therefore this been 
provided by Q2 solutions rather 
than the protocol-defined 
endpoint.


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2.2.
Study Objectives and Endpoints
2.2.1.
Study Objectives
Objectives

To evaluate the efficacy of belimumab in the maintenance of remission following a standard induction 
regimen in subjects with Wegener’s Granulomatosis (WG) or Microscopic Polyangiitis (MPA).

To evaluate the safety of belimumab in subjects with WG or MPA.
NOTE: No PK objective was defined in the protocol.
2.2.2.
Study Endpoints
2.2.2.1.
Efficacy
Primary
Time from Day 0 to the first relapse, defined as 

at least 1 major BVAS item (Appendix 8) OR 

a minimum total BVAS score of 6 (Appendix 8) OR

receipt of prohibited medications (as defined in Section 5.3)
Major Secondary

Time from Day 0 to the first major relapse (defined as experiencing at least 1 major BVAS item, 
Appendix 8).
Other 

Time from Day 0 to first minor or major relapse (defined as experiencing at least 1 minor BVAS item
and/or using a dose of rescue medication).
Note: (1) Rescue medication (prohibited medications resulting in treatment failure) as defined in Section 
5.3. (2) Definition also includes any major relapse, defined as experiencing at least 1 major BVAS item.

Absolute change in Vasculitis Damage Index (VDI) at  DB Week 48 of Year 1 and double-blind Week 
24 of Year 2 and by visit;

Proportion of subjects with any increase in VDI at double-blind Week 48 of Year 1  and double-blind 
Week 24 of Year 2 and by visit;

Absolute change in BVAS at double-blind Week 48 of Year 1 and double-blind Week 28 of Year 2 and 
by visit; 

Proportion of subjects with any increase in BVAS at double-blind Week 48 of Year 1 and double-blind 
Week 28 of Year 2 and by visit; and 

Proportion of subjects with any increase in BVAS organ domains at double-blind Week 48 of Year 1 
and double-blind Week 28 of Year 2 and by visit and by domain.

Proportion of patients in remission (defined as BVAS=0 and corticosteroid dose ≤10 mg/day) at 
double-blind Week 48 of Year 1, double-blind Week 28 of Year 2 and by visit.

Proportion of patients with no relapse at double-blind Week 48 of Year 1, double-blind Week 28 of Year 
2 and by visit.


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Biological Markers and Autoantibodies

Anti-neutrophil cytoplasmic antibody (ANCA – anti-PR3, anti-MPO)

Serum complement (C3, C4)

Serum immunoglobulin isotypes (IgA, IgM, IgG)

C-reactive Protein (CRP)

Erythrocyte sedimentation rate (ESR)

Urinary protein: urinary creatinine ratio

BLyS protein (Day 0 only)

FACS of peripheral lymphocytes:
–
B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived plasma, 
CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, CD138+/CD20+ 
plasmacytoid,  CD19+/CD24b+/CD38b+/CD27-/IgD+/CD10+ transitional)
–
T cell subsets: CD3+/CD4+, CD3+/CD8+
2.2.2.2.
Safety
Safety

Adverse Events & Adverse Events of Special Interest (AESI)

Changes in Laboratory Parameters

Selected serious psychiatric events: Depression, suicide and self-injury

Suicidality Assessment: Columbia-Suicide Severity Rating Scale (C-SSRS)

Immunogenicity


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multi-center, multinational, randomized, parallel-group, double-blind study in 
subjects with WG or MPA following a standard induction regimen followed by a 
6 month open-label extension (OLE) in Belgium only.

Subjects enrolled must have had an initial or relapsing episode of moderate to 
severely active WG or MPA that was treated with corticosteroids and either 
cyclophosphamide (CYC) or rituximab (RTX) in the 6 months leading up to 
randomization. Subjects who between 6 and 26 weeks of starting induction 
therapy, achieve a BVAS V3 score of 0 and are receiving ≤ 10 mg/day oral 
prednisone (or equivalent) on 2 consecutive visits at least 14 days apart may 
enroll. A minimum 6 week period should elapse between initiation of induction 
therapy and randomization.

Double-blind completion will be defined as 12 months having elapsed after the 
final subject is randomized (See Appendix 4).
Dosing

All randomized subjects will be treated with oral azathioprine (AZA) at a target
dose of 2 mg/kg/day. AZA may be initiated as soon as it is clinically indicated 
following administration of induction therapy. AZA should not be initiated any 
later than Day 0. 

Eligible subjects will be randomized in a 1:1 ratio to also receive study agent 
(belimumab 10 mg/kg or placebo) administered intravenously over 1 hour. 

Study agent will be administered at Day 0, 14, 28 and every 28 days thereafter
until 12 months have elapsed following randomization of the last subject. 

In the Belgium-only OLE, all subjects will receive belimumab 10 mg/kg every 
28 days until Week 24, with a final evaluation at Week 28.
Treatment 
Assignment

Approximately N=100 subjects will be randomly assigned to belimumab 10 
mg/kg or placebo (1:1 ratio). 

At randomization (Day 0), subjects will be stratified according to ANCA type 
(anti-PR3 vs. anti-MPO) [1], disease stage at induction (initial diagnosis vs. 
relapsing disease), and induction regimen (IV CYC vs. oral CYC vs. RTX).

During the open-label extension phase, subjects will be assigned to belimumab
Open Label Phase
(Belgium only)

6 months
belimumab 
treatment.

5 subjects 
enrolled.


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Overview of Study Design and Key Features
10 mg/kg.
Interim 
Analysis

No interim analysis is planned for this study.
[1] ANCA type historically assessed
2.4.
Statistical Hypotheses
As the study is exploratory in nature, no formal hypothesis has been specified. However, 
the study will evaluate the superiority of belimumab versus placebo in the time to first 
relapse.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned for this study.
3.2.
Primary and End of Study Analyses
The primary analyses will be performed at the end of the study, when the open-label 
phase is complete. The open-label phase data will be listed only together with the double-
blind data.
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
Six months have elapsed after the last subject receives their first dose of belimumab 
open label.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprise of all subjects who are screened in the 
study, irrespective of whether or not they receive 
study agent.  

Screening 
Failures
Randomized

Comprise of all subjects who are randomized in 
the study, irrespective of whether or not they 
receive study agent.  

Study Population 
(listings)
Intent-To-Treat
(ITT)

Comprise of all randomized subjects who receive
at least one dose of study agent (belimumab or 
placebo).

This population will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Biomarkers

Safety
Per-Protocol 
(PP)

Comprise of all randomized subjects who receive 
at least one dose of study agent and who do not 
incur any protocol deviations that could affect the 
primary efficacy endpoint.

Any subject excluded from the PP population will 
be excluded completely from the PP analysis.

Protocol deviations that would exclude subjects 
from the PP population are defined in Section 4.1
(Protocol Deviations).

A PP analysis of the primary and major secondary 
endpoints will be carried out if this population 
comprises between 50% and 95% of the ITT 
population. 

Efficacy
Pharmacokinetic 
(PK)

Subjects in the ‘ITT’ population randomized to 
belimumab treatment for which a PK sample is 
obtained and analyzed.

PK
NOTES : 

Refer to Appendix 12 which details population to be used for each display generated.
4.1.
Protocol Deviations

Please refer to the Protocol Deviation Management Plan (PDMP): Dated: 12/JAN/17
(Version 2) for full details.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarized and listed.

Important deviations which result in exclusion from the Per-Protocol population will 
also be summarized and listed. (Please refer to PDMP: Dated: 12/JAN/17 (Version 
2)).   

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.


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o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorized on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
10.1
Appendix 1 Time & Events
10.2
Appendix 2 Treatment States and Phases
10.3
Appendix 3 Data Display Standards & Handling Conventions
10.4
Appendix 4 Derived and Transformed Data
10.5
Appendix 5 Premature Withdrawals & Handling of Missing Data
10.6
Appendix 6 B Cell and T Cell Subsets
10.7
Appendix 7 BVAS Activity Assessment Form
10.8
Appendix 8 BVAS Item Scoring
10.9
Appendix 9 Vasculitis Damage Index (VDI)
10.10
Appendix 10 Laboratory Parameters & Adverse Events Grading
5.1.
General Data Considerations

This is a multi-center study and there are no planned adjustments for multiple centers
or regions.
Unless otherwise stated, the following rules will apply:

Data from the double-blind phase only will be displayed in tables and figures.

Data collected in both the double-blind and open-label phases will be listed together 
and sorted by phase.

Listings will be sorted by study phase and treatment group where applicable.

Summaries and figures will present data by treatment group.

The following statistics will be used to summarize the data:
o
Continuous Variables: n, mean, standard deviation (SD), median, minimum and 
maximum.
o
Categorical Variables: n, frequency counts and percentages. 

Summaries by Visit: Only scheduled visits at which parameters are collected as per 
the time and events table will be presented unless otherwise stated e.g. laboratory 
parameters. The “End of Double Blind” visit will not be presented in displays.

Unscheduled visits will be included in the “Anytime post baseline” category for worst 
toxicity grading tables.


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
Unscheduled visits will be listed.

No imputation for missing values will be conducted.
5.2.
Examination of Covariates, Subgroups & Other Strata
5.2.1.
Examination of Strata and Covariates
Randomization (Day 0) included stratification according to the following variables:

Anti-neutrophil Cytoplasmic Antibodies (ANCA) type (anti-PR3 vs. anti-MPO)
historically assessed

Disease stage at induction (initial diagnosis vs. relapsing disease)

Induction regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. rituximab)
Note: The adjustment of induction regimen will be changed to rituximab vs. IV and/or oral 
cyclophosphamide if the number of events (relapse) is less than 5 in subjects using oral 
cyclophosphamide or IV cyclophosphamide.
Efficacy analyses will be adjusted based on the eCRF categorization.
If any factor does not converge it will be removed from the model.
5.2.2.
Examination of Subgroups

As a result of the significant reduction in sample size for this study from ~300 
subjects to ~100 subjects (Protocol HGS1006-C1100 Amend 04 Summary of 
Modifications; GSK Document No.: 2013N167980_02), no subgroup analyses will 
be conducted but interactions with treatment group will be explored.

Selected adverse event displays will be presented by the following subgroups:

Gender

Age (years): < 65 vs. ≥ 65

Induction Regimen: IV cyclophosphamide vs. oral cyclophosphamide vs. 
rituximab

Selected efficacy summaries will be presented by the following subgroups as per the 
eCRF categorization:

Anti-neutrophil Cytoplasmic Antibodies (ANCA) type (anti-PR3 vs. anti-MPO)

Disease stage at induction (initial diagnosis vs. relapsing disease)

Induction regimen (IV cyclophosphamide vs. oral cyclophosphamide vs. 
rituximab)

Selected displays will be presented by age subgroups ≥ 65 years and ≥ 75 years for 
inclusion in the Benlysta Elderly Analysis #3 report.

Other subgroup analyses may be data-driven and conducted post-SAC, to further 
support evaluation of endpoints.


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5.3.
Rules for Relapse/Treatment Failure due to Receipt of Prohibited 
Medication
Subjects that are considered to be treatment failures by the treatment failure rules 
specified in the protocol and those specified by the study team will be adjudicated by 
representatives from safety, clinical and statistics at least once prior to DBR and once 
again after DBR and prior to DBF. Statistics and programming will program the agreed 
rules and output a spreadsheet to be completed by the committee. The adjudications will 
then be reflected back into the database.
5.3.1.
Overview of Treatment Failure Rules as specified in the Protocol
All corticosteroids will be converted to a prednisone equivalent average daily dose 
(mg/day). The definition and derivation of this can be found in Appendix 4.
Concomitant medications will be coded using GSK Drug Dictionary Version 1.3 and 
those to be extracted as part of the treatment failure adjudication process will be 
identified as described in Appendix 4.
Subjects who start prohibited medication or therapies at any time during the double-blind 
phase will be considered as having relapsed as of the time of receipt of the prohibited 
medication and treatment with study agent will be discontinued. However, the subject 
will continue to be followed for survival through at least 12 months after randomization.
The following medications and therapies are prohibited during the study:

Other immunomodulatory investigational agents (biologic or non-biologic).

Rituximab.

Cyclophosphamide.

Other immunosuppressive agents (e.g. cyclosporine) with the exception of 
methotrexate for AZA intolerance described in Section 5.5.3 of Protocol Amendment 
04.

Corticosteroids for vasculitis doses > 20 mg/day prednisone (or equivalent), or IV 
corticosteroid pulses at any dose. 
Note: Doses of prednisone up to a maximum of 20 mg/day (or equivalent) for 
vasculitis, for a maximum of 1 week, are only allowable within the first 2 months of 
the double-blind treatment period.

Corticosteroids for reasons other than vasculitis: at an average daily dose of > 20 
mg/day prednisone (or equivalent) for > 14 days where the average daily dose is 
calculated as the sum of the dose over 7 consecutive days divided by 7, or IV 
corticosteroid pulses > 125 mg prednisone (or equivalent). 
Note: Doses of prednisone (or equivalent) > 20mg/day for ≤ 14 days or IV 
corticosteroid pulses ≤ 125 mg prednisone (or equivalent) for reasons other than 
Vasculitis cannot be given more than once in any 365 day period (See also Protocol 
Amendment 04 Section 5.5.3).

Plasmapharesis.


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In addition to the above rules, subjects that receive more than 25mg of methotrexate in 
any 1 week period will be considered as potential treatment failures and will be 
adjudicated on a case-by-case basis.
5.3.2.
Additional Detail for Treatment Failure Rules

Treatment failures will be assessed from Day 0 until the last visit in the double-blind 
treatment period (see Appendix 4 for further detail).

The time period of 14 days is defined as 14 consecutive days. Similarly, “1 week” is 
defined as 7 consecutive days.

Average daily dose will be calculated for each study day, starting from Day 0 which 
is calculated as the average of the 7 days up to but not including Day 0. For all other 
study days, the average is calculated as the 7 days up to and including the study day 
of interest.

When calculating the average daily dose of “corticosteroids for reasons other than 
vasculitis”, corticosteroids for any indication will be included.

The date at which a subject is considered to be a treatment failure will correspond to 
the date on which they meet the treatment failure rule. For example, a subject that 
receives a daily average dose of corticosteroid > 20mg/day for greater than 14 days is 
considered a treatment failure on the fifteenth day.

For subjects that withdraw from the study, those that begin receiving escalated doses 
of corticosteroid prior to their last visit in the double-blind treatment period (see 
Appendix 4 for further detail) or who start a prohibited medication at the time of, or 
soon after, their last visit in the double-blind treatment period will also be considered
as potential treatment failures. The Medical Monitor (MM) will assess subjects that 
withdraw from the study on a case-by-case basis and exert clinical judgment.

The MM will manually review the concomitant medications record for investigational 
products on an ongoing basis. The MM will inform the Study Statistician via email if 
any cases are found and at the time of final adjudication will send a confirmation 
email of any cases found or no cases found. This email will be forwarded to the 
Group Mail Box.

The MM will manually review the surgery dataset for cases of Plasmapharesis. Any 
cases found will be reported to the Study Statistician via email. At the time of final 
adjudication, the MM will send a confirmation email of any cases found or no cases 
found. This email will be forwarded to the Group Mail Box by the Study Statistician. 

Receipt of prohibited medication that is adjudicated as a treatment failure will be 
further evaluated for its relation to vasculitis (yes or no).


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Intent-to-Treat population, unless 
otherwise specified.
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 12.
Table 3
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Listing
Subject Disposition
Subject-Years on Study (Double-blind Phase)
Y
Subject Disposition (Double-blind Phase)
Y(x3)[1]
Y
Subject Completion Status by Study Year (Double-blind Phase)
Y(x3)[1]
Summary of Screen Failures (Screened Subjects Population)
Y
Y
Subjects by Country and Center (Randomized Subjects Population)
Y
Reasons for Study Treatment Discontinuation
Y[2]
Reasons for Subject Study Withdrawal
Y[2]
Planned and Actual Treatments
Y
Protocol Deviations
Inclusion/Exclusion Criteria Deviations (Double-blind Phase)
Y
Y[3]
Subjects with Important Protocol Deviations (Double-blind Phase)
Y
Y
Populations Analyzed
Summary of Study Populations (Double-blind Phase)
Y
Demographic and Baseline Characteristics 
Demographic Characteristics (Double-blind Phase)
Y(x3)[1]
Y
Baseline Disease Characteristics (Double-blind Phase)
Y(x3)[1]
Randomized and Actual Strata (Double-blind Phase)
Y
Race and Racial Combinations (Double-blind Phase)
Y(x3)[1]
Y[4]
Other Baseline Characteristics
Anti-Neutrophil Cytoplasmic Antibody at Baseline (Double-blind Phase)
Y
Y[2] [5] [6]
Complement (C3, C4) and BLyS Protein at Baseline (Double-blind Phase)
Y
Y[2] [5] [6]
Immunoglobulin (IgA, IgG, IgM) Levels at Baseline (Double-blind Phase)
Y
Y[2] [5] [6]
B Cells (FACS of peripheral lymphocytes) and T Cells at Baseline (Double-
blind Phase)
Y
Y[2] [6]
Prior Medical Conditions and Concomitant Medications
Prior Medical Conditions (Double-blind Phase)
Y
Y
Other Prior Medical Conditions (Double-blind Phase)
Y
Concomitant Medications (Double-blind Phase)
Y
Y[2]
Concomitant Procedures/Surgeries (Double-blind Phase)
Y[2]
Exposure and Treatment Compliance
Duration of Exposure to Study Drug (Double-blind Phase)
Y(x3)[1]
Y[2]
Study Drug Administration
Y[2]
Time to Study Withdrawal (Double-blind Phase)
Y(x3)[1]
Time to Withdrawal from Study Drug (Double-blind Phase)
Y
Subjects switching from Azathioprine to Methotrexate (Double-blind 
Phase)
Y
Treatment Failures (Double-blind Phase)
Y


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NOTES: Y = Yes display generated.
[1] Summary produced for all subjects and elderly subgroups (≥ 65 years and ≥ 75 years).
[2] Listing will display double-blind and open-label phase data.
[3] Listing also includes analysis population exclusions.
[4] Listing of race.
[5] Single listing of specific biomarker results to be generated.
[6] Listing will display all visits.
Time to study withdrawal and time to study treatment discontinuation will also be 
summarized with Kaplan-Meier curves.
6.1.1.
Supplementary Information for Other Baseline Characteristics
and Stratification Factors
A listing of randomized versus actual strata will be provided. Further detail regarding
summary statistics to be produced is given in Table 4.


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Table 4
Baseline Indicators and Stratification Factors
Baseline Indicator
Categories & Summaries at Baseline
Disease Classification

Counts (%) of Granulomatosis with Polyangiitis (GPA) and microscopic 
Polyangiitis (MPA).
Anti-neutrophil 
Cytoplasmic Antibody

Counts (%) of ANCA positive or ANCA negative as per immune-
fluorescence assay (IFA). 

Counts (%) of p-ANCA, c-ANCA or at-ANCA as per IFA.

Median, minimum and maximum summary of ANCA titer value as per IFA.

Counts (%) of ANCA type, anti-MPO or anti-PR3 (historically assessed).

Counts (%) of ANCA type, anti-MPO or anti-PR3 as evaluated by Q2
Solutions.
Disease Duration

Summary Statistics.
Previous 
Cyclophosphamide Use

Counts (%) of yes or no.

Summary statistics of cumulative lifetime exposure in grams.
Vasculitis Damage Index

Counts (%) of subjects with damage by organ domain.
Maintenance Therapy

Counts (%) of Azathioprine and Methotrexate.
Average Daily 
Prednisone Dose 

Summary statistics of average daily prednisone-equivalent use.
Complement & BLyS 
Protein 
Complement

Summary Statistics.

C3 count (%) of low (<90 mg/dL), normal and high (>180 mg/dL).

C4 count (%) of low (<10 mg/dL), normal and high (>40 mg/dL).
BLyS [ng/mL] Protein

Summary statistics and count (%) of results below/above the limit of 
quantification [LOQ]).
Immunoglobulin                 
(IgA, IgG, & IgM [g/L])

Summary statistics.

Count (%) below the lower limit of normal (LLN) and above upper limit of 
normal (ULN).
B Cells and T Cells

Summary statistics.

Only concentration and percentage will be presented.
Induction Regimen

Counts (%) of IV Cyclophosphamide, oral Cyclophosphamide and 
Rituximab as per the eCRF categorization.
Current Disease Stage

Counts (%) of initial and relapsing as per the eCRF categorization.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analysis
The primary endpoint is time from Day 0 to the first relapse, defined as

at least 1 major BVAS item (Appendix 8) OR

a minimum total BVAS score of 6 (Appendix 8) OR

receipt of prohibited medications (as defined in Section 5.3)
The primary efficacy analyses will be based on the Intent-to-Treat population. The 
primary efficacy analysis will be carried out on the double-blind data only.
A per-protocol analysis will be conducted if the PP population comprises between 50% 
and 95% of the ITT population.
Table 5 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 12.
Table 5
Overview of Planned Efficacy Analyses
Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Time from Day 0 to 
First Relapse
Y(x7)[1]
Y(x6)[1]
Y[1]
Relapse
Y
Y(x2)
NOTES :

[1] Double-blind phase only

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
Time to relapse is defined as the number of days from Day 0 until the subject experiences
a relapse (relapse date – Day 0 +1).  Only post-baseline relapses will be considered in 
these analyses. Only relapses occurring up to and including the last visit date in the 
double-blind treatment period will be considered in these analyses (see Appendix 4 for 
further detail).
The following will apply to all statistical analyses of the primary endpoint, including 
sensitivity and exploratory analyses:

A single summary table for each statistical analysis performed will be produced 
and will display model results for treatment group only unless otherwise 
specified. This table will not be produced for exploratory analyses of interaction 
terms.


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
Other covariates included the model for the primary analysis of the ITT 
population only will be summarized in a separate table.

Where interaction terms are explored, a single summary table will present p-
values for interaction terms only.
A listing of relapse status at each visit for all subjects will be provided and will be sorted 
by relapse, center ID, subject ID and date of visit. For subjects that relapse, only visits up 
to and including the visit of relapse will be displayed.
A separate listing will be provided to detail the individual components of relapses due to 
BVAS. The disposition of subjects is defined as follows: 
Subject Disposition
Event Met
Event Date
Subject Experiences Relapse [1]
Subject experiences relapse as per BVAS 
assessment during the study
Yes
Date of BVAS assessment at which relapse is 
captured
Subject experiences relapse due to receipt 
of prohibited medication during the study
Yes
Date of receipt of prohibited medication
[1] If relapse as per BVAS and due to prohibited medication are observed at the same visit, the date of relapse will correspond to the 
earliest event date. If more than one condition for relapse is met on the same date, all reasons for relapse will be summarized and 
listed.
Subject Does Not Experience Relapse
Subject withdraws from the study
No
Censored at last available BVAS assessment
(right censor)
Subject dies during the study
No
Censored at last available BVAS assessment 
(right censor)
Subject completes the study
No
Censored at last available BVAS assessment
(right censor)


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7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Primary Endpoint

Time from Day 0 to the first relapse, defined as 
–
at least 1 major BVAS item (Appendix 8) OR 
–
a minimum total BVAS score of 6 (Appendix 8) OR
–
receipt of prohibited medications (as defined in Section 5.3)
Model Specification

Time to event endpoints will be statistically analyzed using a Cox Proportional Hazards (CPH) 
Model.

Terms fitted in the CPH model will be based on the eCRF categorization and will include:
–
Fixed categorical: ANCA type (anti-PR3 vs. anti-MPO), disease stage at induction (initial 
diagnosis vs. relapsing disease), and induction regimen (rituximab vs. IV 
cyclophosphamide vs. oral cyclophosphamide).
Note: The adjustment of induction regimen will be changed to rituximab vs. IV and/or oral 
cyclophosphamide if the number of events (relapse) is less than 5 in subjects using oral 
cyclophosphamide or IV cyclophosphamide.

If a covariate in the model does not converge it will be removed (with the exception of induction 
regimen which should first be re-categorized as a binary variable).

If a subject withdraws or completes the study up to 12 months after the last subject is 
randomized without a relapse, time to first relapse will be censored at the time of the last 
available BVAS assessment.

Where ties are observed, these will be dealt with using the default method in the latest version 
of SAS (Breslow).
Model Checking & Diagnostics

The assumption of proportional hazards between treatment groups will be assessed using 
appropriate methods.
Model Results Presentation

The hazard ratio representing the estimated relative risk of relapse (belimumab – placebo) 
along with the 95% confidence interval and Wald chi-squared p-value will be presented. The 
same statistics will be presented in a separate table for other covariates from the CPH model.

For subjects who experience a relapse, the study day of the relapse will be summarized and 
the table will display the median, first and third quartiles and minimum and maximum if they are 
estimable. If they are non-estimable, the table will state this.

A Kaplan-Meier plot showing cumulative event rates for time to first relapse will be produced
and Kaplan-Meier estimates will be given in a table.

For relapse due to BVAS a table summarizing organ domain involvement will be presented 
along with a listing of organ domain involvement and BVAS item.

A listing of reasons for treatment failure will be produced.
Sensitivity and Supportive Statistical Analyses

Following review of the data, additional analyses may be conducted to further support the 
primary statistical analyses, if deemed appropriate.

A sensitivity analysis adjusting for covariates based on the randomization strata to which a 


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Sensitivity and Supportive Statistical Analyses
subject was assigned at baseline will be presented. The hazard ratio representing the 
estimated relative risk of relapse (belimumab – placebo) along with the 95% confidence 
interval and Wald chi-squared p-value from the CPH model will be presented. This model will 
be fitted for the ITT population only.

Model estimates for covariates other than treatment group will not be provided.

A sensitivity analysis including interaction terms between treatment group and each covariate 
will be included. Interactions will be fitted one at a time to the primary model (i.e. resulting in 
three independent models) and Wald Chi-Square p-values for interaction terms will be reported
in a single table. These models will be fitted for the ITT population only.

Model estimates for covariates other than interactions will not be provided.

A sensitivity analysis considering only vasculitis-related relapses may be performed if it is 
deemed appropriate. This will be assessed when treatment failures have been evaluated for 
their relation to vasculitis. If this analysis is carried out, subjects experiencing a relapse for 
reasons other than vasculitis will be censored at their previous BVAS assessment. Results will 
be displayed in the same way as for the primary efficacy analysis.Model estimates for 
covariates other than treatment group will not be provided.

Note: A vasculitis-related relapse is defined as a relapse occurring due to a minimum BVAS 
score of 6, any major BVAS item or receipt of a prohibited medication resulting in treatment 
failure that is adjudicated as vasculitis-related by representatives from Safety, Clinical and 
Statistics and Programming.

A per-protocol (PP) analysis will be carried out on the primary efficacy endpoint if the PP 
population comprises of at least 50% and at most 95% of the intent-to-treat (ITT) population. 
The hazard ratio representing the estimated relative risk of relapse (belimumab – placebo) 
along with the 95% confidence interval and Wald chi-squared p-value from the CPH model will 
be presented. A Kaplan-Meier plot showing cumulative event rates for time to first relapse will 
be produced and Kaplan-Meier estimates will be given in a table.

Model estimates for covariates other than treatment group will not be provided.


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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
The secondary efficacy analyses will be based on the Intent-to-Treat population.
8.1.1.
Major Secondary Endpoint
Time from Day 0 to the first major relapse, defined as experiencing at least 1 major 
BVAS item (Appendix 8).
Due to a limited number of events occurring during the study, major relapses will be 
listed only.
Time to event is defined as the number of days from treatment start date (Day 0) until the 
subject meets an event (event date – treatment start date +1).  Only post-baseline events 
will be considered. Only major relapses occurring up to and including the last visit date in 
the double-blind treatment period will be considered (see Appendix 4 for further detail).
8.1.2.
Other Efficacy Endpoints
8.1.2.1.
Overview of Planned Efficacy Analyses
All other efficacy endpoints will be summarized descriptively, in tabular format and 
where appropriate graphically. There are no planned formal statistical analyses.
Table 6 provides an overview of the planned efficacy summaries for other endpoints, 
with further details of data displays being presented in Appendix 12.


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Table 6
Overview of Planned Efficacy Analyses for Other Endpoints
Endpoint 
Absolute
Change from 
Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Time to Event Endpoint
Time from Day 0 to first minor or major relapse (defined 
as at least 1 minor BVAS item and/or using a dose of 
rescue medication [1]).
Y
Y
Minor or Major BVAS item or Receipt of Rescue 
Medication
Y
Continuous Endpoints [2]
Birmingham Vasculitis Activity Score (BVAS)
Y
Y
Y
Vasculitis Damage Index (VDI)
Y
Y
Binary Endpoints
Proportion of subjects with any increase in BVAS
Y
Y
Proportion of subjects with any increase in VDI
Y
Y
Proportion of subjects with any increase in BVAS organ 
domains 
Y
Y
Proportion of patients in remission (defined as BVAS=0 
and corticosteroid dose ≤10 mg/ day) 
Y
Y
Y
Proportion of patients with no relapse
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Rescue medication is defined as a prohibited medication resulting in treatment failure.
[2] BVAS: At double blind Week 48 of Year 1, double-blind Week 28 of Year 2 and by visit. VDI: At double blind Week 
48 of Year 1, double-blind Week 24 of Year 2 and by visit.
8.1.2.2.
Time to Event Endpoint

Time to event is defined as the number of days from treatment start date (Day 0) until 
the subject meets an event (event date – treatment start date +1).  Only post-baseline 
events will be considered. Only events occurring up to and including the last visit 
date in the double-blind treatment period will be considered (see Appendix 4 for 
further detail).

For subjects who experience an event, the study day of the event will be summarized
and the table will display the median, first and third quartiles and minimum and 
maximum where estimable. If they are non-estimable, this will be stated.

A Kaplan-Meier plot showing cumulative event rates for time to first event by 
treatment group and table of Kaplan-Meier estimates will be produced.

A listing of event status by treatment group and visit will be presented. Visits will be 
presented up to the first event only.


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The disposition of subjects for the other secondary time to event endpoint is defined as 
follows:
Subject Disposition
Event Met
Event Date
Subject Experiences Minor or Major Relapse
Subject experiences at least one minor relapse 
as per BVAS assessment during the study
Yes
Date of BVAS assessment at which
minor relapse was captured
Subject receives a prohibited medication
Yes
Date of receipt of prohibited medication
Subject Does Not Experience Minor or Major Relapse
Subject withdraws from the study
No
Censored at last available BVAS 
assessment (right censor)
Subject dies during the study
No
Censored at last available BVAS 
assessment (right censor)
Subject completes the study
No
Censored at last available BVAS 
assessment (right censor)
8.1.2.3.
Continuous Endpoints
For continuous endpoints the following outputs will be produced:

Table of summary statistics including n, mean, standard deviation, median, minimum 
and maximum by treatment group and visit for total score and observed change from 
baseline.

For BVAS, a summary of organ system involvement by visit will be presented.

Listing of VDI by treatment group, organ domain, item and visit.

Listing of BVAS by treatment group, organ domain, item and visit.
8.1.2.4.
Binary Endpoints
For binary endpoints the following outputs will be produced:

Table of frequency counts and percentages by visit and treatment group

Bar chart showing percentage (rather than proportion) of responders by treatment 
group and visit

For the remission endpoint, a listing of remission status by treatment group and visit
Due to decreasing subject numbers figures will present data only to Year 2 Week 28 with 
the exception of VDI which will be displayed to Year 2 Week 24. Tables will summarize 
all visits at which the assessment of interest is scheduled.


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The proportion of subjects with any increase in BVAS and the proportion of subjects with 
any increase in BVAS domains will be presented together in a single stacked bar chart 
and a single summary table.
Remission will be assessed on the date of visit only. If the BVAS assessment date is not 
equivalent to the visit date, remission will be assessed on the date of BVAS assessment 
provided it is no more than ±2 weeks from the visit date.
8.1.3.
Biomarkers
8.1.3.1.
Overview of Planned Biomarker Analyses
Biomarker efficacy analyses will be based on the Intent-to-Treat population. There are no 
planned formal statistical analyses. 
Table 7 provides an overview of the planned biomarker analyses, with further details of 
data displays being presented in Appendix 12.
Table 7
Overview of Planned Biomarker Analyses
Parameter
Change from Baseline (Untransformed)
Summary
Individual
T
F
F
L
Anti-neutrophil cytoplasmic antibody (ANCA – p-
ANCA, c-ANCA; anti-MPO, anti-PR3)
Y [1]
Y[2]
ANCA status over Time, compared to Baseline
Y
Serum Complement (C3, C4)
Y[3]
Y[3]
Y[2]
Serum Immunoglobulin Isotypes (IgA, IgM, IgG)
Y[3]
Y[3]
Y[2]
C-reactive Protein (CRP)
Y[3]
Y[3]
Y[2]
Erythrocyte Sedimentation Rate (ESR)
Y[2]
Urinary Protein: Urinary Creatinine Ratio
Y[3]
Y[3]
Y[2]
Estimated Glomerular Filtration Rate (eGFR)
Y[3]
Y[3]
Y[2]
FACS of Peripheral Lymphocytes [4]
Y [1] [3]
Y [1] [3]
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1]
Display to be produced for all ITT subjects and elderly subgroups (≥65 years and ≥ 75 years)..
[2]
Selected biomarker results combined into a single listing by treatment group and visit.
[3]
Separate summaries of change from baseline and percentage change from baseline will be presented. Only 
change from baseline will be produced for elderly subgroups
[4]
Includes: B lymphocytes (CD19+, CD20+, CD20+/CD69+ activated, CD27hi/CD20- short-lived plasma, 
CD27+/CD20+ memory, CD27-/CD20+ naïve, CD138+/CD20- 138 plasma cells, CD138+/CD20+ plasmacytoid,  
CD19+/CD24b+/CD38b+/CD27-/IgD+/CD10+ transitional), T cell subsets: CD3+/CD4+, CD3+/CD8+.


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8.1.3.2.
Absolute and Percent Change (Observed)
The absolute and percent change from baseline for complement levels (C3 and C4), 
immunoglobulins, C-reactive protein (CRP), estimated glomerular filtration rate (eGFR)
and B cell and T cell subsets will be summarized by treatment group and visit. Other 
biomarkers will be listed by treatment group and visit. These summaries will be
performed based on the observed data. 
A line graph for the mean observed or percent change from baseline, along with 95% 
confidence intervals, in certain biomarkers will be presented by treatment group and visit
up to Year 2 Week 28. Upon visual inspection of the data, if the distribution of any 
biomarker is considerably non-normal the median change will be displayed instead.
8.1.3.3.
B and T cell Subsets
The observed change and percent change from baseline will be calculated for all B and T 
cell subset parameters. Events will not be displayed for any subsets. Percentage and 
concentration will not be displayed for rare B cell subsets; instead normalized count per 
millilitre (cells/mL) will be presented. The complete list of B and T cell subsets are given 
in Appendix 6.
Unit Conversion
All endpoints measured in GI/L should be converted to cells/cumm and presented as such 
using the following formula:
New Result = Old Result * 1000
Rare B Cell Subsets
Rare B cell subsets will then be converted to cells/ml using the following formula:
Normalized count/mL = [(rare cell event count) / (CD19+ event count)] * (CD19+ cells/cumm) * 
1000
Endpoints to be normalized and values to be substituted into the formula are given in 
Table 8.


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Table 8
Rare B cell subsets requiring normalization
PARAM type (rare cell event 
count)
CD19+ Event Count
CD19+ Counts[1]
CD20+ CD138+ Events 
(EVENTS)
CD19+ Events (EVENTS)[2]
CD19+ (cells/cumm)
CD20- CD138+ Events 
(EVENTS)
CD19+ Events (EVENTS) [2]
CD19+ (cells/cumm)
CD20+CD69+ Events 
(EVENTS)
CD19+ Events (EVENTS) [2]
CD19+ (cells/cumm)
CD27+b CD20- Events 
(EVENTS)
CD19+ Events (EVENTS) [2]
CD19+ (cells/cumm)
CD19+ CD24b+ CD38b+ 
CD27-IgD+ CD10 Events 
(EVENTS)
CD19+ Events (EVENTS) [3]
CD19+ (cells/cumm)
[1] Source data require conversion from GI/L to cells/mm3.
[2] CD19+ Events based on the plasma panel assay, i.e. BIMETHCD = FLWPLSM.
[3] CD19+ Events based on the transitional panel assay, i.e. BIMETHCD = FLWTRANS.
The required parameters in the source data can be identified in Table 9.


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Table 9
Source data from Q2 Solutions required for Normalization of Rare B Cell Subsets
OU Name
Client RTC 
(BICATCD)
Client Analyte name
Biomarker test code 
(BITESTCD)
Biomarker testing 
method code 
(BIMETHCD)
Units of Measurement
(BIORRESU)
TBNK
CD19[1]
CD19+
CONC
FLWTBNK
GI/L[1]
PLASMA
CD19
CD19+
EVENTS
FLWPLSM
EVENTS
PLASMA
CDX155
CD20+ CD69+
EVENTS
FLWPLSM
EVENTS
PLASMA
CDX143
CD20- CD138+
EVENTS
FLWPLSM
EVENTS
PLASMA
CDX145
CD20+ CD138+
EVENTS
FLWPLSM
EVENTS
PLASMA
CDX154
CD27+b CD20-
EVENTS
FLWPLSM
EVENTS
TRANS
CDX200
CD19+ CD24b+ CD38b+ 
CD27-IgD+ CD10
EVENTS
FLWTRANS
EVENTS
[1] Requires unit conversion to cell cells/cumm


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B cells and T cells (percentage and concentration or normalized count/ml for rare B cell subsets) will be presented in the following order 
in all displays (BICATCD is given in parentheses for B cells, LBTESTCD is given for T cells as these are contained in the LAB dataset):
1. CD19+ (CD19)
2. CD27-/CD20+ naive (CDX136)
3. CD27+/CD20+ memory (CDX137)
4. CD19+/CD24b+/CD38b+/CD27-/IgD+/CD10+ transitional (CDX200)
5. CD20+/CD69+ activated (CDX141/CDX155)
6. CD20+ (CD20)
7. CD27hi/CD20- short-lived plasma (CDX154)
8. CD138+/CD20- 138 plasma cells (CDX143)
9. CD138+/CD20+ plasmacytoid (CDX145)
10. CD3+/CD4+ (LBTESTCD (CONC) = CD4+_BLC; LBTESTCD (%) = CD4+_BLQ)
11. CD3+/CD8+ (LBTESTCD (CONC) = CD8+_BLC; LBTESTCD (%) = CD8+_BLQ)


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8.2.
Safety Analyses
8.2.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the Intent-to-Treat population, unless otherwise 
specified.
Table 10 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 12.
Additional summaries, adjusting for subject years on study drug, may be performed if an 
imbalance in time on study drug is observed across treatment arms
Table 10
Overview of Planned Adverse Events Analyses
Endpoint
Absolute
Summary
Individual
T
F
L
Pre-treatment Adverse Events by SOC & PT
Y
AE Summary by Year Interval
Y(x3)[1]
Cumulative AE Incidence Over Time
Y
Survival Status at Week 52
Y
Relationship between SOC and Verbatim Text
Y
Adverse Events by SOC
AE by SOC & Year Interval
Y
Serious AE by SOC & Year Interval
Y
Severe AE by SOC & Year Interval
Y
Study Drug Related AE by SOC & Year Interval
Y
AE Leading to PD of Study Drug or WD from Study by SOC & Year 
Interval
Y
Adverse Events Rates by SOC
AE Rate by SOC & Year Interval
Y
Serious AE Rate by SOC & Year Interval
Y
Severe AE Rate by SOC & Year Interval
Y
Study Drug Related AE Rate by SOC & Year Interval
Y
AE Leading to PD of Study Drug or WD from Study Rate by SOC & Year 
Interval
Y
Adverse Events by SOC & PT
AE by SOC & PT  & Year Interval
Y(x3)[1]
Y(x3)[1][2]
Serious AE by SOC & PT & Year Interval
Y(x3)[1]
Y(x3)[1][2]
Severe AE by SOC & PT & Year Interval
Y
Serious or Severe AE Infections
Y[2]
Study Drug Related AE by SOC & PT & Year Interval
Y(x3)[1]
Y[2]
AE Leading to PD of Study Drug or WD from Study by SOC & PT & Year 
Interval
Y(x3)[1]
Y(x3)[1][3]
Deaths by SOC & PT & Year Interval
Y(x3)[1]
Y
Subject Numbers by Individual AE by SOC & PT
Y
Adverse Events Rates by SOC & PT
AE Rate by SOC & PT & Year Interval
Y


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Endpoint
Absolute
Summary
Individual
T
F
L
Adverse Events: Non-Serious, Serious & Fatal Serious by SOC & PT
Common Non-Serious Adverse Events (>=5% incidence in any interval) 
by SOC and PT & Year Interval
Y
Study Drug-Related Serious Adverse Events by SOC and PT & Year 
Interval
Y
Fatal Serious Adverse Events by SOC and PT & Year Interval
Y
Study Drug-Related Fatal Serious Adverse Events by SOC and PT & 
Year Interval
Y
Non-Fatal Serious Adverse Events by SOC and PT & Year Interval
Y
Y[2]
Study Drug-Related Non-Fatal Serious Adverse Events by SOC and PT
& Year Interval
Y
Y[2]
Adverse Events by SOC, PT and Gender
AE by SOC, PT and Gender & Year Interval
Y
Serious AE by SOC, PT and Gender & Year Interval
Y
Adverse Events by SOC, PT and Age (< 65 and ≥ 65)
AE by SOC, PT and Age Group (years) & Year Interval
Y
Serious AE by SOC, PT and Age Group (years) & Year Interval
Y
Adverse Events by SOC and PT and Induction Regimen
AE by SOC, PT and Induction Regimen & Year Interval
Y
Serious AE by SOC, PT and Induction Regimen & Year Interval
Y
Adverse Events by PT
AE by PT & Year Interval 
Y
Serious AE by PT & Year Interval
Y
Severe AE by PT & Year Interval
Y
Study Drug Related AE by PT & Year Interval
Y
AE Leading to PD of Study Drug or WD from Study by PT & Year Interval
Y
Deaths by Category and PT & Year Interval
Y(x3)[1]
Adverse Events by Maximum Intensity
AE by SOC & Maximum Intensity & Year Interval
Y
AE by SOC, PT & Maximum Intensity & Year Interval
Y
Adverse Events occurring Off-Treatment
AE occurring Off-Treatment by SOC
Y
Y[4]
NOTES:

BL = Baseline, PD = Permanent Discontinuation, PT = Preferred Term, SOC = System Organ Class, WD = 
Withdrawal, T = Table, F = Figures, L = Listings, Y = Yes display generated, 

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Data in all displays will be presented by treatment group.
[1]
Display to be produced for all ITT subjects and elderly subgroups (≥ 65 years and ≥ 75 years). 
[2]
Listing generated by Treatment Group, SOC, PT and Verbatim Term.
[3]
Listing generated for AE results in study drug discontinuation
[4]
AE occurring off-treatment will be included in overall AE listing


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8.2.1.1.
Adverse Events

Treatment-emergent AEs are defined as adverse events that emerge on or after the 
first treatment dose, having been absent pre-treatment, or that worsen relative to the 
pre-treatment state.

Only on-treatment adverse events will be summarized in tables and figures with the 
exception of summaries by year interval which will display events that occur during 
follow-up in the “Anytime Post Baseline” category. On-treatment events are defined 
as those occurring during the on-treatment study phase (see Appendix 2 for further 
detail). All treatment-emergent adverse events will be shown in listings.

Adverse events will be coded to MedDRA dictionary version 19.1.

Common AEs will be defined as ≥ 5% incidence in any treatment group.

AEs with partial or missing start and/or stop dates will be assumed to be treatment-
emergent unless there is evidence through comparison of partial dates to suggest 
otherwise.

All treatment-emergent AEs will be listed for the double-blind phase and open-label 
phase together and sorted by study phase.

Duration of AE (days) = Date of AE resolution – AE start date +1
8.2.1.2.
Adverse Event Summaries
An overall summary of AEs will be presented showing the number (%) of subjects with 
at least one of the following: 

AE

Study drug related AE

SAE

Severe AE

SAE and/or severe AE

AE resulting in study drug discontinuation and/or study withdrawal

Death
The number (%) of subjects experiencing an AE by treatment group will be summarized 
for each of the AE categories in Table 11.


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Table 11
Adverse Events Categories
AE’s
Summary Category
By SOC
By SOC & PT
By PT 
All
Y
Y
Y
Serious
Y
Y
Y
Severe
Y
Y
Y
Study Drug Related
Y
Y
Leading to permanent discontinuation of study drug
and/or study withdrawal
Y
Y
Y
Deaths
Y
Y[1]
NOTES: Y = Yes display generated.
SOC = System Organ Class, PT = Preferred Term
[1] Deaths presented by Category and PT
Tabular summaries will be produced for each category of AE listed in Table 11, 
including:

Number of subjects who reported at least one event.

Percentage of subjects who reported at least one event (incidence).

Number of adverse events.
The tables will be sorted by overall decreasing frequency of the SOC and then decreasing 
frequency of PT within the AE. Data in all tables will be presented by treatment group.
Summaries of AEs incidence, by SOC and severity will also be provided.  For these 
displays, the number and percentage of subjects will be summarized as mild, moderate or 
severe based on the maximum severity observed across all PTs within the SOC for a 
given subject.
Total number of events will be calculated for the by SOC and by PT level tables and the 
AESI tables.
Adverse Event Rates

An overall summary of AE event rates will be presented by SOC and PT. All other 
AE rate tables will display data by SOC only.

A second summary will show the number of events reported and the event rate for the 
SOC level tables and the AESI tables.
The event rate of an AE will be calculated as the number of events per 100 subject years:


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Event Rate = 100* Number of Events / Subject Years
Overall 
Subject 
Years
∑All Subjects in Population [(Last Contact Date – 1st Treatment Date + 1)]
365
NOTE: This will be the denominator for the “Any Time Post Baseline” column.
Subject
Years in 
Year k
∑All Subjects in Population (End of Interval Day – Start of Interval Day + 1)
365

Last contact date is the maximum of all assessment and event dates in the 
BEL115466 database excluding the “END OF DOUBLE BLIND”, “LOGS” and 
“SURVIVAL” visits.

AEs will be sorted by MedDRA SOCs, in descending order from the SOC with the 
highest overall ‘Any Time Post Baseline’ incidence/rate for any AE within the class, 
to the SOC with the lowest “Any Time Post Baseline” incidence/rate. 

Only SOCs with observed AE PTs will be presented.  MedDRA PTs within SOC will 
be repeated using the same method. 

Tables which do not report the SOC will be sorted in descending order of incidence 
from the PT with the highest overall ‘Any Time Post Baseline’ incidence/rate group 
to the PT with the lowest ‘Any Time Post Baseline’ incidence/rate. 

If the overall ‘Any Time Post Baseline’ incidence/rate for any two or more adverse 
events is equal, the events will be presented in alphabetical order by SOC/PT as 
applicable.
A listing of which subjects reported each AE will also be produced. AEs will be grouped 
and sorted by SOC and PT. A figure of cumulative incidence of AEs by event type will 
be created for the ITT population.
8.2.2.
Overview of Planned Adverse Event of Special Interest Analyses
Reporting of AESI will follow the principles outlined in the belimumab PSAP (Version 
3, 14DEC2016), to ensure consistency across belimumab studies. Any specific 
BEL115466 modifications, additional AESI reporting or adjudication process 
requirements from the PSAP, are outlined below.
The following modifications from the PSAP (Section 14: AESI Definitions) will be 
applied for reporting the study: 

Preferred terms from MedDRA 19.1 will be used. 
The following modifications from the PSAP (Section 15: GSK SRT Adjudication of 
AESI) will be applied for the study adjudication process: 

The milestone defined in the PSAP (i.e. before database release) for adjudications 
will be “database freeze”.  
Table 12 provides an overview of the planned Adverse Event analyses, with full details 
of data displays being presented in Appendix 12.


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Table 12
Overview of Planned Adverse Events of Special Interest
Endpoint
Absolute
Summary
Individual
T
L
Adverse Events of Special Interest (AESI)
Overall AESI by Category & Year Interval
Y(x3)[1]
Y [2]
Malignant Neoplasm AESI by Category & PT & Year Interval
Y
Infusion/Anaphylaxis/Hypersensitivity Reaction AESI by Category & PT & Year 
Interval
Y
Serious Infusion/Anaphylaxis/Hypersensitivity Reaction AESI by Category & PT & 
Year Interval
Y
Infection AESI by Category & PT & Year Interval
Y
Serious Infection AESI by Category & PT & Year Interval
Y
Severe Infection AESI by Category & PT & Year Interval
Y
Serious/Severe Infection AESI by Category & PT & Year Interval
Y
Infection AESI Leading to Discontinuation by Category & PT & Year Interval
Y
Depression/Suicide/Self-injury AESI by Category & PT & Year Interval
Y
Adverse Events of Special Interest (AESI) by Subgroups
Overall AESI by Category and Induction Regimen & Year Interval
Y
Malignant Neoplasm AESI by Category & PT & Induction Regimen & Year Interval
Y
Infection AESI by Category & PT & Induction Regimen & Year Interval
Y
Serious Infection AESI by Category & PT & Induction Regimen & Year Interval
Y
Adverse Events of Special Interest (AESI) Rates
Overall AESI Rate by Category & Year Interval
Y
Malignant Neoplasm AESI Rate by Category & PT & Year Interval
Y
Infusion/Anaphylaxis/Hypersensitivity Reaction AESI Rate by Category & PT & 
Year Interval
Y
Serious Infusion/Anaphylaxis/Hypersensitivity Reaction AESI Rate by Category & 
PT & Year Interval
Y
Infection AESI Rate by Category & PT & Year Interval
Y
Serious Infection AESI Rate by Category & PT & Year Interval
Y
Severe Infection AESI Rate by Category & PT & Year Interval
Y
Serious/Severe Infection AESI Rate by Category & PT & Year Interval
Y
Infection AESI Leading to Discontinuation Rate by Category & PT & Year Interval
Y
Depression, Suicidality, and Self-injury AESI Rate by Category & PT & Year 
Interval
Y
NOTES: T = Table, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data. 


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[1]
Display to be produced for all ITT subjects and elderly subgroups (≥ 65 years and ≥ 75 years
[2]
Listing generated by Treatment Group, AESI Category, SOC, PT and Verbatim Term.
8.2.3.
Adverse Events of Special Interest Summaries
An overall summary of AESI will be presented by treatment group and each specific 
category of AESI will be presented separately by PT. 
An overall summary of AESI by treatment group and induction regimen will also be 
provided as well as each specific category by PT for malignant neoplasm AESI, infection 
AESI and serious infection AESI.
The number (%) of subjects with at least one occurrence and the number of events of the 
following AESI will be provided:
Malignant Neoplasms

All Including non-melanoma skin cancer (NMSC)

All Excluding NMSC
o
Solid Tumor
o
Hematologic
o
Skin (All)

NMSC

Excluding NMSC
o
Tumors of Unspecified Malignancy per GSK Adjudication
Post-Infusion Systemic Reactions

Post-Infusion Systemic Reactions per Anaphylactic Reaction Customized MedDRA Query (CMQ) 
Narrow Search

Post-Infusion Systemic Reactions per Anaphylactic Reaction CMQ Broad Search

Post-Infusion Systemic Reactions per Anaphylactic Reaction CMQ Algorithmic Search

Serious Anaphylaxis per Sampson Criteria

Serious Acute Post-Infusion Systemic Reactions Hypersensitivity per GSK Adjudication
o
Serious Acute Post-Infusion Systemic Reactions Excluding Hypersensitivity per GSK Adjudication
o
Serious Acute Hypersensitivity Reactions per GSK Adjudication

Serious Delayed Acute Post-Infusion Systemic Reactions per GSK adjudication

Serious Delayed Non-Acute Post-Infusion Systemic Reactions per GSK adjudication


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All Infections of Special Interest

All Infections of Special Interest
o
Serious

All Opportunistic infections per GSK Adjudication.
o
Serious

Opportunistic Infections per GSK Adjudication Excluding Tuberculosis and Herpes Zoster
o
Serious

Active Tuberculosis
o
Serious
o
Non-opportunistic
o
Serious
o
Opportunistic
o
Serious

All Herpes Zoster
o
Serious
o
Non-opportunistic
o
Serious 
o
Opportunistic 
o
Serious

Recurrent

Serious

Disseminated 

Serious

Sepsis
o
Serious
Depression/Suicide/Self-injury

Depression/Suicide/Self-injury
o
Depression
o
Serious
o
Suicide/Self-injury
o
Serious

Serious Suicide/Self-injury per GSK Adjudication
o
Suicidal Behavior per GSK Adjudication
o
Completed Suicide per GSK Adjudication
o
Suicidal Intent per GSK Adjudication

Self-injurious Behavior without Suicidal Intent per GK Adjudication
Deaths

Deaths


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8.2.4.
Overview of Planned Columbia-Suicide Severity Rating Scale (C-
SSRS) Analyses
The safety analyses will be based on the Intent-to-Treat population, unless otherwise 
specified. These analyses will be performed for the double-blind phase only.
“Pre-treatment” is considered to be any time up to but not including Day 0.
Table 13 provides an overview of the planned C-SSRS analyses, with further details of 
data displays being presented in Appendix 12.
Table 13
Overview of Planned C-SSRS Analyses
Endpoint
Absolute
Summary
Individual
T
F
L
C-SSRS Suicidal Ideation or Behavior during Treatment
Y
Treatment Emergent C-SSRS Suicidal Ideation or Behavior Relative to 
Pre-Treatment
Y
Shift of Changes in C-SSRS Categories from Pre-Treatment  to On-
Treatment
Y
Possible Suicidality Related Questionnaire (PSRQ)
Y 
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Data in all displays will be presented by treatment group.

Pre-treatment refers to any time up to Day 0.
8.2.4.1.
C-SSRS Suicidal Ideation
Assessments are completed using the C-SSRS.  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, the investigator will be prompted to complete the Possible Suicidality Related 
Questionnaire (PSRQ).  A listing of the Possible Suicidality Related Questionnaire 
(PSRQ) will be presented.
Listings will be generated for the following:

Suicidal ideation and behavior data for subjects who have any suicidal ideation or 
behavior recorded at any point on the study (including screening) 

Behavior details for subjects who have any suicidal behavior recorded at any 
point on the study (including screening) 

The most severe suicidal ideation details for subjects who have any suicidal 
ideation recorded at any point on the study (including screening).


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8.2.4.2.
C-SSRS Suicidal Ideation or Behavior during Treatment
The number (%) of subjects with each category of suicidal ideation or behavior during 
treatment (including Day 0 assessment onwards) will be presented, selecting the worst 
record a subject has for each category.  The categories of suicidal ideation and behavior
are presented in increasing order of severity from 1 to 10.  
For the rows pertaining to suicidal behavior, the number of subjects who have the 
specified behavior at least once during treatment is presented.   
For the rows pertaining to suicidal ideation, the number of subjects whose maximum 
ideation at any on-treatment assessment is the specified ideation is presented.  
Within each category, subjects may have more than one type of suicidal ideation and 
behavior.
8.2.4.3.
C-SSRS Suicidal Ideation or Behavior Relative to Pre-treatment 
The number (%) of subjects with treatment-emergent suicidal ideation or behavior during 
treatment (including Day 0 assessment onwards) will be presented.  A subject must have 
at least one pre-treatment assessment and at least one on-treatment assessment in order to 
be included in this display. A subject may have more than one treatment-emergent 
suicidal ideation and/or behavior.
8.2.4.4.
C-SSRS Shift Changes in Categories from Pre-treatment to On-
treatment
A summary of the shift from maximum pre-treatment C-SSRS category to maximum on-
treatment (up to and including 4 weeks after the final treatment dose is administered)
category will be produced. The pre-treatment period is based on the lifetime evaluation at 
screening.  
A subject must have at least one pre-treatment assessment and at least one on-treatment 
assessment in order to be included in this display.  
The table will display the number (%) of subjects within the specific shift categories: no 
suicidal ideation or behavior, suicidal ideation, and suicidal behavior.


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8.2.5.
Overview of Planned Laboratory & Immunogenicity Analyses
Table 14 provides an overview of the planned Laboratory, Immunogenicity, 
Immunoglobulins and Vital Signs analyses, with full details of data displays being 
presented in Appendix 12.
All laboratory parameters given in Appendix 6 of the protocol will be summarized with 
the exception of myelocytes, metamyelocytes and neutrophil bands in hematology 
displays. These parameters will be listed only.
Table 14
Overview of Planned Laboratory, Immunogenicity and Vital Signs
Endpoint
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Laboratory Parameters (By Visit)
Lab Parameters 
Y (x5) 
[1][2]
Y (x5)
[2]
Y (x6)      
[1]
Y (x6) 
[1][2][3]
Y (x5)    
[2][4]
Worst Laboratory Toxicity Grade (By Year Interval)
Worst Lab Toxicity Grade
Y (x6) 
[1][4]
Lab Toxicity Grading Worsening by 
At Least 2 Grades from BL
Y (x6)[3]
Grade 3 & 4 Lab Toxicity Results
Y (x6)[3]
Laboratory Reference Range Shifts (By Visit)
Lab Reference Shifts from BL
Y (x6)[3]
Immunogenicity
Immunogenicity Response by  Visit
Y
Y
Immunogenicity Response by Year 
Y
Vital Signs (By Visit)
Vital Signs
Y
Y
NOTES:

BL = Baseline, T = Table, F = Figures, L = Listings, Y = Yes display generated, (xN) = Number of separate 
displays generated, LLN = Lower Limit of Normal.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Data from the double-blind and open-label phases will be listed together.
[1]
A combined display will be generated for absolute and change from baseline for each laboratory parameter. A 
combined display will also be generated for absolute and % change from baseline.
[2]
Separate displays generated for [1] Hematology, [2] Liver Function, [3] Electrolytes, [4] Other Chemistries, [5] 
Immunoglobulins.
[3]
Separate displays generated for [1] Hematology, [2] Liver Function, [3] Electrolytes, [4] Other Chemistries, [5] 
Urinalysis, [6] Immunoglobulins.
[4]
Separate displays generated for [1] % Change from BL & [2] Change from BL.


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8.2.5.1.
Clinical Laboratory Evaluations
Continuous numeric values will be summarized using the mean, standard deviation, 
median, minimum and maximum.
Categorical results will be summarized using counts and percentages. Refer to Appendix 
4 for handling of laboratory values that are above or below the lower limit of 
quantification.  
Baseline is defined as described in Section 10.3.2 and a list of laboratory parameters 
collected and definition of the toxicity grades provided in Appendix 10.  
Toxicities will be reported as derived by the central laboratory, as protocol toxicity 
grading was taken into account.  

For potassium, glucose, calcium, and sodium, toxicities are bi-directional (i.e. 
high and low directions) and both will be summarized by name of the toxicity.  

For example, calcium will have two toxicity sections, one for hypocalcaemia and 
one for hypercalcaemia, each with absolute values defining grades 1 to 4 (see 
Appendix 10 for further detail). Grade 0 will also be derived as any value less 
extreme than grade 1.
8.2.5.2.
Laboratory Summaries by Study Year
Summary statistics (absolute and change from baseline) for each analyte will be 
displayed for each visit within continuation study year. 
Line graphs will be produced for each analyte displaying the mean value by visit and 
treatment group and mean change from baseline value by visit and treatment group.   
8.2.5.3.
Worst laboratory toxicity grade post-baseline
Laboratory toxicity will be graded using Adverse Event Severity Grading Tables 
(Appendix 10) where defined. 
The worst laboratory toxicity grade during treatment for each laboratory parameter within 
each laboratory category (hematology, chemistry, urinalysis, and immunoglobulins) will 
be presented. Only laboratory tests with toxicity grades will be presented.
8.2.5.4.
Laboratory toxicity ≥ 2 grade shift post-baseline
Toxicity grade shifts from baseline of ≥ 2 grades will be summarized (i.e. baseline and 
post baseline data available) during treatment for each laboratory parameter within each 
laboratory category (hematology, chemistry, urinalysis, and immunoglobulins).  
The summary will display the number (%) of subjects with at least one ≥ 2 grade shift as 
well as the specific shift categories: Grade 0 to 2, Grade 0 to 3, Grade 0 to 4, Grade 1 to 
3, Grade 1 to 4, and Grade 2 to 4.  


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8.2.5.5.
Laboratory reference range shifts from baseline by visit
For laboratory tests without toxicity grades, shifts relative to the normal range will be 
summarized for each analyte as shifts ‘to low’ and shifts ‘to high.’  
For the ‘to low category’ the percentage of subjects with at least one low post-baseline 
value relative to the baseline will be displayed using the categories:  no shift to low and 
normal/high to low. 
For the ‘to high category’ the percentage of subjects with at least one high post-baseline 
value relative to baseline will be displayed using the categories:  no shift to high and 
normal/low to high. 
A laboratory value that is above the testing laboratory’s normal range will be considered 
a high abnormal laboratory value. A laboratory value that is below the testing 
laboratory’s normal range will be considered a low abnormal value.
8.2.5.6.
Immunoglobulin reference range shifts from baseline by visit
Reference range shifts will be summarized across all visits based on the baseline normal 
range category.  
For subjects with immunoglobulin values below the LLN, the number (%) of subjects 
who ‘remained low’ or went ‘to normal/high’ post-baseline will be summarized. 
For subjects with immunoglobulin values within the normal range or above the ULN, the 
number (%) of subjects who ‘remained normal/high’ or went ‘to low’ post-baseline will 
be summarized.  
8.2.5.7.
Immunoglobulin below LLN by visit
The number (%) of subjects with immunoglobulin values below the LLN at each visit 
will be presented for all subjects, and repeated for subjects based on their status at 
baseline.
8.2.5.8.
Immunogenicity
Serum samples for anti-belimumab antibody measurements will be obtained from all 
randomized subjects before administration of study drug at the scheduled visits. 
Two types of antibody assays will be performed:

Binding assay:

Screening assessment is performed producing a result that is positive or 
negative.  Negative samples in the screening assay are negative for the 
binding assay.

For samples with a positive screening assessment, a confirmation assay is 
carried out which produces a positive or negative result. A subject is 
confirmed as positive for the assessment at this step.  Samples testing positive 
in the screening assay, but negative in the confirmation assay are negative; 
samples testing positive in both the binding assay and the confirmation assay 
are positive for the binding assay

For samples with a positive binding assay (positive in the screening and 
confirmation) result, a titer value is obtained to quantify the degree of binding 


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BEL115466
49
in a titration assay step.  The titer result is the inverse of the dilution at which 
the sample no longer tests positive in the screening assay.

Neutralizing assay: Subjects who test positive for the binding assay are tested for the 
neutralizing assay, which produces a positive or negative result.
Immunogenicity response will be summarized for the binding antibody assay by
treatment group and visit, as:

Negative 

Transient Positive (i.e. single positive response that does not occur at the final 
assessment); or 

Persistent Positive (i.e. positive response that occurs at least 2 consecutive 
assessments or a single result at the final assessment)
Immunogenicity will also be summarized by study year, with the latest value in the year 
interval being reported if multiple occur during the period.
For the titer value, a table will be produced to include the number and proportion of 
subjects in each result category as follows: 

Positive (titer result ≤ Q1)

Positive (titer result > Q1 - ≤ Q2)

Positive (titer result > Q2 - ≤ Q3)

Positive (titer result > Q3)
Where Q1 – Q3 represents quartiles of all titer values observed in the study.
The table will also summarize the highest binding assay confirmatory result obtained for 
each subject. If a subject has Negative and Positive results, they will be included in the 
Positive category. If a subject has titer results that fall into multiple titer result categories, 
they will be included in the highest category.
If a subject has a positive screening assessment but the confirmatory assessment is 
missing, the immunogenicity response will be considered as “Unknown”.
If titer value is missing, the immunogenicity response will still be assessed but that 
subject will not appear in the titer summary table.
8.3.
Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified.
Serum belimumab concentrations will be listed and summarized by visit and nominal 
time.  Standard summary statistics will be calculated (i.e. mean, standard deviation,
%coefficient of variation (CV) and 95% confidence interval of mean, geometric mean, 95% 
confidence interval for geometric mean, median, minimum and maximum). Individual, mean 
and median PK concentrations profiles will be graphically presented.


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50
9.
REFERENCES
GlaxoSmithKline Document Number 2013N167980_02 Study ID BEL115466. A Multi-
Center, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy and 
Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance 
of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis. Effective Date 
26-Feb-2015. Protocol Amendment 04, Effective Date 26-Feb-2015
GlaxoSmithKline Document Number 2015N245521_00 Study ID BEL115466. A Multi-
Center, Multinational, Randomized, Double-Blind, Study to Evaluate the Efficacy and 
Safety of Belimumab (HGS1006) in Combination with Azathioprine for the Maintenance 
of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis. Protocol 
Amendment 04, Local Amendment 01, Effective Date 06-Jul-2015.
GlaxoSmithKline Document Number 2013N167980_01 Study ID BEL115466. A Phase 
3, Multi-Center, Multinational, Randomized, Double-Blind, Study to Evaluate the 
Efficacy and Safety of Belimumab (HGS1006) in Combination with Azathioprine for the 
Maintenance of Remission in Wegener’s Granulomatosis and Microscopic Polyangiitis.
Protocol Amendment 03 Summary of Modifications, Effective Date 04-Feb-2014.
Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DRW, Jennette JC, Kallenberg 
CGM, Luqmani R, Mahr AD, Matteson EL, Merkel PA, Specks U, Watts RA, for the 
American College of Rheumatology, the American Society of Nephrology, and the 
European League Against Rheumatism. Granulomatosis with polyangiitis (Wegener’s): 
An alternative name for Wegener’s granulomatosis. Arthritis Rheum 2011;63(4):863-
864


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51
10.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.1
Appendix 1
Section 10.2
Appendix 2
Section 10.3
Appendix 3
Section 10.4
Appendix 4
Section 10.5
Appendix 5
Section 10.6
Appendix 6
Section 10.7
Appendix 7
Section 10.8
Appendix 8
Section 10.9
Appendix 9
Section 10.10
Appendix 10
Other RAP Appendices
Section 10.11
Appendix 11
Section 10.12
Appendix 12
Section 10.13
Appendix 13


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52
10.1.
Appendix 1: Time & Events
10.1.1.
Protocol Defined Time & Events
Table 15
Double-blind Treatment Phase Year One
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Written Informed 
Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Eligibility Criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Document Successful 
Induction Regimen
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Obtain Historical Biopsy 
Report (if available)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Randomization
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Clinical Assessments
Complete Physical 
Exam1
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Symptom Driven 
Physical Exam
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs15, 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
12-lead ECG16
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CSSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events3
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X12
X
X
BVAS 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-


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BEL115466
53
Study Visit
Screening
-60 days
Day 
0
Week 
2
± 3 
days
Week 
4
± 3 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit11
8 Week 
Follow 
Up13
Un-
sched
uled
Laboratory 
Assessments
Serum Beta hCG
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HIV, Hepatitis B, C17
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology & Modified 
Chem-20 (non fasting)4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
Coagulation – PT/aPTT 
and INR
X
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test5
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and 
creatinine clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X14
Pharmacokinetic 
Sampling (pre/post 
Belimumab dose)
-
X
Pre
X
Post 
(0-4 
hrs)
-
X
Pre
-
-
-
X
Post 
(0-4
hrs)
-
-
-
-
-
X 
Pre
X
X
-
Pharmacogenetic 
Sampling6
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Immunogenicity (anti-
belimumab antibodies)7
-
X
-
-
X
-
-
-
X
-
-
-
-
-
X
X
X
-
BLyS Protein 
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
T cells/B cell subset 
-
X
-
X
X
X
-
-
X
-
-
X
-
-
X
X
X
-
C3/C4 and ANCA
X
X
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum IgG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgA  & IgM
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
CRP & ESR
X
X
-
-
-
X
-
-
X
-
-
X
-
-
X
X
X
Protocol Treatments
Study agent 
(Belimumab/Placebo)8, 9, 
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration10
X
X
←Throughout the Study →
-
-
-
Footnotes on next page:


CONFIDENTIAL
BEL115466
54
Table 15 Footnotes:
1.
Complete physical examination, including height and weight.  
2.
Any SAEs occurring prior to the start of study agent administration and assessed as related to study participation (eg, protocol-mandated procedures, invasive tests) will be recorded on the SAE 
worksheet and reported as described in Section 7.2 of Protocol Amendment 04 from the time a subject consents to participate in the study.
3.
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of 
study agent should be recorded on the Adverse Event Case Report Form (AE eCRF).  SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, 
possibly or probably related to study agent must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
4.
Refer to Appendix 6 of Protocol Amendment 04 for laboratory assessments to be completed.
5.
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) of Protocol Amendment 04 for definition of those 
exempted from pregnancy testing.
6.
In consenting subjects only (Appendix 9 of Protocol Amendment 04). 
7.
Immunogenicity samples are collected pre-dose at all time points.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity 
was assessed if 8-week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose 
of study agent or after completion and/or unblinding of the study, whichever is later. 
8.
Subjects who discontinue treatment with study agent (belimumab/placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1 of Protocol 
Amendment 04.
9.
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.
10.
Subjects naïve to azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by 
severe nausea and vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described 
above a switch to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be permitted. For subjects previously identified as being intolerant to azathioprine, or for 
subjects identified as having undetectable or reduced activity of thiopurine methyltransferase (TPMT), it may be permissible for methotrexate to be used as an alternative to azathioprine for the 
maintenance of remission from the outset following discussion with the medical monitor.
11.
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 4 weeks after the last dose of study agent). The Exit Visit should only be completed for subjects who 
discontinue the double blind treatment phase early or for subjects that have successfully completed the double-blind treatment phase and do not wish to participate in the open label extension 
phase. Subjects who discontinue treatment but have not relapsed will remain on the double blind study visit schedule.  For subjects who complete the double blind phase and enter the open 
label phase, refer to Table 17 for visit details.
12.
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent.  After this time, all SAEs, 
regardless of relationship to study drug, will be collected until relapse or the study is analyzed for the primary endpoint, whichever occurs first.
13.
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent. 
14.
Hematology and Modified Chem 20, Urinary protein, urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be 
clinically indicated by the Principal Investigator.  
15.
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
16.
Complete prior to dosing.
17.
HIV, Hepatitis B surface antigen, anti-HBc, anti-HBs and hepatitis C antibody (if hepatitis C antibody positive, HCV RNA-PCR assay will be performed on a subsequent blood sample to confirm 
the results).


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55
Table 16
Double-blind Treatment Phase Additional Years
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess/Record 
Adverse Events1
X
X
X
X
X
X
X
X
X
X
X
X
X8
X
X
BVAS
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
VDI
-
-
X
-
-
X
-
-
X
-
-
X
X
-
-
Laboratory Assessments
Hematology & Modified Chem-
20 (non fasting)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X10
Coagulation – PT/aPTT and INR
-
-
-
-
-
X
-
-
-
-
-
X
X
-
-
Routine Urinalysis
-
-
X
-
-
X
-
-
X
-
-
X
-
-
-
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Urinary protein:  urinary 
creatinine  and creatinine 
clearance
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X10
Pharmacokinetic Sampling (pre 
or post Belimumab dose)
-
-
-
-
-
X 
Pre
-
-
-
-
-
X 
Pre
X
X
-
Immunogenicity (anti- belimumab 
antibodies)4
-
-
-
-
-
X
-
-
-
-
-
X
X
X
-
T cells/B cells 
X
-
-
-
-
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Serum IgG
-
-
X
-
-
X
-
-
X
-
-
X
X
X
-
Serum IgA & IgM
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-
CRP & ESR
-
-
X
-
-
X
-
-
-
-
-
-
X
X
-


CONFIDENTIAL
BEL115466
56
Study Visit
Week 
4
± 7 
days
Week 
8
± 7 
days
Week 
12
± 7 
days
Week 
16
± 7 
days
Week 
20
± 7 
days
Week 
24
± 7 
days
Week 
28
± 7 
days
Week 
32
± 7 
days
Week 
36
± 7 
days
Week 
40
± 7 
days
Week 
44
± 7 
days
Week 
48
± 7 
days
Exit7
8 Week 
Follow 
Up9
Un-
scheduled
Protocol Treatments
Study Agent 
(Belimumab/Placebo)5
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
-
-
-
Table 16 Footnotes:
1.
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of 
study agent should be recorded on the Adverse Event Case Report Form (AE eCRF).    SAEs that occur after the 8 week follow-up period that are assessed by the investigator as definitely, 
possibly or probably related to study agent must be reported to the Drug Safety designee on the SAE worksheet.  (Post study SAEs will not be documented on the AE eCRF.)
2.
Refer to Appendix 6 of Protocol Amendment 04 for laboratory assessments to be completed.
3.
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) of Protocol Amendment 04 for definition of those 
exempted from pregnancy testing.
4.
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity 
was assessed if 8-week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose 
of study agent or after completion and/or unblinding of the study, whichever is later.
5.
Subjects who discontinue treatment with study agent (belimumab/Placebo) will continue to be followed per this calendar schedule until relapse as defined in Section 8.5.1 of Protocol 
Amendment 04.
6.
Subjects naïve to  azathioprine who develop Grade 3 or 4 leukopenia or thrombocytopenia, AST or ALT > 2 times ULN, or a severe gastrointestinal hypersensitivity reaction, characterized by 
severe nausea and vomiting, following initiation of azathioprine will be permitted to reduce the dose to no less than 1mg/kg/day. If the patient continues to experience the toxicities described 
above a switch to methotrexate at doses of up to 25 mg/week as an alternative to azathioprine will be permitted.
7.
Any visit in which the subject discontinues treatment becomes the Exit visit (ie, generally 1-4 weeks after the last dose of study agent). The Exit Visit should only be completed for subjects who 
discontinue the double blind treatment phase early or when subjects have successfully completed the double-blind treatment phase and do not wish to participate in the open label extension 
phase. For subjects who complete the double blind phase and enter the open label phase, refer to Table 17 for visit details.
8.
In subjects who discontinue study agent all AEs and SAEs will be reported on the AE eCRF through 8 weeks following administration of the last dose of study agent. After this time, all SAEs, 
regardless of relationship to study drug, will be collected until relapse or the study is analyzed for the primary endpoint, whichever occurs first.
9.
The 8 week follow-up visit is to occur approximately 8 weeks after the last dose of study agent.
10.
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be 
clinically indicated  by the Principal Investigator.
11.
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12.
Complete prior to dosing.


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Table 17
Open Label Extension Phase
Study Visit
Day 07
Week 4
± 7 days
Week 8
± 7 days
Week 12
± 7 days
Week 16
± 7 days
Week 20
± 7 days
Week 24
± 7 days
Week 28/ 
Exit8
8 Week 
Follow Up9
Un-
scheduled
Clinical Assessments
Symptom Driven Physical Exam
X
X
X
X
X
X
X
X
-
-
Weight
X
X
X
X
X
X
X
X
-
-
Vital Signs11, 12
X
X
X
X
X
X
X
X
X
-
Record Concurrent Medications
X
X
X
X
X
X
X
X
X
X
Assess/Record Adverse Events1
X
X
X
X
X
X
X
X
X
X
BVAS
X
-
-
-
-
-
X
X
-
-
VDI
X
-
-
-
-
-
X
X
-
-
Laboratory Assessments
Labs: Hematology & Modified Chem-
20 (non fasting)2
X
-
-
-
-
-
X
X
X
X10
Urine Pregnancy Test3
X
X
X
X
X
X
X
X
-
-
Urinary protein: urinary creatinine  
and  creatinine clearance
X
-
-
-
-
-
X
X
-
X10
Immunogenicity (anti- belimumab 
antibodies)4
X
-
-
-
-
-
X
X
X
-
T cells/B cell subset 
X
-
-
-
-
-
X
X
X
-
C3/C4 and ANCA
X
-
-
-
-
-
X
X
X
-
Serum IgG
-
-
X
-
-
-
X
X
-
-
Serum IgA & IgM
-
-
-
-
-
-
X
X
-
-
CRP & ESR
X
-
-
-
-
-
X
X
X
-
Protocol Treatments
Study agent (belimumab)5
X
X
X
X
X
X
X
-
-
-
AZA administration6
X
←Throughout the Study →
X
-
-
Footnotes on next page:


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Table 17 Footnotes:
1.
All adverse events (AEs) and serious adverse events (SAEs) that are identified from the start of study agent administration (Day 0) through 8 weeks following administration of the last dose of 
study agent should be recorded on the Adverse Event Case Report Form (AE eCRF).
2.
Refer to Appendix 6 of Protocol Amendment 04; Local Amendment 01 for Belgium for laboratory assessments to be completed.
3.
Results of urine pregnancy test at subsequent visits, if required, must be available prior to dosing. See Section 6.1 (Screening Procedures) of Protocol Amendment 04; Local Amendment 01 for 
Belgium for definition of those exempted from pregnancy testing.
4.
Immunogenicity samples are collected pre-dose at all timepoints.  For any subject who had a positive antibody response at the 8-week follow-up visit (or last study visit at which immunogenicity 
was assessed if 8-week follow-up immunogenicity sample is not available), an attempt will be made to obtain a serum sample for anti-belimumab antibodies at least 6 months after the last dose 
of study agent or after completion and/or unblinding of the study, whichever is later.
5.
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 infusions. Should symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment.
6.
AZA/MTX continued at the discretion of the investigator.
7.
Day 0 is first visit in the extension phase of the trial and represents the first belimumab administration for placebo subjects.  
8.
Any visit in which the subject discontinues treatment becomes the Exit visit (ie generally 1-4 weeks after the last dose of study agent).
9.
The 8 week follow-up visit is not required for subjects who participate in the separate continuation protocol.  
10.
Hematology, Modified Chem 20, Urinary protein/urinary creatinine and creatinine clearance are not mandatory at Unscheduled Visits and should be obtained only when determined to be 
clinically indicated by the Principal Investigator.
11.
Vital signs include temperature, sitting blood pressure (systolic and diastolic) and heart rate.
12.
Complete prior to dosing.


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10.2.
Appendix 2: Treatment States and Phases
10.2.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start date of study treatment (Day 0).
Treatment Phase
Definition
Pre-Treatment 
Date < First Exposure Date
On-Treatment
Subjects not entering open-label phase: First Exposure Date  ≤ Date ≤ Last Exposure 
Date + 4 Weeks
Subjects entering open-label phase: First Exposure Date  ≤ Date ≤ Open-Label 
Treatment Start Date
Post-Treatment
Subjects not entering open-label phase: Date > Last Exposure Date + 4 Weeks
Open-Label 
Treatment[1]
Open-Label Treatment Start Date < Date ≤ Open-Label Treatment Stop Date + 4 
Weeks
Post-Open-Label 
Treatment[1]
Date > Open-Label Treatment Stop Date + 4 Weeks
[1] For subjects entering the Open-Label phase only.
10.2.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
10.2.2.1.
Treatment States for Adverse Events
The following rules will be used for allocating AEs to study year: 

Each AE will be reported in the year it started. 

AEs continuing for more than one treatment year will only be reported in the year 
they first occurred. 

If distinct episodes (start and stop date) of an AE are reported in multiple years, the 
AE will be reported once in each study year in which the unique event began. 
o
AEs with partial start and/stop dates will be assumed to have occurred on 
treatment unless there is evidence through comparison of partial dates to suggest 
otherwise. 
o
Where possible the non-missing information will be used to assign the AE to a 
study year, if the non-missing information is insufficient to assign the AE to a 
study year then the AE will be assigned to the earliest plausible study year. 

If the AE onset date is missing assume the start date was in Year 0-1. The event will 
be reported in Year 1 and “Any Time Post Baseline.”

If the AE end date is missing assume the AE continued until the end of study. The AE 
will be reported in year of onset and “Any Time Post Baseline.” 

AEs that begin and end on the first day of treatment will count in the Year 0-1 period 
and for “Any Time Post Baseline.”


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Table 18
Example of Assigning AEs to Study Years
Scenario
Pre-Treatment
Year
0-1
Year
1-2
Year
2-3
Year
3-4
Year
4-5
After End of Treatment
A
B
C
D
NOTE: Arrow indicates the start and stop date of a single AE.
Scenario
Assignment of AE to Study Year
Any Time Post-Baseline
Year 0-1
Year 1-2
Year 2-3
Year 3-4
Year 4-5
A
No
No
No
No
No
No
B
Yes
Yes
No
No
No
No
C
Yes
Yes
No
No
No
No
D
Yes
No
Yes
No
No
No


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10.3.
Appendix 3: Data Display Standards & Handling 
Conventions
10.3.1.
Study Treatment & Subgroup Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
1
Belimumab 10 mg/kg
Belimumab
2
0
Placebo
Placebo
1
NOTES:

Order represents treatments being presented in TFL, as appropriate.
For the open-label phase, descriptions for listings will be as follows:

Placebo to Belimumab

Belimumab to Belimumab
10.3.2.
Baseline Definition & Derivations
10.3.2.1.
Baseline Definitions
Day 0 is defined as date of first exposure.
For all endpoints the baseline value will be the latest pre-initial-dose assessment. 
10.3.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given time point
   and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.3.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.


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10.3.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported version of SAS software will be used.
Reporting Area
HARP Server
: us1salx00259
HARP Area
: \arprod\gsk1550188\bel115466\final\
QC Spreadsheet
: \arwork\gsk1550188\bel115466\documents\QC_BEL115466.xlsm
Analysis Datasets 

POP, DS, DSYEAR, TRT, AE, AEANAL, AEMQ, CONMEDS, CMANAL, DV, ELIG, MEDHIST, 
DEMO, RACE, EXPOSURE, VITALS, VSANAL, LAB, LABTOX, IMMUNO, IMMUNTOX, 
IMMUNOGLO, CSSRSV4, CSSRSSUM, SURVIVAL, PK, BVAS, TTE, VDI, BIOMARK, 
RELAPSE, REMISION, MEDDRA, PKCNC, TF1, TF2
Generation of RTF Files

RTF files will be generated for all reporting efforts.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DPs.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.


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Reporting Standards
Unscheduled Visits

Unscheduled visits will not be included in summary tables with the exception of certain 
summaries by year interval in which unscheduled visits may appear in the “anytime post 
baseline” category where specified e.g. worst laboratory toxicity grades.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.4.
Appendix 4: Derived and Transformed Data
10.4.1.
General
Date of Last Double-blind Treatment Period Visit
Efficacy endpoints will be assessed from Day 0 to the last double-blind treatment period visit.
Last treatment period visit date in the double-blind phase will be defined in the following 
hierarchical order for all subjects:
1.
Exit visit
2.
Date of death
3.
Last contact (this includes adverse events dates, concomitant medications dates, 
unscheduled visits and follow-up visit but does not include “END OF DOUBLE-BLIND” or 
“SURVIVAL” visits)
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables.
Study Day

Calculated as the number of days from randomization date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date    

Ref Data ≥ Randomization Date   → Study Day = (Ref Date – Randomization Date) + 1    
Study Completion

Subjects that receive their final dose of IP at any time on or after 28 days prior to the published 
window (20MAY2016 – 17JUN2016) will automatically be eligible for study completion. 

Any subject that is declared a completer on the end of double-blind form prior to this time point 
will be queried at the site-level. Based on the response, a study team decision will be made as 
to whether the completion flag should be amended.

A subject is therefore considered a completer if they are declared a completer on the end of 
double-blind form.


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For subject completion status by year interval, overall status will be determined as follows:

DSFAIL = “Y” “Withdrawn”

COMPL = “Y” “Completed”
Where DSFAIL is the flag for premature study withdrawal and COMPL is the subject completion 
flag
A subject’s status within a given year interval in the double-blind treatment period will be 
ascertained using the following conditions:
ASTDT is the start date of the year interval, AENDT is the end date of the year interval and 
DBEXITDT is the double-blind exit date.
Condition
Subject Status
DSFAIL = “N” and COMPL = “N” 
“ongoing”
DSFAIL = “N” and COMPL = “Y” and 
DBEXITDT > AENDT
“ongoing”
DSFAIL = “N” and COMPL = “Y” and 
ASTDT ≤ DBEXITDT ≤ AENDT
“completed”
DSFAIL = “Y” and COMPL = “N” and 
DBEXITDT ≤ ASTDT
“ongoing”
DSFAIL = “Y” and COMPL = “N” and 
ASTDT ≤ DBEXITDT ≤ AENDT
“withdrawn”
Study Drug Completion


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A subject’s IP completion status within a given year interval in the double-blind treatment period will 
be ascertained using the following conditions:
Condition
Subject IP Completion Status
SDSTOPP = “N” and max(EXSTDT) > 
AENDT 
“ongoing”
SDSTOPP = “N” and ASTDT ≤ 
max(EXSTDT) ≤ AENDT
“completed”
SDSTOPP = “Y” and max(EXSTDT) ≤ 
ASTDT
“ongoing”
SDSTOPP = “Y” and ASTDT ≤ 
max(EXSTDT) ≤ AENDT
“withdrawn”
ASTDT is the start date of the year interval, AENDT is the end date of the year interval and 
SDSTOPP is the flag for premature IP discontinuation.
EXSTDT is exposure start date.
The maximum exposure includes double-blind treatment exposure only.
10.4.2.
Study Population
Demographics
Age

Age will be calculated from birth date to Day 0.

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure
Double-blind Phase

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = (Last Exposure Date – First Exposure Date) + 28

Subjects who were randomized but did not report a treatment start date will be categorized as 
having zero days of exposure. 
Open-label Phase


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Extent of Exposure
Subjects that received placebo during the double-blind phase

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = (Last Open-label Exposure Date – First Open-label 
Exposure Date) + 28
Subjects that received belimumab during the double-blind phase

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = (Last Open-label Exposure Date – First Double-blind 
Exposure Date) + 28

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
Time to Withdrawal from Study Treatment

Time to withdrawal from treatment will be calculated based on the formula:
Time to Withdrawal from IP in Days = (Last Exposure Date – First Exposure Date) + 1

Subjects that complete the double-blind period (i.e. do not discontinue treatment prematurely)
will be censored at the final dose of IP.
Time to Withdrawal from Study

Subjects that withdraw from the study prematurely will be identified using DS.DSFAIL = “Y”.

Time to withdrawal from the study will be calculated based on the formula:
Time to Study Withdrawal (Days) = (Exit Visit Date – Treatment Start Date) + 1

Where exit visit is not available, the last visit in the double-blind treatment period will be used.

Subjects that complete the double-blind phase will be censored at their last visit in the double-
blind treatment period. (See Appendix 4 for further detail).
10.4.3.
Safety
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Decimal Places =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Decimal Place   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Places = ‘< x’ becomes x – 1    


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Medications Categories and Prohibited Medication

Concomitant medications are defined as medications that start on or before the first exposure 
date to study treatment, and end on or after the first exposure date to study treatment, or 
medications that start after the first exposure date to study treatment. Note that medications 
with partial or missing start and/or stop dates will be assumed to be concomitant unless there is 
evidence through comparison of partial dates to suggest otherwise.

Concomitant medications will be reviewed and may be assigned to one of two categories 
(corticosteroids or immunosuppressants), based on their GSK Drug Dictionary Version 1.3 
coded terms, for summarization throughout the course of the study and defined as:
Medication Category
Definition
Corticosteroids
ATC code starts with “H02” and route is considered to be systemic 
(intravenous, intramuscular, subcutaneous, intra-dermal, and oral 
routes, intra-arterial, intrapleural, intraperitoneal, parenteral, rectal, 
sublingual, transdermal).
Immunosuppressants
ATC code starts with “L04A”, or the WHO Drug term contains 
CYCLOPHOSPHAMIDE or MERCATOPURINE or
METHOTREXATE.
Average Daily Steroid Dose

BEL115466 collects concomitant medications, including corticosteroids, throughout the study.  
Note that to determine average daily steroid dose and for the analysis of steroid use, all steroid 
dosages are converted to a prednisone equivalent dosage in milligrams.  

The average daily prednisone dose takes into account all steroids taken systemically for both 
vasculitis and non-vasculitis reasons except where specified in the treatment failure rules. At 
baseline, the average daily prednisone dose is the sum of all prednisone doses over 7 
consecutive days up to, but not including Day 0, divided by 7.

While on treatment, the average daily prednisone dose is the sum of all prednisone doses over 
7 consecutive days up to and including the day of interest, divided by 7, unless otherwise 
specified.  


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Prednisone Equivalent Daily Dose Conversions

Corticosteroids with CMTYPCD equal to 154 do not require conversion to prednisone 
equivalent as these are maintenance therapies which are required to be entered into the eCRF 
as prednisone equivalent.

Reported dose for systemic steroid is converted to prednisone equivalent dose using 
conversion factor for each particular medication (refer to online calculator 
http://www.globalrph.com/corticocalc.htm).
DOSE2 (prednisone equivalent dose in mg) = DOSE (collected dose in mg) x Conversion Factor
DD (daily dose in mg/day) = DOSE2 (prednisone equivalent dose in mg) x Frequency Factor
Preferred Term
Conversion Factor for Prednisone-Equivalent Dose (mg)
BETAMETHASONE
8.33
BETAMETHASONE DIPROPIONATE
8.33
BETAMETHASONE SODIUM PHOSPHATE
8.33
BETAMETHASONE VAL
8.33
CELESTONA BIFAS
8.33
CORTISONE
0.2
CORTISONE ACETATE
0.2
DEFLAZACORT
5/6
DEPO-MEDROL MED LIDOKAIN
1.25
DEXAMETHASONE
6.67
DEXAMETHASONE SODIUM PHOSPHATE
6.67
FLUOCORTOLONE
3
HYDROCORTISONE
0.25
HYDROCORTISONE ACETATE
0.25
HYDROCORTISONE SODIUM SUCCINATE
0.25
MEPREDNISONE
1.25
METHYLPREDNISOLONE
1.25
METHYLPREDNISOLONE ACEP
1.25
METHYLPREDNISOLONE ACETATE
1.25
METHYLPREDNISOLONE SODIUM SUCCINATE
1.25
PARAMETHASONE
2.5
PREDNISOLONE
1
PREDNISOLONE SODIUM PHOSPHATE
1
PREDNISONE
1
PREDNISONE ACETATE
1
TRIAMCINOLONE
1.25
TRIAMCINOLONE ACETONIDE
1.25


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10.4.4.
Efficacy
Time to Event

Time to event will be defined as:
Time to Event = Event Date – Treatment Start Date +1
BVAS

BVAS is assessed at Day 0 and then at every visit during the double-blind treatment phase.

Absolute change in BVAS at Visit X is interpreted as “observed” change and will be calculated 
based on the formula:
Absolute Change in BVAS at Visit X = BVAS at Visit X – BVAS at Day 0

An increase in BVAS is defined as one or more points higher than that assessed at baseline.
Major Items

Major BVAS items can be identified as follows:
Organ System
Description
Disease Code
Cutaneous
Gangrene (Extensive tissue necrosis)
2.5
Mucous 
membranes/Eyes
Sudden visual loss (Acute loss of vision
3.9
Retinal changes 
(vascular/thrombosis/exudates/hemorrhage)
3.11
ENT
Sensorineural hearing loss
4.6
Chest
Massive haemoptysis/alveolar hemorrhage
5.7
Respiratory failure
5.8
Cardiovascular
Ischemic cardiac pain
6.5
Cardiomyopathy
6.6
Congestive cardiac failure
6.7
Abdominal
Ischemic abdominal pain
7.4
Renal
Rise in creatinine > 30% or creatinine 
clearance fall > 25%
8.5
Nervous system
Cerebrovascular accident
9.6
Spinal cord lesion
9.7
Cranial nerve palsy
9.8
Mononeuritis multiplex
9.10

For the primary endpoint, where a subject attains a total score ≥ 6 and a major BVAS item at 
an assessment, both reasons for relapse should be presented in relevant displays. If a subject 
relapses due to receipt of prohibited medication on the same day as a BVAS relapse, both 
reasons for relapse will be given. If all three conditions are met, all three reasons for relapse 
will be displayed.

Similarly, where the endpoint is any minor or major item, if a subject attains both categories at a 
single assessment, both reasons for relapse should be presented in relevant displays.


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BVAS
Vasculitis-related Relapse
Vasculitis-related relapses include all relapses occurring as a result of a BVAS ≥ 6 or a major BVAS 
item or receipt of a prohibited medication resulting in treatment failure that has been adjudicated by 
clinical, safety and statistics representatives as being required for a vasculitis indication.
Prohibited medications adjudicated as “vasculitis-related” are extracted from the TF2 dataset using 
the flag VASFL = “Y”.
Subjects adjudicated as treatment failures with VASFL = “N” will be censored at their most recent 
BVAS assessment, prior to the treatment failure date.
VDI 

VDI is assessed at Day 0 and then every 12 weeks during the double-blind treatment phase
and should be presented as such.

Absolute change in VDI at Visit X is interpreted as “observed” change and will be calculated 
based on the formula:
Absolute Change in VDI at Visit X = VDI Score at Visit X – VDI Score at Day 0

An increase in VDI is defined as one or more points higher than that assessed at Day 0.
Remission

Remission is defined as a BVAS = 0 and corticosteroid dose ≤10 mg/day.
B Cell and T Cell Subsets

All endpoints in units GI/L will be converted from GI/L to cells/cummusing the following 
conversion formula:
New Result = Original Result * 1000

Rare B cells will be normalized using the following formula:
Normalized count/mL = [(rare cell event count) / (CD19+ event count)] * (CD19+ cells/mm3 or uL) * 
1000


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10.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
10.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion for the double-blind phase (i.e. as specified in the 
protocol) is defined as when 12 months have elapsed following randomization of 
the last subject with further details given in section 10.4.1. 

Withdrawn subjects are not replaced in the study.

All available data from subjects who are withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.5.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :

These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 

Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.5.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications

Where CMSTDT is completely missing but CMENDT is on or after Day 0, the 
CMSTDT will be imputed as TRTSDT.

Where CMSTDT is completely missing but CMONGOING = “Y”, the CMSTDT 
will be imputed as TRTSDT and the medication will be considered as ongoing.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:

Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
2.

Missing Stop Day: Last day of the month will be used, unless this is after the 


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Element
Reporting Detail
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
Relapse

If the date of relapse is completely missing, no imputation will be applied and 
subjects will be censored at the last available BVAS assessment.
10.5.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

For records where the year of the partial date is prior to or after the year of 
TRTSDT, impute with 01 for day and January for month, as needed, to assume 
that the duration of the concomitant medication was the longest possible 
duration.

For records where year matches the year of TRTSDT: 

If month is available & month is prior to or after the month of TRTSDT, set 
day to 01.

If the month is the same as the month of TRTSDT, set the day to the same 
day as TRTSDT, to assume the AE started on treatment and with the 
longest possible duration.

If month is not available, set the entire date to TRTSDT.

End dates for concomitant medications will not be imputed, and the medication 
will be considered ongoing.
Adverse 
Events

For partial or missing dates AE start dates, imputations will be performed 
conservatively to place the AE on or after TRTSDT (Treatment Start Date): 
unless there is evidence to the contrary:  

For records where the year of the partial date is prior to or after the year of 
TRTSDT, impute with 01 for day and January for month, as needed, to assume 
that the duration of the AE was the longest possible duration.

For records where year matches the year of TRTSDT: 

If month is available & month is prior to or after the month of TRTSDT, set 
day to 01.

If the month is the same as the month of TRTSDT, set the day to the same 
day as TRTSDT, to assume the AE started on treatment and with the 
longest possible duration.

If month is not available, set the entire date to TRTSDT, again to assume that 
the AE is treatment emergent and has the longest possible duration.
Relapse

No imputation for partial dates will be performed. 

Subjects will be censored at the last available BVAS assessment.


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10.6.
Appendix 6: B Cell and T Cell Subsets
BICATCD (B Cells)
LBTESTCD (T Cells)
Client Analyte name
CD19
Total CD19+ B-cells (CD19+)
CD20
Absolute B cell subsets CD20+
CDX136
CD20+/27– naïve
CDX137
CD20+/27+ memory
CDX141*/CDX155*[1]
CD20+/69+activated
CDX143*
CD138+/CD20- 138 plasma cells
CDX145*
CD138+/CD20+ plasmacytoid
CDX154*
CD27hi/CD20- short-lived plasma
CDX200*[2]
CD19+ CD24b+ CD38b+ CD27-
IgD+ CD10
Concentration: CD4+_BLC
Percentage: CD4+_BLQ
CD3+/CD4+
Concentration: CD8+_BLC
Percentage: CD8+_BLQ
CD3+/CD8+
* Denotes rare B cell subset
[1] Concentration and percentage of CD20+/69+ correspond to BICATCD CDX141, whereas 
events correspond to CDX155.
[2] CD10+ transitional B cells are represented by CDX200 CD19+(CD24b+CDCD38b+CD27-
IgD+CD10)


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10.7.
Appendix 7: BVAS Activity Assessment Form
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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10.8.
Appendix 8: BVAS Item Scoring
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws and therefore have been 
excluded.


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10.9.
Appendix 9: Vasculitis Damage Index (VDI)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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10.10.
Appendix 10: Laboratory Parameters & Adverse Events 
Grading
10.10.1.
Laboratory Parameters


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10.10.2.
Adverse Events Grading


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10.11.
Appendix 11: Abbreviations & Trade Marks
10.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Events of Special Interest
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
ANCA
Anti-Neutrophil Cytoplasmic Antibody
Anti-MPO
Anti- myeloperoxidase
Anti-PR3
Anti-proteinase 3
at-ANCA
Atypical Antineutrophil Cytoplasmic Antibody
AZA
Azathioprine
BLyS
B lymphocyte Stimulator
BVAS
Birmingham Vasculitis Activity Score
C3
Complement Factor 3
C4
Complement Factor 4
c-ANCA
Cytoplasmic Antineutrophil Cytoplasmic Antibody
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CRP
C-Reactive Protein 
CS
Clinical Statistics
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
CYC
Cyclophosphamide
DOB
Date of Birth
DP
Decimal Places
ECL
Electrochemiluminescence
eCRF
Electronic Case Record Form
eGFR
Estimated Glomerular Filtration Rate
ESR
Erythrocyte Sedimentation Rate
FACS
Florescence activated cell sorting
GPA
Granulomatosis with Polyangiitis
GSK
GlaxoSmithKline
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IFA
Immune-fluorescence Assay
Ig
Immunoglobulin
IMMS
International Modules Management System
IP
Study agent


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Abbreviation
Description
ITT
Intent-To-Treat
IV
Intravenous
LLN
lower limit of normal
LOC
Last Observation Carries Forward
LOQ
Limit of Quantification
OLE
Open-label Extension
MedDRA
Medical Dictionary for Regulatory Activities
MPA
Microscopic Polyangiitis
NMSC
Non-melanoma Skin Cancer
p-ANCA
Perinuclear Antineutrophil Cytoplasmic Antibody
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per-Protocol
PSRQ
Possible Suicidality Related Questionnaire
PT
Preferred Terms
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RTX
Rituximab
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
VDI
Vasculitis Damage Index
ULN
Upper Limit of Normal
WG
Wegener’s Granulomatosis
10.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
BLyS
SAS


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10.12.
Appendix 12: List of Data Displays
10.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Biomarker
5.1 to 5.n
5.1 to 5.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
10.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Biomarker
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column.
10.12.3.
Deliverable
Delivery
Description
H
Headline Results
SAC
Statistical Analysis Complete


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10.12.4.
Study Population Tables
Study Population Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
ITT
POP_T1
Summary of Subject-Years on Study (Double-blind Phase)
Study Specific
H, SAC
1.2.
ITT
ES1
Summary of Subject Disposition (Double-blind Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
H, SAC
1.3.
Subgroup of 
ITT
ES1
Summary of Subject Disposition (Age ≥ 65 Yrs) (Double-blind 
Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.4.
Subgroup of 
ITT
ES1
Summary of Subject Disposition (Age ≥ 75 Yrs) (Double-blind 
Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.5.
ITT
POP_T2
Summary of Subject Completion Status by Study Year (Double-
blind Phase)
Study Specific. Please include 
summary of study withdrawal on first 
page and summary of treatment 
withdrawal on second page.
SAC
1.6.
Subgroup of 
ITT
POP_T2
Summary of Subject Completion Status by Study Year (Age ≥ 
65 Yrs) (Double-blind Phase)
Study Specific
SAC
1.7.
Subgroup of 
ITT
POP_T2
Summary of Subject Completion Status by Study Year (Age ≥ 
75 Yrs) (Double-blind Phase)
Study Specific
SAC
1.8.
Screened
ES6
Summary of Screen Failures (Screened Subjects Population)
(Double-blind Phase)
Journal Requirements
SAC
1.9.
Randomized
NS3
Summary of Subjects by Country and Center (Randomized 
Subjects Population) (Double-blind Phase)
EudraCT
SAC
Protocol Deviation
1.10.
Randomized
DV1
Summary of Subjects with Important Protocol Deviations 
(Double-blind Phase)
ICH E3
SAC
1.11.
ITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations (Double-
blind Phase)
SAC


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Study Population Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
Population Analyzed
1.12.
Screened
SP1
Summary of Study Populations (Double-blind Phase)
IDSL
H, SAC
Demographic and Baseline Characteristics
1.13.
ITT
DM1
Summary of Demographic Characteristics (Double-blind Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
Please give age categories as: <= 45, > 
45 - < 65, >= 65 - < 75, >= 75  
H, SAC
1.14.
Subgroup of 
ITT
DM1
Summary of Demographic Characteristics (Age ≥ 65 Yrs) 
(Double-blind Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
Please give age categories as: <= 45, > 
45 - < 65, >= 65 - < 75, >= 75  
SAC
1.15.
Subgroup of 
ITT
DM1
Summary of Demographic Characteristics (Age ≥ 75 Yrs) 
(Double-blind Phase)
ICH E3, GSK CTR, FDAAA, EudraCT
Please give age categories as: <= 45, > 
45 - < 65, >= 65 - < 75, >= 75  
SAC
1.16.
ITT
POP_T3
Summary of Baseline Disease Characteristics  (Double-blind 
Phase)
H, SAC
1.17.
Subgroup of 
ITT
POP_T3
Summary of Baseline Disease Characteristics (Age ≥ 65 Yrs)  
(Double-blind Phase)
SAC
1.18.
Subgroup of 
ITT
POP_T3
Summary of Baseline Disease Characteristics  (Age ≥ 75 Yrs) 
(Double-blind Phase)
SAC
1.19.
ITT
DM5
Summary of Race and Racial Combinations (Double-blind 
Phase)
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.20.
Subgroup of 
ITT
DM5
Summary of Race and Racial Combinations (Age ≥ 65 Yrs)  
(Double-blind Phase)
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.21.
Subgroup of 
ITT
DM5
Summary of Race and Racial Combinations (Age ≥ 75 Yrs)  
(Double-blind Phase)
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
Other Baseline Characteristics


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Study Population Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
1.22.
ITT
POP_T4
Summary of Anti-Neutrophil Cytoplasmic Antibody (ANCA) at 
Baseline (Double-blind Phase)
SAC
1.23.
ITT
POP_T5
Summary of Complement (C3, C4) and BLyS Protein at 
Baseline (Double-blind Phase)
Study Specific: Include C3, C4 and 
BLyS
SAC
1.24.
ITT
POP_T6
Summary of Immunoglobulins (IgA, IgG, IgM) Levels At Baseline 
(Double-blind Phase)
Study Specific
SAC
1.25.
ITT
POP_T7
Summary of B Cells (FACS of Peripheral Lymphocytes) at 
Baseline (Double-blind Phase)
Study Specific
SAC
Prior Medical Conditions and Concomitant Medications
1.26.
ITT
POP_T8
(MH4)
Summary of Prior Medical Conditions (Double-blind Phase)
ICH E3
SAC
1.27.
ITT
CM1
Summary of Concomitant Medications (Double-blind Phase)
ICH E3
SAC
Exposure and Treatment Compliance
1.28.
ITT
POP_T9
Summary of Duration of Exposure to Study Drug (Double-blind 
Phase)
ICH E3
SAC
1.29.
Subgroup of 
ITT
POP_T9
Summary of Duration of Exposure to Study Drug (Age ≥ 65 Yrs) 
(Double-blind Phase)
ICH E3
SAC
1.30.
Subgroup of 
ITT
POP_T9
Summary of Duration of Exposure to Study Drug (Age ≥ 75 Yrs) 
(Double-blind Phase)
ICH E3
SAC
1.31.
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Study 
Withdrawal (Double-blind Phase)
Study withdrawals can be identified 
where DS.DSFAIL = “Y”
SAC
1.32.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Study 
Withdrawal (Age ≥ 65 Yrs) (Double-blind Phase)
SAC
1.33.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Study 
Withdrawal (Age ≥ 75 Yrs) (Double-blind Phase)
SAC


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Study Population Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
1.34.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Study 
Treatment Withdrawal (Double-blind Phase)
Treatment withdrawals can be identified 
where SDSTOPP = “Y”
SAC


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10.12.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
Primary Endpoint (Time from Day 0 to first relapse)
2.1.
ITT
EFF_T1
Summary of Analysis of Time to Relapse (Double-blind Phase)
Event summary will be “BVAS Score ≥ 
6”, “Major BVAS Item” and “Prohibited 
Medication”
H, SAC
2.2.
Subgroup of 
ITT
EFF_T1
Summary of Analysis of Time to Relapse (Age ≥ 65 Yrs)
(Double-blind Phase)
As above. No analysis is required, 
please do not include.
SAC
2.3.
Subgroup of 
ITT
EFF_T1
Summary of Analysis of Time to Relapse (Age ≥ 75 Yrs)
(Double-blind Phase)
As above. No analysis is required, 
please do not include.
SAC
2.4.
PP
EFF_T1
Summary of Analysis of Time to Relapse (Per-Protocol 
Population) (Double-blind Phase)
As above. (Only produce if required).
SAC
2.5.
ITT
EFF_T1
Summary of Analysis of Time to Relapse: Sensitivity Analysis 
adjusting for Randomization Strata (Double-blind Phase)
The strata to which a subject was 
assigned can be found in the Randall 
dataset.
SAC
2.6.
ITT
EFF_T1
Summary of Analysis of Time to Relapse: Sensitivity Analysis of 
Vasculitis-Related Relapses (Double-blind Phase)
Only produce if required. Derived from 
TF adjudication.
SAC
2.7.
ITT
EFF_T2
Summary of Organ Domain Involvement for Subjects with 
Relapse due to BVAS (Double-blind Phase)
SAC
2.8.
ITT
TTE4
Summary of Analysis of Time to Relapse (Model Estimates for 
Other Covariates) (Double-blind Phase)
Include model estimates for covariates 
other than treatment group (i.e. ANCA 
type, induction regimen and disease 
stage).
SAC
2.9.
ITT
EFF_T3
Summary of Analysis of Time to Relapse: Exploratory Analysis 
adjusting for Interactions (Double-blind Phase)
Please add treatment:covariate 
interaction terms, Treatment:ANCA 
Type, Treatment:Induction Regimen, 
Treatment:Disease Stage, one at a time 
to the primary model.
SAC


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
2.10.
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse 
(Double-blind Phase)
H, SAC
2.11.
PP
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse (Per-
Protocol Population) (Double-blind Phase)
H, SAC
2.12.
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse: 
Sensitivity Analysis of Vasculitis-Related Relapses (Double-blind 
Phase)
Only produce if required. Derived from 
TF adjudication.
SAC
2.13.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse by 
ANCA Type (anti-MPO vs. anti-PR3) (Double-blind Phase)
SAC
2.14.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse by 
Induction Regimen (IV Cyclophosphamide vs. Oral 
Cyclophosphamide vs. Rituximab) (Double-blind Phase)
SAC
2.15.
Subgroup of 
ITT
TTE7
Summary of Kaplan-Meier Estimates of Time to Relapse by 
Disease Stage at Induction (Initial vs. Relapsing) (Double-blind 
Phase)
SAC
Time from Day 0 to first Minor or Major Relapse or Receipt of Rescue Medication
2.16.
ITT
EFF_T1
Summary of Study Day of First Minor or Major Relapse or 
Receipt of Rescue Medication (Double-blind Phase)
No analysis for this endpoint so no HR 
to be produced. Events will be “Minor 
BVAS Item”, “Major BVAS Item” and 
“Recue Medication” with a footnote 
“Rescue medication is any prohibited 
medication as defined in the protocol”.
SAC
Birmingham Vasculitis Activity Score
2.17.
ITT
EFF_T4
Summary of BVAS Organ System Involvement by Visit (Double-
blind Phase)
H, SAC
2.18.
ITT
EFF_T5
Summary of BVAS Total Score (Observed and Change from 
Baseline) by Visit (Double-blind Phase)
H, SAC


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
2.19.
ITT
EFF_T6
Summary of Proportion of Subjects with any increase from 
Baseline in BVAS Organ Domains by Visit (Double-blind Phase)
Use EFF_T6 and modify based on 
data. Include only organ domains 
where an increase is seen. Otherwise 
present only total BVAS. Include 
footnote “Note: Only organ domains for 
which the proportion of subjects with an 
increase in BVAS is greater than zero 
are displayed.”
H, SAC
VDI
2.20.
ITT
EFF_T5
Summary of VDI Total Score (Observed and Change from 
Baseline) by Visit (Double-blind Phase)
SAC
2.21.
ITT
EFF_T6
Summary of Proportion of Subjects with any increase from 
Baseline in VDI by Visit (Double-blind Phase)
SAC
Other
2.22.
ITT
EFF_T6
Summary of Proportion of Subjects in Remission by Visit
(Double-blind Phase)
Use EFF_T6 and modify based on 
data. Give definition of remission as 
footnote.
SAC
2.23.
ITT
EFF_T6
Summary of Proportion of Subjects with no Relapse from 
Baseline by Visit (Double-blind Phase)
Use EFF_T6 and modify based on 
data.


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10.12.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
Primary Endpoint
2.1.
ITT
TTE10
Kaplan-Meier Plot of Time to Relapse (Double-blind Phase)
Please produce 1 – KM to indicate 
“Proportion with Relapse” on y axis
H, SAC
2.2.
PP
TTE10
Kaplan-Meier Plot of Time to Relapse (Per-Protocol Population) 
(Double-blind Phase)
Only generate if required. Please 
produce 1 – KM to indicate “Proportion 
with Relapse” on y axis
H, SAC
2.3.
ITT
TTE10
Kaplan-Meier Plot of Time to Relapse: Sensitivity Analysis of 
Vasculitis-Related Relapses (Double-blind Phase)
Only generate if required. Please 
produce 1 – KM to indicate “Proportion 
with Relapse” on y axis
SAC
2.4.
Subgroup of 
ITT
TTE10
Kaplan-Meier Plot of Time to Relapse by ANCA Type (anti-MPO 
vs. anti-PR3) (Double-blind Phase)
Please produce 1 – KM to indicate 
“Proportion with Relapse” on y axis
SAC
2.5.
Subgroup of
ITT
TTE10
Kaplan-Meier Plot of Time to Relapse by Induction Regimen (IV 
Cyclophosphamide vs. Oral Cyclophosphamide vs. Rituximab) 
(Double-blind Phase)
Please produce 1 – KM to indicate 
“Proportion with Relapse” on y axis
SAC
2.6.
Subgroup of 
ITT
TTE10
Kaplan-Meier Plot of Time to Relapse by Disease Stage at 
Induction (Initial vs. Relapsing) (Double-blind Phase)
Please produce 1 – KM to indicate 
“Proportion with Relapse” on y axis
SAC
Time to First Minor or Major Relapse or Receipt of Rescue Medication
2.7.
ITT
TTE10
Kaplan-Meier Plot of Time to First Minor or Major Relapse or 
Receipt of Rescue Medication (Double-blind Phase)
Please produce 1 – KM to indicate 
“Proportion with Minor or Major Relapse 
or Receipt of Rescue Medication” on y 
axis
SAC
Birmingham Vasculitis Activity Score
2.8.
ITT
EFF_F1
Proportion of Subjects with any increase from Baseline in BVAS 
Organ Domains by Visit (Double-blind Phase)
Stacked bar chart. Only show visits up 
to Yr2 Wk28.
H, SAC
Vasculitis Damage Index


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
2.9.
ITT
EFF_F1
Proportion of Subjects with any increase from Baseline in VDI by 
Visit (Double-blind Phase)
Bar chart. Only show visits up to Yr2 
Wk24 
SAC
Other
2.10.
ITT
EFF_F1
Proportion of Subjects in Remission by Visit (Double-blind 
Phase)
Bar chart. Add definition of remission to
footnotes. Only show visits up to Yr2 
Wk28
SAC
2.11.
ITT
EFF_F1
Proportion of Subjects with no Relapse by Visit (Double-blind 
Phase)
Bar char. Only show visits up to Yr2 Wk 
28
SAC


CONFIDENTIAL
BEL115466
96
10.12.7.
Safety Tables
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
Adverse Events
3.1.
ITT
AE1
Pre-Treatment Adverse Events by SOC and PT (Double-blind 
Phase)
SAC
3.2.
ITT
SAFE_T1
Adverse Events Summary by Year Interval (Double-blind Phase)
H, SAC
3.3.
ITT
SAFE_T1
Adverse Events Summary by Year Interval (Age ≥ 65 Yrs)
(Double-blind Phase) 
SAC
3.4.
ITT
SAFE_T1
Adverse Events Summary by Year Interval (Age ≥ 75 Yrs)
(Double-blind Phase) 
SAC
Adverse Events by SOC
3.5.
ITT
SAFE_T2
Adverse Events Summary by SOC and Year Interval (Double-
blind Phase)
SAC
Adverse Events by SOC (Serious & Severe)
3.6.
ITT
SAFE_T2
Serious Adverse Events by SOC and Year Interval (Double-blind 
Phase)
SAC
3.7.
ITT
SAFE_T2
Severe Adverse Events by SOC and Year Interval (Double-blind 
Phase)
SAC
Adverse Events by SOC (Drug-Related and Leading to Permanent Discontinuation or Withdrawal)
3.8.
ITT
SAFE_T2
Study Drug-Related Adverse Events by SOC and Year Interval
(Double-blind Phase)
SAC
3.9.
ITT
SAFE_T2
Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study by SOC and Year Interval
(Double-blind Phase)
H, SAC
Adverse Events occurring Off-Treatment


CONFIDENTIAL
BEL115466
97
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.10.
ITT
SAFE_T3
Adverse Events occurring Off-Treatment by SOC (Double-blind 
Phase) 
Off-treatment is defined as events 
occurring more than 28 days after final 
study drug exposure.
SAC
Adverse Events Rates by SOC (Serious and Severe)
3.11.
ITT
SAFE_T4
Adverse Event Rate by SOC and Year Interval (Double-blind 
Phase)
SAC
3.12.
ITT
SAFE_T4
Serious Adverse Event Rate by SOC and Year Interval (Double-
blind Phase)
SAC
3.13.
ITT
SAFE_T4
Severe Adverse Event Rate by SOC and Year Interval (Double-
blind Phase)
SAC
3.14.
ITT
SAFE_T4
Study Drug-Related Adverse Event Rate by SOC and Year 
Interval (Double-blind Phase)
SAC
3.15.
ITT
SAFE_T4
Adverse Event Rate Leading to Permanent Discontinuation of 
Study Drug or Withdrawal from Study by SOC and Year Interval
(Double-blind Phase)
SAC
Adverse Events by SOC and PT
3.16.
ITT
SAFE_T5
Adverse Events by SOC and PT and Year Interval (Double-blind 
Phase)
H, SAC
3.17.
ITT
SAFE_T5
Adverse Events by SOC and PT and Year Interval (Age ≥ 65 
Yrs) (Double-blind Phase)
SAC
3.18.
ITT
SAFE_T5
Adverse Events by SOC and PT and Year Interval (Age ≥ 75 
Yrs) (Double-blind Phase)
SAC
Adverse Events by SOC and PT (Serious & Severe)
3.19.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Year Interval
(Double-blind Phase)
H, SAC
3.20.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Year Interval (Age 
≥ 65 Yrs) (Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
98
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.21.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Year Interval Age 
≥ 75 Yrs) (Double-blind Phase)
SAC
3.22.
ITT
SAFE_T5
Severe Adverse Events by SOC and PT and Year Interval
(Double-blind Phase)
SAC
Adverse Events by SOC and PT (Drug-Related and Leading to Permanent Discontinuation or Withdrawal)
3.23.
ITT
SAFE_T5
Study Drug-Related Adverse Events by SOC and PT and Year 
Interval (Double-blind Phase)
H, SAC
3.24.
ITT
SAFE_T5
Study Drug-Related Adverse Events by SOC and PT and Year 
Interval  (Age ≥ 65 Yrs) (Double-blind Phase)
SAC
3.25.
ITT
SAFE_T5
Study Drug-Related Adverse Events by SOC and PT and Year 
Interval  (Age ≥ 75 Yrs) (Double-blind Phase)
SAC
3.26.
ITT
SAFE_T5
Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study by SOC and PT and Year 
Interval (Double-blind Phase)
SAC
3.27.
ITT
SAFE_T5
Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study by SOC and PT and Year 
Interval  (Age ≥ 65 Yrs) (Double-blind Phase)
SAC
3.28.
ITT
SAFE_T5
Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study by SOC and PT and Year 
Interval (Age ≥ 75 Yrs) (Double-blind Phase)
SAC
Adverse Events By SOC and PT (Death)
3.29.
ITT
SAFE_T5
Deaths by SOC and PT and Year Interval (Double-blind Phase)
H, SAC
3.30.
ITT
SAFE_T5
Deaths by SOC and PT and Year Interval (Age ≥ 65 Yrs)
(Double-blind Phase)
SAC
3.31.
ITT
SAFE_T5
Deaths by SOC and PT and Year Interval (Age ≥ 75 Yrs)
(Double-blind Phase)
SAC
Adverse Events: Non-Serious, Serious & Fatal Serious by SOC and PT


CONFIDENTIAL
BEL115466
99
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.32.
ITT
SAFE_T5
Common Non-Serious Adverse Events (>=5% incidence in any 
interval) by SOC and PT and Year Interval (Double-blind Phase)
The ‘ANY EVENT’ rows are based 
on the number of subjects that have 
non-serious adverse events that 
meet the threshold.
Do not give ‘ANY EVENT’ for the 
individual SOC. Only display 
overall.
SAC
3.33.
ITT
SAFE_T5
Study Drug-Related Serious Adverse Events by SOC and PT
and Year Interval (Double-blind Phase)
SAC
3.34.
ITT
SAFE_T5
Fatal Serious Adverse Events by SOC and PT and Year Interval
(Double-blind Phase)
SAC
3.35.
ITT
SAFE_T5
Study Drug-Related Fatal Serious Adverse Events by SOC and 
PT and Year Interval (Double-blind Phase)
SAC
3.36.
ITT
SAFE_T5
Non-Fatal Serious Adverse Events by SOC and PT and Year 
Interval (Double-blind Phase)
SAC
3.37.
ITT
SAFE_T5
Study Drug-Related Non-Fatal Serious Adverse Events by SOC 
and PT and Year Interval (Double-blind Phase)
SAC
Adverse Event Rates by SOC and PT
3.38.
ITT
SAFE_T4
Adverse Event Rate by SOC and PT and Year Interval (Double-
blind Phase)
Include “Preferred Term” in column 1, 
similar to SAFE_T5.
SAC
Adverse Events by Subgroups


CONFIDENTIAL
BEL115466
100
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.39.
ITT
SAFE_T5
Adverse Events by SOC and PT and Gender and Year Interval
(Double-blind Phase)
SAC
3.40.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Gender and Year 
Interval (Double-blind Phase)
SAC
3.41.
ITT
SAFE_T5
Adverse Events by SOC and PT and Age (<65 Yrs vs. ≥ 65 Yrs)
and Year Interval (Double-blind Phase)
SAC
3.42.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Age (<65 Yrs vs. ≥ 
65 Yrs) and Year Interval (Double-blind Phase) 
SAC
3.43.
ITT
SAFE_T5
Adverse Events by SOC and PT and Induction Regimen and 
Year Interval (Double-blind Phase)
SAC
3.44.
ITT
SAFE_T5
Serious Adverse Events by SOC and PT and Induction Regimen 
and Year Interval (Double-blind Phase)
SAC
Adverse Events by PT
3.45.
ITT
SAFE_T5
Adverse Events by PT and Year Interval (Double-blind Phase)
SAC
Adverse Events by PT (Serious & Severe)
3.46.
ITT
SAFE_T5
Serious Adverse Events by PT and Year Interval (Double-blind 
Phase)
SAC
3.47.
ITT
SAFE_T5
Severe Adverse Events by PT and Year Interval (Double-blind 
Phase)
SAC
Adverse Events By PT (Drug-Related and Leading to Permanent Discontinuation or Withdrawal)
3.48.
ITT
SAFE_T5
Study Drug-Related Adverse Events by PT and Year Interval
(Double-blind Phase)
SAC
3.49.
ITT
SAFE_T5
Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study by PT and Year Interval (Double-
blind Phase)
SAC
Adverse Events By PT (Death)
3.50.
ITT
SAFE_T5
Deaths by Category, PT and Year Interval (Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
101
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.51.
ITT
SAFE_T5
Deaths by Category, PT and Year Interval (Age ≥ 65 Yrs)
(Double-blind Phase)
SAC
3.52.
ITT
SAFE_T5
Deaths by Category, PT and Year Interval (Age ≥ 75 Yrs)
(Double-blind Phase)
SAC
Adverse Events By Maximum Intensity
3.53.
ITT
SAFE_T6
Adverse Events by SOC, Maximum Intensity and Year Interval
(Double-blind Phase)
SAC
3.54.
ITT
SAFE_T7
Adverse Events by SOC, PT, Maximum Intensity and Year 
Interval (Double-blind Phase)
SAC
Adverse Events Relationship Between SOC and Verbatim Text
3.55.
ITT
AE2
Relationship between System Organ Class and Verbatim Text
(Double-blind Phase)
SAC
Adverse Events of Special Interest
3.56.
ITT
SAFE_T8
Adverse Events of Special Interest by Category and Year 
Interval (Double-blind Phase)
See RAP for definitions of AEs of 
special interest.
H, SAC
3.57.
ITT
SAFE_T8
Adverse Events of Special Interest by Category and Year 
Interval (Age ≥ 65 Yrs) (Double-blind Phase)
See RAP for definitions of AEs of 
special interest.
SAC
3.58.
ITT
SAFE_T8
Adverse Events of Special Interest by Category and Year 
Interval (Age ≥ 75 Yrs) (Double-blind Phase)
See RAP for definitions of AEs of 
special interest.
SAC
3.59.
ITT
SAFE_T9
Malignant Neoplasm Adverse Events of Special Interest by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.60.
ITT
SAFE_T9
Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events 
of Special Interest by Category, PT and Year Interval (Double-
blind Phase)
SAC


CONFIDENTIAL
BEL115466
102
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.61.
ITT
SAFE_T9
Serious Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse 
Events of Special Interest by Category, PT and Year Interval
(Double-blind Phase)
SAC
3.62.
ITT
SAFE_T9
Infection Adverse Events of Special Interest by Category, PT 
and Year Interval (Double-blind Phase)
SAC
3.63.
ITT
SAFE_T9
Serious Infection Adverse Events of Special Interest by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.64.
ITT
SAFE_T9
Severe Infection Adverse Events of Special Interest by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.65.
ITT
SAFE_T9
Serious/Severe Infection Adverse Events of Special Interest by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.66.
ITT
SAFE_T9
Infection Adverse Events of Special Interest Leading to 
Discontinuation by Category, PT and Year Interval (Double-blind 
Phase)
SAC
3.67.
ITT
SAFE_T9
Depression/Suicide/Self-injury Adverse Events of Special 
Interest by Category, PT and Year Interval (Double-blind Phase)
SAC
Adverse Events of Special Interest by Subgroups


CONFIDENTIAL
BEL115466
103
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.68.
ITT
SAFE_T8
Adverse Events of Special Interest by Category and Induction 
Regimen and Year Interval (Double-blind Phase)
See RAP for definitions of AEs of 
special interest.
SAC
3.69.
ITT
SAFE_T9
Malignant Neoplasm Adverse Events of Special Interest by 
Category, PT and Induction Regimen and Year Interval (Double-
blind Phase)
SAC
3.70.
ITT
SAFE_T9
Infection Adverse Events of Special Interest by Category, PT
and Induction Regimen and Year Interval (Double-blind Phase)
SAC
3.71.
ITT
SAFE_T9
Serious Infection Adverse Events of Special Interest by 
Category, PT and Induction Regimen and Year Interval (Double-
blind Phase)
SAC
Adverse Events of Special Interest Rates
3.72.
ITT
SAFE_T10
Adverse Events of Special Interest Rate by Category and Year 
Interval (Double-blind Phase)
SAC
3.73.
ITT
SAFE_T11
Malignant Neoplasm Adverse Events of Special Interest Rate by
Category, PT and Year Interval (Double-blind Phase)
SAC
3.74.
ITT
SAFE_T11
Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events 
of Special Interest Rate by Category, PT and Year Interval
(Double-blind Phase)
SAC
3.75.
ITT
SAFE_T11
Serious Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse 
Events of Special Interest Rate by Category, PT and Year 
Interval (Double-blind Phase)
SAC
3.76.
ITT
SAFE_T11
Infection Adverse Events of Special Interest Rate by Category, 
PT and Year Interval (Double-blind Phase)
SAC
3.77.
ITT
SAFE_T11
Serious Infection Adverse Events of Special Interest Rate by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.78.
ITT
SAFE_T11
Severe Infection Adverse Events of Special Interest Rate by 
Category, PT and Year Interval (Double-blind Phase)
SAC
3.79.
ITT
SAFE_T11
Serious/Severe Infection Adverse Events of Special Interest 
Rate by Category, PT and Year Interval (Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
104
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.80.
ITT
SAFE_T11
Infection Adverse Events of Special Interest Leading to 
Discontinuation Rate by Category, PT and Year Interval
(Double-blind Phase)
SAC
3.81.
ITT
SAFE_T11
Depression, Suicidality, and Self-injury Adverse Events of 
Special Interest Rate by Category, PT and Year Interval
(Double-blind Phase)
SAC
C-SSRS
3.82.
ITT
CSSRS1
Subjects with C-SSRS Suicidal Ideation or Behavior during 
Treatment (Double-blind Phase)
SAC
3.83.
ITT
CSSRS2
Subjects with Treatment Emergent C-SSRS Suicidal Ideation or 
Behavior Relative to Pre-Treatment (Double-blind Phase)
SAC
3.84.
ITT
CSSRS3
Subjects with Shift of Changes in C-SSRS Categories from Pre-
Treatment to On-Treatment (Double-blind Phase)
SAC
Laboratory
3.85.
ITT
SAFE_T12
Laboratory Results (Observed and Change from Baseline) by 
Visit: Hematology (Double-blind Phase)
SAC
3.86.
ITT
SAFE_T12
Laboratory Results (Observed and Change from Baseline) by 
Visit: Liver Function (Double-blind Phase)
SAC
3.87.
ITT
SAFE_T12
Laboratory Results (Observed and Change from Baseline) by 
Visit: Electrolytes (Double-blind Phase)
SAC
3.88.
ITT
SAFE_T12
Laboratory Results (Observed and Change from Baseline) by 
Visit: Other Chemistries (Double-blind Phase)
SAC
3.89.
ITT
SAFE_T12
Laboratory Results (Observed and Change from Baseline) by 
Visit: Immunoglobulins (Double-blind Phase)
SAC
Worst Laboratory Toxicity Grade (By Year Interval)
3.90.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: Hematology
(Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
105
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.91.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: Liver Function
(Double-blind Phase)
SAC
3.92.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: Electrolytes
(Double-blind Phase)
SAC
3.93.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: Other 
Chemistries (Double-blind Phase)
SAC
3.94.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: Urinalysis
(Double-blind Phase)
SAC
3.95.
ITT
SAFE_T13
Worst Laboratory Toxicity Grade by Year Interval: 
Immunoglobulins (Double-blind Phase)
SAC
3.96.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Hematology (Double-blind Phase)
SAC
3.97.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Liver Function (Double-blind Phase)
SAC
3.98.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Electrolytes (Double-blind Phase)
SAC
3.99.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Other Chemistries (Double-blind 
Phase)
SAC
3.100.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Urinalysis (Double-blind Phase)
SAC
3.101.
ITT
SAFE_T14
Laboratory Toxicity Grade Worsening of at Least 2 Grades from 
Baseline by Year Interval: Immunoglobulins (Double-blind 
Phase)
SAC
Laboratory Reference Range Shifts (By Visit)


CONFIDENTIAL
BEL115466
106
Safety: Tables
No.
Population
Example Shell
(IDSL)
Title
Programming Notes
Deliverable
3.102.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: 
Hematology (Double-blind Phase)
SAC
3.103.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: Liver 
Function (Double-blind Phase)
SAC
3.104.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: 
Electrolytes (Double-blind Phase)
SAC
3.105.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: Other 
Chemistries (Double-blind Phase)
SAC
3.106.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: 
Urinalysis (Double-blind Phase)
SAC
3.107.
ITT
SAFE_T15
Laboratory Reference Range Shifts from Baseline by Visit: 
Immunoglobulins (Double-blind Phase)
SAC
Immunogenicity
3.108.
ITT
SAFE_T16
Immunogenic Response by Visit (Double-blind Phase)
SAC
3.109.
ITT
SAFE_T17
Immunogenic Response by Year Interval (Double-blind Phase)
SAC
3.110.
ITT
SAFE_T18
Immunogenic Summary (Double-blind Phase)
SAC
3.111.
ITT
SAFE_T18
Immunogenic Summary (Age ≥ 65 Yrs) (Double-blind Phase)
SAC
3.112.
ITT
SAFE_T18
Immunogenic Summary (Age ≥ 75 Yrs) (Double-blind Phase)
SAC
Vital Signs
3.113.
ITT
SAFE_T19
Vital Signs by Visit (Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
107
10.12.8.
Safety Figures
Safety: Figures
No.
Population
Example Shell
Title
Programming Notes
Deliverable 
3.1.
ITT
TTE10
Kaplan-Meier Plot of Time to Study Withdrawal (Double-blind 
Phase)
Withdrawals can be identified where 
DS.DSFAIL = Y
SAC
3.2.
ITT
TTE10
Kaplan-Meier Plot of Time to Study Treatment Withdrawal 
(Double-blind Phase)
Treatment withdrawals can be identified 
where SDSTOPP = Y
SAC
3.3.
ITT
SAFE_F1
Cumulative AE Incidence Over Time (Double-blind Phase)
Order categories per order mock shell.
SAC
Laboratory
3.4.
ITT
SAFE_F2
Laboratory Results by Visit: Hematology (Double-blind Phase)
Figures 3.5 to 3.13: Use figure format 
and if applicable, modify based on data.
For “Change from Baseline” Figures: 
amend y-axis label to be “Change from 
Baseline”.
SAC
3.5.
ITT
SAFE_F2
Laboratory Results by Visit: Liver Function (Double-blind Phase)
SAC
3.6.
ITT
SAFE_F2
Laboratory Results by Visit: Electrolytes (Double-blind Phase)
SAC
3.7.
ITT
SAFE_F2
Laboratory Results by Visit: Other Chemistries (Double-blind 
Phase)
SAC
3.8.
ITT
SAFE_F2
Laboratory Results by Visit: Immunoglobulins (Double-blind 
Phase)
SAC
3.9.
ITT
SAFE_F2
Laboratory Results Change from Baseline by Visit: Hematology
(Double-blind Phase)
SAC
3.10.
ITT
SAFE_F2
Laboratory Results Change from Baseline by Visit: Liver 
Function (Double-blind Phase)
SAC
3.11.
ITT
SAFE_F2
Laboratory Results Change from Baseline by Visit: Electrolytes
(Double-blind Phase)
SAC
3.12.
ITT
SAFE_F2
Laboratory Results Change from Baseline by Visit: Other 
Chemistries (Double-blind Phase)
SAC
3.13.
ITT
SAFE_F2
Immunoglobulin Levels Change from Baseline by Visit (Double-
blind Phase)
SAC


CONFIDENTIAL
BEL115466
108
10.12.9.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
4.1.
PK
PK_T1
Belimumab Concentrations (Observed) (Double-Blind Phase)
SAC
10.12.10. Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
4.1.
PK
PK_F1
Median belimumab Concentrations (Observed) (Double-Blind 
Phase)
SAC
4.2.
PK
PK_F1
Mean belimumab Concentrations (Observed) (Double-Blind 
Phase)
SAC
4.3.
PK
PK_F1
Individual belimumab Concentrations (Observed) (Double-Blind 
Phase)
SAC


CONFIDENTIAL
BEL115466
109
10.12.11. Pharmacokinetic Listings
Pharmacokinetic : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
4.1.
PK
PK_L1
Serum belimumab PK Concentration-Time Data
SAC
10.12.12. Biomarker Tables
Biomarker : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
5.1.
ITT
PD_T1
Summary of ANCA Status over Time (Double-blind Phase)
SAC
5.2.
Subgroup of 
ITT
PD_T1
Summary of ANCA Status over Time (Age ≥ 65 Yrs) (Double-
blind Phase)
SAC
5.3.
Subgroup of 
ITT
PD_T1
Summary of ANCA Status over Time (Age ≥ 75 Yrs) (Double-
blind Phase)
SAC
5.4.
ITT
PD_T2
Summary of ANCA Status Over Time, Compared to 
Baseline (Double-blind Phase)
SAC
5.5.
ITT
PD_T3
Complement Levels (Observed and Change from Baseline) by 
Visit (Double-blind Phase)
SAC
5.6.
ITT
PD_T3
Complement Levels (Observed and Percentage Change from 
Baseline) by Visit (Double-blind Phase)
SAC
5.7.
ITT
PD_T3
Immunoglobulin Levels (Observed and Change from Baseline) 
by Visit (Double-blind Phase)
SAC
5.8.
ITT
PD_T3
Immunoglobulin Levels (Observed and Percentage Change from 
Baseline) by Visit (Double-blind Phase)
SAC
5.9.
ITT
PD_T3
C-Reactive Protein (CRP) Levels (Observed and Change from 
Baseline) by Visit (Double-blind Phase)
SAC


CONFIDENTIAL
BEL115466
110
Biomarker : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
5.10.
ITT
PD_T3
C-Reactive Protein (CRP) Levels (Observed and Percentage 
Change from Baseline) by Visit (Double-blind Phase)
SAC
5.11.
ITT
PD_T3
Urinary Creatinine Ratio (Observed and Change from Baseline) 
by Visit (Double-blind Phase)
SAC
5.12.
ITT
PD_T3
Urinary Creatinine Ratio (Observed and Percentage Change 
from Baseline) by Visit (Double-blind Phase)
SAC
5.13.
ITT
PD_T3
Estimated Glomerular Filtration Rate (eGFR) (Observed and 
Change from Baseline) by Visit (Double-blind Phase)
SAC
5.14.
ITT
PD_T3
Estimated Glomerular Filtration Rate (eGFR) (Observed and 
Percentage Change from Baseline) by Visit (Double-blind 
Phase)
SAC
5.15.
ITT
PD_T3
B Cells (FACS of Peripheral Lymphocytes) (Observed and 
Change from Baseline) by Visit (Double-blind Phase)
Please include all B cell and T cell 
subsets. Concentration and percentage 
BIMETHCD only.
SAC
5.16.
Subgroup of 
ITT
PD_T3
B Cells (FACS of Peripheral Lymphocytes) (Observed and 
Change from Baseline) by Visit (Age ≥ 65 Yrs) (Double-blind 
Phase)
SAC
5.17.
Subgroup of 
ITT
PD_T3
B Cells (FACS of Peripheral Lymphocytes) (Observed and 
Change from Baseline) by Visit (Age ≥ 75 Yrs) (Double-blind 
Phase)
SAC
5.18.
ITT
PD_T3
B Cells (FACS of Peripheral Lymphocytes) (Observed and 
Percentage Change from Baseline) by Visit (Double-blind 
Phase)
SAC


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10.12.13. Biomarker Figures
Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
5.1.
ITT
SAFE_F2
Complement Levels Change from Baseline by Visit (Double-
blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.2.
ITT
SAFE_F2
Complement Levels Percentage Change from Baseline by Visit 
(Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.3.
ITT
SAFE_F2
Immunoglobulin Levels Change from Baseline by Visit (Double-
blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.4.
ITT
SAFE_F2
Immunoglobulin Levels Percentage Change from Baseline by 
Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.5.
ITT
SAFE_F2
C-Reactive Protein (CRP) Levels Change from Baseline by Visit 
(Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.6.
ITT
SAFE_F2
C-Reactive Protein (CRP) Levels Percentage Change from 
Baseline by Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.7.
ITT
SAFE_F2
Urinary Creatinine Ratio Change from Baseline by Visit (Double-
blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.8.
ITT
SAFE_F2
Estimated Glomerular Filtration Rate (eGFR) Change from 
Baseline by Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC
5.9.
ITT
SAFE_F2
Estimated Glomerular Filtration Rate (eGFR) Percentage 
Change from Baseline by Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change.
SAC


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Biomarker: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
5.10.
ITT
SAFE_F2
B Cells (FACS of Peripheral Lymphocytes) Change from 
Baseline by Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change. Please repeat for all B 
cell & T cell subsets
SAC
5.11.
Subgroup of 
ITT
SAFE_F2
B Cells (FACS of Peripheral Lymphocytes) Change from 
Baseline by Visit (Age ≥ 65 Yrs) (Double-blind Phase)
SAC
5.12.
Subgroup of 
ITT
SAFE_F2
B Cells (FACS of Peripheral Lymphocytes) Change from 
Baseline by Visit (Age ≥ 75 Yrs) (Double-blind Phase)
SAC
5.13.
ITT
SAFE_F2
B Cells (FACS of Peripheral Lymphocytes) Percentage Change 
from Baseline by Visit (Double-blind Phase)
Display all visits to Year 2 Week 28. If 
distribution looks non-normal plot 
median change. Please repeat for all B 
cell & T cell subsets
SAC


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10.12.14. ICH Listings
ICH : Listings (Safety)
No.
Population
Example Shell 
Title
Programming Notes
Deliverable 
Subject Disposition
1.
Randomized
POP_L1
Listing of Subject Disposition (Double-blind Phase)
SAC
2.
Screened
ES7
Listing of Reasons for Screening Failure (Double-blind Phase)
SAC
3.
Randomized
ES2
Listing of Reasons for Subject Withdrawal (Double-blind and 
Open-label)
SAC
4.
Randomized
ES2
Listing of Reasons for Subject Study Treatment Withdrawal 
(Double-blind Phase)
SAC
5.
Randomized
POP_L2
Listing of Planned and Actual Treatment Arms (Double-blind 
Phase)
SAC
Inclusion / Exclusion Criteria
6.
Randomized
IE3
Listing of Eligibility Criteria Not Met (Double-blind Phase)
SAC
Protocol Deviations
7.
Randomized
DV2
Listing of Important Protocol Deviations
SAC
Baseline Demographic Characteristics
8.
Randomized
DM2
Listing of Demographic Characteristics (Double-blind Phase)
SAC
9.
Randomized
COV2
Listing of Randomized and Actual Strata (Double-blind Phase)
Treatment group can go at top-left of 
table rather than being a column. Have 
Center ID / Subj. ID as one column to 
be consistent.
SAC
10.
Randomized
DM9
Listing of Race and Racial Combinations (Double-blind Phase)
SAC
Medical History
11.
Randomized
MH2
Listing of Prior Medical Conditions (Double-blind Phase)
Please include footnote “Prior medical 
conditions as reported by 
Investigators.”
SAC


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ICH : Listings (Safety)
No.
Population
Example Shell 
Title
Programming Notes
Deliverable 
12.
Randomized
MH2
Listing of Other Prior Medical Conditions (Double-blind Phase)
Include all “other” medical conditions 
that could not be merged to MedDRA.
SAC
13.
Randomized
CM3
Listing of Concomitant Medications (Double-blind and Open-
label)
SAC
14.
Randomized
POP_L3
Listing of Concomitant Procedures/Surgeries (Double-blind and 
Open-label)
SAC
Exposure and Treatment Compliance
15.
Randomized
POP_L4
Listing of Study Drug Exposure (Double-blind and Open-label)
SAC
16.
Randomized
POP_L5
Listing of Study Drug Administration (Double-blind and Open-
label)
SAC
17.
Randomized
POP_L6
Listing of Subjects switching from Azathioprine to Methotrexate
SAC
18.
Randomized
POP_L7
Listing of Treatment Failures (Double-blind Phase)
SAC
Adverse Events
19.
Randomized
SAFE_L1
Listing of All Adverse Events (Double-blind and Open-label)
SAC
20.
Randomized
SAFE_L1
Listing of All Adverse Events (Age ≥ 65 Yrs) (Double-blind and 
Open-label)
SAC
21.
Randomized
SAFE_L1
Listing of All Adverse Events (Age ≥ 75 Yrs) (Double-blind and 
Open-label)
SAC
22.
Randomized
SAFE_L1
Listing of Serious Adverse Events (Double-blind and Open-label)
SAC
23.
Randomized
SAFE_L1
Listing of Serious Adverse Events (Age ≥ 65 Yrs) (Double-blind 
and Open-label)
SAC
24.
Randomized
SAFE_L1
Listing of Serious Adverse Events (Age ≥ 75 Yrs) (Double-blind 
and Open-label)
SAC
25.
Randomized
SAFE_L1
Listing of Serious or Severe Infections (Double-blind and Open-
label)
SAC
26.
Randomized
SAFE_L1
Listing of Study Drug-Related Adverse Events (Double-blind and 
Open-label)
SAC


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ICH : Listings (Safety)
No.
Population
Example Shell 
Title
Programming Notes
Deliverable 
27.
Randomized
SAFE_L1
Listing of Non-Fatal Serious Adverse Events (Double-blind and 
Open-label)
SAC
28.
Randomized
SAFE_L1
Listing of Fatal Adverse Events  (Double-blind and Open-label)
SAC
29.
Randomized
SAFE_L1
Listing of Adverse Events Resulting in Study Drug 
Discontinuation or Study Withdrawal (Double-blind and Open-
label)
SAC
30.
Randomized
SAFE_L1
Listing of Adverse Events Resulting in Study Drug 
Discontinuation or Study Withdrawal (Age ≥ 65 Yrs) (Double-
blind and Open-label)
SAC
31.
Randomized
SAFE_L1
Listing of Adverse Events Resulting in Study Drug 
Discontinuation or Study Withdrawal (Age ≥ 75 Yrs) (Double-
blind and Open-label)
SAC
32.
Randomized
SAFE_L1
Listing of Deaths (Double-blind and Open-label)
SAC
33.
Randomized
SAFE_L2
Listing of Adverse Events of Special Interest (Double-blind and 
Open-label)
SAC
34.
Randomized
SAFE_L3
Listing of Subject Numbers for Individual Adverse Events 
(Double-blind and Open-label)
SAC
Laboratory
35.
Randomized
SAFE_L4
Listing of Laboratory Results: Hematology (Double-blind and 
Open-label)
SAC
36.
Randomized
SAFE_L4
Listing of Laboratory Results: Liver Function (Double-blind and 
Open-label)
SAC
37.
Randomized
SAFE_L4
Listing of Laboratory Results: Electrolytes (Double-blind and 
Open-label)
SAC
38.
Randomized
SAFE_L4
Listing of Laboratory Results: Other Chemistries (Double-blind 
and Open-label)
SAC
39.
Randomized
SAFE_L4
Listing of Laboratory Results: Urinalysis (Double-blind and 
Open-label) 
SAC


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ICH : Listings (Safety)
No.
Population
Example Shell 
Title
Programming Notes
Deliverable 
40.
Randomized
SAFE_L4
Listing of Laboratory Results: Immunoglobulins (Double-blind 
and Open-label)
SAC
41.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: 
Hematology (Double-blind and Open-label)
SAC
42.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: Liver 
Function  (Double-blind and Open-label)
SAC
43.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: 
Electrolytes  (Double-blind and Open-label)
SAC
44.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: Other 
Chemistries (Double-blind and Open-label)
SAC
45.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: 
Urinalysis (Double-blind and Open-label)
SAC
46.
Randomized
SAFE_L5
Listing of Grade 3 or Grade 4 Laboratory Toxicity Results: 
Immunoglobulins (Double-blind and Open-label)
SAC
Immunogenicity and Biomarkers
47.
Randomized
SAFE_L6
Listing of Immunogenicity Results (Double-blind and Open-label)
SAC
48.
Randomized
SAFE_L7
Listing of Biomarker Results (Double-blind and Open-label)
Please list all biomarkers including 
eGFR.
SAC
49.
Randomized
SAFE_L7
Listing of B Cell (FACS of Peripheral Lymphocytes) Results 
(Double-blind and Open-label)
Please modify SAFE_L7 by giving B 
cell parameter rather than biomarker 
name
SAC
Vital Signs
50.
Randomized
SAFE_L8
Listing of Vital Signs (Double-blind and Open-label)
SAC
C-SSRS
51.
Randomized
CSSRS4
Listing of C-SSRS Suicidal Ideation and Behavior Data (Double-
blind Phase)
SAC
52.
Randomized
CSSRS5
Listing of C-SSRS Suicidal Behavior Details (Double-blind 
Phase)
SAC


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ICH : Listings (Safety)
No.
Population
Example Shell 
Title
Programming Notes
Deliverable 
53.
Randomized
CSSRS6
Listing of Details of Most Severe C-SSRS Suicidal Ideation at 
Each C-SSRS Assessment (Double-blind Phase)
SAC
54.
Randomized
SAFE_L9
Listing of Possible Suicidality Related Questionnaire (Double-
blind Phase)
SAC
55.
Randomized
SAFE_L10
Listing of Survival Status at Week 52 (Double-Blind Phase)
SAC
10.12.15. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint
56.
Randomized
EFF_L1
Listing of Relapses (Double-blind Phase)
Please sort by relapse then Center
ID/Subj ID, then visit
SAC
57.
Randomized
EFF_L2
Listing of Domain and Item Scored for BVAS Relapses by Visit 
(Double-blind Phase)
SAC
Time to First Minor or Major Relapse or Receipt of Rescue Medication
58.
Randomized
EFF_L1
Listing of Minor or Major Relapse or Receipt of Rescue 
Medication (Double-blind and Open-label)
Please change relapse column to 
“Event[1]” and add footnote “[1] Event 
defined as any minor or major BVAS 
item experienced or receipt of 
prohibited medication”. Change 
“Relapse Date” to “Event Date”
SAC
Other Binary Endpoints
59.
Randomized
EFF_L3
Listing of Remission Status by Visit (Double-blind and Open-
label)
SAC
Vasculitis Damage Index


CONFIDENTIAL
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
60.
Randomized
EFF_L4
Listing of Vasculitis Damage Index (VDI) by Organ Domain and 
Visit (Double-blind and Open-label)
Please sort by phase.
SAC
Birmingham Vasculitis Activity Score
61.
Randomized
EFF_L5
Listing of Birmingham Vasculitis Activity Score (BVAS) by Organ 
Domain and Visit (Double-blind and Open-label)
Use EFF_F2 and modify based on 
data.
SAC
Other
62.
Statistical Analysis of Time to First Relapse (SAS Output)
No example given, please provide SAS 
output for the primary.
SAC


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119
10.13.
Appendix 13: Example Mock Shells for Data Displays
Please refer to mock example document: RAP-BEL115466-Mock-Shells.doc