Clinical trial NCT04767698
Conditions: Multiple Sclerosis
Sponsor: Johns Hopkins University
Start date: 2021-10-01; Completion date: 2022-05-10
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multiple sclerosis is the most common inflammatory disease of the central nervous system and a common cause of disability in young adults. Depleting B cells from the circulation with an anti-cluster of differentiation (CD) 20 antibodies has proven to be an effective strategy in reducing relapses and disability in patients with the relapsing-remitting disease. However, continuous and long-term depletion of B-cells can result in reduced immunoglobulin levels, immunosuppression, and an increased tendency for severe infections and perhaps, even malignancy.

Blocking B-cell Activating Factor (BAFF) is effective for the treatment of several autoimmune disorders. Belimumab, a BAFF blocking antibody, has been approved by the Food and Drug Administration for the treatment of systemic lupus erythematosus. Belimumab has been shown to have immunomodulatory properties, without resulting in overt immunosuppression.

The investigators hypothesize that belimumab, given to patients who received a short course of treatment with B-cell depleting antibody (ocrelizumab), will be safe and equally effective in reducing MS disease activity (as compared to patients receiving continuous treatment with ocrelizumab); while resulting in less immunosuppression, as measured by antibody response to pneumococcal vaccination. Currently, available treatment strategies in relapsing MS sacrifice higher efficacy for long-term safety or vice versa. The proposed strategy in this application combines the long-term safety and high efficacy to treat patients with relapsing-remitting multiple sclerosis (RRMS) and, if eventually proven effective, can be adopted in a large proportion of patients with this chronic disease.

This is a randomized, open-labeled trial. Forty eligible participants will be randomized 1:1 to either receiving a form of standard of care, ocrelizumab (300 mg two infusions two weeks apart at baseline and then 600 mg as a single infusion every six months) or belimumab (200 mg subcutaneous (SC) weekly for 36 months) plus two courses of ocrelizumab (300 mg two infusions two weeks apart at baseline and 600 mg as a single infusion six months later). Co-primary outcomes of the study include pneumococcal vaccine antibody response, the return of MS disease activity, and proportions of patients with adverse events and serious adverse events.

Detailed description:

Arms: arm 1: Participants will receive Belimumab and Ocrelizumab. arm 2: Participants will receive Ocrelizumab only.
Interventions: intervention 1: Belimumab intervention 2: Short-course Ocrelizumab intervention 3: Continued Ocrelizumab
Intervention descriptions: intervention 1: 200 mg SC weekly for 36 months intervention 2: 300 mg, two infusions two weeks apart and then 600 mg as a single infusion after six months (only one time) (total of two courses of treatment) intervention 3: 300 mg, two infusions two weeks apart and then 600 mg as a single infusion every six months for a total of 36 months

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Page 1 of 25 
 
Addition of Belimumab to B cell depletion to produce 
prolonged remission of relapsing-remitting multiple 
sclerosis disease activity 
 
 
NCT04767698 
 
 
4/1/2022 


 
 
 
 
Page 2 of 25 
 
Date: __04/01/2022  __________________    
Principal Investigator: __Pavan Bhargava, MD; Bardia Nourbakhsh, MD, MAS_______________ 
Application Number: ___________ 
 
 
 
 
Addition of Belimumab to B cell depletion to produce prolonged remission of relapsing-
remitting multiple sclerosis disease activity 
 
 
1. 
Abstract 
Multiple sclerosis is the most common inflammatory disease of the central nervous system and a common 
cause of disability in young adults. Depleting B cells from the circulation with anti-CD20 antibodies has 
proven to be an effective strategy in reducing relapses and disability in patients with the relapsing-remitting 
disease. However, continuous and long-term depletion of B-cells can result in reduced immunoglobulin 
levels, immunosuppression and increased tendency for severe infections and perhaps, even malignancy.  
Blocking B-cell Activating Factor (BAFF) is effective for the treatment of several autoimmune disorders. 
Belimumab, a BAFF blocking antibody, has been approved by the Food and Drug Administration for the 
treatment of systemic lupus erythematosus. Belimumab has been shown to have immunomodulatory 
properties, without resulting in overt immunosuppression.  
We hypothesize that belimumab, given to patients who received a short course of treatment with B-cell 
depleting antibody (ocrelizumab), will be safe and equally effective in reducing MS disease activity (as 
compared to patients receiving continuous treatment with ocrelizumab); while resulting in less 
immunosuppression, as measured by antibody response to pneumococcal vaccination. Currently, available 
treatment strategies in relapsing MS sacrifice higher efficacy for long-term safety or vice versa. The 
proposed strategy in this application combines the long-term safety and high efficacy to treat patients with 
RRMS and if eventually proven effective, can be adopted in a large proportion of patients with this chronic 
disease. 
 
2. 
Objectives  
 
Objectives 
Endpoints 
Co-primary 
 Pneumococcal vaccine antibody 
response: To estimate the difference 
between the pneumococcal titer in 
the 
serum 
four 
weeks 
after 
immunization 
with 
a 
23-valent 
pneumococcal vaccine administered 
at month 24 of the study 
The proportion of patients with positive antibody responses to 
>=1 of the 23 pneumococcal vaccine serotypes 
measured four weeks post-vaccination. A positive antibody 
response is defined as a two-fold 
increase from pre-vaccination levels against >=1 of 
the 23 pneumococcal serotypes measured. 


 
 
 
 
Page 3 of 25 
 
 
 
 
Safety: To assess the difference in 
safety and tolerability between the 
two treatment groups at month 24 
 
 
 
AEs and  SAEs,  including AEs  of  special  interest 
(opportunistic infections, herpes zoster, malignancies, 
hypersensitivity  and  infusion  reactions, suicidal ideation, 
intent or behavior and  all-cause mortality); Incidence  and  
severity  of all  infections  and  serious infection; all 
assessed by month 24  
Secondary and Exploratory 
 
 
 
To assess the difference in safety 
and tolerability between the two 
treatment groups at month 36 
AEs  and  SAEs,  including AEs  of  special  interest 
(opportunistic infections, herpes zoster, malignancies, 
hypersensitivity  and  infusion  reactions, suicidal 
ideation, intent or behavior, and  all-cause mortality); 
Incidence  and  severity  of all  infections  and  serious 
infection; Change   from   baseline   and   number   of   
subjects outside  the  normal  range  for clinical  
chemistry and hematology parameters, with particular 
attention to white blood cell count and 
immunoglobulin levels; all assessed by month 36 
To estimate the difference between 
the two treatment groups in pro / 
anti-inflammatory cytokine ratio of 
repopulating B-cells at month 36 
GM-CSF/IL-10 and IL-6/IL-10 ratio (produced by 
stimulated repopulated B-cells at month 36. 


 
 
 
 
Page 4 of 25 
 
Assessment of return of disease 
activity by month 24 and 36 
Return of the disease activity, as objectively 
demonstrated by development of new T2 
hyperintense lesions or Gd-enhancing lesions on 
the MRI (noted on a scan performed more than six 
months after treatment initiation) or a clinical 
relapse, defined as new or worsening neurologic 
symptom(s) with an objective change on the EDSS 
of at least 1.5 points for participants with baseline 
EDSS scores of 0 or 0.5 and at least 1-point 
change for participants with EDSS of 1 or more, 
as determined by the examining neurologist. 
Symptoms must have been attributable to MS, last 
≥48 hours, been present at normal body 
temperature, and preceded by at least 30 days of 
clinical stability. 
Assessment 
of 
clinical 
disease 
activity by month 24 and 36  
 
 
 
 
 
 
 
Annualized relapse rate (ARR) by month 24 and 
36. 
A clinical relapse is defined as  new or worsening 
neurologic symptom(s) with an objective change 
on the EDSS of at least 1.5 points for participants 
with baseline EDSS scores of 0 or 0.5 and at least 
1-point change for participants with EDSS of 1 or 
more, as determined by the examining 
neurologist. Symptoms must have been 
attributable to MS, last ≥48 hours, been present at 
normal body temperature, and preceded by at 
least 30 days of clinical stability. 
Assessment of disability progression 
by month 24 and 36 
Change in MSFC at month 24 and 36 as compared 
to baseline  
Three-month confirmed increase in EDSS by 
month 24 and 36  
Three-month confirmed decrease in EDSS by 
month 24 and 36 
Assessment of radiological disease 
activity by month 24 and 36 
Presence of any new Gd-enhancing lesions on an 
MRI obtained after the baseline 
Presence of any new or enlarging T2 lesions on an 
MRI compared to the MRI obtained at month 6 
Assessment of a serum biomarker of 
neuroaxonal degeneration by month 
24 and 36 
Change in serum NfL at month 24 and 36 
compared to baseline 


 
 
 
 
Page 5 of 25 
 
Analysis of B cell sub-populations 
and T cell function 
Change in naïve, transitional and memory B cells 
from baseline to month 24 and 36 
 
Change in the expression of co-stimulatory and 
antigen presentation molecules on B cells from 
baseline to month 24 and 36 
 
Change in T cell memory subsets and pro-
inflammatory cytokine production (Th1 & Th17) 
from baseline to month 24 and 36 
 
 
3. 
Background  
Multiple sclerosis is the most common inflammatory disease of the central nervous system1. The antibody-
independent pathogenic role of B-cells in multiple sclerosis (MS) has been clearly demonstrated by a 
profound and rapid cessation of inflammatory disease activity in patients with MS who receive B-cell 
depleting anti-CD20 monoclonal antibodies2. Currently, the standard of care is to indefinitely continue B-
cell depleting therapies in MS since we do not know whether a sustained remission of disease activity can 
be attained with a limited duration of B cell depletion. This approach, while providing high efficacy, in 
terms of preventing disease relapses, is also associated with greater risks such as infections and 
malignancy2,3.   
 
However, some previous data suggest that a prolonged remission may be possible following a short course 
of B cell depletion, and one hypothesis for this effect of B-cell depletion is that reconstituting B-cells 
demonstrate a decrease in pro-inflammatory (IL-6 and GM-CSF) and an increase in anti-inflammatory 
(IL-10) cytokine production4. This shift in B cell phenotype has effects on both the myeloid and T cell 
compartments and could prevent relapse of disease activity even after B cell reconstitution5. Studies 
demonstrating this shift observed these changes in early reconstitution – at which time the balance of naïve 
to memory B cells had been shifted towards the former, possibly explaining the skewed cytokine profiles 
(since inflammatory cytokines are predominantly produced by memory B cells). Long-term data post B 
cell cessation is lacking, and hence it is unclear whether memory cells that produce GM-CSF and IL-6 
would eventually return and lead to new inflammatory disease activity.  
 
BAFF is critical for the proliferation and development of B cells6. Belimumab is a humanized monoclonal 
antibody that binds to BAFF and prevents its effects at the BAFF-, BCMA- and TACI receptors. 
Belimumab is currently FDA approved for the treatment of SLE – a condition with elevated BAFF levels. 
In MS, elevated levels of BAFF in the CSF have been linked to greater cortical lesion load. Additionally, 
BAFF levels are elevated in the setting of B cell depletion therapy, and the effects of this elevation on the 
immunophenotype of reconstituting B cells are unknown5.  In a recent study in renal transplantation 
belimumab, in addition to standard treatment, demonstrated a trend towards a reduction in naïve B cells, a 
reduction in memory B cells and an increase in the ratio of IL-10 to IL-6 in both memory and transitional 
B cells7. Additionally, blocking BAFF in vitro led to an increase in IL-10 production even from memory B 
cells7. These effects would be expected to be beneficial in MS based on the effects of B cell depletion, as 
well as other disease-modifying therapies that reduce MS disease activity8.    
 
A recent trial of tabalumab in RRMS (NCT00882999) that was reported at the 2018 AAN meeting showed 
no increase in disease activity in the Tabalumab group compared to placebo – based on the primary 
outcome of Gd-enhancing T1-weighted lesions. Data was posted to clinicaltrial.gov in late 2018 and there 
appears to no serious safety signal in any of the tabalumab groups, with an apparently lower ARR noted in 
the tabalumab groups. Also, there was a decrease in the mature naïve B cell number with tabalumab 
treatment with smaller reductions in the memory B cells. Based on this data, we would hypothesize that 


 
 
 
 
Page 6 of 25 
 
blocking BAFF in MS would be safe unlike the neutralization of APRIL that led to increased disease 
activity9.  
Patients with MS who receive immunomodulatory and immunosuppressive therapies are at increased risk 
of infections. As a result, vaccination against pathogens is an important part of the management of patients 
with MS receiving DMTs. However, immunization response is lower in many patients who receive 
immunosuppressive therapies. For example, long-term B-cell depletion in patients with rheumatoid 
arthritis receiving rituximab has been shown to impair vaccination response to non-T-cell dependent 
antigens10. In contrast, belimumab had no detrimental effect on immunization response with non-T-cell 
dependent antigens in patients with systemic lupus erythematosus11.  
 
We hypothesize that belimumab, given to patients who received a short course of treatment with B-cell 
depleting antibody (ocrelizumab), will be safe and equally effective in reducing the MS disease activity (as 
compared to patients receiving continuous treatment with ocrelizumab); while resulting in less 
immunosuppression, as measured by antibody response to pneumococcal vaccination. Currently, available 
treatment strategies in relapsing MS sacrifice the high efficacy for long-term safety or vice versa. The 
proposed strategy in this application combines the long-term safety and high efficacy of treating patients 
relapsing MS and can be adopted in a large proportion of patients with this chronic disease.    
We propose an open-label experimental medicine trial to assess the safety and activity of adding 
belimumab to a short course of ocrelizumab in patients with active RRMS. 
 
 
 
 
4. 
Study Procedures 
 
A. Study design, including the sequence and timing of study procedures   
 
This is an open-label, randomized, single center trial. Patients fulfilling the eligibility criteria will be 
randomized 1:1 to either receiving a form of standard of care, ocrelizumab (300 mg two infusions two 
weeks apart at baseline and then 600 mg as a single infusion every six months if ocrelizumab-naïve; 
continued 600 mg infusions every six months if already on ocrelizumab) or belimumab (200 mg SC weekly 
for 36 months) plus two courses of ocrelizumab (300 mg two infusions two weeks apart at baseline and 600 
mg as a single infusion six months later if ocrelizumab-naïve; scheduled next two 600 mg infusions six 
months apart if already on ocrelizumab). In the group receiving belimumab, belimumab will be initiated 
four weeks before the first infusion of ocrelizumab or four weeks before the next scheduled ocrelizumab 
infusion if they are already on ocrelizumab. The belimumab group will only receive two courses of 
ocrelizumab (three infusions if ocrelizumab-naive), while the continued ocrelizumab group will continue 
with ocrelizumab infusions every six months throughout the study. If a recruited participant was on an MS 
disease-modifying treatment other than ocrelizumab, there will be at least 30 days of washout between 
stopping the disease-modifying treatment and the start of the study medication (either belimumab or 
ocrelizumab). Given the current COVID19 pandemic, we will recommend one dose of Evusheld 
(tixagevimab/cilgavimab) – two human monoclonal antibodies against the spike protein of SARS-Cov-2 
administered via two separate intramuscular injections – to participants that are already on ocrelizumab and 
have not received a booster dose or received at least one of the doses while on ocrelizumab, as a 
prophylaxis against COVID-19 infection. 
 
 
 
 
 
 


 
 
 
 
Page 7 of 25 
 
 
 
Timeline of ocrelizumab-naïve participants 
 
 
 
Timeline of participants already on ocrelizumab 
 
 
The evaluation will include a screening visit, then monthly clinic visits for the first six months that will 
incorporate the use of remote safety visits, then every three months for 36 months.  The participants will 
undergo research brain MRIs with gadolinium-based contrast agent (ProHance®) every six months. The 
baseline (month 0) time in the belimumab group is the time of the start of belimumab and in the continued 
ocrelizumab group, the first infusion of the ocrelizumab or the next scheduled ocrelizumab infusion if the 
participant has been already on ocrelizumab and fulfills the eligibility criteria. So, in the belimumab group, 
in which belimumab starts one month before the first ocrelizumab infusion or one month before the next 
scheduled ocrelizumab infusion if the participant has been already on ocrelizumab, the ocrelizumab 
infusions will happen in the months one and seven.  
 
All ocrelizumab infusions, in both groups, are considered standard of care (and according to the medication 
label) and will be done as part of routine clinical care.  
 
 
 


 
 
 
 
Page 8 of 25 
 
 
Schedule of Activities 
 
Schedule of activities in the belimumab group 
Visit activity 
Screening 
Baseline 
(Month 0) 
Months 1 and 7 
ocrelizumab 
infusions 
 
 
 
Safety Visits 
Month 1, 2, 4, 5 
Follow-up visits 
(clinical 
monitoring) 
Month 3,9,15,21, 
27, 33 
Follow-up visits 
(MRI monitoring) 
Month 6, 12, 18, 24, 
30 
Month 24 and 25 
vaccination and 
antibody 
assessment  
End-of-study     
 
Month 36 
Informed consent, 
screening/baseline 
evaluation 
X 
 Medical history, 
relapse assessment 
X 
 
 
X 
X 
X 
 
X 
MRI review 
X 
 
 
 
 
X 
 
X 
Medication review 
X 
 
 
X 
X 
X 
 
X 
Blinded EDSS 
X 
 
 
 
X 
X 
 
X 
MS Functional 
Composite 
(MSFC)  
X 
 
 
 
X 
X 
Visit Activity 
Screening 
Baseline 
(Month 0) 
Months 1 and 7 
Ocrelizumab 
infusions 
Safety Visits 
Month 1, 2, 4, 5 
Follow up Visits 
(clinical 
monitoring) Month 
3, 9, 15, 21, 27, 33 
Follow up visits 
(MRI monitoring) 
Month 6, 12, 
18, 24, 30 
Month 24 and 25 
vaccination and 
antibody 
assessment 
End-of-study     
 
Month 36 
Symbol Digit 
Modalities Test 
X 
 
 
 
 
X 
 
 
Brain MRI 
X 
 
 
 
 
X 
 
X 
Phlebotomy for 
serum and PBMC 
collection  
X 
 
 
 
 
X 
 
X 
Safety/ Adverse 
event assessment 
 
 
 
X 
X 
X 
 
X 
Safety labs 
X 
(S) 
 
 
X 
X 
X 
 
 
Start of belimumab 
injections 
 
X 
 
 
 
 
 
 
Ocrelizumab 
infusions 
 
 
X 
 
 
 
 
 
Pneumococcal 
vaccination and 
antibody test  
 
 
 
 
 
 
X 
 
 
 


 
 
 
 
Page 9 of 25 
 
 
Schedule of activities in the continued ocrelizumab group 
 
 
Visit activity 
Screening 
Baseline 
(month 0) 
Safety Visits 
Month 1, 2, 4, 5 
Follow-up visits 
(clinical 
monitoring) 
Month 3,9,15,21, 
27, 33 
Month 6 
ocrelizumab 
infusion  
Follow-up visits 
(MRI monitoring) 
Month 6, 12, 18, 
24, 30 
Month 24 and 25
vaccination and 
antibody  
assessment 
End-of-study     
 
Month 36 
Informed consent, 
screening/baseline 
evaluation 
X 
 Medical history, 
relapse assessment 
X 
 
X 
X 
 
X 
 
X 
MRI review 
X 
 
 
 
 
X 
 
X 
Medication review 
X 
 
X 
X 
 
X 
 
X 
Visit Activity 
Screening 
Baseline 
(Month  0) 
Safety Visits 
Month 1, 2, 4, 5 
Follow-up visits 
(clinical 
monitoring) 
Month 3, 9, 15, 
21, 27, 33 
Month 6 
ocrelizumab 
infusion 
Follow-up visits 
(MRI monitoring) 
Month 6, 12, 
18, 24, 30 
Month 24 and 
25 
vaccination and 
antibody 
assessment 
End-of-study     
 
Month 36 
Blinded EDSS 
X 
 
 
X 
 
X 
 
X 
MS Functional 
Composite 
(
S C)
X 
 
 
X 
 
X 
Symbol Digit 
Modalities Test 
X 
 
 
 
 
X 
 
 
Brain MRI 
X 
 
 
 
 
X 
 
X 
Phlebotomy for 
serum and PBMC 
collection  
X 
 
 
 
 
X 
 
X 
Safety/ Adverse 
event assessment 
 
 
X 
X 
 
X 
 
X 
Safety labs 
X 
(S) 
 
X 
X 
 
X 
 
X 
Ocrelizumab 
infusion 
 
X 
 
 
X 
X 
 
X 
Pneumococcal 
vaccination and 
antibody test 
 
 
 
 
 
 
X 
 
 
 
Labs and assessments include: 
1. Vital signs assessed and recorded at screening, at baseline, and each visit immediately before 
infusion and during infusion. 


 
 
 
 
Page 10 of 25 
 
 
2. Complete blood count with differential (CBC), at screening, baseline and monthly through the first 
six months and then every three months. 
 
3. Chemistry at screening, baseline, and monthly through the first six months and then every three 
months. 
 
4. Pregnancy testing for WCBP and results before each dosing.  
Urine or serum pregnancy testing acceptable 
1. Timing of pregnancy test must be < 7 days before first dose 
2. Pregnancy testing- at each follow-up visit and safety visit  
3. At least four months (5 half-lives) post last dose 
 
5. LFT frequency: at screening, baseline, and monthly through the first six months and then every 
three months. 
 
6. Serum IgG:  at screening, baseline, and at monthly through the first six months and then every three 
months. 
 
 
7.  HIV and hepatitis B and C serologies and tuberculosis (T-spot or Quntiferon Gold): at screening. 
 
8. Suicidality assessed at screening, baseline and every visit using the Columbia Suicide Severity Rating 
Scale (CSSRS http://www.cssrs.columbia.edu/)  
 
 
B. Study duration and number of study visits required of research participants 
 
Participants will be in the study for 36 months. The total number of study visits required is 19 – not 
including any unscheduled visits.  
 
 
C. Blinding, including the justification for not blinding the trial. 
 
This is an open-label trial. One of the main reasons for this design is practical considerations – since 
blinding would require placebo infusions every 6 months in one arm in addition to administration of 
steroids and anti-histaminic medications before these placebo infusions – which are logistically challenging 
to set up and could potentially expose patients to unnecessary harm.  
 
The other important consideration is that the majority of outcomes are not subjective – vaccine response, 
imaging, and immunological outcomes and hence would not be significantly affected by the lack of 
blinding. Additionally, for more subjective outcomes, we will have independent assessing and treating 
physicians to help avoid bias.  
 
 
D. Description of what happens to participants receiving therapy when the study ends or if a  
     participant’s participation in the study ends prematurely. 
 
At the end of the trial, participants in the continuous ocrelizumab arm will continue treatment with this 
agent. Participants in the belimumab arm will be transitioned to an alternative disease-modifying therapy 
by their treating physician based on a discussion of various available options.  


 
 
 
 
Page 11 of 25 
 
 
If participants are removed or leave the study prematurely from either arm, they will be transitioned to an 
alternative disease-modifying therapy by their treating physician based on a discussion of risk versus 
benefit profile of various available options.  
 
E. Definition of treatment failure or participant removal criteria. 
 
Participant participation in the study may be terminated for the following reasons or if the investigator 
deems it to be in the best interest of the patient.  
 
- 
Develop of PML or other opportunistic infection (see Risks section below) 
- 
Develop abnormal liver functions as detailed below 
- 
New infection with hepatitis B, hepatitis C, HIV or TB detected on routine safety testing 
- 
Develop breakthrough MS disease activity (see below) 
- 
Hypersensitivity to any of the study agents 
- 
Pregnancy   
- 
Develop suicidal ideation, intent or behavior 
 
 
• 
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). 
 
• 
IP should be discontinued if any of the following criteria are met   
• 
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 the 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 
 
▪ 
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 


 
 
 
 
Page 12 of 25 
 
 
Actions: 
 
• 
Immediately discontinue study treatment 
 
• 
Report the event to GSK within 24 hours 
 
• 
Perform liver event follow up assessments (as stated below) 
 
• 
Monitor the subject until liver chemistries resolve, stabilize, or return to within baseline (see MONITORING 
below) 
 
• 
Do not rechallenge the subject with study treatment. 
• 
In the event that liver stopping criteria are met as a result of DILI, or if there is any reasonable likelihood that 
the liver event is related to study treatment, IP may not be resumed (i.e., rechallenged). 
In the occasional circumstance in which there is a clear underlying cause, other than drug-induced liver injury 
(DILI) of the liver stopping event (e.g., biliary obstruction, pancreatic events, hypotension, acute viral hepatitis), 
with evidence of resolution, and compelling evidence of benefit from belimumab, restart of investigational 
product (IP) may be considered, but only following consultation with GSK medical affairs Physician or PPL and 
GSK GCSP Physician.  [It should be noted that internal GSK governance processes would be required prior to 
permitting the resumption of IP]. GSK will communicate the outcome of an internal review to Study Sponsor.  
Restart is not permitted following liver stopping event when the underlying cause was alcohol-related.  
 
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 
 


 
 
 
 
Page 13 of 25 
 
• 
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 computerized tomography) and /or liver biopsy to evaluate 
liver disease 
 
 
 
Increased Monitoring Criteria with Continued Therapy 
 
Criteria 
  
 
• 
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. 
 
In the event of Treatment Restart (Appendix 2) 
 
• 
Liver chemistries must be followed at least once weekly following study treatment restart until stable liver 
chemistries have been demonstrated and then standard laboratory monitoring may resume as per protocol. 
 
• 
If after study treatment restart participant again meets protocol-defined liver chemistry stopping criteria, 
study treatment must be permanently discontinued. 
 
Additional stopping criteria 
 


 
 
 
 
Page 14 of 25 
 
Participants in the belimumab arm who experience a relapse (as defined in Section 8 under criteria for 
initiation of rescue medication) and begin rescue medication (ocrelizumab 600 mg every 6 months) will 
stop further treatment with belimumab.   
 
 
 
 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion criteria:  
• 
Diagnosis of RRMS based on McDonald criteria 2017 
• 
Age > 18 
• 
A clinical relapse in the past 12 months OR an enhancing lesion on brain/ spinal cord MRI 
in the past 6 months OR a new T2/FLAIR/STIR lesion on a brain/spinal cord MRI obtained 
in the past 6 months (compared to a previous MRI obtained within one year from the latest 
MRI). This criterion does not apply to the subgroup of people that are already on 
ocrelizumab.  
• 
Female Subjects: Not pregnant or nursing and at least one of the following conditions apply: 
a. Non- childbearing potential defined as pre-menopausal females with a documented tubal 
ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous 
amenorrhea. b. Child-bearing potential and agrees to use one of the contraception methods 
as described by the investigator or designee, from Day 0 until 24 weeks after the last dose of 
study medications (See details below). 
• 
Liver function at the time of screening: alanine aminotransferase (ALT) < 2x upper limit of 
normal (ULN); bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%). 
• 
Fully vaccinated against COVID-19 defined as 2 weeks after the second dose in a 2-dose 
series RNA vaccines (such as the Pfizer or Moderna vaccines) or 2 weeks after a single-dose 
viral vector vaccine (such as Johnson & Johnson’s Janssen vaccine).  
Exclusion criteria:  
• 
Prior therapy: 
- 
Currently on ocrelizumab and the first dose of ocrelizumab was given more than two 
years before the screening visit) [patients whose last MS DMT was ocrelizumab and the 
first dose of ocrelizumab was given within two years prior to the screening visit can be 
eligible for this study] 
- 
Has ever received any of the following B-cell targeted therapy: rituximab, other anti-
CD20 agents besides ocrelizumab, anti-CD22 (epratuzumab), anti-CD52 (alemtuzumab), 
BLyS-receptor fusion protein (BR3), TACI fragment, crystallizable (Fc), or belimumab 
• 
Prior use of cladribine, mitoxantrone, cyclophosphamide or HSCT  
• 
Lymphopenia: a lymphocyte count <500/ millimeter (mm)^3 
• 
Neutrophils <1.5X10E9/L. 
• 
Drug sensitivity: a history of sensitivity to any  of  the  study  medications,  or  components  
thereof  or  a history of drug or other allergies including a previous anaphylactic reaction to 
parenteral administration contrast agents, human or murine proteins or monoclonal 
antibodies 
• 
Treatment with steroids in the last 30 days  
• 
Clinically unstable medical or psychiatric disorder 


 
 
 
 
Page 15 of 25 
 
• 
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, poses a significant suicide risk 
• 
Have a history of an anaphylactic reaction to parenteral administration of contrast agents, 
human or murine proteins or monoclonal antibodies 
• 
Substance abuse: has evidence of current drug or alcohol abuse or dependence 
• 
365 Day prior therapy: has received a biologic investigational agent other than B-cell 
targeted therapy [e.g., abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC 131; 
investigational agent applies to any drug not approved for sale in the country in which it is 
being used] 
 
• 
30 Day prior therapy: has received any of the following within 30 days before Day 0: a) Any 
other MS disewasew-modifying therapy, not mentioned above (including fumaric acid 
esters, S1P receptor modulators, teriflunomide, and natalzimaub). Glatiramer acetate and 
interferons are permitted up to the day of starting the investigational medication  . 
Intravenous, oral, and Inhaled steroids and new topical immunosuppressive agents (e.g., eye 
drops, topical creams) are allowed. 
• 
30 Day prior therapy: has received a live virus vaccine or a non-biologic investigational 
agent.  
• 
Malignancy: has a history of malignancy in the past 5 years except for adequately treated 
cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix. 
• 
Have a history of a primary immunodeficiency 
• 
Have a significant IgG deficiency (IgG level < 400 mg/dL)  
• 
Have an IgA deficiency (IgA level < 10 mg/dL) 
• 
Infection history: 
- 
Currently on any suppressive therapy for chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical 
mycobacteria) 
- 
Hospitalization for treatment of infection within 60 days of Day 0. 
- 
Use of parenteral (IV or IM) antibiotics (anti-bacterial, antiviral, anti-fungal, or anti-
parasitic agents) within 60 days of Day 0 
• 
Other disease/conditions: has any of the following: a) clinical evidence of significant 
unstable or uncontrolled acute or chronic diseases (i.e., cardiovascular, pulmonary, 
hematologic, gastrointestinal, hepatic, neurological, malignancy or infectious diseases) 
which, in the opinion of the investigator, could confound the results of the study or put the 
subject at undue risk; b) a surgical procedure planned in the 6 months after Day 0; c) a known 
history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or 
condition (e.g., poor venous access) that, in the opinion of the investigator, makes the subject 
unsuitable for the study 
• 
Hepatitis status: 
- 
Serologic evidence of current or past Hepatitis B (HB) infection based on the 
results of testing for HBsAg and HBcAb as follows: Patients positive for HBsAg 
or HBcAb are excluded 
- 
A positive test for Hepatitis C antibody 
• 
HIV: known to have a historically positive HIV test or tests positive at screening for HIV. 
• 
Laboratory abnormalities: has an abnormal laboratory assessment, which is judged clinically 
significant by the investigator. 
• 
Drug Sensitivity: has a history of sensitivity to any of the study medications, or components 
thereof or a history of drug or other allergies including a previous anaphylactic reaction to 
parenteral administration contrast agents, human or murine proteins or monoclonal 
antibodies that, in the opinion of the investigator or Medical Monitor, contraindicates their 


 
 
 
 
Page 16 of 25 
 
participation. 
• 
Any contraindication to undergoing MRI 
• 
TB: tests positive at screening for tuberculosis. 
• 
History of severe allergic reaction after a previous dose of the 23-valent pneumococcal 
vaccines, and history of a severe allergy to any component of this vaccine. 
• 
Impaired decision making capacity or impaired ability to provide informed consent. 
 
 
Contraception Requirements 
 
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%. 
Abstinence 
Abstinence from penile-vaginal intercourse must be consistent with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
 
Contraceptive Methods with a Failure Rate of < 1% 
• Oral contraceptive, either combined or progestogen alone 
• Injectable progestogen 
• Implants of etonogestrel or levonorgestrel 
• Estrogenic vaginal ring 
• Percutaneous contraceptive patches 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <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 
• 
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent (foam/gel/film/cream/suppository) 
 
 
6. 
Drugs/ Substances/ Devices 
Ocrelizumab: Participants, in both groups will receive ocrelizumab, an FDA-approved 
medication for the treatment of relapsing forms of MS, according to the medication label. One 
group will stop the infusions after two courses and one group will continue the infusions every 
six months through the end of the study. Overall, ocrelizumab is administered as an FDA-
approved medication according to its label in this study. 
 
Belimumab: The common name of the investigational product is BENLYSTA. The generic 
United States Adopted Name / International Non-Proprietary Name (USAN/INN) is belimumab; 
the GlaxoSmithKline (GSK) code for the drug is GSK1550188. 
 
Belimumab drug product for subcutaneous (SC) use will be provided as a liquid formulation in 
sterile prefilled syringes assembled into two different devices. For the prefilled syringe 
presentation, belimumab liquid is filled into USP Type I glass syringes with a staked needle (27-
gauge thin wall), sealed with a latex-free rubber stopper, and stored at 2 to 8C protected from 
light. The liquid prefilled syringes are also assembled into two devices: (1) a safety shielding 
device and (2) an autoinjector device.  
 


 
 
 
 
Page 17 of 25 
 
Belimumab will be supplied as 1 mL prefilled syringe containing 200 mg liquid belimumab 
(200 mg/mL). The medication will be administered subcutaneously once a month (starting at 
baseline).  The first subcutaneous injection of belimumab will be under the supervision of a 
healthcare professional. Subjects will remain under clinical supervision for 3 hours thereafter.  
 
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. after the first supervised injection 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.  After the first dose, 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 (e.g., a caregiver) to administer the subcutaneous injection.  
 
Patients or their caregivers will not administer the study agent until they receive proper training 
in subcutaneous injection technique. 
 
Subjects will 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 the event of its development. 
 
COVID-19 booster shot: It is possible that during the course of the study, a COVID-19 booster 
shot will be recommended to the participants due to the immunosuppressive nature of the 
medications. Several studies have shown that people with MS that take ocrelizumab have an 
impaired antibody response to COVID-19 vaccines compared to the general population12,13. 
There is not enough information about belimumab and the effectiveness of the vaccines, but 
based on its immunomodulatory action it may have an impact on it.  
 
 
7. 
Study Statistics 
Sample size calculations: based on Chatham et al. and Bingham et al. more than 95% of 
belimumab-treated SLE patients responded to pneumococcal vaccination, while only 55% of 
patients of rituximab-treated RA patients mounted a response against pneumococcal antigens.   
Assuming 95% antibody response in the belimumab group and 55% antibody response in the 
continuous ocrelizumab group, 14 participants in each group will provide 80% power (with an 
alpha of 0.05) to show a difference between the two groups. We will plan on 20 participants per 
arm to account for dropouts (anticipated rate is approximately 20%).  
 
Analysis plan for primary, secondary and exploratory outcomes: 
No formal statistical hypotheses will be tested in this study. Because the study includes no 
prospectively defined formal hypothesis testing, no adjustment for multiplicity will be required 
for the primary and secondary endpoints. 
 
Primary outcome variables 
Response to pneumococcal vaccination - One of the primary endpoints of the study is the 
proportion of patients with positive antibody responses to >=1 of the 23 pneumococcal vaccine 
serotypes measured four weeks post-vaccination. A positive antibody response is defined as a 
two-fold increase from pre-vaccination levels against >=1 of the 23 pneumococcal serotypes 
measured. For patients with unquantifiable pre-vaccination levels, a positive antiboy response is 


 
 
 
 
Page 18 of 25 
 
considered to be a post-vaccination level of >0.6 mg/mL (>2-fold increase above the lower limit 
of quantification [>0.3 mg/mL] for this assay).  
 
Safety - The other co-primary endpoint is the proportion of participants experiencing an AE/ 
SAE. We will use chi-square test to compare the proportions between the two groups.  
 
Secondary outcome variables 
 
Disease activity – Measured by Annualized relapse rate (ARR). A clinical relapse is 
defined as a new or worsening neurologic symptom(s) with an objective change on the 
EDSS of at least 1.5 points for participants with baseline EDSS scores of 0 and at least 
1-point change for participants with EDSS of 1 or more, as determined by the 
examining neurologist. Symptoms must have been attributable to MS, last ≥48 hours, 
been present at normal body temperature, and preceded by at least 30 days of clinical 
stability. 
 
 
Disability progression – Measured by the change in MSFC scores, EDSS scores and by the 
proportion of patients in each group that demonstrate a worsening of their EDSS score 
(sustained for three months).  
 
Radiological disease activity – Measured by the number of new Gd-enhancing lesions on any 
scan following the baseline or the number of new/ enlarging T2 lesions on any scan as 
compared to the month-6 MRI brain.   
 
Immunological outcomes – Measured by the proportion of various B cell subsets – naïve. 
transitional or memory, and the expression of co-stimulatory and antigen presentation related 
molecules on B cells. For T cells, this would be measured as the proportion of various T cell 
subsets – naïve, effector, effector memory or central memory and the expression of various 
cytokines (IFNg, IL-17, and GM-CSF).  
 
The majority of secondary and exploratory analyses will utilize a mixed model for repeated 
measures approach with fixed categorical effects of treatment, visit, and treatment-by-visit 
interaction and fixed continuous covariates of baseline values and baseline values-by-visit 
interaction. An unstructured covariance structure will be used to model the within-patient errors, 
shared across treatments. 
 
 
 
8. 
Risks  
 
Currently, B-cell depleting agents such as ocrelizumab are utilized in relapsing-remitting MS on a continual basis 
(every 6 months infusion indefinitely). While this is an effective strategy in terms of reducing inflammatory disease 
activity (clinical or radiographic), the adverse effects include increased risk for infections (URI, herpes viral 
infections, reactivation of hepatitis B14), hypogammaglobulinemia, reduced efficacy of vaccines and possibly 
increased malignancy risk2,15. This trial will assess the ability of belimumab therapy as an add-on to ocrelizumab to 
produce a prolonged remission of multiple sclerosis disease activity in the setting of discontinuation of B-cell 
depletion (to avoid these long-term adverse effects).  
 
Potential Risks:  


 
 
 
 
Page 19 of 25 
 
The major concerns for a strategy of discontinuation of B cell therapy along with belimumab treatment would include 
the return of inflammatory disease activity or increased immunosuppression-related complications. Risk mitigation 
strategies are listed below for each of these aspects.  
 
• 
Disease activity 
There is a potential for the return of disease activity following cessation of B cell depletion and B cell reconstitution. 
Hence, we would need to monitor closely for increased/ return of disease activity in both study arms with both 
clinical and imaging metrics.    
• 
This would occur clinically in trial visits as judged by the treating physician – every three months and at 
unscheduled visits as needed  
• 
Using MRI to look for the presence of new T2/ T1 Gd-enhancing lesions - every six months during the study.  
The overall risk is low given prior data from a phase-2 study using ocrelizumab and intensive monitoring is likely to 
identify recurrence of inflammatory disease activity and institute rescue therapy to prevent further relapses and 
progression of the disease. Additionally, given the increased relapse rate noted in the ATAMS trial9, there is a 
theoretical risk of worsening of inflammatory disease activity with belimumab. This is mitigated by the additional 
treatment with ocrelizumab and the recent data from the trial of tabalumab in RRMS which showed no worsening of 
disease activity at five different doses of tabalumab.  
 
See the criteria for beginning rescue medication below.  
 
• 
Complications related to immunosuppression 
We will also closely monitor patients for infectious complications at each study visit or at unscheduled visits as 
needed.  
We will include an infectious diseases expert on the DSMB to assist with decisions regarding the association of any 
detected infections with belimumab.    
 
• 
Suicidality 
 
Some autoimmune diseases have an increased risk of suicidal behavior and/or ideation [Bachen, 2009; Timonen, 
2003; Stenager, 1992].  In a recent one-year, randomized, double-blind, placebo-controlled post-marketing study 
(BEL115467) of 4,003 subjects with SLE (1:1 randomization): 
 
o 
Serious adverse events (SAE) of suicidal ideation or behavior or self-injury were reported in 0.7% (n= 15) of 
subjects receiving belimumab intravenously 10mg/kg (IV) vs. 0.2% (n=5) of subjects taking placebo. 
 
o 
No suicide-related deaths were reported. 
 
o 
SAEs of depression were reported in 0.3% (n=7) of subjects receiving belimumab 10mg/kg IV vs. <0.1% 
(n=1) taking placebo. 
 
o 
On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (n=48) subjects on belimumab 10mg/kg IV 
reported suicidal ideation or behavior and 2.0% (n=39) subjects on placebo reported suicidal ideation or behavior 
 
For this reason, patients should be clinically assessed for suicidal ideation and/or behavior at each visit. 
 
• 
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, the 
study agent should be discontinued and consideration should be given to stopping immunosuppressant therapy. 
 


 
 
 
 
Page 20 of 25 
 
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. 
 
 
Rescue Medication and criteria for initiation 
Participants that have evidence of clinical or radiological breakthrough as noted below will receive rescue medication 
– Ocrelizumab 600 mg every 6 months. Additionally, participants will also receive steroids for the treatment of 
relapses as determined by their treating neurologist. 
 
Criteria for beginning rescue medication (ocrelizumab) include:  
1) a confirmed clinical relapse (as defined above) 
 
or 
  
2) presence of new T2/ Gd-enhancing lesions on an MRI more than six months after beginning the trial.  
This will ensure that patients who have a return of disease activity are treated in a timely manner to prevent any 
worsening of their lesion load. Belimumab treatment will be discontinued if a participant in the belimumab arm 
requires rescue medication.   
 
Stopping rules for the study: 
If more than 4 participants in  belimumab plus ocrelizumab arm require re-treatment with ocrelizumab during the 
follow-up period, we will put the trial on hold until the DSMB can convene and decide whether the trial can 
continue. 
 
If there is an occurrence of an opportunistic infection that has not previously been linked to B cell depletion in the 
belimumab arm, this would lead to immediate cessation of the study until reviewed by the DSMB.  
 
Additionally, any deaths that are potentially linked to the use of belimumab will also lead to cessation of the study 
pending review by the DSMB. 
 
 
Data safety monitoring board: 
The study will also include a data safety monitoring board that will monitor the safety of the study and will meet 
routinely throughout the conduct of the study and help with decisions regarding whether to continue the trial.  
This will include – at least one biostatistician, one infectious disease expert and a neurologist with expertise in MS 
 
 
Standard Adverse Event Information 
 
Adverse Events 
 
The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the 
definition of an AE or SAE. 
 
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: 
 


 
 
 
 
Page 21 of 25 
 
 
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 concomitant 
medication (overdose per se will not be reported as an AE/SAE) unless this is an intentional overdose taken with 
possible suicidal/self- harming intent. This should be reported regardless of sequelae 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. 
However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they 
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 does 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 
 
Definition of an SAE 
 
A serious adverse event is any untoward medical occurrence that, at any dose: 
 
a. Results in death 
 
b. Is life-threatening 
 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death if it were 
more severe. 
 
c. 
Requires hospitalization or prolongation of 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 
physician’s office or outpatient 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. 
 
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 


 
 
 
 
Page 22 of 25 
 
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 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 the 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 judgment of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or 
SAEs. 
 
Pregnancy 
 
Any pregnancy that occurs during study participation must be reported to GSK. To ensure subject safety, each 
pregnancy must be reported within two weeks of learning of its occurrence. The pregnancy must be followed up to 
determine the outcome (including premature termination) and the 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 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 of consent 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. 


 
 
 
 
Page 23 of 25 
 
 
 
Serious Hypersensitivity or Infusion Reactions 
 
Serious infections, including herpes zoster and opportunistic infections 
 
Malignancy 
 
Suicidal thought, intent or behavior 
 
Fatal events 
 
 
 
Communicating Safety Information: 
 
SAE reporting to GSK should be accomplished via one GSK point of contact, as follows: 
 
 
For studies conducted in multiple countries: 
 
 
GSK Central Safety Department Global Mailbox:  Safety information from studies conducted in multiple countries 
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. 
 
o 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).  . 
 
o 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. 
 
 
For studies conducted in a single country: 
 
 
GSK Local Operating Company safety department:  In single country studies, report all unblinded SAEs reported for 
subjects who received belimumab, through the GSK Local Operating Company (LOC) safety department via their 
local mailbox or central safety at GSK US.NAPS@gsk.com (to be established at the time of contract negotiation). 
The local mailbox will be provided as appropriate at the time of contract development. 
 
o 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). 
 
o 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. 
 
 
 
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. 


 
 
 
 
Page 24 of 25 
 
 
 
 
9. 
Benefits 
Potential benefits: 
The potential benefit of belimumab therapy in the setting of B cell depletion would involve a 
skewing of the reconstituting B cells to an anti-inflammatory phenotype and potentially a prolonged 
duration of disease remission following discontinuation of B cell therapy.  
Additionally, in the long run, this could result in a reduction in adverse effects related to prolonged 
immunosuppression that is currently associated with the use of ocrelizumab on an ongoing basis 
(see above).  
Another potential benefit would be the mobilization of B cells from compartments such as the brain 
and meninges, which could then be targeted more readily by B cell depleting therapy and may result 
in greater benefit for MS patients. This provides a rationale for beginning Belimumab treatment 
prior to the first infusion of ocrelizumab. 
 
 
10. 
Payment and Remuneration 
Participants will be paid US$20 for each study visit for the compensation of travel costs and 
parking. Participants who finish all the study procedures will receive an additional US$75 at the end 
of the participation.  
 
 
11. 
Costs 
The cost of the initial set of labs that may determine the eligibility of patients for receiving 
ocrelizumab, as well as the cost of ocrelizumab and ocrelizumab infusions (which are all part of the 
standard of care) will be billed to participants and their insurance. The rest of the study procedures, 
including clinic visits, belimumab, brain MRIs and labs during the study will be part of the study 
and will not be billed to the participants and their insurance.  
 
If the patient needs testing or treatment outside of the score of the study; such as more frequent 
brain MRI, spinal cord MRIs or treatment for relapses, as part of the standard of care, they will also 
be billed to the participants and their insurance.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Page 25 of 25 
 
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