Conditions: Myositis
Keywords: Inflammatory Myositis Dermatomyositis Polymyositis Muscle Pain Myositis Refractory myositis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
The goal of the trial is to evaluate the efficacy and safety of belimumab as a maintenance therapy in adults with refractory Idiopathic inflammatory myositis (IIM) as compared with standard of care. This is a multicentre double-blind, placebo-controlled trial.

Detailed description:
Adults with refractory IIM will be enrolled. IIM is defined as Dermatomyositis (DM) or Polymyositis (PM), meeting the Bohan \& Peter (1975) diagnostic criteria for definite or probable DM or PM. Refractory IIM is defined as chronic active IIM with a history of inadequate response or intolerance to three months of glucocorticoids and/or at least a history of inadequate response or intolerance to three months of one other immunosuppressive agent (IS) (azathioprine, methotrexate, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, cyclophosphamide, Rituximab or intravenous gamma globulin \[IVIG\]).

Arms:
arm 1: Patients in this arm will be given belimumab with a background of standard of care therapy during the randomized controlled treatment period.

Patients in this arm will continue to receive belimumab during the open label phase of the study (week 40 - week 64) arm 2: Patients in this arm will be given a placebo with a background of standard of care therapy during the randomized controlled treatment period.

Patients in this arm will receive belimumab during the open label phase of the study (week 40 - week 64).

Interventions: intervention 1: Belimumab intervention 2: Placebo
Intervention descriptions: intervention 1: Randomized phase: Week 0 - Week 40 intervention 2: Randomized phase: Week 0 - Week 40

Protocol document:
Prot_SAP_000.pdf: 
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Protocol 
Version date: August 29, 2019 
Amendment 6 
 
 
 
Belimumab for Maintenance Therapy in Idiopathic Inflammatory Myositis 
Principal Investigator: 
Galina Marder, MD 
Division of Rheumatology 
Northwell Health 
865 Northern Boulevard 
Suite 302 
Great Neck, NY 10021 
Email: gmarder@northwell.edu 
Tel: 516-708-2550 
Fax: 516-708-2574 


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TABLE OF CONTENTS 
 
Background  
 
 
 
 
 
 
 
 
 
4 
 
Target Population 
 
 
 
 
 
 
 
 
 
4 
 
Study Objectives       
 
 
 
 
 
 
 
 
4 
 
Study Design       
 
 
 
 
 
 
 
 
 
4 
• Study Procedures and Schedule 
 
 
 
 
 
 
5 
• Randomization 
 
 
 
 
 
 
 
 
6 
• Stratification  
 
 
 
 
 
 
 
 
7 
• Blinding 
 
 
 
 
 
 
 
 
 
7 
• Concurrent Medications 
 
 
 
 
 
 
 
8 
• Medication and Therapies Prohibited for Concomitant Use 
 
 
9 
• Packaging, Labeling, Preparation and Storage 
 
 
 
 
9 
• Data Management 
 
 
 
 
 
 
 
 
10 
 
Definitions 
 
 
 
 
 
 
 
 
 
 
10 
 
Endpoints 
 
 
 
 
 
 
 
 
 
 
12 
• Primary 
 
 
 
 
 
 
 
 
 
12 
• Secondary 
 
 
 
 
 
 
 
 
 
12 
 
Inclusion Criteria 
 
 
 
 
 
 
 
 
 
12 
 
Exclusion Criteria 
 
 
 
 
 
 
 
 
 
14 
 
Study Drug Administration  
 
 
 
 
 
 
 
15 
 
Safety Consideration and Adverse Events  
 
 
 
 
 
16 
• Adverse Events (AE) 
 
 
 
 
 
 
 
16 
• Serious Adverse Events (SAE) 
 
 
 
 
 
 
16 
• Laboratory and Other Safety Assessment Abnormalities 
 
 
18 
• Adverse Events of Special Interest  
 
 
 
 
 
18 
 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
19 
Adverse Event and Serious Adverse Event Reporting 
 
 
 
 
19 
Time Period and Frequency of Detecting AEs and SAEs  
 
 
 
20 
 
 
 


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TABLE OF CONTENTS 
 
Study Procedures & Assessments  
 
 
 
 
 
 
20 
 
Data Safety Monitoring Plan 
 
 
 
 
 
 
 
21 
 
Feinstein Biostatistics BUDDY System: Data Management 
 
 
 
21 
 
Statistical Considerations 
 
 
 
 
 
 
 
 
22 
• Specific Statistical Aims 
 
 
 
 
 
 
 
22 
• Statistical Methods  
 
 
 
 
 
 
 
22 
• Safety Data  
 
 
 
 
 
 
 
 
24 
• Sample Size Considerations  
 
 
 
 
 
 
24 
 
References 
 
 
 
 
 
 
 
 
 
 
26 
 
Appendix A: Study Schedule 
 
 
 
 
 
 
 
26 
 
Appendix B: Bohan & Peter (1975) Diagnostic Criteria  
 
 
 
28 
 
Appendix C: Liver Chemistry Stopping & Follow Up Criteria  
 
 
29 
• Liver Chemistry Stopping Criteria  
 
 
 
 
 
29 
• Required Actions 
 
 
 
 
 
 
 
 
30 
• Monitoring 
 
 
 
 
 
 
 
 
 
30 
• Follow Up Assessments 
 
 
 
 
 
 
 
31 
• Increased Monitoring Criteria w/Continued Therapy 
 
 
 
32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Background :  
Idiopathic inflammatory myositis (IIM) is a systemic inflammatory disorder characterized by 
chronic inflammation involving muscle tissue and could be accompanied by inflammation in the 
skin and other organs ( lungs, heart, intestinal tract) . It typically results in symmetrical, proximal 
muscle weakness, characteristic skin rash and could cause interstitial lung disease and heart 
failure. Given some of the similarities between systemic lupus erythematosus (SLE) and IIM, the 
objective of this study is to explore whether the B Lymphocyte Stimulator (BLyS) pathway plays 
an important role in the pathogenesis of IIM as it does in SLE.  BLyS overexpression in 
transgenic mice leads to B cell hyperplasia and the development of severe autoimmune 
disease.1,2,3  Marked  tissue up-regulation of the BAFF transcript was demonstrated in IIM: 14-
fold increase in Polymyositis and 12-fold increase in Dermatomyositis  compared with normal 
muscle4. Circulating BLyS levels were shown to be elevated in the sera of patients with myositis.  
Moreover, independent correlations were observed between serum BLyS levels and: 1) markers 
of myositis disease activity, 2) the presence of interstitial lung disease, and 3) CRP and CPK 
blood levels.5 The highest BLyS serum concentrations were found in dermatomyositis and in 
those patients who were anti-Jo-1 positive.6 Studies have shown that treatment with 
corticosteroids induced a marked decrease in BLyS concentrations in patients with SLE7and in 
IIM8,9. Similar data showing decreased BLyS expression is available for other 
immunosuppressives8, suggesting that not only steroids, but other immunosuppressive therapies, 
affect the BLyS pathway in patients with IIM. These observations suggest that BLyS may be an 
important therapeutic target in IIM.  
We propose a multicentre double-blind, placebo-controlled trial to evaluate the efficacy and 
safety of belimumab as a maintenance therapy in adults with refractory IIM. 
 
Target Patient Population:   
Adults with refractory IIM will be enrolled. IIM  is defined as Dermatomyositis (DM) or 
Polymyositis (PM), meeting the Bohan & Peter (1975) diagnostic criteria for definite or probable 
DM or PM. Refractory IIM is defined as chronic active IIM with a history of inadequate 
response or intolerance to three months of glucocorticoids and/or at least a history of inadequate 
response or intolerance to three months of one other immunosuppressive agent (IS) 
(azathioprine, methotrexate, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, 
cyclophosphamide, Rituximab or intravenous gamma globulin [IVIG]).  
 
Study Objectives:  
a. To compare the clinical response rates in refractory IIM patients on stable background 
treatment receiving monthly intravenous (IV) belimumab to patients receiving placebo. 
b. To assess the safety of monthly IV belimumab in patients with IIM. 
c. To evaluate the steroid-sparing effect of monthly IV belimumab added to background 
treatment of IIM. 
d. To evaluate the biologic effects of belimumab treatment on various B cell populations and 
inflammatory cytokine levels. 
 
Study Design: 
This is a multicenter randomized double-blind placebo controlled trial to evaluate the efficacy 
and safety of Belimumab as a maintenance therapy in adults with refractory idiopathic 
inflammatory myositis (IIM). 


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The Northwell Health Department of Rheumatology will be the coordinating site for this multi-
center clinical trial. We plan to enroll 30 patients into the trial. Enrollment is competitive. Study 
enrollment will be carried out for two years and each patient will be followed for a total of 84 
weeks. 
 
a. Study Procedures and Schedule: 
A simplified flowchart of the study procedure is given in Figure 1. 
After consent, a patient will be randomized to either Belimumab+ standard of care (B) or 
Placebo+ standard of care (P).  Randomization will be according to the two important 
stratification variables, namely, disease type (Polymyositis vs. Dermatomyositis) and disease 
severity (severe vs less severe) and will occur at week 0 (first infusion).  There will be two major 
study phases: the randomized phase of the study and the open-label phase of the study, described 
below. 
Screening: Once the patient signs the consent form, a screening period of up totwo weeks will 
initiate to determine the patient’s eligibility for the study, prior to entering the randomization 
phase. Only eligible patients will enter the randomization phase.  
Randomized Phase: Monthly infusions (of either B or P) will start at week 0 and continue every 
four weeks until week 36 (10 months) for the “randomized” phase of the study.  In addition, 
there will be a “loading dose” at week 2 (per drug [IND] specifications).  The loading dose will 
consist of either Belimumab or Placebo (saline) in the B or P treatment arms, respectively.   


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Open Label Phase: Monthly infusions (of B) will start at week 40 and continue every four weeks 
until week 64 (6 months) for the “open-label” phase of the study.   
A comprehensive evaluation of the patient (Physical exam and history, vital signs, AEs, CBC 
and metabolic panel, GGT, myoglobin, pregnancy test, urinalysis,  ESR, CRP, CPK, 
immunoglobulins,  muscle and health evaluations, physician global assessment, patient self-
assessments, serum level sampling) will be conducted at weeks 0, 8, 16, 24, 32, 39-40, 52, 64.  A 
less comprehensive set of evaluations (vital signs, AEs, CBC and metabolic panel, GGT, 
pregnancy test) will be conducted at weeks 2, 4, 12, 20, 28, 36, 40, 44, 48, 56, 60. A detailed 
schedule of visits and procedures is outlined in appendix A. 
A telephone follow-up conversation will also be conducted at weeks 72 and 84. 
Optional Exploratory Studies 
Blood based biomarker assessments and blood based RNA assessments will be performed on 
stored samples for consenting patients at Northwell Health only. See Appendix A (schedule of 
events).  
 
b. Randomization: 
The Biostatistics Unit at the Feinstein Institute for Medical Research [BU-FIMR] will develop a 
web based randomization plan for the study.  A randomization schema will be generated by the 
BU-FIMR for each participating site using the method of permuted blocks.  Subjects will be 
randomly assigned in a 1:1 ratio to either Belimumab or Placebo, according to two stratification 
variables, namely, disease type (Polymyositis or Dermatomyositis) and disease severity (severe 
or less severe). The Biostatistics Randomization Management System (BRMS) is a secure, 
HIPAA-compliant, web-based application that allows investigators to randomize subjects into 
randomized clinical trials (RCTs) using their personal computer. The BRMS allows for multi-
center, stratified, and single/double blinded RCTs, using permuted blocks. Randomization 
notifications are automatically sent to the PI and other authorized personnel. Using BRMS is a 
good way to maintain compliance in RCTs.   
 
c. Stratification:  
Randomization will be according to the two important stratification variables: disease type 
(Polymyositis vs. Dermatomyositis) and disease severity (severe vs less severe) and will occur at 
week 0 (first infusion). The number of immunosuppressive agents used by the patient over the 
last year (corticosteroids are not included) will be used as a surrogate of disease activity: one or 
less IS agent over last year versus more than 1 IS agent over last year.  
d. Blinding:  
This is a double-blind study; both the investigator and the patient will be blinded to the treatment 
assignment in the randomized phase of the trial. At the end of the 40 week randomized treatment 
phase all subjects will start the 20 week open label phase and therefore the drug will be 
dispensed in the unblinded fashion.  


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For each study site, there will be a designated unblinded research coordinator (URC) and a 
blinded research coordinator (BRC). The URC will be responsible for obtaining randomization 
assignments from the BU-FIMR and will oversee the preparation of infusions prior to drug 
administration.  The BRC will be responsible for coordinating patient visits and administration or 
the infusion (infusion will be masked and not identifiable through any physical characteristics 
such as color or consistency, as the drug is of a powder form mixed in saline solution). 
Belimumab and placebo will be supplied as open-label vials and 3rd party unblinding will be 
employed. The study agent will be reconstituted and diluted by the unblinded site pharmacist or 
designee, independent of the study (person responsible for receiving and dispensing study agent). 
Separate monitors will be responsible for the clinical (blinded monitor) and study agent 
(unblinded monitor) aspects of the study. 
If a medical emergency occurs and a decision regarding the subject’s condition requires 
knowledge of the treatment assignment, the study blind may be broken for the specific subject. 
Whenever possible, the investigator should consult with the principal investigator of the study 
and data safety monitoring board prior to unblinding any subject. Any broken blind will be 
clearly justified and explained. The lead site and sponsor must be notified of any broken blind 
regardless of whether it was done for emergency or non-emergency reasons.  
e. Concurrent Medications: 
Corticosteroids: Patients that are on glucocorticoids at the time of screening will be required to 
be on a stable background dose for at least 2 weeks prior to screening (prednisone (or equivalent) 
dose < 15 mg daily).  
The prednisone dose will remain stable until week 24 of the study, at which time a taper will be 
allowed at the discretion of the site investigator and principal investigator. 
An increase in the dose of oral prednisone will be permitted, if clinically necessary, during the 
first 8 weeks after randomization without accounting it as a disease flare. In this case, the dose of 
prednisone must be tapered (to less than or equal to 25% of the baseline dose) by week 12. 
However, if the dose of prednisone cannot be tapered by week 12, the event will be considered 
as disease flare at that time.  
Any increase of the prednisone dose after week 8 for IIM disease activity or the use of pulse 
steroids at any time during the study will be considered a disease flare. An increase of the 
prednisone dose at any time during the study for an event other than worsening of IIM disease 
activity will require the patient to return to the baseline dose of prednisone within 10 days, 
without accounting the event as a disease flare. Patients that are considered treatment failures 
will be allowed to remain in the study, in respective groups, at the discretion of the treating 
physician and PI.  
Immunosuppressive agents (IS): Enrolled patients could have had a history of treatment with 
any of the following IS agents: azathioprine, methotrexate, mycophenolate mofetil, leflunomide, 


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tacrolimus, cyclosporine, cyclophosphamide, Rituximab, or intravenous gamma globulin [IVIG]. 
Patients are not required to be on an IS agent at the time of enrollment.  
During the enrollment and study period, the only allowed IS agents are: azathioprine, 
methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine or intravenous gamma globulin 
[IVIG].  
Patients that are on background immunosuppressive (IS) therapy at the time of screening will be 
required to be on a stable IS agent for > 2 months prior to screening( ≥3 months for IVIG), and 
on a stable dose of IS agent for ≥ 2 weeks prior to screening (except IVIG; no dose change 
allowed). Dose reduction due to poor tolerance of IS agent will be allowed on a case by case 
basis.   
Therapeutic Agent 
Treatment Duration prior to 
Screening ≥ 
Dose Increase prior to 
Screening ≥ 
Azathioprine 
2 months 
2 weeks 
Methotrexate 
2 months 
2 weeks 
Mycophenolate mofetil 
2 months 
2 weeks 
Tacrolimus 
2 months 
2 weeks 
Cyclosporine 
2 months 
2 weeks 
IVIG 
3 months 
none 
If a dose increase in IS agent or initiation of a new IS agent is clinically necessary during the 
randomization phase, this will be considered as a disease flare. The patient will be allowed to 
continue in their respective assigned group at the discretion of the treating physician and PI. 
f. Medications and Therapies Prohibited for Concomitant Use: 
a. Anti-B-cell therapy: 
i. Wash out of 5 therapeutic half-lives after prior B-cell therapy, or until 
pharmacodynamic effect would be minimal (e.g., 1 year following 
Rituximab)  
• IgG levels should be measured monthly in this situation 
• Benlysta should be discontinued in subjects with IgG levels 
<250 mg/dL associated with a severe or serious infection 
ii. If Rituximab use was medically indicated after the patient’s 
enrolment to the clinical trial, the patient will no longer receive the 
investigational drug, but enhanced safety monitoring will be required. 
b. Intravenous Cyclophosphamide 
i. 180 Days Prior to Belimumab  
• IgG levels should be measured monthly in this situation 
• Benlysta should be discontinued in subjects with IgG levels 
<250 mg/dL associated with a severe or serious infection 


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ii. If cyclophosphamide use was medically indicated after the patient’s 
enrolment to the clinical trial, the patient will no longer receive the 
investigational drug, but enhanced safety monitoring will be required. 
c.  A live vaccine. (Live vaccines should not be given within 30 days prior to 
administration or concurrently with belimumab)  
d. Any Biologic Investigational Agent (e.g., abetimus sodium, anti CD40L antibody, 
BG9588/ IDEC 131) or any other investigational agent not approved for sale in 
the country in which it is being used 
i. 365 days Prior to Belimumab: 
e. Any Non-Biologic Investigational Agent (investigational agent applies to any 
drug not approved for sale in the country in which it is being use) 
i. 30 Days Prior to Belimumab (or 5 half-lives, whichever is greater) 
g. Packaging, Labeling, Preparation and Storage: 
Belimumab will be supplied in a 20mL vial containing 400mg of belimumab. Belimumab should 
be stored at 2-8°C. After reconstitution and dilution in normal saline, the material is stable for up 
to 8 hours at 2-8°C, or at room temperature. The 400 mg single use vial of study agent will be 
reconstituted with 4.8 mL SWFI, to yield a final concentration of 80 mg/mL of belimumab.  
The study agent label will contain, at a minimum, the following information: 
• Product name; 
• Concentration; 
• Lot number; 
• Storage conditions; 
• Investigational drug statement; and 
• Manufacturer’s name and address. 
The calculated dose of study agent to be administered to the subject is determined in milligrams 
(mg) by the assigned treatment group and the subject's body weight in kilograms (kg). The 
reconstituted study agent will be diluted in 250 mL normal saline for intravenous infusion. An 
amount of normal saline, equal to the calculated amount of product to be added, should be 
removed from the infusion bag prior to adding the product. After adding the reconstituted 
product, gently invert the bag to mix the solution. Subjects receiving placebo will receive 250mL 
of normal saline for intravenous infusion.  
h. Data Management: 
The Biostatistics Unit (BU), within The Feinstein Institute for Medical Research (FIMR), 
provides state-of-the-art statistical and data management support to the research investigators at 
Northwell Health, as well as other medical research institutions in the New York area. Its staff of 
ten PhD and Masters level statisticians and two senior applications programmers has extensive 
experience in the design, data management, and analysis of hundreds of clinical research 


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projects, including over 250 clinical trials.  Primary expertise is in clinical trials, diagnostic 
testing and screening, the development of predictive models for prognosis, and development of 
protocols and grant applications. 
Definitions: 
All patients are required to meet the Bohan & Peter (1975) diagnostic criteria for definite or 
probable DM or PM (see Appendix B) and be positive for at least one autoantibody (ANA >1:80 
or RNP or SSA/SSB or any of the myositis specific autoantibody). Patients with the diagnosis of 
definite or probable PM will require the presence of at least one myositis specific auto-antibody 
(antisynthetase autoantibodies (anti-Jo-1, PL-7, PL-12, EJ, OJ), anti-SRP, anti-Mi-2, anti-
p140[also known as anti-MDA5], anti-p155/140 [also known as anti-TIF], anti-NXP-2 [also 
known as MJ]). Patients with the diagnosis of definite or probable PM in the absence of myositis 
specific auto-antibodies will require review of the muscle biopsy results and adjudication of the 
diagnosis by a committee of 3 experts that will be predetermined in advance.  
Refractory Myositis: Refractory myositis is defined as chronic IIM with an inadequate response 
or intolerance to at least three months of corticosteroids and/or an inadequate response or 
intolerance to at least three months of at least one other immunosuppressive agent (azathioprine, 
methotrexate, mycophenolate mofetil, leflunomide, cyclophosphamide, tacrolimus, cyclosporine 
or IVIG). 
Core Set Measures (CSM): All enrolled subjects will be required to have active disease based on 
the clinical core set measures,  which is a standard instrument for assessing myositis disease 
activity.  Active disease using the CSM is defined by International Myositis Assessment and 
Clinical Studies Group 11: 
1. Manual muscle testing (MMT-8) with a score < 125/150 
2. Elevation of at least one muscle enzyme (creatinine kinase [CK]; myoglobin; 
alanine aminotransferase [ALT]; or aspartate aminotransferase [AST]) to a 
minimum level of 1.3 times the upper limit of normal. 
3. Physician Global Assessment > 2.0 cm using a visual analogue scale (VAS) 10.0 
cm in length. 
4. Patient Global Assessment > 2.0 cm using a visual analogue scale (VAS) 10.0 
cm in length. 
5. Global extra muscular disease activity score > 1.0 cm using a visual analogue 
scale (VAS) 10.0 cm in length.  This score is based on the investigator’s 
composite assessment of disease activity of the constitutional, cutaneous, 
skeletal, gastrointestinal, pulmonary and cardiac scales on the Myositis Disease 
Activity Assessment Tool (MDAAT).  
6. HAQ disability index with a minimum value of 0.25. 
 
The patient will be required to meet an MMT 8 score of <125/150 as a major CSM criterion and 
at least 2 other CSM criteria to classify as an active disease.  
 
In addition, for patients with > 7 years of IIM, muscle biopsy or muscle MRI within 4 months 
prior to enrollment will be required to document active myositis to avoid enrolling patients with 


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significant index of damage/ muscle atrophy. This is not applicable to DM patients with a 
cutaneous VAS score of  >3 cm on a 10 cm VAS scale (MDAAT).  
 
Response rate: The response rate will be assessed by the percentage of patients meeting the 
definition of improvement (DOI). DOI is based on the definition of improvement developed by 
the International Myositis Assessment and Clinical Studies Group utilizing 6 core set measures.  
 
DOI: DOI is defined as ≥ 20% improvement in any 3 of the CSM, with no more than 2 CSM 
worsening by ≥ 25% (excluding MMT)11.  
 
Definition of Worsening (DOW): Determination of worsening of the disease activity will based 
on the definition of worsening (DOW) criteria developed by the International Myositis 
Assessment and Clinical Studies Group (IMACS) utilizing 6 core set measures11:  
1. worsening of Manual Muscle testing by >20% and or Physician Global worsening of 
> 2cm on a 10 cm VAS or 
2. Global extra muscular organ disease activity worsening by > 2cm on a 10 cm VAS on 
MDDAT, or 
3. 3 of 6 CSM worse by > 30%  
Disease Flare: IIM Disease Flare is recorded when the patient: 
1. reaches DOW; 
2. new start or dose increase of corticosteroid or immunosuppressive agent for 
treatment of IIM after study week 8; 
3. an increased dose of corticosteroid before study week 8 and did not return to <25% 
above the baseline dose by week 12. 
Endpoints: 
1. Primary Endpoint: 
a. 
Response rate at 40 weeks defined as percentage of patients meeting definition of 
improvement (DOI) in IIM patients treated with belimumab and standard therapy 
compared to the percentage of patients meeting DOI treated with placebo and 
standard therapy.  
 
2. Secondary Endpoints: 
a) 
Incidence of flares: flare rates during 40 weeks randomization period in patients with 
IIM treated with belimumab and patients treated with placebo and at week 64 in each 
group. 
b) Time to achieve initial improvement defined as the time to reaching DOI. 
c) 
Duration of improvement; quantified as the time from achieving improvement to the 
time of worsening or a disease flare. (Time from 1st DOI to 1st DOW or disease flare 
event). This will be based on the subset of subjects who achieve improvement.  
d) Percent change in muscle enzyme levels (CPK and myoglobin) from baseline to 
week 40 and 64 in each respective group  
1. <20% reduction: no response 
2. 20-70% reduction: partial response 
3. >70% reduction: complete response 
e) 
Percent change in manual muscle assessment (MMT-8) from baseline to week 40 
and week 64 in each respective group. 


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1. <20% reduction: no response 
2. 20-70% reduction: partial response 
3. >70% reduction: complete response 
f) 
Percent change in prednisone dose from baseline to week 40 and week 64 in each 
respective group 
g) Proportion of subjects, among those on steroids at baseline, able to reduce the 
prednisone dose to < 5 mg daily at week 40 and week 64 in each respective group. 
h) Flare rate in placebo group during the 40 week randomized treatment phase as 
compared to that group in the 20 week open label phase. 
i) 
Serious adverse event and adverse event rates 
j) 
Changes in B cell populations from baseline to week 40 and week 64 
k) Changes in autoantibody titers from baseline to week 40 and week 64 
l) 
Changes in immunoglobulin concentrations from baseline to week 40 and week 64 
 
Inclusion Criteria:  
Subjects enrolled in the study must meet the following inclusion criteria: 
1) Adults >18 years of age  
2) Have a diagnosis of:  
a. definite or probable dermatomyositis (DM) by modified Bohan & Peter criteria or  
b. Definite or probable diagnosis of polymyositis (PM) with presence of one of 
myositis specific antibodies. In the absence of myositis specific auto-antibodies, the 
diagnosis of PM will require review of the muscle biopsy and adjudication by the 
predetermined committee of experts. 
3) Presence of positive autoantibody (ANA >1:80 or RNP or SSA/SSB or any of the myositis 
specific autoantibody anti-synthetase autoantibodies (anti-Jo-1, PL-7, PL-12, EJ, OJ), anti-
SRP, anti-Mi-2, anti-p140  also known as anti-MDA5], anti-p155/140 [also known as anti-
TIF], anti-NXP-2 [also known as MJ]).). 
4) Have refractory IIM as defined by inadequate response or intolerance to at least 3 months 
of glucocorticoids and/or an inadequate response or intolerance to at least 3 months at least 
one other immunosuppressive agent, such as azathioprine, methotrexate, IVIG, 
mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine cyclophosphamide, and 
Rituximab. 
5) Have active IIM at screening.  This requires at least 3 criteria from the CSM (listed above) 
to be met for enrollment.  
6) Dermatomyositis patients that do not meet the MMT criteria, must have: 
a. a cutaneous VAS score of  >3 cm on a 10 cm VAS scale (MDAAT) will be 
required:  
b. elevation of at least one muscle enzyme (creatine kinase [CK]; myoglobin; alanine 
aminotransferase [ALT]; or aspartate aminotransferase [AST]) to a minimum level 
of 1.3 times the upper limit of normal, 
c. and 1 additional core set measure   
7) For patients with ≥ 7 years of IIM, muscle biopsy or muscle MRI within 4 months prior to 
enrollment will be required to document active myositis to avoid enrolling patients with 
significant index of damage/ muscle atrophy. This is not applicable to DM patients with a 
cutaneous VAS score of >3 cm on a 10 cm VAS scale (MDAAT). 
8) Have a stable background glucocorticoid therapy for at least 2 weeks prior to screening   


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(Prednisone (or equivalent) dose < 15 mg daily) 
9) Immunosuppressive therapy (IS) at the time of enrollment is not required. However, a 
patient receiving IS therapy at the time of enrollment must be on a stable regimen 
(azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine for > 2 months prior to 
screening. Patients on intravenous gamma globulin (IVIG) have to be on a stable dose and 
frequency regimen for ≥ 3 months. 
 
Therapeutic Agent 
Treatment Duration prior to 
Screening ≥ 
Dose Increase prior to 
Screening ≥ 
Azathioprine 
2 months 
2 weeks 
Methotrexate 
2 months 
2 weeks 
Mycophenolate mofetil 
2 months 
2 weeks 
Tacrolimus 
2 months 
2 weeks 
Cyclosporine 
2 months 
2 weeks 
IVIG 
3 months 
none 
10) Have the ability to understand the requirements of the study and provide written informed 
consent (including consent for the use and disclosure of research-related health 
information) and comply with the study protocol procedures (including required study 
visits)  
11) Female subjects of childbearing potential must have a negative urine pregnancy test at 
screening  and agree to 1 of the following:   
a. 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  
b. Consistent and correct use of 2 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  
1) Oral contraceptive, either combined or progestogen alone 
2) Injectable progestogen 
3) Implants of levonorgestrel or etonogestrel 
4) Estrogenic vaginal ring 
5) Percutaneous contraceptive patches 
6) Intrauterine device (IUD) or intrauterine system (IUS) with <1% 
failure rate as stated in the product label 
7) Male partner sterilisation (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. 


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8) Double barrier method:  condom and occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent 
(foam/gel/film/cream/suppository)  
 
 
Exclusion Criteria: 
 Subjects meeting any of the following criteria will be excluded from the study: 
1. Have severe muscle damage as defined by a Muscle Damage Index (MDI) > 5.0 cm using 
a visual analogue scale (VAS) 10.0 cm in length  
2. History of malignant neoplasm within the last 5 years, except for adequately treated 
cancers of the skin (basal or squamous cell). 
3. Have a history of a primary immunodeficiency 
4. Have a significant IgG deficiency (IgG level < 400 mg/dl) Have an IgA deficiency (IgA 
level < 10 mg/dL) 
5. Discontinuation IS agent < 3 months prior to Screening. Including: azathioprine, 
methotrexate, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, or 
intravenous gamma globulin [IVIG] 
6. Have received Rituximab within 365 days prior to Screening. 
7. Have received cyclophosphamide within 180 days prior to Screening 
8. Have received treatment with: 
a. Initiated IVIG less than 3 months prior to Screening 
b. Pulse steroids 2 months prior to Screening 
9. Have received treatment with Belimumab at any time prior to Screening 
10. Have received a biologic investigational agent within 365 days prior to Screening. 
11. Have received a non-biologic investigational agent within 30 days or 5 half-lives of the 
agent (whichever is longer) prior to Screening.  
12. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies. 
13. Infection history: 
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis – 
including latent tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, 
herpes zoster and atypical mycobacteria). 
NOTE: Testing for latent TB is a standard of care for patients on 
immunosuppressive therapy and results will be obtained from their medical record. 
If no TB history is found for these patients, a Quantiferon Gold or PPD test will be 
performed prior to Day 0 as part of standard of care. 
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. 
14. Have a historically positive HIV test or test positive at screening for HIV. 
15. Have a history of autoimmune hepatitis 
16. Hepatitis status will be obtained from patients’ medical records. If unavailable, testing 
will be done as part of standard of care.  Patients are excluded if there is evidence of 
chronic or active Hepatitis B infection with: 
a. Hepatitis B:  


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i. Presence of positive Hep B surface antigen independent of history of previous 
exposure to IVIG. 
ii. Positive hepatitis B core antibody for patients with no exposure to IVIG 
iii. Patients who previously received IVIG and have positive core antibody 
(Hepatitis B coreAb) and  negative Hep B surface antibodies with or without  
the presence of positive HBVDNA by PCR  
• 
Note: Patients who previously received IVIG and with Hep B core IgG pos and Hep B sAB pos. 
are allowed to be enrolled but additional safety monitoring procedures must be followed on 
these patients – please see Appendix C: Follow Up Assessments. The table below describes 
which types of patients would be eligible based on different Hep B core/surface ab positivity. 
Hep Bs ag 
  + 
  -/ + 
  -/ +  
  _ 
  _ 
   _ 
Hep B s ab 
-/ + 
  + 
 -/ + 
  _ 
  _ 
   + 
Hep B core 
ab IgM 
  -/ + 
  + 
 -/ + 
  _ 
  _ 
   _ 
Hep B core 
ab IgG 
  -/ + 
 -/ +  
-/ + 
  +  
  +  
repeat  
   _ 
   + 
Hep B by 
PCR  
  -/ + 
 -/ + 
  + 
   _ 
_ 
   _ 
 
STATUS: 
Not eligible 
Not eligible 
Not eligible 
Not eligible 
Eligible 
Eligible 
 
b. Hepatitis C:  
c. Positive hepatitis C antibody with confirmatory hepatitis C viral load by PCR.  
17. Clinically significant elevation of GGT (>1.5xULN), bilirubin (>1.25xULN, direct 35%), 
or INR (>1.2, excluding patients on anti-coagulant therapies) or other clinically 
significant abnormal laboratory value in the opinion of the investigator.  
18. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse 
or dependence within 364 days prior to Day 0. 
19. Have evidence of serious suicide risk including any history of suicidal behaviour 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.  
20. Have any concurrent significant medical or psychiatric illness that the investigator 
considers would make the candidate unsuitable for the study.  
 
 


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Study Drug Administration: 
1. The study agent will be administered by 10mg/kg dose at 2 weeks intervals for the 
first 3 doses and every 4 weeks thereafter. It is administered IV over a minimum of 1 
hour. During the study visit at each dosing the patient will be monitored and routine 
laboratory testing will be performed according to standard of care. See Appendix A for 
infusion dosing schedule. 
 
2. Study agent should be administered by investigators/site personnel prepared to 
manage infusion reactions and anaphylaxis. The infusion rate may be slowed or 
interrupted if the subject develops an infusion reaction. Investigators/site personnel 
should be aware of the risk of hypersensitivity reactions, which may present as infusion 
reactions, and monitor subjects closely. In the event of a serious reaction, study agent 
administration must be discontinued immediately and the appropriate medical therapy 
administered.  
 
3. Subjects should remain under clinical supervision for 3 hours after completion of 
the first 2 infusions.  In the post-marketing setting, delayed onset of symptoms of acute 
hypersensitivity reactions has been observed. Infusion reactions occurred more frequently 
on the first two infusion days and tended to decrease with subsequent infusions. Delay in 
the onset of acute hypersensitivity reactions has been observed and recurrence of 
clinically significant reactions after initial resolution of symptoms following appropriate 
treatment, have been observed.  Therefore, patients should be monitored during and for 
an appropriate period of time after administration of belimumab. Subjects should remain 
under clinical supervision for 3 hours after completion of the first 2 infusions.  Should 
symptoms of acute hypersensitivity occur, an extended period of monitoring may be 
appropriate, based on clinical judgment. This may include, but is not limited to, 
monitoring vital signs and observing any untoward reactions. Beyond the first 2 
infusions, subjects should be monitored during and for an appropriate period of time after 
infusion according to the study sites’ guidelines or standard operating procedure for IV 
infusions. 
 
4. Subjects should be made aware of the signs and symptoms of delayed-type, non-acute 
hypersensitivity reactions that have been observed. These include symptoms such as rash, 
nausea, fatigue, myalgia, headache, and facial edema. Subjects should be made aware of 
the potential risk, the signs and symptoms of such reactions, and the importance of 
immediately seeking medical attention.  
Safety Considerations and Adverse Events: 
The investigator or site staff will be responsible for detecting, documenting and reporting events 
that meet the definition of an Adverse Event (AE) or Serious Adverse Event (SAE). 
 
Adverse Event (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) 


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temporally associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 
 
Events meeting the definition of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 
• 
New conditions detected or diagnosed after study treatment administration even though 
it may have been present prior to the start of the study 
 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae. 
  
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 
 
Common adverse events seen in the belimumab lupus trials include; nausea, diarrhea, pyrexia, 
nasopharyngitis, bronchitis, pain in the extremities, depression, migraine and pharyngitis 
 
Serious Adverse Event (SAE): A serious adverse event is any untoward medical occurrence that, 
at any dose: 
a. 
Results in death 
NOTE: Any death that occurs during study participation must be reported within 
24 hours to the lead site and study sponsor. The investigator must identify 
etiology, relationship to study drug and an SAE case report form must be 
completed. 
b. Is life-threatening.  
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event 
in which the subject was at risk of death at the time of the event.  It does not refer 
to an event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization.  
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 


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IRB#: 14-621 
physician’s office or out-patient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
NOTE: Hospitalization for elective treatment of a pre-existing condition that did 
not worsen from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
g. All events of possible liver injury defined as ALT  3x ULN and elevated GGT  3x 
ULN (without elevated CPK, and/or myoglobin) 
h. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT  3xULN (without elevated CPK, and/or myoglobin) and bilirubin  2xULN 
(>35% direct)  
i. 
All events of possible liver injury with increased INR defined as  ALT  3xULN 
(without elevated CPK, and/or myoglobin) 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.   (See Appendix C).  
 
NOTE:  
 
ULN (Upper Limit of Normal) as determined by the reference range of the local lab 
 
All liver toxicities must be reported to the Sponsor (Northwell Health) and GSK.  
 


19 | P a g e  
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Subjects that meet liver stopping criteria (See Appendix C) MUST be reported to GSK 
within 24 hours.  
 
In the case of a LIVER STOPPING EVENT, follow up assessments should be 
completed (see Appendix C).  
 
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 judgment 
of the investigator are to be recorded as AEs or SAEs.  
NOTE: However, any clinically significant safety assessments that are associated 
with the underlying disease, unless judged by the investigator to be more severe 
than expected for the subject’s condition, are not to be reported as AEs or SAEs. 
 
Adverse Events of Special Interest: The following AEs should be monitored closely and reported 
to the study sponsor immediately.  
1. Serious hypersensitivity reaction or Infusion Reactions (See Section: Study Drug 
Administration and Considerations) 
2. Suicidality: 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. If destructive tendencies are suspected, the 
subject should be referred to a psychologist or other appropriate specialist for evaluation. 
3. Malignancy 
4. Serious infections, including herpes zoster and opportunistic infections 
5. Progressive multifocal leukoencephalopathy (PML). PML resulting in neurological 
deficits, including fatal cases has been reported in SLE patients receiving 
immunosuppressant pharmacotherapy, including belimumab. A diagnosis of PML should 
be considered in any subject presenting with new-onset or deteriorating neurological 
signs and symptoms. The subject should be referred to a neurologist or other appropriate 
specialist for evaluation. If PML is confirmed, study agent should be discontinued and 
consideration should be given to stopping immunosuppressant therapy. If PML is 
suspected, this should be immediately reported to the Medical Monitor. The 
appropriateness of continuing study agent, while the case is being assessed, should be 
discussed. 
6. Abnormal liver enzymes (See Appendix C). While previous studies of belimumab in 
lupus have shown no causal relationship between the drug and liver toxicity, liver 
function will be monitored in all subjects throughout the study (See Appendix C).  
 
Pregnancy:   
Any pregnancy that occurs during study participation must be reported using clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported within 2 weeks of 
learning of its occurrence to the lead site and sponsor.  The pregnancy must be followed up to 


20 | P a g e  
IRB#: 14-621 
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. Pregnancy testing will occur at every study 
visits and at 16 weeks after the last treatment dose.  
NOTE: Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to the lead site as well as 
GSK. 
 
Adverse Event and Serious Adverse Event Reporting: 
The investigator or site staffs are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.  
• All AEs must be reported to the coordinating site.  
• All SAEs must be reported to the coordinating site and local IRB within 24 hours. The 
coordinating site will report all SAEs to the coordinating site’s IRB, the sponsor and the 
FDA.  
All AEs and SAEs must be reported on an Adverse Event/Serious Adverse Event case report 
form. The study investigator is responsible for noting the relationship of the event to the study 
drug, the severity of the drug (criteria for grading toxicity will be based on NCI’s Common 
Terminology Criteria for Adverse Events version 4.03), the actions taken with the investigational 
product, and any other medications used to treat the adverse event or serious adverse event.  
  
Time Period and Frequency of Detecting AEs and SAEs:  
The investigator or site staffs are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. AEs will be collected from the start of the study 
treatment until the end of the study. SAEs will be collected from the start of the study treatment 
until the end of the study. All SAEs will be reported to the coordinating site, sponsor and IRB 
within 24 hours.  
NOTE: 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.  
Study Procedures & Assessments: 
The following assessments will occur throughout the study (see Appendix A for schedule of 
events):   
 
• Informed Consent and Inclusion/Exclusion Criteria will be assessed at the screening visit. 
After a subject signs the informed consent they will enter the screening period (≤ 2 
weeks) and have eligibility determined prior to Day 0.  
Laboratory assessments:  
a. CBC, Comprehensive metabolic, GGT, ESR, CRP, CPK, serum myoglobin, 
immunoglobulins, urinalysis and urine pregnancy test will be collected at screening. 
b. CBC, Comprehensive metabolic, GGT, ESR, CRP, CPK, serum myoglobin, 
immunoglobulins and urinalysis collected within 2 weeks prior to screening can 
be used for eligibility determination. 


21 | P a g e  
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c. Testing for latent TB is a standard of care for patients on immunosuppressive 
therapy and results will be obtained from their medical record. If no TB history is 
found for these patients, a Quantiferon Gold or PPD test will be performed prior to 
Day 0 as part of standard of care. 
d. Hepatitis status will be obtained from patients’ medical records. If unavailable, 
testing will be done as part of standard of care during the screening period.   
• Vital signs will be assessed prior to infusion and after the infusion at every visit. 
• Adverse events assessed at every visit. Criteria for grading toxicity will be based on 
NCI’s Common Terminology Criteria for Adverse Events version 4.03.  (Adverse 
Events/Serious Adverse Events (CTCAE Version 4.03) 
• A Physical Exam will be performed by the Investigator at Screening, Day 0, Week 8, 16, 
24, 32, 40, 52, & 64. 
• Urine Pregnancy testing for WOCBP will be conducted at each study visit and 16 weeks 
after last dose. Urine pregnancy tests must be completed < 7 days prior to the first dose 
and prior to each IP administration, but not more than once a month. In the event that the 
urine pregnancy test is indeterminate, a serum pregnancy test will be done.  
• Laboratory tests: CBC, Comprehensive metabolic, GGT, ESR, CRP, CPK, myoglobin 
and urinalysis will be collected at every study visit and follow up week 64. 
• An immunoglobulin panel will be collected and assessed at: Screening, Week 40, & 64. 
Under special circumstances monthly IgG monitoring may be required (see Section: 
Study Design, part f) and will be performed as part of standard of care. 
• Flow Cytometry and RNA-seq are collected at: Day 0, Week 8, 40, Week 48, & Week 60 
or 64. 
• Cytokine levels (and optional research Northwell only) will be measured at: Day 0, Week 
40, & Week 60 or Week 64.  
• Patients should be clinically assessed for suicidal ideation and/or behaviour at each study 
visit using the Columbia Suicide Severity Scale (C-SSRS) 
• The Investigator will complete a Physician Global Assessment (PGA, a VAS scale of 
10cm), Manual Muscle Test-8 (MMT-8), & Myositis Disease Activity Assessment Tool 
(MDAAT) at Screening, Day 0, Week 8, 16, 24, 32, 40, 52, & 64 
• The Investigator will complete a Muscle Damage Index (MDI) assessment at Screening, 
Week 40 and Week 64  
• Health Assessment Questionnaire (HAQ) and Patient Global Assessment (PGA, a VAS 
scale of 10cm) will be completed by subjects at Screening, Day 0, Week 8, 16, 24, 32, 40, 
52, & 64 
• Post study follow up phone call with subject conducted at Week 72 and 84. 
• Patients who previously received IVIG and with Hep B core IgG positive and Hep B sAB 
positive will undergo surveillance with Liver function test, Hepatitis Panel and Viral Load every 3 
months. 
 
Data Safety Monitoring Plan: 
The principal investigator and two independent physicians, designated by the Principal 
Investigator, will be responsible for the oversight of the data safety monitoring plan.  The 
committee will meet every 6 months to evaluate the rate of unanticipated adverse events. If any 


22 | P a g e  
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safety signals are identified, recommendations to changes in the protocol or consent will be 
defined by the committee. Benefit-to-risk assessment will be made in order to determine if the 
study should continue. The results of these regular meetings will be recorded and disseminated to 
all participating clinical sites. 
 
Feinstein Biostatistics Unit BUDDY System: Data Management 
The Biostatistics Unit (BU), within The Feinstein Institute for Medical Research (FIMR), 
provides state-of-the-art statistical and data management support to the research investigators at 
Northwell Health as well as other medical research institutions in the New York area. Its staff of 
ten PhD and Masters level statisticians and two senior applications programmers has extensive 
experience in the design, data management, and analysis of hundreds of clinical research 
projects, including over 250 clinical trials.  Primary expertise is in clinical trials, diagnostic 
testing and screening, the development of predictive models for prognosis, and development of 
protocols and grant applications. 
 
The Biostatistics Unit provides data management support through its “BUDDY” system 
(“Biostatistics Unit Database Designed for You”).  BUDDY is a highly customized, secure, 
HIPAA-compliant, web-based database application.  It is particularly suited to studies with 
longitudinal and relational data structures, especially clinical trials.  The cost of database 
development may vary depending upon features requested by the user, including, but not limited 
to: case report form development, number of unique data screens, transfer of data between 
another system and BUDDY, data validation checks between screens, image file storage, special 
queries or reports, translation of adverse event descriptions into MedDRA, and data submission 
tracking.  
The Biostatistics Randomization Management System (BRMS) is a secure, HIPAA-compliant, 
web-based application that allows investigators to randomize subjects into randomized clinical 
trials (RCTs)  using their personal computer. The BRMS allows for multi-center, stratified, and 
single/double blinded RCTs, using permuted blocks.  Randomization notifications are 
automatically sent to the PI and other authorized personnel.  Using BRMS is a good way to 
maintain compliance in RCTs. 
 
Statistical Considerations 
SPECIFIC STATISTICAL AIMS  
The primary objective of the study is to compare subjects in the Belimumab group and subjects 
in the placebo group with respect to response (improvement) at week 40. 
 
The specific aims of the study are to compare the two treatment arms (Belimumab vs. Placebo [P 
vs. B]), during the 40-week randomized phase of the study, with respect to the following: 
1. Response at week 40. 
2. Flare rates during the 40-week treatment period. 
3. Time-to-achieve (initial) improvement during the 40-week randomized phase of the study 
4. Duration of improvement during the 40-week randomized phase of the study, among 
those who achieved improvement (this is essentially a time-to-flare/relapse analysis from 
the time that you achieved improvement) 
5. Change in muscle enzyme levels (CPK, myoglobin) from baseline to week 40 
6. Change in MMT-8 from baseline to week 40 
7. Change in prednisone dose from baseline to week 40 


23 | P a g e  
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8. Proportion of subjects able to reduce prednisone dose to ≤5 mg at week 40 
9. Change in B cell populations, immunoglobulin levels and BLys levels from baseline to 
week 40. 
10. Change in autoantibody titers from baseline to week 40. 
11. Rates of SAEs and AEs experienced 
 
STATISTICAL METHODS 
All subjects will be analyzed according to the intention-to-treat [ITT] principle. A subject will be 
considered evaluable and will be included in the intention-to-treat analysis if he/she received at 
least the first five of the planned infusions during the randomized phase of the study.  Subjects 
who do not get the first five infusions will be considered ‘drop-outs’.  It should be noted that the 
study protocol calls for patients remaining on their treatment assignment. However, adjustments 
in dosages of medications used in their ‘standard care’ are permitted during the first 8 weeks. 
Analyses that take into account the actual treatment received (e.g. accounting for compliance, 
etc.) will be carried out as a secondary analysis (per protocol [PP] analysis). 
 
1. For specific aim 1, the two treatment arms [B vs. P] will be compared with respect to the 
proportion of subjects who respond to treatment at 40 weeks (improvement according to 
definition), using either a chi-square test or Fisher’s exact test, as appropriate. 
 
2. For specific aim 2, either a chi-square test or Fisher’s exact test, as appropriate, will be 
conducted to compare the proportion of subjects who had any flares during the 40-week 
randomized phase.  For this analysis, each subject will be categorized at the end of 40 
weeks as having had one or more flares or not having had any flares.  In addition, we can 
also examine the total number of days that a subject had a specific flare during the course 
of the 40-week treatment, and compare the two treatment arms using the ‘Incidence 
density ratio’ method. 
 
3. For specific aim 3, standard methods for survival analysis will be carried out.  The 
Kaplan-Meier (KM) product limit method will be used to estimate overall “time-to-
achieve (initial) response/improvement”. Ninety-five percent confidence intervals will be 
calculated using Greenwood’s formula for computing the standard error.  Subjects who 
have not achieved improvement as of week 40 will be considered ‘censored’ for the event 
(event=improvement/response). 
 
4. For specific aim 4, similar methods as indicated for specific aim 3 will be conducted.  
The analysis for this aim will be limited to the subset of subjects in each treatment arm 
who show improvement at anytime during the randomized phase of the trial.  A subject 
who has not flared/worsened/relapsed as of week 40 will be considered ‘censored’ for the 
event (event=flare/relapse). 
 
5. For specific aims 5, 6, 7, 9 and 10, each of the outcome variables of interest (uncensored 
continuous or categorical) will be analyzed separately, using a mixed model approach to 
repeated measures analysis of variance (MMRMANOVA) with the main effects of 
treatment arm (B vs. P), Disease type (PM vs DM), Disease Severity (Severe vs. Less 
Severe) and time (baseline vs. 40 weeks).   If feasible, statistical interactions between 


24 | P a g e  
IRB#: 14-621 
treatment and time (baseline vs. week 40; or all available data at each study visit) or other 
factors of interest will be examined (e.g. Treatment X Disease Type; Treatment X 
Disease Severity).  The treatment-by-time interaction term, will demonstrate whether the 
trajectories (or patterns of change) in the outcomes of interest are different between 
treatment groups. Data transformations may be used, in order to meet the necessary 
assumptions for the mixed models analyses. If transformations do not achieve the 
assumptions needed, a rank transformation or an appropriate non-parametric method will 
be considered. 
 
If the analysis using a mixed model approach is not feasible due to the pattern of the data, 
then, a simplified analysis comparing the two treatment arms with respect to percent 
change (reductions) in muscle enzymes, MMT-8 and prednisone dose will be carried out 
using either a t-test or the Mann-Whitney test, as appropriate.  A chi-square test or 
Fisher’s exact test, as appropriate, may also be used if the continuous measures are 
grouped according to pre-specified categories (e.g. reduction in CPK will be categorized 
as No Response, Partial Response or Complete Response according to whether the 
percent reduction was <20% vs. 20%-70% vs. >70%, respectively). 
 
6. For specific aim 8, the proportion of subjects who were able to reduce their daily 
prednisone dose to ≤5 mg at week 40, will be compared using either a chi-square test or 
Fisher’s exact test, as appropriate.  
 
7. For specific aim 11, either a chi-square test or Fisher’s exact test, as appropriate, will be 
conducted to compare the proportion of subjects who experienced any SAEs or AEs 
during the randomized phase of the study.  For this analysis, each subject will be 
categorized at the end of 40 weeks as having had any SAEs/AEs or not having any 
SAEs/AEs.   
 
Multivariable analyses (logistic, cox) will be conducted for the above outcomes, if feasible.  
However, this may be limited by the sample size. 
 
SAFETY DATA 
There will be no formal interim analyses or formal statistical stopping rules. However, statistical 
summaries of adverse event rates using 95% exact confidence intervals will be provided to the 
data safety monitoring board as need. During regular bi-annual meetings the data safety 
monitoring board will evaluate the overall rate of adverse events and unanticipated problems. 
Upon review the group will determine whether there are any changes needed to the anticipated 
benefit-to-risk assessment and if the study should continue. The results of these regular meetings 
will be recorded and disseminated to the other participating clinical sites. Safety data will be 
collected in the form of adverse events (AEs), serious AEs (SAEs) and laboratory parameters 
(e.g., hematology, chemistry, etc.). AEs will be recorded with the date of onset, severity, 
relationship to study drug, and disposition. AEs will be translated into a standard classification 
system such as COSTART or MedDRA. AE data will be summarized according to incidence 
rates, by treatment arm and by whether or not the AE was treatment related. AEs will be 
summarized using descriptive statistics and tabulated according to treatment group for each 
strata. The AE report will be descriptive, rather than inferential. 


25 | P a g e  
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SAMPLE SIZE CONSIDERATIONS   
We plan to enroll 30 evaluable patients with 15 in each of two treatment arms [B vs. P].  
 
From available trials in IIM, there is an observed placebo effect of 0%-40% at 12 weeks9,10 and 
0% at 52 weeks9.  These results demonstrate that the placebo response rate at 40 weeks can be 
very variable. One clinical study looking at rituximab in myositis was the first prospective, 
double-blind, randomized trial in myositis and the largest clinical trial ever performed in the 
inflammatory myopathies16. This trial employed a unique design; subjects were divided into two 
groups: early-start and delayed-start of rituximab. Overall, 83% of enrolled subjects (with severe 
refractory disease) met the DOI by the end of the trial, despite lack of statistical significance 
between groups. An alternate double-blind, placebo-controlled trial of etanercept (50 mg 
subcutaneously weekly for 52 weeks) where 16 subjects were randomized showed that:  all 5 
subjects receiving placebo were treatment failures (median time to treatment failure: 148 days)17. 
In contrast, 5 of 11 subjects in the etanercept arm were successfully weaned off prednisone; the 
median time to treatment failure in this group was 358 days (p = 0.0002). This data shows that 
for myositis trials, placebo response is often close to 0%. In order to achieve a clinically 
meaningful difference between study treatment arms, the response rate of the treatment group 
would need to be at least50%. 
 
We hypothesize (optimistically) the response rate at 40 weeks in the placebo arm to be 5%.  We 
further assume that a magnitude of difference of 45% would be clinically meaningful (this 
corresponds to a 50% response rate in the Belimumab arm.  
 
Based on the assumption that a difference of 45% in response rates at 40 weeks between Placebo 
and the investigational agent, Belimumab, would be clinically meaningful, then, a two group chi-
square test (alpha=0.05, two sided test) will yield 80% power to detect a difference between the 
Placebo arm week 40 response rate of 5% and a Belimumab-treated arm week 40 response rate 
of 50% (Odds ratio=19) when the sample size in each group is 15, assuming the dropout rate is 
0%. 
 
Table 1 below shows the sample size requirements for various pairs of (hypothesized) 40-week 
response rates and assumptions on what would be a clinically meaningful difference between 
treatment arms. Corresponding sample sizes are provided for the specified range of parameters. 
Calculations were based on a two-sided chi-square test to achieve 80% power (alpha=0.05).  
 
 
 
Table 1.  Sample Size Requirements (N) for Various Effect Sizes (80% power, two-sided chi-
square test, alpha=0.05), attrition rate =0%. 
Index 
PLACEBO 
RESPONSE 
BELIMUMAB 
RESPONSE 
Difference ODDS 
RATIO 
REQUIRED N 
PER GROUP 
TOTAL N,  
(assuming no 
1
15% 
60%
45%
8.5
17
17
2
15% 
55%
40%
6.9
22
44


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Index 
PLACEBO 
RESPONSE 
BELIMUMAB 
RESPONSE 
Difference ODDS 
RATIO 
REQUIRED N 
PER GROUP 
TOTAL N,  
(assuming no 
3
10% 
60%
50%
13.5
14
28
4
10% 
55%
45%
11
16
32
5 
5% 
60% 
55% 
28.5 
11 
22 
6
5%
55%
50%
23
12
24
7
5%
50%
45%
19
15
30


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References: 
1. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, 
Browning JL. Mice transgenic for BAFF develop lymphocytic disorders along with 
autoimmune manifestations. J Exp Med ; 1999; 190:1697-1710. 
2. Gross JA, Johnston J, Mudri S et al. TACI and BCMA are receptors for a TNF homologue 
implicated in B-cell autoimmune disease. Nature; 2000; 404:995-999  
3. Khare SD,  Sarosi I, Xia XZ, McCabe S, Miner K,  Solovyev I. Severe B cell hyperplasia 
and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA; 2000; 
97:3370-3375 
4. Salajegheh M, Pinkus JL, Amato AA, Morehouse C, Jallal B, Yao Y , Greenberg S. 
Permissive Environment for B cells maturation in Myositis Muscle in the absence of B 
cell Follicles. Muscle & Nerve; 2010; October; 576-583 
5. Krystufkova O, Vallerskog T, Helmers SB , Mann H, Putova I,  Belacek J, Malmstrom V, 
Trollmo C, Vencovsky J, Lundberg I E. Increased serum levels of B cell activating factor 
(BAFF) in subsets of patients with idiopathic inflammatory myopathies. Ann Rheum Dis; 
2009;68:836–843. 
6. Krystufkova O, Modra M, Mann H, Putova I, Lundberg IE., Vencovsky J. Positive 
Correlations Between Serum Levels of B-Cell Activating Factor of the TNF Family/BLyS 
(BAFF), Anti-Jo-1 Autoantibodies and Muscle Enzymes in Patients with Polymyositis or 
Dermatomyositis [abstract]. Arthritis Rheum; 2009; 60 Suppl 10 :81 
7. Stohl W, Metayas S, Tan SM, Cheema GS et al N lymphocyte stimulator overexpression 
in patients with SLE: longitudinal observation. Arthritis Rheum; 2003; 48:3475-86 
8. Consuelo M. Lopez De Padilla, Kelly T McNallan, Cynthia S Crowson et al. BAFF 
expression correlates with Idiopathic Inflammatory Myopathy Disease Activity Measures 
and Autoantibodies The Journal of Rheumatology; 2013; 40:3 
9. The Muscle Study Group. A Randomized, Pilot Trial of Etanercept in Dermatomyositis. 
Ann Neurol 2011;70:427–436  
10. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, 
McCrosky S. A controlled trial of highdoseintravenous immune globulin infusions as 
treatment for dermatomyositis. N Engl J Med; 1993; 329:1993–2000 
11. Rider LG, Edward H, Giannini HI, Brunner NR, James-Newton J, Reed AM, Lachenbruch 
PA, Miller FW. International Consensus on Preliminary Definitions of Improvement in 
Adult and Juvenile Myositis Arthritis & Rheumatism; 2004, Vol. 50, No. 7, pp 2281–
2290. 
12. Sultan, Shabina M., and David A. Isenberg. "Re-classifying myositis 30 years on from 
Bohan and Peter." Rheumatology (2009): kep355. 
13. James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
14. Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients.  J 
Clin Microbiol. 2005;43(5):2363–2369. 
15. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a 
metadata-driven methodology and workflow process for providing translational research 
informatics support. J Biomed Inform. 2009;42(2):377-381.  


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16. Chester V. Oddis, Ann M. Reed, Rohit Aggarwal, Lisa G. Rider, Dana P. Ascherman, 
Marc C. Levesque, Richard J. Barohn, Brian M. Feldman, Michael O. Harris-Love, Diane 
C. Koontz, Noreen Fertig, Stephanie S. Kelley, Sherrie L. Pryber, Frederick W. Miller, 
Howard E. Rockette, and Rituximab in Myositis (RIM) Study Group. Rituximab in the 
Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A 
Randomized, Placebo-phase Trial Arthritis Rheum. 2013 February ; 65(2): 314–324.   
17. Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann 
Neurol. 2011;70(3):427–436. 
 


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Appendix A. Study Schedule  


31 | P a g e  
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SCREENING 
PHASE
Screening
Day 
0
Week 
2*
Week 
4*
Week 
8
Week 
12*
Week 
16
Week 
20*
Week 
24
Week 
28*
Week 
32
Week 
36*
Week 
40
Week 
40
Week 
44*
Week 
48*
Week 
52  
Week 
56*
Week 
60*
Week 
64
Week 
72
Week 
76
Week 
84
Clinical 
/Physical
Informed 
Consent
X
Inclusion/Excl
usion Criteria
 X 
Physical 
Exam and 
History
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Vital Signs
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Assess AE
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
MMT 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
MDAAT
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Physician 
Global 
Assessment
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
MDI
 X 
 X 
   
 X 
C-SSRS
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
HAQ 
(completed 
by subject)
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Patient Global 
Assessment 
(completed 
by subject)
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Post Study 
Follow Up 
Phone Call 
w/Subject
X
X
Study Agent 
Administratio
n 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Laboratory
CBC 
w/differential
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Comprehensi
ve Metabolic 
Panel (AST, 
ALT, ALP 
incl.)
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
GGT Liver 
Enzyme
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
ESR
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
CRP
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
CPK total
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Serum 
Myoglobin
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Urinalysis 
w/Microscop
y
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Immunoglobul
ins (IgG, IgA, 
IgM)
 X 
 X 
 X 
Pregnancy 
test 
(WOCBP)§
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Flow 
Cytometry
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
RNA-Seq 
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
 X ǂ 
Cytokine 
Levels
 X¤ 
 X¤ 
 X¤ 
 X¤ 
Optional 
Research 
Sampling 
(Northwell 
Only)
 X£ 
 X£ 
 X£ 
 X£ 
 X£ 
 X£ 
* Note: Patients will be monitored, assessed and have routine blood tests performed according to standard of care at each infusion visit
§ Note: Pregnancy testing will occur at each outlined study visit and at 16 weeks after the last treatment dose
ǂ Note: Blood samples should be collected at the following time points: Day 0, Week 8, 40, Week 48, Week 60 or 64
¤ Note: Blood samples should be collected at the following time points: Day 0, 40, Week 60 or 64
£ Note: Optional Blood samples should be collected at the following time points: Day 0, Week 8, Week 40, Week 48, Week 60 or Week 64
Post Treatment Follow Up
RANDOMIZED TREATMENT PHASE
OPEN LABEL TREATMENT PHASE


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Appendix B. Bohan & Peter (1975) Diagnostic Criteria for Polymyositis and 
Dermatomyositis12 
 
 
 
 


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Appendix C.: Liver Chemistry Stopping and Follow Up Criteria 
Liver chemistry 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).  These criteria have been amended for this myositis protocol 
to accommodate for a specific population of myositis patients with ALT/AST abnormalities 
as a result of muscle injury. Baseline bilirubin, GGT and INR must be at or near normal. 
(Note: ULN – upper limit of normal as determined by the reference range of the local lab. 
All liver toxicities must be reported to the Sponsor (Northwell Health). Subjects that meet 
liver stopping criteria MUST be reported to GSK within 24 hours.) 
• 
ALT Absolute:  
o ALT  8xULN (without elevated CPK, and/or myoglobin) 
o If ALT  8xULN and serum GGT  3xULN (irrespective of CPK and/or 
myoglobin values) 
• ALT Increase: 
o ALT  5xULN but <8xULN  (without elevated CPK, and/or myoglobin) and 
GGT 3xULN,  persists for 2 weeks 
o ALT  3xULN but <5xULN  (without elevated CPK, and/or myoglobin) and 
GGT 3xULN,  persists for 4 weeks 
• Bilirubin: ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) a, b 
• INR: ALT  3xULN and INR>1.5, if INR measured b 
• Cannot Monitor: 
o ALT  5xULN but <8xULN (without elevated CPK, and/or myoglobin) and 
GGT 3xULN and labs cannot be monitored weekly for 2 weeks 
o ALT  3xULN but <5xULN (without elevated CPK, and/or myoglobin) and 
GGT 3xULN and labs cannot be monitored weekly for 4 weeks 
• Symptomatic: ALT  3xULN (without elevated CPK, and/or myoglobin) and GGT 
3xULN associated with symptoms (new or worsening) believed to be related to  liver 
injury or hypersensitivity c 
a) 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 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.  
b) All events of ALT  3xULN(without elevated CPK, and/or myoglobin) and 
GGT 3xULN   


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c) All events of ALT  3xULN (without elevated CPK, and/or myoglobin) 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 
d) 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 and Follow up Assessments following ANY Liver Stopping Event 
Actions: 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete SAE data collection tool if the event also 
meets the criteria for an SAE  
o All events of ALT  3xULN (without elevated CPK, and/or myoglobin) and 
elevated GGT 3xULN or  
o All events of ALT  3xULN (without elevated CPK, and/or myoglobin) and 
bilirubin  2xULN (>35% direct bilirubin) or  
o All events of ALT  3xULN (without elevated CPK, and/or myoglobin) and 
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s 
Law’), must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants) 
• Perform liver event follow up assessments  
• Monitor the subject until liver chemistries resolve , stabilize, or return to within baseline 
(see MONITORING below) 
• Do not restart/rechallenge subject with study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, GGT,  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:  


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• Repeat liver chemistries (include ALT, AST, GGT,  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) 
For subjects who have had IVIG in the past and with Hep B core IgG pos and Hep B sAB pos. 
additional safety monitoring procedures must be followed. HBVDNA testing must be done every 2 
months and when ALT or AST elevations increase > 2.5xULN during the study   
•  
• Blood sample for pharmacokinetic (PK) analysis, obtained within [insert time interval 
recommended by clinical pharmacokinetics representative] after last dose (PK sample 
may not be required for subjects known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  Not required for single-dose studies 
• Serum GGT, creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin2xULN 
• Obtain complete blood count with differential to assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on the concomitant medications report form 
including acetaminophen, herbal remedies, other over the counter medications 
• Record alcohol use on the liver event alcohol intake case report form 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: not required in China  


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• Liver imaging (ultrasound, magnetic resonance, or computerised tomography) and /or 
liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRF 
forms. 
 
 
Increased monitoring criteria with continued therapy 
Criteria 
• For subjects who have had IVIG in the past, additional HBVDNA testing must be 
completed when ALT or AST elevations increase to >2.5xULN during the study   
• If ALT 5xULN and <8xULN (without elevated CPK, and/or myoglobin) 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  (without elevated CPK, and/or myoglobin) and bilirubin 
<2xULN without symptoms believed to be related to liver injury or hypersensitivity, and 
who can be monitored weekly for 4 weeks 
• If ALT 5xULN and <8xULN (without elevated CPK, and/or myoglobin) and GGT is   
1.5xULN to < 3xULN 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  (without elevated CPK, and/or myoglobin) and GGT is   
1.5xULN to < 3xULN without symptoms believed to be related to liver injury or 
hypersensitivity, and who can be monitored weekly for 4 weeks 
 
Required Actions 
• Notify the Sponsor (Northwell Health) and 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, GGT, 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  5x ULN and <8xULN to ≥3xULN but <5xULN (without 
elevated CPK, and/or myoglobin) and GGT is   1.5xULN to < 3xULN, continue to 
monitor liver chemistries weekly.  
• 
If, after 4 weeks of monitoring, ALT <3xULN (without elevated CPK, and/or myoglobin) 
and bilirubin <2xULN and/or GGT is <2xULN, monitor subjects twice monthly until 
liver chemistries normalize or return to within baseline. 


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NOTE: If any of above rules are met, but the investigator feels that laboratory changes are 
due to myositis activity and not liver injury, the investigator will discuss with the Sponsor 
(Northwell Health) and GSK to determine the continuation of the subject in the protocol.