A Randomized, Double-Blind, Placebo-Controlled Study of Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis
Phase: PHASE2
Conditions: Systemic Sclerosis
Sponsor: Hospital for Special Surgery, New York

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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GLAXOSMITHKLINE 
A Randomized, Double-Blind, Placebo-
Controlled study of Belimumab and 
Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous 
Systemic Sclerosis 
GSK – Investigator Initiated Study 
 
 
Version Date 01/10/2019 
NCT# Pending 
 
 
 
 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Protocol Synopsis 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled 
Study of Belimumab and Rituximab Combination 
Therapy for the Treatment of Diffuse Cutaneous 
Systemic Sclerosis 
Supporter 
GSK, Investigator Initiated Study 
Site 
Hospital for Special Surgery 
535 East 70th Street 
United States of America, New York, NY, 10021 
Research Hypothesis: 
In this randomized controlled study, we will test 
the hypothesis that Rituximab and Belimumab 
combination therapy with Mycophenolate Mofetil 
background therapy will improve fibrosis in SSc 
skin when compared to treatment with placebo and 
Mycophenolate Mofetil (MMF, Cellcept) in a 
group of patients with early SSc  
Study Schema:  
Two infusions of 1000 mg of rituximab two weeks 
apart and Belimumab subcutaneous once every 
week (200 mg) and background MMF (2-3 g po, 
qd) vs two placebo Rituximab infusions two weeks 
apart and placebo Belimumab subcutaneous once 
every week and background MMF (2-3 g po, qd) 
administered over a 12 month period. 
 
Study objectives: 
Primary Safety 
The proportion of participants who experience at 
least one Grade 3 or higher adverse event at or 
before 12 months 
Primary Efficacy 
 
Change in the CRISS at 12 months 
Secondary Safety and Efficacy 
 
Proportion of patients who experience at least 
one grade 2 or higher adverse event 
 
All infectious adverse events 
 
All infusion reactions 
 
All injection site reactions 
 
All adverse events 
 
Change in the CRISS at 6 months 
 
Change in the MRSS at 6 and 12 months 
 
Change in Forced Vital Capacity (FVC)  
 
Change in the short form-36 (SF-36) 
 
Change in the scleroderma health assessment 
questionnaire-disability index (sHAQ-DI) 
 
Change in PROMIS-29 
 
Change in GIT score 
 
Change in Scleroderma Skin Questionnaire 
 
Change in the DAS-28 
 
Change in joint count 
 
Change in CDAI 
 
Change in Global Combined Response Index 
 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Table of Contents 
Introduction ................................................................................................................................................... 6 
Overall Risk/Benefits Assessment ............................................................................................................ 6 
Research Hypothesis ................................................................................................................................. 6 
Study Rationale ......................................................................................................................................... 6 
Study Objectives ......................................................................................................................................... 10 
Primary Objectives .................................................................................................................................. 10 
Secondary Objectives .............................................................................................................................. 10 
Tertiary Objectives .................................................................................................................................. 10 
Ethical Considerations .............................................................................................................................. 101 
Good Clinical Practice .......................................................................................................................... 111 
Institutional Review Board/Independent Ethics Committee ................................................................... 11 
Informed Consent.................................................................................................................................... 11 
Confidentiality ........................................................................................................................................ 11 
Investigational Plan ..................................................................................................................................... 12 
Study Design and Duration ..................................................................................................................... 12 
Study Population ..................................................................................................................................... 12 
Inclusion Criteria ................................................................................................................................ 12 
Exclusion Criteria ............................................................................................................................... 12 
Discontinuation of Subjects from Treatment ...................................................................................... 14 
Contraceptive requirements for women of child bearing potential ..................................................... 14 
Special Considerations: Mycophenolate Mofetil ................................................................................ 16 
Progressive Multifocal Leukoencephalopathy (PML) ........................................................................ 14 
Combination Anti-B Cell Theraphy Considerations ........................................................................... 14 
Liver Chemistry Stopping Criteria  ............................................................................................................. 19 
Stopping Criteria ..................................................................................................................................... 19 
Required Actions, Monitoring and follow up Assessment following any liver stooping event ................. 17 
Actions .................................................................................................................................................... 19 
Monitoring .............................................................................................................................................. 19 
Follow up Assessments ........................................................................................................................... 19 
Increased Monitoring CriteriaW/Continued therapy .................................................................................. 19 
Treatments................................................................................................................................................... 19 
Study Treatment ...................................................................................................................................... 19 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Definition of Investigational Product .................................................................................................. 19 
Definition of Non-Investigational Product.......................................................................................... 19 
Handling and Dispensing .................................................................................................................... 19 
Drug Ordering and Accountability ......................................................................................................... 20 
Initial Orders ....................................................................................................................................... 20 
Re-Supply ........................................................................................................................................... 20 
Method of Assigning Subjects to Treatment ....................................................................................... 20 
Blinding/Unblinding ........................................................................................................................... 21 
Concomitant Treatments ..................................................................................................................... 21 
Other Restrictions and Precautions ..................................................................................................... 21 
Study Assessments and Procedures ............................................................................................................ 21 
Study Outcome Assessments .................................................................................................................. 21 
Schedule of Assessments ........................................................................................................................ 23 
Schedule of Events (List) ........................................................................................................................ 23 
Screening Visit (Visit 0, Day -28 to Day 0) ........................................................................................ 25 
II. Baseline 1 (Visit 1, Day 1, may occur over 2 days) ....................................................................... 25 
III. Baseline 2 (Visit 2, 4 weeks after baseline 1) ............................................................................... 26 
IV. Infusion 2 (Visit 2, 2 weeks after infusion 1) ............................................................................... 26 
V. Study Visits (Visit 1, Visit 2, Visit 3, Visit 4) ............................................................................... 26 
VI. End of Study Visit– Visit 5 ........................................................................................................... 27 
VII. 3-month Follow-up ...................................................................................................................... 27 
Safety Assessments ................................................................................................................................. 28 
Efficacy Assessments .............................................................................................................................. 28 
Primary Efficacy Assessments ............................................................................................................ 28 
Secondary Efficacy Assessments ........................................................................................................ 28 
Adverse Event Reporting ............................................................................................................................ 32 
Adverse Events ....................................................................................................................................... 32 
Serious Adverse Events .......................................................................................................................... 32 
Unexpected Adverse Events ................................................................................................................... 35 
Assignment of Adverse Event Intensity .................................................................................................. 35 
Relation to Study Therapy ...................................................................................................................... 35 
Collection and Reporting ........................................................................................................................ 36 
Serious Adverse Event Collecting and Reporting ................................................................................... 36 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Drug Side Effects .................................................................................................................................... 36 
Belimumab .......................................................................................................................................... 37 
Recommended Subcutaneous Dosage Regimen ................................................................................. 37 
Administration Instructions for Subcutaneous Injection ..................................................................... 37 
Rituximab ............................................................................................................................................ 36 
Risks .................................................................................................................................................... 37 
Rituximab Dosage and Administration ............................................................................................... 37 
Rituximab Storage .............................................................................................................................. 39 
Rituximab Overdose ........................................................................................................................... 39 
Data Monitoring ...................................................................................................................................... 39 
Statistical Plan ............................................................................................................................................. 40 
Sample Size ............................................................................................................................................. 40 
References ................................................................................................................................................... 40 
 
 
 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Introduction 
Overall Risk/Benefits Assessment  
This is a randomized, double-blind, placebo-controlled study to assess efficacy of Rituximab and 
Belimumab combination therapy in patients with diffuse cutaneous Systemic sclerosis (SSc, 
Scleroderma).  Scleroderma is a significant rheumatic disease, and is associated with substantial 
morbidity and disability, and many detrimental effects on health-related quality of life. There are 
currently no Food and Drug Administration (FDA) approved drugs for SSc.  
Research Hypothesis 
In this randomized controlled study, we will test the hypothesis that Rituximab and Belimumab 
combination therapy with Mycophenolate Mofetil background therapy will improve fibrosis in SSc skin 
when compared to treatment with placebo and Mycophenolate Mofetil (MMF, Cellcept) in a group of 
patients with early SSc without internal organ complications. 
Study Rationale  
Scleroderma is a multi-system inflammatory disease where dysregulated fibrosis, autoimmunity, and 
vasculopathy lead to disability, organ failure, and accelerated mortality. There are two main subtypes of 
SSc: limited cutaneous (lc) SSc and diffuse cutaneous (dc) SSc, with disease subtype determined by 
distribution of skin involvement and with different patterns of internal organ involvement observed in the 
two subtypes.  SSc has an estimated prevalence of 276 per million in the United States,1 and the ten-year 
mortality rates range from 23 percent to 45 percent.1,2 There is currently no satisfactory disease modifying 
agent for this potentially devastating disease. Frequently employed treatments include 
cyclophosphamide,3 methotrexate,4 and mycophenalate mofetil5 and improved therapy for SSc is an 
urgent and unmet need.  
B-Cell abnormalities are part of the immune dysregulation seen in systemic sclerosis.  Belimumab 
(Benlysta) decreases B-Cell survival and is a therapeutic agent with high potential in SSc. 
Anti–B-cell therapy has already been shown to be effective in treating rheumatoid arthritis (RA), systemic 
lupus erythematosus (SLE), chronic graft-versus-host disease and other related autoimmune diseases.   
Recent assessment has indicated that B-cells function as immunoregulatory cells in the induction and 
maintenance of systemic autoimmunity. These cells display a variety of functions, including antigen 
presentation, production of cytokines, lymphoid organogenesis, differentiation of T-effector cells and 
modulation of dendritic cell function through cytokine production, and in the activation of T cells in 
addition to production of autoantibodies.6 Abnormalities in B-cell development and/or function could 
contribute to autoimmunity in addition to or independently of autoantibody production.  
Several investigations have shown that B cells play an important role in the pathogenesis of SSc.  The 
presence of antinuclear antibodies (ANAs) has been detected in 90% of patients with SSc and is thought 
to be a central feature of immune activation in the disease.7  Specific autoantibodies (e.g. anti-Scl70, anti-
centromere and anti-RNA polymerase III antibodies) associate strongly with individual disease 
phenotypes, and their presence is evidence of abnormal B-cell activation in patients with SSc.8 
Hypergammaglobulinemia, hyperactivity of polyclonal and memory B-lymphocytes and altered B-cell 
homeostasis have been detected in SSc patients.9,10 In addition, gene expression analysis using DNA 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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microarrays has revealed an upregulation of B-cell related genes in SSc skin lesions.11 Immunochemical 
analysis suggests that the B lymphocyte signature observed on these arrays is from CD20+ B cells.  
Perivascular B-cell infiltration has been found in the skin of SSc patients,12 and B-Cells have been 
observed in the lungs of patients with SSc-related interstitial lung disease.13 Levels of circulating naive B 
cells (CD27-) are increased in SSc patients, while memory B cells (CD27 medium), although reduced in 
number, show markers of activation (CD 80, 86, 95).14 Both naïve and memory B cell populations exhibit 
increased expression of CD19, a critical cell surface signal transduction molecule expressed by early pre-
B cells from the time of heavy chain rearrangement until plasma cell differentiation. Flow-cytometric 
analyses of blood from patients with scleroderma have indicated that surface CD19 density in 
scleroderma B cells are 20% higher than those from healthy controls.15  
Polymorphisms of the CD19 promoter region were found to correlate with higher CD19 expression on B 
cells, whereas polymorphisms of CD22, a negative regulator of B-cell receptor signaling, led to decreased 
CD22 surface expression on B cells in SSc patients.15,16 In the tight skin (TSK) mouse, a commonly 
employed murine model of systemic fibrosis, B-cells exhibit a hyper responsive phenotype with 
decreased IgM expression and increased IgG and autoantibody production.  CD19 signaling is augmented 
in this model, and knock-out of CD19 leads to decreased skin fibrosis.17 In addition, CD19 deficiency 
correlates with hyperg-globulinemia and elevated autoantibody levels including anti-topoisomerae I 
antibody. Reciprocally, in transgenic mice overexpressing CD-19, antitopoisomerase I antibody levels are 
significantly increased.17 CD 19–null mice treated with bleomycin show a reduced fibrotic response in the 
skin and lungs as well as reduced levels of the profibrotic cytokines IL-6 and TGF-β. However, TSK mice 
with increased expression of CD19 do not exhibit increased skin thickness. Thus, exaggerating B-cell 
activation through the increase of CD19 does not lead to further skin fibrosis though silencing B-cell 
activation can reduce skin fibrosis.17 
In addition to the aforementioned B-cell abnormalities, serum BAFF levels have been shown to be 
elevated in SSc patients when compared to healthy controls, these levels correlated positively with extent 
of skin fibrosis, and decreasing BAFF levels were accompanied by improvement in the MRSS.  BAFF 
receptor expression on B cells was increased in SSc patients relative to healthy controls.18,19 BAFF 
mRNA expression was found to be up-regulated in the affected skin of patients with early dcSSc (as 
defined as less than three years of disease duration from the first non-Raynaud’s symptom of SSc) when 
compared to those with late dcSSc, scar tissue, or healthy controls. Furthermore, serum BLyS levels were 
found to be elevated in the tight skin (TSK/+) mouse,20 a genetic model for SSc. A BLyS antagonist 
downregulated the expression of fibrogenic type 2 cytokines, such as IL-6 and IL-10, and inhibited 
autoantibody generation, development of skin fibrosis and hyper-gammaglobulinemia in the TSK/+ 
mouse. Skin fibrosis in TSK mice is improved with a parallel reduction in IL-6 production from B cells 
(20). BAFF induced IL-6 production by TSK B cells could play an important role in the development of 
skin fibrosis, and  BAFF antagonist attenuates skin fibrosis with a decrease in IL-6 production.18,19 BAFF 
stimulation enhances CD19 expression and also phosphorylation of CD19 by B cell antigen receptor. 
Thus, excess BAFF may contribute to B cell hyperactivity through the overexpression of CD19.21  
 
As new studies shed light on the pathogenic roles of B-cells in SSc, there have been promising initial 
investigations looking at Rituximab, a chimeric mAB against human CD20 that depletes peripheral B-
cells, in the treatment of SSc with four small published trials4,5,22 to date. The medication was found to be 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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tolerable in all of the studies, with little associated toxicity and no reported serious adverse events 
attributable to Rituximab. Three of the studies showed improvement in the MRSS, and potential 
improvement in pulmonary function was shown as well.  Daoussis, et al performed a randomized, 
controlled trial, open-label trial with 14 patients which showed an improved FVC (improvement of 
10.25% in treated vs deterioration of 5.04% in controls) and DLCO (improvement of 19.46% in the 
treated group vs deterioration of 7.5% in the control group.)  In this study the MRSS improved from 13.5 
+/- 6.84 vs 8.37 +/- 6.45 at baseline vs 1 year, respectively, P = 0.0003).  There was no significant change 
in the control group.   In Lafyatis, et al. a study which recruited all patients with less than 18 months 
disease duration, no significant change was seen in 15 patient in the MRSS.  This group did observe 
depletion of cutaneous B-Cell infiltrates.  In an open label study by Smith, et al.  the MRSS improved 
from 24.8 to 14.3 which was a mean improvement of 43%, p<0.001.  Significant improvements were 
noted in the dermal hyalinised collagen content and dermal myofibroblast numbers as well.  As a whole 
these studies point favorably to B-Cell directed therapies for this incurable disease. 
Belimumab (Benlysta®), a recombinant, fully human monoclonal antibody, has been FDA approved as 
an add on therapy to SoC in sero-positive SLE.   Belimumab binds to soluble human B lymphocyte 
stimulator (BLyS) with high affinity and inhibits its biologic activity.  The background above provides a 
robust rationale for the investigation of belimumab in the treatment of dcSSc.   
In a recently completed double-blind, placebo-controlled pilot study completed by our center, the safety 
and efficacy of belimumab was tested in patients with early dcSSC treated with background MMF. 
Patients were then randomized 1:1 to either intravenous belimumab or placebo. In both treatment groups, 
an improvement in mRSS was observed, and although the median difference was greater in the actively 
treated as compared to the placebo group, this did not achieve statistical significance in this relatively 
small study. However, significant decreases in expression of B-cell signaling and pro-fibrotic genes and 
pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo 
group.23     
The clinical and translational findings of this pilot trial strongly support potential efficacy of belimumab 
in the treatment of dcSSc and further exploration of anti-B cell strategies in this rheumatic disease. 
In recent years, there has been an increasing interest in treating patients with SSc with rituximab, 
especially for patients with interstitial lung disease (ILD). One randomized controlled trial focused on 
patients with SSc <2 years, and found that rituximab treatment, in comparison to the placebo group, 
caused a small improvement in lung function, but this difference did not reach statistical significance.23 A 
chart review of 14 late disease SSc-ILD patients demonstrated that the median forced vital capacity 
increased compared to baseline, although not statistically significant, and skin scores remained stable at 
the end of follow-up.24 In a series of 10 case reports (5 patients with early disease, 5 with late disease), 
rituximab was found to be most effective in treating early and rapidly progressive forms of SSc.25 These 
studies demonstrate the need for further studies analyzing rituximab and especially its usage in early 
disease.  
Utilizing belimumab and rituximab as a combination therapy in SSc has not previously been studied, but 
this approach has been considered in other autoimmune disorders. A completed study of rituximab and 
belimumab for SLE was successful in proving this combination therapy superior to placebo.27Case reports 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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have demonstrated efficacy of belimumab after rituximab as maintenance therapy in several patients with 
SLE.27 Additionally, there is an ongoing study focusing on this combination therapy in Sjogren’s, and 
another study is planned for ANCA Associated Vasculitis. We propose similarly administering two 
infusions of 1000 mg of rituximab two weeks apart in this SSc trial.  This dosing regimen has been 
demonstrated in a previous uncontrolled pilot trial conducted by Lafayatis et al. to deplete B cells in both 
peripheral blood and skin for patients with SSc.  Importantly,  a significant reduction of the myofibroblast 
score in the skin biopsies of the RTX was demonstrated, and safety and tolerability was acceptable.  This 
same Rituximab dosing strategy was used in the ongoing trial of Rituximab, Belimumab and 
Cyclophosphamide combination therapy in SLE (CALIBRATE).  
This combination is of interest to us as an option for patients with SSc.   
There is no standard treatment for patients with dcSSc.  Treatments employed commonly include 
methotrexate, MMF, and cyclophosphamide.3,5,28 None of these treatment options have a high level of 
evidence or a dramatic benefit. MMF has been used in conjunction with Belimumab in SLE as has 
methotrexate. Because of no clear superior treatment (MTX vs MMF in SSc) in the literature, the 
investigators have chosen MMF as baseline therapy due to a perceived balance of benefit in SSc as well 
as experience using it with Belimumab.  All patients are offered active treatment with MMF. 
In this 52 week, single center, randomized, double-blind, placebo-controlled study, we will address the 
following specific aims: 
1. Determine whether Belimumab used in combination with Rituximab (Rituxan), compared to 
placebo in the context of background therapy with  mycophenolate mofetil (MMF, Cellcept) is 
safe and tolerable in the treatment of patients with early diffuse cutaneous (dc)SSc (Disease 
duration < 3 years) as assessed by comparison of adverse and serious adverse effects.  
2. Determine whether Belimumab used in combination with Rituximab is more effective than 
placebo when used in combination with MMF, as measured by change in modified Rodnan Skin 
Score (mRSS), forced vital capacity (FVC), hemoglobin corrected diffusion capacity (DLCO), 
Medsger Severity Scale (MSS), and by other physician and patient derived outcome measures.  
3. Determine the biological activity of rituximab/belimumab/mmf vs placebo/placebo/mmf as 
assessed by effect on histology of skin, gene expression of skin and blood, change in B-Cell 
profiles including assessment of B regulatory cells, effect on BLyS levels, and effect on 
serological and cutaneous biomarkers of disease activity.    
 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Study Objectives 
Primary Safety Objectives 
The primary safety outcome of the study is as follows: 
 
The proportion of participants who experience at least one Grade 3 or higher adverse event at or 
before 12 months 
Primary Efficacy Objectives 
The primary efficacy outcome of the study is as follows: 
 
Change in the CRISS at 12 months 
Secondary Objectives 
Secondary safety and efficacy endpoints will include:   
 
Proportion of patients who experience at least one grade 2 or higher adverse event 
 
All infectious adverse events 
 
All infusion reactions 
 
All injection site reactions 
 
All adverse events 
 
Change in the CRISS at 6 months 
 
Change in the MRSS at 6 and 12 months 
 
Change in Forced Vital Capacity (FVC)  
 
Change in the short form-36 (SF-36) 
 
Change in the scleroderma health assessment questionnaire-disability index (sHAQ-DI) 
 
Change in PROMIS-29 
 
Change in GIT score 
 
Change in Scleroderma Skin Questionnaire 
 
Change in the DAS-28 
 
Change in joint count 
 
Change in CDAI 
 
Change in Global Combined Response Index 
Tertiary Objectives 
 
Change in gene expression in the skin as assessed by DNA microarray 
 

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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 
Change in B-Cell subsets as assessed by flow cytometry 
 
Change in gene expression in the PBMC 
 
Change in histopathology 
Ethical Considerations 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50).  
The study will be conducted in compliance with the protocol. The protocol, any amendments, and the 
participant informed consent will receive Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approval/favorable opinion before initiation of the study.  
Study personnel involved in conducting this study will be qualified by education, training, and experience 
to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or where there 
has been scientific misconduct or fraud (e.g., loss of medical licensure). 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigators will have written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, consent form, participant recruitment materials/process (e.g., advertisements), 
and any other written information to be provided to participants. The investigator or sponsor should also 
provide the IRB/IEC with a copy of the Package Insert or product labeling information to be provided to 
participants, and any updates.  
The investigator will provide the IRB/IEC with reports, updates, and other information (e.g., expedited 
safety reports, amendments, and administrative letters) according to regulatory requirements or institution 
procedures. 
Informed Consent 
The consent process will occur in a private clinic room at HSS at the beginning of the patient's screening 
visit. Informed consent will be obtained before any study procedures are performed. The rights, safety, 
and well-being of the study participants are the most important considerations and should prevail over 
interests of science and society. 
Confidentiality 
The Investigator will ensure that the subject’s confidentiality is maintained. On the case report forms or 
other documents, subjects will be identified by unique initials and a subject study number only. 
Documents that are not for submission to the Sponsor or designee (e.g., signed informed consent/assent 
forms) will be kept in strict confidence by the Investigator. 

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A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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Investigational Plan 
Study Design and Duration 
This study is a randomized, double-blind, placebo-controlled study. Eligible participants will be 
randomized 2:1 to favor active treatment. The active treatment is two infusions of 1000 mg of Rituximab 
two weeks apart followed by 200 mg of subcutaneous Belimumab once a week for 48 weeks vs two 
placebo infusions two weeks apart, followed by placebo subcutaneous injections once a week for 48 
weeks. All patients will be on background Mycophenolate Mofetil (2-3 g a day). 
Study Population 
Before any study procedures are performed, participants will have the details of the study described to 
them, and they will be given a written informed consent document to read. Then, if participants consent to 
participate in the study, they will indicate that consent by signing and dating the informed consent 
document in the presence of study personnel. 
This study will enroll 30 patients total. 
For entry into the study, the following criteria MUST be met: 
Inclusion Criteria 
1. Age greater than or equal to eighteen years and less than or equal to 80. 
2. Classification of systemic sclerosis (SSc), as defined using the 2013 American College of 
Rheumatology/European Union League Against Rheumatism classification of SSc. 
3. Diagnosis of dcSSc, as defined by LeRoy and Medsger.  
4. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-
Raynaud’s symptom.  
5. A modified Rodnan Skin Score (mRSS) of > 14 
Exclusion Criteria 
1. Inability to render informed consent in accordance with institutional guidelines. 
2. Disease duration of greater than 3 years. 
3. Patients with mixed connective tissue disease or “overlap” unless the dominant features of the 
illness are diffuse systemic sclerosis.  
4. Limited scleroderma. 
5. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic 
rapeseed oil, vinyl chloride, or bleomycin. 
6. The use of other anti-fibrotic agents including colchicine, D-penicillamine, or tyrosine kinase 
inhibitors (nilotinib, imatinib, dasatinib) in the month prior to enrollment.  
7. Use in the prior month of corticosteroids at doses exceeding the equivalent of prednisone 10 mg 
daily.  Use of corticosteroid at < 10 mg of prednisone can continue during the course of the study. 
8. Concurrent serious medical condition which in the opinion of the investigator makes the patient 
inappropriate for this study such as uncontrollable CHF, arrhythmia, severe pulmonary or 
systemic hypertension, severe GI involvement, hepatic impairment, serum creatinine of greater 
than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, 
malignancy, HIV, or severe peripheral vascular disease. 

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A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
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9. A positive pregnancy test at entry into this study.  Men and women with reproductive potential 
will be required to use effective means of contraception through the course of the study, such as 
(1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) double-barrier methods 
(such as a condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent 
(foam/gel/film/cream/suppository)(3) an intrauterine device (IUD) or intrauterine system (IUS) 
(4) estrogenic vaginal ring (5) percutaneous contraceptive patches, or (6) implants of 
levonorgestrel or etonogestrel. Approved hormonal contraceptives (such as birth control pills, 
patches, implants or injections) may interact with and reduce the effectiveness of MMF so 
women receiving MMF who are using oral contraceptives for birth control should employ an 
additional method (e.g. barrier method). Contraceptive measures such as Plan B (TM), sold for 
emergency use after unprotected sex, are not acceptable methods for routine use. 
10. Women not willing to use effective birth control for the duration of the study 
11. Breastfeeding.   
12. Participation in another clinical research study involving the evaluation of another investigational 
drug within ninety days of entry into this study. 
13. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of 
predicted or requiring supplemental oxygen and forced vital capacity (FVC) of less than 45% of 
predicted. 
14. Grade 3 hypogammaglobulinemia  
15. Have a significant IgG deficiency (IgG level < 400 mg/dL) 
16. Have an IgA deficiency (IgA level < 10 mg/dL) 
17. Have a historically positive HIV test or test positive at screening for HIV 
18. Neutrophils <1.5X10E9/L 
19. Hepatitis status: 
a) Serologic evidence of current or past Hepatitis B (HB) infection based on the results of 
testing for HBsAg and HBcAb as follows: 
1. Patients positive for HBsAg or HBcAb are excluded 
b) Positive test for Hepatitis C antibody 
20. Known active bacterial, viral, fungal, mycobacterial, or other infection or any major episode of 
infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening, or 
oral antibiotics within 2 weeks prior to screening 
21. Infection history: 
a) Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria) 
b) Hospitalization for treatment of infection within 60 days of Day 0. 
c) Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-
parasitic agents) within 60 days of Day 0 
22. Suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, 
herpes zoster and atypical mycobacteria)  
23. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug or that may affect the interpretation of the results or render the patient at high 
risk from treatment complications 

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24. Prior use of Belimumab, Rituximab, or other B-Cell depleting therapies ever 
25. The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within the washout 
period mandated in the table below for each particular drug:  
Drug 
Washout Period 
Tocilizumab 
1 month for patients on 2mg/kg or 4 mg/kg.  
2 months for patients on 8mg/kg. 
Cyclophosphamide (oral or IV) 
3 months 
Abatacept 
2.5 months 
TNF Inhibitors 
Etanercept – 1 mo  
Infliximab – 2 mo 
Adalimumab – 2.5 mo 
Any biologic investigational agent (e.g., 
abetimus sodium, anti CD40L antibody, 
BG9588/ IDEC 131) 
365 days prior to belimumab 
Any non-biologic investigational agent  
30 days prior to belimumab 
26. Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 
months and/or any suicidal ideation in the last 2 months or who in the investigator’s judgment, 
pose a significant suicide risk.  
27. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence 
within 364 days prior to Day 0.  
28. History of an anaphylactic reaction to parenteral administration of contrast agents, human or 
murine proteins or monoclonal antibodies 
29. Live vaccines within 30 days prior to baseline 
30. Have a history of malignant neoplasm within the last 5 years with the exception of basal cell or 
squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the 
uterine cervix treated locally and with no evidence of metastatic disease for 3 years 
31. Have a history of a primary immunodeficiency 
32. Have any other clinically significant abnormal laboratory value in the opinion of the investigator 
33. Have any intercurrent significant medical or psychiatric illness that the investigator considers 
would make the candidate unsuitable for the study 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and non-investigational product at the discretion of 
the investigator) for any of the following reasons:  
 
A two-times increase in modified Rodnan Skin Score within 6 months 
 
Progressive Systemic Sclerosis related Interstitial Lung Disease at 6 months, defined as:  
o Absolute decline in FVC % predicted, attributable to SSc-ILD, by >15%, and 
o Absolute decline in DLCO% predicted, attributable to SSc-ILD, by >20%, and 
 
Must be confirmed by repeat pulmonary function testing within 1 month. 
 
Presence of new inflammatory infiltrates on HRCT, which are deemed SSc-related by study 
investigators 

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 
Onset of new Scleroderma Renal Crisis 
 
Onset of new heart failure 
 
Investigator decision that removal from trial is in subject’s best interest 
 
Neutrophils <1X10E9/L. 
Any subject removed from the trial will continue to be seen according to protocol and will be treated by 
the best medical decision of the investigators. A minimum of 2 follow-up visits will be documented when 
a patient is removed from the study. 
Subjects will be monitored for late onset neutropenia at 6 months post rituximab or other 
immunosuppressive agent.  Monitor patients for signs and symptoms of infection, monitor laboratory 
values, request that patients report signs of infection. Treat infections immediately and appropriately. 
Contraceptive requirements for women of childbearing potential 
Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of < 1%. 
Therefore, 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 (Sexual inactivity by abstinence must 
be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception) 
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: 
 
Oral contraceptive, either combined or progestogen alone  
 
Injectable progestogen 
 
Implants of levonorgestrel or etonogestrel 
 
Estrogenic vaginal ring 
 
Percutaneous contraceptive patches 
 
Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the 
product label 
 
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female 
subject's entry into the study, and this male is the sole partner for that subject. For this 
definition, “documented” refers to the outcome of the investigator's/designee’s medical 
examination of the subject or review of the subject's medical history for study eligibility, as 
obtained via a verbal interview with the subject or from the subject’s medical records 
 
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent (foam/gel/film/cream/suppository) 

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These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the product label. The investigator is responsible for ensuring subjects understand how to 
properly use these methods of contraception. 
Special Considerations: Mycophenolate Mofetil 
 
Mycophenolate can cause fetal harm when administered to a pregnant female. Use of 
mycophenolate during pregnancy is associated with an increased risk of first trimester pregnancy 
loss and an increased risk of congenital malformations. 
 
Mycophenolate affects the metabolism of oral contraceptives and may reduce their effectiveness. 
As such, women receiving MMF who are using oral contraceptives for birth control should 
employ an additional method (e.g., barrier method) resulting in two reliable forms of 
contraception being used simultaneously before starting study treatments, during therapy, and for 
6 weeks after stopping therapy; unless abstinence is the chosen method of contraception 
 
For women of childbearing potential, two serum or urine pregnancy tests are required, separated 
by 8 – 10 days and with the second immediately preceding initiation of study related therapy 
 
For sexually active men, condoms should be used during, and for at least 90 days after cessation 
of mycophenolate treatment. No sperm donation should be made during this period of time. For 
female partners of male subjects, it is recommended to use highly effective contraception during 
treatment and for 90 days after the last dose of mycophenolate 
 
No blood donation should be made by the study subjects during mycophenolate treatment and for 
at least 6 weeks after stopping mycophenolate treatment 
Progressive multifocal leukoencephalopathy (PML) 
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 GSK. The appropriateness of continuing 
study agent, while the case is being assessed, should be discussed. 
Combination anti-B cell therapy considerations 
 
All subjects should be monitored closely for infection 
 
Serum IgG levels should be measured monthly in this situation 
 
Stopping / withdrawal criteria: 
o Benlysta should be discontinued in subjects with IgG levels <400 mg/dL associated with 
a severe or serious infection. 
o If a subject experiences any IgG levels < 250 mg/dL not associated with severe or serious 
infection, the dose of study agent must be withheld and GSK must be consulted before 
administering any subsequent dose of study agent. Increased vigilance for infection is 
required. Clinical judgment should be applied with respect to the appropriateness of 
continuing study therapy in these subjects. 

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If a subject experiences a clinically significant, potentially life-threatening (Grade 4) adverse event (AE) 
that the investigator believes is definitely, possibly or probably related to study agent, then treatment with 
study agent will be discontinued. The subject should be withdrawn from study agent and followed at 
regularly scheduled study visits as specified by protocol or until resolution of the AE(s), whichever is 
longer. 
Liver Chemistry Stopping Criteria 
Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject safety 
and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). 
 
ALT Absolute: ALT ≥ 8xULN 
 
ALT Increase: 
o ALT ≥ 5xULN but <8xULN persists for ≥2 weeks 
o ALT ≥ 3xULN but <5xULN persists for ≥4 weeks 
 
Bilirubin: ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) 
o 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 
o 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 
 
INR: ALT ≥ 3xULN and INR>1.5, if INR measured 
 
Cannot Monitor: 
o ALT ≥ 5xULN but <8xULN and labs cannot be monitored weekly for ≥2 weeks 
o ALT ≥ 3xULN but <5xULN and labs cannot be monitored weekly for ≥4 weeks 
 
Symptomatic: ALT ≥ 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
o 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) 
 
Required Actions, Monitoring and follow up Assessments following ANY Liver Stopping Event 
Actions 
 
Immediately discontinue study treatment 
 
Report the event to GSK within 24 hours 
 
Perform liver event follow up assessments (as stated below) 

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 
Monitor the subject until liver chemistries resolve, stabilize, or return to within baseline (see 
MONITORING below) 
 
Do not restart/rechallenge subject with study treatment 
Monitoring 
For bilirubin or INR criteria: 
 
Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within 24 hrs 
 
Monitor subjects twice weekly until liver chemistries resolve, stabilize or return to within 
baseline 
 
A specialist or hepatology consultation is recommended 
For All other criteria: 
 
Repeat liver chemistries (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within 24-72 hrs 
 
Monitor subjects weekly until liver chemistries resolve, stabilize or return to within baseline 
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) 
 
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 including acetaminophen, herbal remedies, other over the 
counter medications 
 
Record alcohol use 
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 
Increased Monitoring Criteria with Continued Therapy 
Criteria 

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 
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 
Required Actions 
 
Notify GSK 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, stabilize 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. 
Treatments 
Study Treatment 
Definition of Investigational Product  
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical 
study, including products already with a marketing authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, or used for an unauthorized indication, or when 
used to gain further information about the authorized form. In this protocol, the investigational products 
are Rituximab and Benlysta.  
Definition of Non-Investigational Product 
Other medications used in the study as support or escape medication for preventative, diagnostic, or 
therapeutic reasons as components of a given standard of care. In this protocol, the non-investigational 
product is MMF, which all patients will be on a stable dose of throughout the trial.  
Handling and Dispensing 
Upon receipt, the shipment of medications and placebo will be stored in a secure area. At each study 
office visit, patients will be dispensed enough study medication to last them until their next study office 
visit. Institutional Pharmacy Accountability Logs may be used to document receipt of study drug and 
dispensing of drug to participants via the Study Coordinator. The investigator is responsible for ensuring 
that it is dispensed only to study participants and only from the official study site by authorized personnel.  
The investigator is responsible for ensuring that the investigational product is stored under the appropriate 
environmental conditions (temperature, light, and humidity), as described below:  

Hospital for Special Surgery 
A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
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MMF pills (tablet or capsule) and corresponding placebo should be stored in a closed container at room 
temperature, away from heat, moisture, and direct light. Keep the medicine tightly closed. 
Care should be taken when handling the drug products that are used in this protocol. Proper aseptic 
techniques must be used when preparing and administering products. Products should be inspected 
visually for particulate matter prior to administration. Refer to the Package Insert for additional 
information regarding handling, preparation, and storage of Benlysta and MMF.  
If concerns regarding the quality or appearance of the investigational product arise, do not dispense the 
investigational product, and contact the DCC immediately.  
Drug Ordering and Accountability 
Initial Orders 
After study activation occurs, the initial drug supply will be sent to the site.  
Re-Supply 
Subsequent drug supply will be shipped to HSS based on study activity. 
Method of Assigning Subjects to Treatment 
Patients will be assessed at an initial screening visit during which time a history and physical examination 
will take place as well as a full review of medical records. A full review of the patient’s history and 
physical, clinical laboratories, as well as review of records will be performed at the screening visit. The 
physician will require a PFT within the last 6 months of the patient’s Baseline 1 visit. The physician may 
order repeat tests to confirm the patient’s entry into the study. During the baseline visit, eligible patients 
will be seen for a baseline visit when PFTs, MRSS, skin biopsy, and patient derived endpoints will be 
performed.  Safety assessments will be performed at every visit.   
After patients maintain a dose of MMF for at least 1 month, patients will be randomized to treatment with 
either Belimumab & Rituximab or placebo. Patients will be receiving Belimumab subcutaneously and 
Rituximab intravenously. Placebo injections and infusions will be of normal saline.  
Patients will be randomized after all screening assessments have been completed and the investigator has 
verified that eligibility criteria have been met. At the time of randomization, patients will be assigned a 
unique randomization number; no participant may begin treatment prior to randomization. Eligible 
participants will be randomized to one of 2 groups:  
• 
Group 1 (20 patients):Two infusions of 1000 mg of Rituximab , weekly subcutaneous 
injections of 200 mg of Benlysta, and background MMF, 1000 -1500 mg twice daily.  
• 
Group 2 (10 patients): Two placebo infusions, weekly placebo subcutaneous injections, and 
background MMF, 1000 -1500 mg twice daily. 
Randomization into each group is done in a 2:1 manner, Group 1:Group 2. The statistician Jackie Finik 
will prepare the randomization schedule, using computer-generated block randomization with the block 
sizes. A secure web-based application will be built that will be used by the coordinators to enter 
participant information (e.g., participant ID) and to obtain the randomization number. The information 
can be printed and sent and/or emailed directly to the site pharmacists. 

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Blinding/Unblinding 
This is a double-blind study. The study staff and the patient are blinded to the treatment assignment.  
Blinding is critical to the integrity of this clinical study. However, in the event of a medical emergency or 
pregnancy in a participant, in which knowledge of the investigational product is critical to the 
participant's management, the blind for that participant may be broken.  
The DSMB will be blinded to study therapy that subjects have been assigned during the course of the 
study, but may recommend un-blinding as needed. 
Before breaking the blind of an individual participant’s treatment, the investigator should have 
determined that the information is necessary, i.e., that it will alter the participant’s immediate 
management. A discussion with the protocol chairs will occur and authorization to proceed or not with 
unblinding will be given to the investigator. In many cases, particularly when the emergency is not 
investigational product-related, the problem may be properly managed by assuming that the participant is 
receiving active product without the need for unblinding.  
Concomitant Treatments 
Patients are allowed to take their medications for underlying comorbidities, including pain medication. 
Full exclusionary medications are listed under the exclusion section of this protocol.  
Other Restrictions and Precautions 
Physicians will exercise caution when considering the use of study medication in patients with a history 
of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, 
or localized infections. Patients who develop a new infection while undergoing treatment in this study 
will be monitored closely with administration of study drug discontinued if a patient develops a serious 
infection.  
Study Assessments and Procedures 
Study Outcome Assessments 
Study-related procedures and outcome measures that will be performed as part of this protocol are listed 
below. Specific times at which each test will be performed are summarized in the schedule of events 
table.  
Complete medical history. Medical history will be performed as per standard medical care.  
Physical examination. A standard complete physical examination will be performed, with the addition of 
the assessment of modified Rodnan Skin Score (MRSS), 28-tender joint count, 28-swollen joint count, 
tendon friction rubs, joint contractures and digital ulcers. 
Vital signs. Vital signs will include: pulse, blood pressure, respiratory rate, temperature (C º), height 
(cm), weight (kg) and body mass index.  
Pulmonary function tests (PFTs) Spirometry: Carried out by either certified pulmonary function 
technologists (National Board of Respiratory Care) or experienced staff that meets American Thoracic 
Society (ATS) recommendations. All spirometry equipment and procedures will conform to the most 
recently published standards of the ATS/ERS Task Force. Forced expiratory maneuvers will be performed 

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A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
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at least in triplicate with the minimal requirement that three maneuvers are “acceptable” and that two of 
these maneuvers meet end-of-test and repeatability criteria for FVC and FEV1.  
Skin Biopsies: Skin biopsies will be performed at baseline 1, and Visit 5. The skin biopsies will consist 
of 2 3-mm punch biopsies of involved skin on the forearm. Skin biopsies will be subjected to 
histopathology, immunohistochemistry, and RNA extraction for gene expression analysis by qPCR and 
microarray. Additionally, a blinded investigator will compare the pre and post dose biopsies to determine 
change in inflammation and fibrosis.  
Blood: Blood will be drawn for both clinical labs and translational blood tests. Studies on blood will 
include flow cytometry to assess B-Cell subsets on PBMC, gene expression analysis on peripheral blood 
mononuclear cells (PBMC), assessment of biomarker and cytokine levels including autoantibodies, CRP, 
ESR, CMP, CBC and CPK. 
Urine pregnancy tests: All women of childbearing potential will have to undergo a urine pregnancy test 
every study visit. The results of the pregnancy test must be available prior to each dosing. 
 
 

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Schedule of Assessments 
 
Visit 
Screening 
Baseline 
1 
Rituximab 
infusion 1/ 
Baseline 2 
Rituximab 
infusion 2 
Visit 
1 
Between 
visits 
(monthly) 
Visit 2 
Between 
visits 
(monthly) 
Visit 3 
Between 
visits 
(monthly) 
Visit 4 
Between 
visits 
(monthly) 
Visit 5 
(end 
of 
study 
visit) 
Follow-
up 
Time 
Month -1 
to 0 
Month -
1 to 0 
Day 0 
Week 2 
+/- 3 days  
Week 
4 +/- 3 
days 
 
Month 
3 +/- 7 
days 
 
Month 
6 +/- 7 
days 
 
Month 
9 +/- 7 
days 
 
Month 
12  +/- 
7 days 
Month 
15 +/- 7 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
(including joint 
count) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
MRSS 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hep B, Hep C test, 
HIV, IgA  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine pregnancy 
test (for women of 
childbearing 
potential) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
CBC, CMP 
X 
X 
X* 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESR, CRP 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
CPK 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
LFT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CD-19 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Patient and 
physician global 
assessments, SF-
36, SHAQ-DI, 
PROMIS-29, 
SSPRO, CSSRS  
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 

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DAS-28, CDAI, 
tender joint counts 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Full PFT and 
DLCO 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
FVC ONLY 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Two 3mm punch 
biopsies *** 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
MMF dosing** 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Daily stable 
Cellcept 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Rituximab 
infusion 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Subcutaneous 
Belimumab 
injections weekly 
 
 
 
 
X**** 
X 
X 
X 
X 
X 
X 
X 
X 
 
*Lab tests must be performed prior to rituximab/placebo infusion, can be performed up to one week before the study visit. **If the 
patient is not yet on MMF, they will begin taking it here, increasing until on a stable 2-3 g a day dose before first rituximab infusion. 
***These will be performed at Weill Cornell Medical Center by Dr. Horatio Wildman. ****The first belimumab injection includes a 3 
hour observation.  

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Schedule of Events (List) 
Screening Visit (Visit 0, Day -28 to Day 0) 
Participants will undergo procedures to establish inclusion/exclusion criteria and will sign the 
informed consent form. The following clinical assessments and laboratory evaluations will be 
performed during this visit:  
• Informed Consent 
• Inclusion and Exclusion criteria 
• Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
• Patient & Physician Global Assessments 
• Demographics 
• Medical history (including scleroderma history and medication review) 
• Physical exam with height, weight and vital signs 
• Serum IgG and  IgA 
• Hepatitis B, hepatitis C, HIV antibody 
• Laboratory tests including CBC, CMP 
• Modified Rodnan Skin Score measurement 
• Review of medical records  
• If a pulmonary function test (FVC) has not been performed within 6 months of screening 
or if the physician advises repeat testing, the test(s) will be scheduled before the next 
visit (Baseline 1)  
II. Baseline 1 (Visit 1, Day 1, may occur over 2 days) 
During the first MMF treatment visit (baseline visit), the following clinical research procedures 
will be conducted: 
 Review of medical history, including a detailed medication review 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Patient & Physician Global Assessments 
 Two 3 mm punch biopsies of involved skin on the forearm  
 Physical exam with height, weight and vital signs 
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP, CD-19 (must be done before rituximab infusion, can be done up to one 
week before study visit), PBMC 
 Modified Rodnan Skin Score measurement 
 Dispensation of MMF, wash in period begins. Patients will spend the next 4 weeks 
increasing their dose, week by week, to the final 2-3 g per day dose.  

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 If patients are already on the appropriate MMF dose, they will 
remain on the same dose for the remainder of the study and will not 
complete a Baseline 1 visit. 
 Full PFT with DLCO will be performed at this visit 
III. Baseline 2/Rituximab Infusion 1 (Visit 2, 4 weeks after baseline 1)  
During the Rituximab treatment visit, the following clinical research procedures will be 
conducted: 
 Review of medical history, including a detailed medication review 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Patient & Physician Global Assessments 
 Physical exam with height, weight and vital signs 
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP 
 Modified Rodnan Skin Score measurement, tender joint count 
 Dispensation of MMF 
 Rituximab infusion 
 Full PFT with DLCO will be performed at this visit 
The patient should be on their final, stable (2-3 g a day) Cellcept dose by this visit.  
IV. Infusion 2 (Visit 2, 2 weeks after infusion 1)  
During the Rituximab treatment visit, the following clinical research procedures will be 
conducted: 
 Review of medical history, including a detailed medication review 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Patient & Physician Global Assessments 
 Physical exam with height, weight and vital signs 
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP 
 Modified Rodnan Skin Score measurement, tender joint count 
 Dispensation of MMF 
 Rituximab infusion 
V. Study Visits (Visit 1, Visit 2, Visit 3, Visit 4) 
 Review of medical history, including a detailed medication review 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Patient & Physician Global Assessments 

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 Physical exam with height, weight and vital signs 
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP 
 Modified Rodnan Skin Score, tender joint count 
 Dispensation of MMF 
 Dispensation of Belimumab 
 First two subcutaneous injections will be performed under the supervision of a 
healthcare professional. The rest of the injections will be done at home. 
 FVC will be completed at Visit 3 
 PBMC at visit 2 and 3 
 
NOTE: Between study visits, subjects will make trips monthly (two times before the next 
study visit) to the study center for CBC, CMP, LFT, Serum IgG, and pregnancy tests (if a 
woman is of childbearing potential).  
VI. End of Study Visit– Visit 5  
No drug will be dispensed at this visit. 
 Review of medical history, including a detailed medication review  
 Physical exam with height, weight and vital signs  
 Two 3mm punch biopsies of involved skin on forearm  
 PBMC 
 Modified Rodnan Skin Score, tender joint count 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Physical & Patient Global Assessments  
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP 
 Full PFT with DLCO will be performed at this visit 
VII. 3-month Follow-up  
 Review of medical history, including a detailed medication review 
 Physical exam with height, weight and vital signs 
 Modified Rodnan Skin Score, tender joint count 
 Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, 
UCLA SCTC GIT 2.0) 
 Patient & Physician Global Assessments 
 Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in 
WOCBP 

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Safety Assessments 
Safety assessments will include the evaluation of adverse events, lab assessments, and physical 
examination.  
• 
An adverse event is any occurrence or worsening of an undesirable or unintended symptom, sign, 
laboratory result, radiological finding, or disease state that is temporally associated with the use 
of a medical product, whether or not related to the medical product. Adverse events will be 
categorized by body system; general, CNS, cutaneous, cardiovascular, ENT. Gastrointestinal, 
genitourinary, hematologic, pulmonary, musculoskeletal, and PNS. The major categories of 
adverse events are mortality, hospitalizations, infections, malignancies, and drug-induced cystitis. 
The presence of these adverse events will be checked for and recorded at each visit. All adverse 
events will be appropriately collected, graded and reported by the study investigators. Throughout 
the study, the physician investigator will treat participants with adverse events appropriately and 
observe them at suitable intervals until the events resolve or stabilize.  
• 
Unexpected adverse events are those that are not listed or identified in the package insert or in the 
investigator’s protocol 
• 
Serious adverse events (SAE) or reaction is defined as any adverse event occurring at any dose 
that suggests a significant hazard, contraindication, side effect or precaution. This includes, but 
may not be limited to, death, life-threatening occurrences, inpatient hospitalization or 
prolongation of existing hospitalization, persistent or significant disability or incapacity, 
congenital anomaly or birth defect, or any event that required intervention to prevent permanent 
impairment or damage.  Adverse events classified as serious according to the definition set forth 
by the health authorities will be reported promptly to the appropriate health authorities. 
Efficacy Assessments 
Primary Efficacy Assessments 
American College of Rheumatology Composite Response Index in Diffuse Cutaneous Systemic 
Sclerosis (ACR CRISS): The primary efficacy assessment is the change in CRISS at 1 year. The ACR 
CRISS was developed using expert consensus and data driven approaches for use in clinical trials 
(Khanna et al, 2016). The exponential algorithm determines the predicted probability of improvement 
from baseline, incorporating change in the mRSS, FVC percent predicted, physician and patient global 
assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 – 100%). A 
higher score indicates greater improvement. Subjects are not considered improved (ACR CRISS score = 
0) if they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and 
confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%); or 4) new 
pulmonary artery hypertension on right heart catheterization requiring treatment. 
Secondary Safety and Efficacy Assessments 
The Modified Rodnan skin score: The MRSS is a validated physical examination method for estimating 
skin induration. It is correlated with biopsy measures of skin thickness and reflects prognosis and visceral 
involvement, especially in early disease2, 4. It is scored on a 0 (normal) to 3+ (severe induration) ordinal 
scales over 17 body areas, with a maximum score of 51 and is used to categorize severity of SSc. 
Minimally clinically significant difference in MRSS is 3-5 points (Amjadi et al., American College of 

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Rheumatology; Aug 2009; 2493-2494) It has been extensively used as primary/ secondary outcome in 
RCT with Scleroderma. This will be collected at every study visit. 
Patient global assessment for Overall Health (PtGA): This assessment represents the patient’s 
assessment of the patient’s global scleroderma on a 0-10 Likert scale. “On a scale of 0-10, how was your 
overall health in the last week? 0=Excellent; 10=Extremely Poor. Assessed at every study visit.  
Physician global assessment for overall disease (MDGA): This assessment represents the physician’s 
assessment of the patient’s current disease activity on a 0-10 Likert scale. “On a scale of 0-10, how was 
your patient’s overall health in the last week? 0=Excellent; 10=Extremely Poor”. Assessed at every study 
visit.  
Scleroderma Health Assessment Questionnaire – Disability Index (SHAQ-DI): The SHAQ-DI is a 
disease-targeted, musculoskeletal-targeted measure intended for assessing functional ability in 
scleroderma. It is a self-administered 20-question instrument that assesses a patient’s level of functional 
ability and includes questions that involve both upper and lower extremities. The SHAQ-DI score ranges 
from 0 (no disability) to 3 (severe disability). It has a 7 day recall period and has been extensively used in 
SSc65, 67. 5 visual analog scales are included in the scleroderma-HAQ assessing burden of digital ulcers, 
Raynaud’s, gastrointestinal involvement, breathing, and overall disease 68. Assessed at every study visit. 
Pulmonary function tests, Forced Vital Capacity (FVC), diffusing capacity of the lungs for carbon 
monoxide (DLCO): Forced expiratory maneuvers will be performed at least in triplicate with the 
minimal requirement that three maneuvers are “acceptable” and that two of these maneuvers meet end-of-
test and repeatability criteria for FVC and FEV1. DLCO is a measure of lung disease severity. Lung 
testing will be performed at visits Baseline 1, Visit 3, Visit 5, with a full PFT with DLCO being measured 
at Baseline 1, and Visit 5. 
 
Short Form-36 (SF-36): On Short Form-36 (SF-36) forms, individuals with SSc score significantly 
lower than healthy controls in domains of physical component score, mental component score, physical 
functioning, role-physical, bodily pain, general health, and mental health (Iudici et al, 2013). 
 
PROMIS-29: The PROMIS-29 Short Form, most current version (currently Version 2.0), will be used to 
assess patient-reported state of health on Visits 1, 3, and 5. The National Institutes of Health established 
the Patient Reported Outcomes Measurement Information System (PROMIS) (www.nihpromis.org) to 
create a standardized and uniformly scored set of patient-reported-outcomes instruments. The PROMIS 
network developed item (question) banks and short forms in more than 20 health domains as well as a set 
of global health items and 29-, 43-, and 57-item profile measures. To create a brief, practical-yet-inclusive 
short profile, a consensus-building process was used to identify 7 of these 20 domains to produce the 
PROMIS-29. The 7 domains specifically relate to physical, mental and social health and cover the most 
relevant areas of self-reported health for most people with chronic illness: pain, fatigue, depression, 
anxiety, sleep, physical function, and sexual function. The PROMIS-29 includes 4 items each from these 
7 core PROMIS domains as well as one 11-point rating scale for pain intensity. Norm-based scores have 
been calculated for each domain, such that a score of 50 represents the mean of the general population 
(standard deviation = 10). High scores represent more of the domain being measured. Thus, on symptom-
oriented domains of PROMIS-29 (anxiety, depression, fatigue, pain interference, and sleep disturbance), 
higher scores represent worse symptomatology. On the function-oriented domains (physical functioning 
and social role), higher scores represent better functioning.  

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The PROMIS-29 includes a single-item pain numerical rating scale for pain, which is a segmented 
numerical version of a VAS in which the respondent selects a whole number (0-10 integers) that best 
reflects the intensity of their pain. The numerical rating score is anchored by 2 terms describing average 
pain severity extremes, “no pain” (score of 0) and “worst pain imaginable” (score of 10). The recall 
period is 24 hours.  
The use of PROMIS-29 has been validated in SSc (Hinchcliff et al, 2011). A single-item numerical rating 
score for pain in this format has been validated for scleroderma (El-Baalbaki et al, 2011, reviewed in 
Hawker et al, 2011). 
UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Symptoms Questionnaire 
(UCLA SCTC GIT 2.0): The UCLA SCTC GIT 2.0 is a standardized set of outcome measures 
developed through literature review, patient focus groups and cognitive debriefing among patients with a 
variety of gastrointestinal disorders including irritable bowel syndrome, inflammatory bowel disease, 
other common gastrointestinal disorders, SSc, and a census-based US general population control sample 
(Khanna et al, 2009). The scale consists of eight domains relating to gastroesophageal reflux (13 items), 
disrupted swallowing (7 items), diarrhea (5 items), bowel incontinence/soilage (4 items), nausea and 
vomiting (4 items), constipation (9 items), belly pain (6 items), and gas/bloat/flatulence (12 items). The 
scales correlated significantly with both generic and disease-targeted legacy instruments, and demonstrate 
evidence of reliability. 
Scleroderma Skin Patient Reported Outcome (SSPRO): The SSPRO includes patient-reported 
answers to 18 questions about how scleroderma affects the skin and how those skin problems affect how 
the person feels and does things. Each question is followed by 7 boxes with numbers 0-6, spaced 
equidistant in between. The boxes are anchored by 2 verbal descriptors, “Not at all” (box labeled 0) and 
“Very Much” (box labeled 6). The subject selects a box labeled by an integer in response to the question. 
The recall period is 1 week. The sum of the numbers associated with the answers to each question is the 
score. A higher score indicates worse skin symptoms.  
 
Disease Activity Score 28 (DAS-28): The DAS28 (Disease Activity Score 28) is a system developed and 
validated by the EULAR (European League Against Rheumatism) to measure the progress and 
improvement of Rheumatoid Arthritis. DAS28 is often used in clinical trials for the development of RA. 
DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A DAS 28 
below the value of 2.6 is interpreted as Remission. The DAS28 is a development of the DAS which is 
more complex with regards to assessment. "28" describes the number of different joints including in the 
measurement: proximal interphalangeal joints (10 joints) metacarpophalangeal joints (10) wrists (2) 
elbows (2) shoulders (2) and knees (2). When looking at these joints, both the number of joints with 
tenderness upon touching and swelling are counted. In addition, the erythrocyte sedimentation rate is 
measured. Also, the patient makes a subjective assessment of disease activity during the preceding 7 days 
on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". 
 
Clinical Disease Activity Index (CDAI): The Clinical Disease Activity Index is calculated by adding the 
swollen joint count, tender joint count, patient global assessment, and the evaluator global assessment.  
Global Rank Composite Score: The global rank composite score is an analytic tool that accounts for 
multiple disease manifestations simultaneously but does not measure disease activity or severity. It 
reflects how participants compare with one another on the basis of a hierarchy of ordered outcomes: 
death, event-free survival (survival without respiratory, renal, or cardiac failure), FVC, the score on the 
Disability Index of the Health Assessment Questionnaire (HAQ-DI; range, 0 to 3, with higher scores 
indicating more disability), and the modified Rodnan skin score. Participants who were alive at 54 months 
rank higher than those who died; those who survived event-free rank higher than those who had an event, 
and so forth down the hierarchy. With the assumption that transplant recipients would have worse early 

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outcomes but could fare better long-term than participants in the comparison group, the global rank 
composite score is intentionally constructed to treat early and late deaths (or events of organ failure) as 
equal, irrespective of timing. Variables that were used to define an event included death, respiratory 
failure (decrease from baseline of >30% in percent predicted DLco or >20% in percent predicted FVC), 
renal failure (long-term dialysis or renal transplantation), or cardiac failure (clinical congestive heart 
failure or left ventricular ejection fraction <30%). 
The lowest three components of the global rank composite score are ordinal. They were defined by 
improvement (increase of ≥10% in the percentage of the predicted FVC, decrease of >0.4 in the HAQ-DI 
score, or decrease of ≥25% in the modified Rodnan skin score, as compared with baseline values), no 
change (neither improvement nor worsening), or worsening (decrease from baseline of ≥10% in the 
percentage of the predicted FVC, increase of >0.4 in the HAQ-DI score, or increase of ≥25% in the 
modified Rodnan skin score, as compared with baseline values). eft ventricular ejection fraction <30%). 
Joint Count: A joint count is the most specific clinical method to quantify abnormalities in patients with 
rheumatoid arthritis (RA). The swollen joint count reflects the amount of inflamed synovial tissue and the 
tender joint count is associated more with the level of pain.  
 
American College of Rheumatology Composite Response Index in Diffuse Cutaneous Systemic 
Sclerosis (ACR CRISS): The ACR CRISS was developed using expert consensus and data driven 
approaches for use in clinical trials (Khanna et al, 2016). The exponential algorithm determines the 
predicted probability of improvement from baseline, incorporating change in the mRSS, FVC percent 
predicted, physician and patient global assessments, and HAQ-DI. The outcome is a continuous variable 
between 0.0 and 1.0 (0 – 100%). A higher score indicates greater improvement. Subjects are not 
considered improved (ACR CRISS score = 0) if they develop new: 1) renal crisis; 2) decline in FVC% 
predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure 
(systolic ejection fraction < 45%); or 4) new pulmonary artery hypertension on right heart catheterization 
requiring treatment. 
 
Columbia Suicide Severity Rating Scale (CSSRS): Some autoimmune diseases have an increased risk 
of suicidal behavior and/or ideation [Bachen, 2009; Timonen, 2003; Stenager, 1992]. For this reason in 
studies of patients with autoimmune disease, patients should be clinically assessed for suicidal ideation 
and/or behavior at each visit. The CSSRS rates an individual's degree of suicidal ideation on a scale, 
ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent and behaviors." 
Questions are phrased for use in an interview format, but the C-SSRS may be completed as a self-report 
measure if necessary. The scale identifies specific behaviors which may be indicative of an individual's 
intent to complete suicide. An individual exhibiting even a single behavior identified by the scale was 8 to 
10 times more likely to complete suicide. The Screener contains 6 "yes" or "no" questions in which 
respondents are asked to indicate whether they have experienced several thoughts or feelings relating to 
suicide over the past month and behaviors over their lifetime and past 3 months. Each question addresses 
a different component of the respondent's suicide ideation severity and behavior. An answer of "yes" to 
any of the six questions may indicate a need for referral to a trained mental health professional and an 
answer of "yes" to questions 4, 5 or 6 indicate high-risk. 

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Adverse Event Reporting 
Adverse Events 
Definition of an AE 
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 anAE/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 fulfill 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 Events (SAE) 
Definition of an SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 

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1. Results in death 
2. Is life-threatening 
3. 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. 
4. 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 outpatient 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. 
5. Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE 
6. 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 
7. Is a congenital anomaly/birth defect 
8. Medical or scientific judgement 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 jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalisation, or development of drug dependency or drug 
abuse 
9. 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. 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from 
baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are 
to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated 

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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. 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to GSK. To ensure subject safety, 
each pregnancy must be reported within 2 weeks of learning of its occurrence. 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 reported to GSK within 24 hours. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting events that meet the 
definition of an AE or SAE. 
AEs will be collected from the start of study treatment and until the follow up contact. 
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed 
as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or 
change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a 
subject consents to participate in the study up to and including any follow up contact. 
Adverse Events of Special Interest: 
In addition to the standard safety protocol language the following adverse events of special interest should 
be mentioned in the protocol and assessed for frequency in the final report. 
 
Serious Hypersensitivity or Infusion Reactions 
 
Serious infections, including herpes zoster and opportunistic infections 
 
Malignancy 
 
Suicidal thought, intent or behaviour 
Communicating Safety Information:Safety information should be sent via email notification within 24 
hours of awareness for all unblinded SAEs reported for subjects who received belimumab, regardless of 
Investigator/designee/Institution causality assessments to the GSK Central Safety Department: 
US.NAPS@gsk.com.  
 
These SAEs include events reported from open-label studies and from subjects 
randomized to belimumab in double-blind studies in which the blind was broken (in 
stream and/or at end of study).  Placebo cases should not be reported).  
 
In addition, all SAEs arising from the study that remain blinded on the Institution database during 
the course of the study, will be forwarded to GSK retrospectively by Institution using copies of 
regulatory reports (e.g., CIOMS 1 or MedWatch) and within five working days of Institution 
database unblinding, where study participants are exposed to belimumab, regardless of 
Investigator/designee/Institution causality assessments against belimumab. 
In single country studies, there may be preference to carry out this reporting through the GSK Local 
Operating Company (LOC) safety department via their local mailbox. These details may be negotiated 

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and agreed upon at the time of contract development. Ultimately, there should be one point of contact 
within GSK to which this reporting is accomplished.. Spontaneous abortions must be reported as an SAE. 
Regulatory Reporting Requirements for SAEs by Study Sponsor 
The study Sponsor, is responsible for, and undertakes to, assess all clinical safety information arising 
during the Clinical Trial in order to generate all safety reports as required.  Such safety reports will 
include, but may not be limited to, Individual Case Safety Reports (“ICSRs”) for Suspected Unexpected 
Serious Adverse Reactions (“SUSARs”) and, Development Safety Update Report(s) (“DSURs”).  The 
study Sponsor is responsible for submitting such reports to all concerned regulatory authorities in all 
countries and regions where the Clinical Trial will be conducted, relevant Independent Ethics 
Committee(s) (“IEC”) and individual Clinical Trial investigator(s), as required, within applicable 
timelines. 
Unexpected Adverse Events 
Unexpected adverse events are those that are not listed or identified in the package insert or in the 
investigator’s protocol. 
Assignment of Adverse Event Intensity 
All adverse events will be recorded and classified according to the most recent version of the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. The purpose of using this 
grading system is to provide a standard language to describe toxicities, to facilitate tabulation and analysis 
of data, and to facilitate the assessment of the clinical significance of all adverse events. Adverse events 
will be recorded and graded 1 to 5 according the grades provided below: 
 
Grade 1 = Mild adverse event 
 
Grade 2 = Moderate adverse event 
 
Grade 3 = Severe and undesirable adverse event 
 
Grade 4 = Life-threatening or disabling adverse event 
 
Grade 5 = Death 
Relation to Study Therapy 
The relation or attribution of an adverse event to an investigational product will be determined by the 
investigator and then recorded on the appropriate form. Adverse events will be assessed against the study 
therapy. Therefore, in determining the relatedness of an adverse event to study therapy, the investigator 
will have to report it as one of the following categories, also defined by the NCI’s Common Terminology 
Criteria for Adverse Events: 
1. Unrelated – the adverse event is clearly not related to the investigational agent. 
2. Unlikely – the adverse event is doubtfully related to the investigational agent. 
3. Possible – the adverse event may be related to the investigational agent. 
4. Probable – the adverse event is likely related to the investigational agent. 
5. Definite – The adverse event is clearly related to the investigational agent.  

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Collection and Reporting  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. To prevent reporting bias, participants should not be questioned regarding the 
specific occurrence of one or more adverse events.  
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual 
symptoms. The following information should be captured for all AEs: onset, duration, intensity, 
seriousness, relationship to investigational product, action taken, and treatment required. If treatment for 
the event was administered, it should be recorded in the medical record. 
Serious Adverse Event Collecting and Reporting  
Following the participant’s written consent to participate in the study, all AE/SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur within 30 days of discontinuation of dosing. 
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a follow-
up skin biopsy).  
The investigator should report any SAE occurring after these time periods that is believed to be related to 
study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
 All SAEs will be reported to the IRB within 5 working days of our being made aware of the SAE. Death 
will be reported immediately to the IRB. Additionally, all SAEs will be reported to the DSMB and GSK 
within one business day. 
Drug Side Effects 
Belimumab 
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. 
Recommended Subcutaneous Dosage Regimen 
The recommended dosage is 200 mg once weekly given as a subcutaneous injection in the abdomen or 
thigh. Subcutaneous dosing is not based on weight. The injection is a clear to opalescent, and colorless to 
pale yellow solution in a single dose prefilled autoinjector or a single-dose prefilled glass syringe. The 
syringes will be packaged in a sleeve so that the placebo is not distinguishable from the active drug. 
 

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Administration Instructions for Subcutaneous Injection 
 
When given subcutaneously, It is recommended that the first two subcutaneous injections of 
belimumab should be under the supervision of a healthcare professional. Investigators/site 
personnel should be aware of the risk of hypersensitivity reactions, which may present as 
injection related systemic reactions, and monitor subjects closely. The healthcare professional 
must provide proper training in subcutaneous technique and education about signs and symptoms 
of hypersensitivity reactions. A patient may subsequently self-inject or a patient caregiver may 
administer belimumab after the healthcare professional determines that it is appropriate 
 
In the post-marketing setting, delayed onset of symptoms of acute hypersensitivity reactions has 
been observed with intravenous belimumab. Subjects should remain under clinical supervision for 
3 hours after completion of the first 2 infusions/injections. Should symptoms of acute 
hypersensitivity occur, an extended period of monitoring may be appropriate, based on clinical 
judgment. This may include, but is not limited to, monitoring vital signs and observing any 
untoward reactions. 
o In studies utilizing the SC formulation, after the first 2 supervised injections and at the 
discretion of the investigator, subjects who are adequately trained may self-administer all 
subsequent doses at home. Comprehensive written instructions on injection technique are 
required to be provided to the study subject by the investigator. (Appendix 1) After the 
first and the second doses, subjects who do not feel adequately trained with self-injection 
may return to the site for further training. Patients who cannot self-administer the study 
agent must have a reliable resource (eg, a caregiver) to administer the subcutaneous 
injection. Patients or their caregivers should not administer the study agent until they 
receive proper training in subcutaneous injection technique. 
 
Subjects should be made aware of the potential risk of delayed onset acute hypersensitivity, the 
signs and symptoms of such reactions, and the importance of immediately seeking medical 
attention in event of its development. For further information, see the belimumab IB. 
 
Subjects should remain under clinical supervision for 3 hours after completion of the first 2 SC 
injections. Should symptoms of acute hypersensitivity occur, an extended period of monitoring 
may be appropriate, based on clinical judgment. This may include, but is not limited to, 
monitoring vital signs and observing any untoward reactions. Delayed- type, non-acute 
hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, 
fatigue, myalgia, headache, and facial edema. Patients treated with belimumab, including those 
receiving the subcutaneous formulation , should be made aware of the potential risk, the signs and 
symptoms of such reactions, and the importance of immediately seeking medical attention. 
Rituximab 
Rituxan® (rituximab) is a genetically engineered IgG1 kappa chimeric murine/human monoclonal 
antibody containing murine light- and heavy-chain variable region sequences and human constant region 
sequences. The chimeric antibody is produced by mammalian cell (Chinese Hamster Ovary) suspension 
culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final 
product. Rituximab is composed of 1,328 amino acids, and has an approximate molecular weight of 145 
kilo Dalton (kD). 
 
The antibody reacts specifically with the CD20 antigen found on the surface of malignant and normal B 
cells, and established B cell lines. Studies have shown that rituximab binds via its Fc domain to human 
complement and lyses lymphoid B cell lines by complement dependent cytotoxicity through the induction 
of apoptosis and via antibody-dependent cell mediated cytotoxicity. The drug is manufactured by 
Genentech, Inc. and by Biogen IDEC, Inc. Rituximab is supplied as a sterile, clear, colorless, 
preservative-free liquid concentrate for intravenous (IV) administration in either 100 mg (10 mL) or 500 
mg (50 mL) single-use vials, which must be diluted before administration. 

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Risks 
Given the enhanced B Cell suppression and more profound hypogammaglobulinemia anticipated as result 
of immunosuppressive combination therapy, potential risks include, but are not limited to, infection (both 
routine and opportunistic), psychiatric events, malignancy, and possible impact on effect of 
immunizations. In addition to these events of special interest associated with belimumab, other identified 
and potential risks for both agents should be considered in the risk mitigation strategy.   
 
Rituximab:  The rate of serious infections with rituximab in the Rheumatoid arthritis (RA) population is 
4% per year.  Reactivation of hepatitis B has also been very rarely reported in RA patients receiving 
rituximab.  Late onset neutropenia occurs rarely in patients treated with rituximab.  Belimumab:  The rate 
of serious infections for SLE is 5% of subjects receiving either belimumab or placebo.  Belimumab and 
Rituximab Coadministration Risks:    Infections are expected events for both belimumab and rituximab.  
Cases of PML have been very rarely reported, including fatal events, for both rituximab and belimumab 
in autoimmune diseases.  There is preclinical evidence for prolonged B cell suppression and more 
complete B cell depletion as well as effect on IgG1+ plasma cells in the long-lived bone marrow niche 
thought to be less sensitive to immunotherapy30 with dual B cell immunotherapy. Assessment of the 
translatability of the IgG reductions to humans is difficult to make due to species differences in B cell 
biology and different treatments; however, the mouse data raises the hypothetical risk that 
immunoglobulin levels may reduce more with co-administration treatment. 
Rituximab Dosage and Administration 
 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  Do not infuse rituximab 
concomitantly with another IV solution or other IV medications. 
Preparation for Administration: Use appropriate aseptic technique. Withdraw the necessary amount of 
rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% 
Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard 
any unused portion left in the vial.  Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration.  
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Infusion and 
hypersensitivity reactions may occur.  Premedication, consisting of acetaminophen and diphenhydramine, 
should be considered before each infusion of rituximab. Premedication with methylprednisolone 100mg 
IV x 1 will also be administered.  Premedication may attenuate infusion-related events. Since transient 
hypotension may occur during rituximab infusion, consideration should be given to withholding anti-
hypertensive medications 12 hours prior to rituximab infusion. 
Administration Guidelines for Adult Patient Population 
First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate 
of 50 mg/hr. Rituximab should not be mixed or diluted with other drugs. If hypersensitivity or infusion-
related events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr.   
Rituximab infusion should be interrupted for severe reactions.  In most cases, the infusion can be resumed 
at a 50% reduction in rate (e.g., from 100mg/hr to 50mg/hr) when symptoms have completely resolved.  

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Most patients who have experienced non-life-threatening infusion-related reactions have been able to 
complete the full course of rituximab therapy 
Subsequent Infusions: If the subject tolerated the first infusion well, subsequent rituximab infusions can 
be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute 
intervals, to a maximum of 400 mg/hr as tolerated.  If the first infusion was not well tolerated, the 
guidelines for the first infusion should be followed for the subsequent infusions. 
Rituximab Storage 
Rituximab vials are stable at 2° to 8°C (36° to 46°F).  Do not use beyond expiration date stamped on 
carton. Rituximab vials should be protected from direct sunlight. 
Rituximab solutions for infusion are stable at 2° to 8°C (36° to 46°F) for 24 hours and at room 
temperature for an additional 24 hours. However, since rituximab solutions do not contain a preservative, 
diluted solutions should be stored refrigerated (2° to 8°C ).  No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. 
Rituximab Overdose 
There has been no experience with overdose of rituximab in human clinical trials.  
Data Monitoring 
A monitoring plan and data safety monitoring board (DSMB) will be established to review safety data and 
to make recommendations regarding continuation, termination, or modification of the study. The DSMB 
will review all safety issues on a quarterly basis or more frequently if required. Safety assessment will be 
the primary purpose of this quarterly interim analysis. The DSMB will also monitor closely for infections, 
immunoglobulin levels, and cytopenias. Treatment will be discontinued if immunoglobulin AEs become 
grade 4. If liver enzymes increase to >3 times the upper limit of normal, we will hold medication and 
check weekly liver function tests (LFTs) until enzymes return to normal range. The study may be stopped 
or amended because of significant safety concerns. The safety evaluations will be conducted on 
conventional safety variables, such as serious adverse events, laboratory tests, and vital sign changes. The 
DSMB may recommend that the study be stopped only for safety concerns. The DSMB will evaluate the 
study every quarter. All serious adverse events will be reported to the DSMB within 24 hours of 
occurrence. As the DSMB will be reviewing frequent safety reports and listing of SAEs, it can request to 
stop enrollment in the trial or stop study medications. Enrollment in the study will be stopped and 
administration of all study related medications will be suspended if any of the following occurs:  
 
One or more deaths within 24 hours of belimumab, rituximab, and/or MMF administration that is 
felt to be directly related to the medication by the investigator or the DSMB. In the event of such 
a case, the DSMB would be unblinded to treatment assignment, and only deaths directly related 
to Belimumab, rituximab, and/or MMF would count towards termination of the trial.  
 
Two of the first 5 patients enrolled experience Grade IV serious adverse events attributable to 
study medication 
 
Two of the first 5 patients enrolled exhibit a greater than 5 point increase in the Modified Rodnan 
Skin Score in 2 consecutive assessments 

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Statistical Plan 
Sample Size  
A total of 30 patients will be enrolled: 20 of whom will receive treatment with Belimumab and Rituximab 
and 10 of whom will receive placebo. This sample size provides 80% power at an 0.05 significance level 
to detect a ratio of mean CRISS scores of 1.2 when the ratio under the null hypothesis is 1.0 using a two-
sided, two-sample t-test. This power calculation is valid as long as the coefficient of variation (COV) does 
not exceed 0.2.  
 
For the primary endpoint analysis, the distribution of CRISS scores within each study arm will be 
assessed using the Shapiro-Wilk test. If scores are not approximately normally distributed, appropriate 
transformations will be made prior to analysis. Raw scores will be summarized within each study arm by 
mean ± standard deviation and median [interquartile range]. Comparisons of scores will be made using a 
two-sided, two-sample t-test.  
 
The safety endpoint will be analyzed by reporting the proportion of patients within each study arm who 
experience one or more adverse events and who experience one or more serious adverse events. 
Comparisons will be made using Fisher’s exact test. The total number of adverse events and of serious 
adverse events experienced by each patient will be compared between study arms using the Wilcoxon 
rank-sum test.  
 
Other secondary endpoints will be evaluated similarly to the primary endpoint, using the Shapiro-Wilk 
test to determine the distribution of values and appropriately transforming if necessary. Comparisons will 
be made using two-sided, two-sample t-tests or Wilcoxon rank-sum tests if values cannot be appropriately 
transformed.  
 
Although self-injection in this population is not expected to be a barrier to adherence, as-treated analysis 
will be done as well.  
 
References 
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A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
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A Randomized, Double-Blind, Placebo-Controlled study of Belimumab and Rituximab Combination Therapy for the 
Treatment of Diffuse Cutaneous Systemic Sclerosis 
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placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351-1358. doi:10.1002/1529-
0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I. 
 

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Appendix 1: Patient Subcutaneous Self-dosing instructions (pre-filled syringe) 
1. Remove a syringe from the kit allowing it to warm to room temperature for no longer than 30 
minutes. 
2. Visually inspect the medication in the syringe. Only use the syringe if the: 
• 
Liquid is clear and free of particles 
• 
Liquid is colorless to light yellow in appearance 
3. Obtain the following: 
• 
Alcohol swab 
• 
Sterile gauze 
• 
Container for syringe disposal 
4. Wash your hands thoroughly with soap and water. 
5. Choose an injection site: either left or right side of the abdomen or upper thigh. Choose a 
different site for each injection. 
Injectable areas
  
6. Using a circular motion, clean the injection site with an alcohol swab and allow to 
dry. 
7. Remove the protective cap from the syringe and discard. 
8. Hold the syringe in the hand with which you will inject yourself. 
9. Using your other hand, gently pinch the skin around the swabbed injection site. 
10. Insert the entire needle at a slight angle (45° angle) into the pinched area of the skin. 
11. Release the pinched skin and slowly push the plunger down until the entire contents 
of the syringe is injected. 
12. Withdraw the needle from the skin and dispose the syringe in the proper container. 
13. Wipe the injection site with gauze. 

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14. Remember to place used syringes in the container for syringe disposal and return the 
container to the study site at each visit.