Clinical trial NCT04667117
Conditions: Relapsing Multiple Sclerosis
Keywords: ofatumumab multiple sclerosis
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-14; Completion date: 2023-07-06
Enrollment: 63 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess whether participants treated with ofatumumab 20 mg subcutaneous (s.c.) administered once every 4 weeks (q4) can mount an adequate immune response to inactivated influenza vaccine as measured by humoral responses compared to participants on an iDMT.

Detailed description:
Vaccinations against influenza are an important part of effective management of multiple sclerosis (MS).

Ofatumumab is a human anti-CD20 monoclonal antibody (mAb) which depletes B-cells, a component of the immune system. This study investigates if ofatumumab treated patients can have an immune response that may be protective after receiving the influenza vaccine.

There were 3 study periods:

* Screening Period of up to 1 week to assess eligibility requirements.
* Investigational Period of 4 weeks All participants received an inactivated influenza vaccine within 9 calendar days after the Screening Visit, before the Week 0 Visit occurred.

Participants in Cohort 1 received loading doses of 20 mg ofatumumab administered subcutaneously (s.c.) at Weeks 2, 3, and 4.

Participants in Cohort 2 continued taking their prescribed ofatumumab as per their dosing schedule throughout the Investigational Period.

Participants in Cohort 3 continued administration of their prescribed injectable disease modifying therapy (iDMT) as per their dosing schedule in the Investigational Period.

• Optional, 6-month open-label Extension Period Participants in Cohort 1 were administered their first dose of ofatumumab at Week 6; thereinafter, they continued monthly dosing until the final dose at Week 26.

Participants in Cohort 2 continued to receive ofatumumab monthly until the final dose at Week 28.

Participants in Cohort 3 did not enter the open-label Extension Period.

Arms: arm 1: Patients with relapsing multiple sclerosis (MS) receiving a 2020-2021, 2021-2022, or 2022-2023 inactivated influenza vaccine two weeks prior to ofatumumab start arm 2: Patients with relapsing MS receiving a 2020-2021, 2021-2022, 2022-2023 inactivated influenza vaccine at least 4 weeks after ofatumumab start arm 3: Patients with relapsing MS currently on iDMT receiving a 2020-2021, 2021-2022, or 2022-2023 inactivated influenza vaccine
Interventions: intervention 1: Quadrivalent influenza vaccine intervention 2: Ofatumumab intervention 3: iDMT
Intervention descriptions: intervention 1: 2020-2021, 2021-2022, or 2022-2023 inactivated quadrivalent influenza vaccine. Participants received the vaccine within 9 calendar days after the Screening Visit, before the Week 0 Visit occurred. intervention 2: Auto-injector containing 20 mg ofatumumab (20 mg/0.4mL) for subcutaneous (s.c.) administration.

* Participants in Cohort 1 received loading doses of 20 mg ofatumumab s.c. at Weeks 2, 3, and 4 in the Investigational Period. In the open-label Extension Period, they administered the first dose of ofatumumab at Week 6 and continued monthly dosing until the final dose at Week 26. Novartis supplied participants in Cohort 1 with ofatumumab treatment.
* Participants in Cohort 2 continued on their commercially prescribed ofatumumab treatment during the Investigational Period. In the open-label Extension Period, they continued to administer ofatumumab monthly until the final dose at Week 28. Cohort 2 participants in the extension could have either remained on their prescribed ofatumumab or switched to study supplied ofatumumab. intervention 3: Participants in Cohort 3 continued on their commercially prescribed injectable disease modifying therapy (iDMT) during the Investigational Period.

Protocol documents:
Prot_000.pdf: 
Dfgv1Novartis Research and Development
OMB157G/Ofatumumab
Synopsis/Clinical Trial Protocol COMB157GUS12 / NCT04667117
An open-label multicenter study to assess response to 
influenza vaccine in participants with multiple sclerosis 
treated with ofatumumab 20 mg subcutaneously
Document type:
Amended Protocol Version
EUDRACT number:
NA
Version number:
03 (Clean)
Clinical Trial Phase:
IV
Release date:
12-Mar-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................4
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................7
Amendment 3 ......................................................................................................................9
Summary of previous amendments .....................................................................................9
Protocol summary..............................................................................................................10
1
Introduction .......................................................................................................................13
1.1
Background............................................................................................................13
1.2
Purpose ..................................................................................................................13
2
Objectives and endpoints...................................................................................................14
2.1
Primary estimands .................................................................................................14
2.2
Secondary estimands .............................................................................................15
3
Study design ......................................................................................................................15
4
Rationale............................................................................................................................17
4.1
Rationale for study design .....................................................................................17
4.2
Rationale for dose/regimen and duration of treatment ..........................................18
4.3
Rationale for choice of control drugs (comparator/placebo).................................18
4.4
Purpose and timing of interim analyses/design adaptations..................................19
4.5
Risks and benefits..................................................................................................19
5
Study Population ...............................................................................................................19
5.1
Inclusion criteria ....................................................................................................20
5.2
Exclusion criteria...................................................................................................20
6
Treatment...........................................................................................................................21
6.1
Study Treatment.....................................................................................................21
6.1.1
Investigational and control drugs..........................................................21
6.1.2
Treatment cohorts/group .......................................................................22
6.1.3
Post-Trial Access ..................................................................................23
6.2
Other treatments.....................................................................................................23
6.2.1
Concomitant therapy.............................................................................23
6.2.2
Prohibited medication ...........................................................................23
6.2.3
Recommended treatment of MS Relapse..............................................24
6.3
Participant numbering, treatment assignment........................................................25
6.3.1
Participant numbering...........................................................................25


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6.3.2
Treatment assignment ...........................................................................25
6.4
Treatment blinding.................................................................................................25
6.5
Dose escalation and dose modification..................................................................25
6.6
Additional treatment guidance...............................................................................25
6.6.1
Treatment compliance...........................................................................25
6.6.2
Emergency breaking of assigned treatment code..................................26
6.7
Preparation and dispensation.................................................................................26
6.7.1
Handling of study treatment and additional treatment..........................26
6.7.2
Instruction for prescribing and taking study treatment .........................26
7
Informed consent procedures ............................................................................................28
8
Visit schedule and assessments .........................................................................................29
8.1
Rescreening............................................................................................................36
8.2
Information to be collected on screening failures..................................................36
8.3
Participant demographics/other baseline characteristics .......................................36
8.4
Efficacy..................................................................................................................36
8.5
MS Relapse............................................................................................................36
8.5.1
Laboratory evaluations..........................................................................37
8.5.2
Pregnancy and assessments of fertility .................................................37
8.6
Additional assessments..........................................................................................37
9
Study discontinuation and completion ..............................................................................37
9.1
Discontinuation and completion............................................................................37
9.1.1
Study treatment discontinuation and study discontinuation..................37
9.1.2
Withdrawal of informed consent...........................................................39
9.1.3
Lost to follow-up...................................................................................39
9.1.4
Study stopping rules..............................................................................39
9.1.5
Early study termination by the sponsor.................................................39
9.2
Study completion and post-study treatment ..........................................................40
10 Safety monitoring and reporting........................................................................................40
10.1
Definition of adverse events and reporting requirements......................................40
10.1.1
Adverse events ......................................................................................40
10.1.2
Serious adverse events ..........................................................................41
10.1.3
SAE reporting........................................................................................42
10.1.4
Pregnancy reporting ..............................................................................43
10.1.5
Reporting of study treatment errors including misuse/abuse................43
10.2
Additional Safety Monitoring................................................................................44
11 Data Collection and Database management......................................................................44


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11.1
Data collection.......................................................................................................44
11.2
Database management and quality control............................................................44
11.3
Site monitoring ......................................................................................................45
12 Data analysis and statistical methods ................................................................................45
12.1
Analysis sets ..........................................................................................................46
12.2
Participant demographics and other baseline characteristics.................................46
12.3
Treatment...............................................................................................................46
12.4
Analysis of primary endpoint(s)/estimand(s) ........................................................46
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................46
12.4.2
Statistical model, hypothesis, and method of analysis..........................46
12.4.3
Handling of remaining intercurrent events of primary estimand..........47
12.4.4
Handling of missing values not related to intercurrent event ...............47
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................47
12.4.6
Supplementary analysis.........................................................................47
12.4.7
Similar analyses will be performed by using observed 
data.Supportive analyses.......................................................................47
12.5
Analysis of secondary endpoint(s)/estimand(s).....................................................47
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................47
12.5.2
Safety endpoints....................................................................................47
12.6
Analysis of exploratory endpoints.........................................................................48
12.7
Interim analyses.....................................................................................................48
12.8
Sample size calculation..........................................................................................49
12.8.1
Primary endpoint(s)...............................................................................49
13 Ethical considerations and administrative procedures ......................................................49
13.1
Regulatory and ethical compliance........................................................................49
13.2
Responsibilities of the investigator and IRB .........................................................49
13.3
Publication of study protocol and results...............................................................49
13.4
Quality Control and Quality Assurance.................................................................50
14 Protocol adherence ............................................................................................................50
14.1
Protocol amendments.............................................................................................50
15 References .........................................................................................................................51
List of tables
Table 2-1
Objectives and related endpoints ..........................................................14
Table 6-1
Investigational and control drugs..........................................................22
Table 6-2
Prohibited medication at enrollment.....................................................24
Table 6-3
Dose and treatment schedule.................................................................28


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Table 8-1
Assessment schedule for participants (cohort 1)...................................31
Table 8-2
Assessment schedule for participants (cohort 2)...................................33
Table 8-3
Assessment schedule for participants (cohort 3)...................................35
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................44
List of figures
Figure 3-1
Study Design (cohort 1) ........................................................................16
Figure 3-2
Study Design (cohort 2) ........................................................................16
Figure 3-3
Study Design (cohort 3) ........................................................................17


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List of abbreviations
AE
Adverse Event
CMO&PS 
Chief Medical Office and Patient Safety
CQA
Clinical Quality Assurance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
EDC
Electronic Data Capture
EOS
End of Study
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBV
Hepatitis B Virus
HI
Hemagglutination Inhibition
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
iDMT
Injectable Disease Modifying Therapy
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
mg
milligram(s)
mL
milliliter(s)
QMS 
Quality Management System
sc
subcutaneous
SAE
Serious Adverse Event
SUSAR
Suspected Unexpected Serious Adverse Reaction


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or at 
a later point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained 
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same participants under different treatment 
conditions being compared. Attributes of an estimand include the population, 
variable (or endpoint) and treatment of interest, as well as the specification of 
how the remaining intercurrent events are addressed and a population-level 
summary for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent 
events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication 
number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease


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Participant
A trial participant (can be a healthy volunteer or a patient)
Participant 
number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization 
number
A unique identifier assigned to each randomized participant
Run-in Failure
A participant who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to participant’s intervention or 
other treatment)
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Withdrawal of 
study consent
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
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Amendment 3
Amendment Rationale
By the time of this amendment, it is projected that the study will not be able to enroll all 
planned number of patients in all three cohorts.  Thus, the protocol is modified by extending 
the study to the next flu season (2022-2023) to allow for completing the enrollment. In 
addition, to continue with annual monitoring of safety and efficacy, the second interim 
analysis is included in this amendment. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes herein affect 
the Informed Consent. Sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this protocol amendment.
Summary of previous amendments
Amendment 2 (15-Mar-2021)
This protocol has been modified to give participants in Cohort 2 the option to continue taking 
their prescribed ofatumumab during the open-label extension period of the study, correct 
inconsistencies related to when study drug should be administered in relation to the titer sample 
and to update inclusion criteria from planning to receive a 2020-2021 flu vaccine to willing to 
receive the 2020-2021 flu vaccine.
Amendment 1 (13-Jan-2021)
The protocol was modified to exclude participants with a history of Guillain-Barre syndrome 
within 6 weeks of receiving the influenza vaccination as recommended by the FDA.  Additional 
modifications included permitting sites to administer the quadrivalent influenza vaccine from 
their site supply in lieu of a participant receiving it from a local pharmacy. 


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Protocol summary
Protocol 
number
COMB157GUS12
Full Title
An open-label multicenter study to assess response to influenza vaccine in 
multiple sclerosis participants treated with ofatumumab 20 mg subcutaneously
Brief title
A multicenter study to assess response to influenza vaccine in multiple sclerosis 
participants treated with ofatumumab 
Sponsor and 
Clinical Phase
Novartis 
Clinical phase IV
Investigation 
type
Biological/Vaccine
Study type
Interventional, 3-cohort arm 
Purpose and 
rationale
The objective of this study is to assess whether participants treated with 
ofatumumab 20 mg subcutaneous (s.c.) administered once every 4 weeks (q4) 
can mount an adequate immune response to inactivated influenza vaccine as 
measured by humoral responses compared to participants on an iDMT. 
Primary 
Objective(s) 
To characterize those achieving seroprotection to the 2020-2021, 2021-2022, or 
2022-2023 seasonal quadrivalent influenza vaccine in participants treated with 
ofatumumab 20 mg sc once every 4 weeks.  
Secondary 
Objectives

To characterize those achieving seroconversion after receiving the 2020-
2021, 2021-2022, or 2022-2023 seasonal quadrivalent influenza vaccine in 
participants treated with ofatumumab 20 mg sc once every 4 weeks 

Safety
Study design
This is a three cohort, multicenter, prospective study of up to 66 relapsing MS 
participants. The first cohort will be participants who will received 2020-2021, 
2021-2022, or 2022-2023 inactivated influenza vaccine at least two weeks prior to 
ofatumumab start. The second cohort will be participants who will receive a 2020-
2021, 2021-2022, or 2022-2023 inactivated influenza vaccine at least four weeks 
after beginning ofatumumab. The third cohort will be participants currently on an 
iDMT who will receive a 2020-2021, 2021-2022, or 2022-2023 inactivated 
influenza vaccine. All groups will undergo an HI titer prior to vaccination and then 
again four weeks after vaccination.  Upon completing the study, participants in 
cohort 1 and 2 will have the option to continue into a 6 month open-label Extension 
Period.
Participants will obtain the quadrivalent influenza vaccine at no cost from their 
local pharmacy using a pharmacy card supplied by Novartis or from investigational 
site supply.   Participants should receive the vaccine within 9 calendar days after 
the Screening Visit, before the Week 0 Visit occurs.
Study 
population
Adult (ages 18-55) relapsing MS participants
Key Inclusion 
criteria
1.
Written informed consent for the study must be obtained before any study 
assessment is performed
2.
Age 18-55 years old
3.
Diagnosis of relapsing MS by 2017 revised McDonald criteria


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4.
Must be willing to comply with the study schedule
5.
Willing to receive a 2020-2021, 2021-2022, or 2022-2023 inactivated influenza 
vaccine
6.
Planning to start treatment with ofatumumab or already on commercially 
prescribed ofatumumab for at least 2 weeks prior to the screening visit
Participants in Cohort 3 must fulfill criteria 1-5 above in addition to the following:
7.
Participant must currently be receiving iDMT
Key Exclusion 
criteria
1.
Already has received the 2020-2021 season influenza vaccine
2.
Known hypersensitivity to any component of the influenza vaccine
3.
Any safety finding including low IgG and/or low IgM levels requiring an 
ofatumumab treatment interruption within the 12 weeks immediately prior to 
Week 0
4.
Any major episode of infection requiring hospitalization or treatment with 
intravenous antibiotics within 4 weeks prior to the first vaccination or oral 
antibiotics within two weeks prior to Week 0
5.
Known clinical diagnosis of influenza infection during the 2020-2021 influenza 
season prior to starting the study based on investigator’s or subject’s personal 
physician’s judgement (laboratory report of confirmed influenza infection is not 
required)
6.
Prior treatment with B-cell targeted therapies (e.g., rituximab or ocrelizumab), 
lymphocyte-trafficking 
blockers, 
alemtuzumab, 
anti-CD4, 
cladribine, 
cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, 
cyclosporine, 
methotrexate, 
total 
body 
irradiation, 
bone 
marrow 
transplantation.  Treatment with a natalizumab within 6 months of week 0
7.
Treatment 
with 
an 
S1P 
modulator 
within 
60 
days 
prior 
to 
Week 0
8.
Participants with any known active systemic bacterial, fungal or viral or fungal 
infections (such as hepatitis, progressive multifocal leukocencephalopathy, 
COVID-19 or HIV), or known to have acquired immunodeficiency syndrome 
(AIDS)
9.
Participation in another interventional clinical trial within 14 days prior to the 
Screening Visit/Week -1
Study 
treatment
Participants in Cohort 1:  Initial dosing includes 20 mg sc ofatumumab 
administered at Week 2, 3 and 4. 
Subsequent dosing includes 20 mg sc 
administered monthly starting at Week 6. 
Participants in Cohort 2:  Will continue to take prescribed ofatumumab as per 
their current dosing schedule.
Participants in Cohort 3: Will continue to take iDMT as per their current dosing 
schedule.
During the Investigational Period, open-label ofatumumab will be provided for 
Cohort 1.  Open-label ofatumumab will be provided during the optional 6-month 
Extension Period for both Cohort 1 and 2.
Treatment of 
interest
Inactivated influenza vaccine


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Efficacy 
assessments
None
Key safety 
assessments
Primary: Seroprotection as defined by a postvaccination antibody titer ≥ 40 
(yes/no)
Secondary:  
1.
Seroconversion as defined by either:  

≥ 4-fold increase in HI titers after vaccination (in participants with 
prevaccination HI titers ≥10) (yes/no) or

postvaccination HI titers ≥40 (in participants with prevaccination HI 
titers < 10) (yes/no)
2.
Change in HI titers
3.
AEs, SAEs, events leading to discontinuation
Data analysis
Sample size calculations were based on the proportion of subjects who responded 
to influenza vaccination.
The sample size of 20 participants per arm is selected based on budget and need 
for early availability of results. The sample size of 20 subjects will provide 
estimates with margin of error (half-width of a 95% confidence interval) of 20.1%, 
19%, and 17.5% corresponding to response rates of 70%, 75%, and 80%, 
respectively. Adjusting for 10% drop-out, 22 subjects will be enrolled in each arm.
Key words
Influenza, vaccine, ofatumumab, HI titer, open-label


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1
Introduction
1.1
Background
Multiple sclerosis (MS) is a common cause of neurologic disability in young adults.  In this 
disease, damage is caused by an autoimmune attack of the central nervous system.  Recent 
phase 3 trials have demonstrated that antibodies that bind and cause CD20 B cells apoptosis 
have a powerful anti-inflammatory effect as measured by relapse and MRI activity, and leave 
participants with less disability than active comparators (Hauser et al 2020 and Hauser et al 
2017).
The US Centers for Disease Control recommends that all persons aged > 6 months who do not 
have contraindications receive an influenza vaccination. MS is not considered a 
contraindication.  Instead, it is considered important for people with MS to receive vaccination 
to prevent the sequelae of influenza infection, including possible relapse for MS participants.  
MS disease modifying treatments target the immune system and in so doing may diminish 
vaccine efficacy (Farez et al 2019).  Questions have arisen whether therapies that affect B cells 
might also abrogate vaccine response.  Though other medications also impact B cells, anti-
CD20 antibodies have the most selective and potent impact on B cells.  These antibodies impact 
memory B cells which are believed to be an important component in maintaining immunologic 
memory but also preserve immunoglobulin secreting plasma cells which function to recognize 
and remove pathogens.  
Research with an anti-CD20 B cell agent, ocrelizumab, indicates that an immune response can 
occur after influenza vaccination but that the proportion of participants with an adequate 
response is diminished relative to a control group (Bar-Or et al 2020). Specifically, 
seroprotection rates against five influenza strains ranged from 55.5-80% and 75-97% in healthy 
controls.  
Ofatumumab is a subcutaneously administered anti-CD20 therapy that received FDA approval 
for treatment of relapsing forms of MS in August 2020.  Data is currently lacking regarding 
whether MS participants on ofatumumab can mount an appropriate immune response to 
vaccines, including the influenza vaccine.  In this study, MS participants will receive the 
influenza vaccination and follow-up titers to assess whether they are able to mount a response 
to influenza vaccine.  Because the ability to mount an immune response varies depending on 
the influenza strain administered, a reference cohort of participants on injectable disease 
modifying treatments (interferon or glatiramer acetate) is included.  In a prior study, interferon 
and glatiramer acetate did not diminish influenza vaccine response (Olberg et al 2018.)
1.2
Purpose
Vaccinations against influenza comprise an important strategy for effective management of 
participants with MS.  Ofatumumab is a human anti-CD20 monoclonal antibody (mAb) that 
induces B-cell depletion.  Considering the role of B-cells in immune-mediated responses, 
participants treated with ofatumumab may be at an increased risk of developing influenza.  They 
also may incur an increased chance of morbidity and mortality should they become infected. 
Therefore, it is important to assess if participants treated with ofatumumab are able to mount 
protective immune responses against the influenza vaccine.


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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)

To characterize those achieving 
seroprotection after receiving the 2020-
2021, 2021-2022, or 2022-2023 seasonal 
quadrivalent influenza vaccine in 
participants treated with ofatumumab 20 mg 
sc once every 4 weeks
Endpoint(s) for primary objective(s) 

Achieving seroprotection as defined by  
a postvaccination antibody titer ≥ 40 
(yes/no)
Secondary Objective(s)

To characterize those achieving 
seroconversion after receiving the 2020-
2021, 2021-2022, or 2022-2023 seasonal 
quadrivalent influenza vaccine in 
participants treated with ofatumumab 20 mg 
sc once every 4 weeks 

Safety
Endpoint(s) for secondary objective(s)

Achieving seroconversion as defined by 
either: (a) a ≥4-fold increase in 
Hemagglutination Inhibition (HI) titers 
after vaccination (in participants with 
prevaccination HI titers ≥10) or (b) 
postvaccination HI titers ≥40 (in 
participants with prevaccination HI titers 
<10) (yes/no)

Change in HI titers

AEs, SAEs, events leading to 
discontinuation
2.1
Primary estimands
The primary clinical question of interest is: Do relapsing MS participants who receive 
ofatumumab treatment mount an immune response to the 2020-2021, 2021-2022, or 2022-2023
influenza vaccine?  
The justification for the primary estimand is that it will capture whether ofatumumab treated 
participants generate antibodies to influenza vaccine as assessed by HI titers.
The primary estimand is described by the following attributes:

Population: Relapsing MS participants subdivided into three cohorts. (1) Receiving 
inactive influenza vaccine two weeks prior to starting ofatumumab 20 mg subcutaneous 
treatment; (2) Receiving inactive influenza vaccine after at least 4 weeks of commercial 
ofatumumab 20 mg subcutaneous treatment (3) receiving inactive influenza vaccine 
while on injectable disease modifying therapy (iDMT).  

Variable: Achieving seroprotection as defined by a postvaccination antibody titer ≥ 40 
(yes/no) at Week 4

Treatment of interest: Inactivated influenza vaccination either two weeks prior to 
ofatumumab start or at least 4 weeks after ofatumumab start or while on iDMT.

Intercurrent event: None

Summary measure: Proportion of subjects achieving seroprotection


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2.2
Secondary estimands
Not applicable.
3
Study design
This is a three-cohort, multicenter prospective study in up to 66 participants with relapsing 
multiple sclerosis. Up to 44 of the participants will begin treatment with ofatumumab or already 
be on commercial ofatumumab, the remaining 22 participants will remain on their iDMT. In 
this study, participants must receive the 2020-2021, 2021-2022, or 2022-2023 inactivated 
influenza vaccine.  Participants also must meet inclusion criteria and not meet exclusion criteria.
There are 3 study periods:
1. Screening Period: 
Participants will enter a Screening Period of up to 1 week to assess eligibility requirements.    
Participants in Cohort 1 without Hepatitis B virus (HBV) and serum immunoglobulin results 
within the past 6 months prior to screening will require central labs drawn.  Participants with 
Hepatitis B virus (HBV) and serum immunoglobulin results within the past 6 months prior to 
screening will not require the labs to be drawn.  
2. Investigational Period:
All participants should receive an inactivated influenza vaccine within 9 calendar days after the 
Screening Visit, before the Week 0 Visit occurs. Participants will obtain the quadrivalent 
influenza vaccine at no cost to them from their local pharmacy using a pharmacy card supplied 
by Novartis or from the investigational site supply.  Patients should be instructed to provide
pharmacy documentation of vaccine administration to the Study Doctor at the next scheduled 
on-site study visit.
Participants in Cohort 1:  Loading doses of 20 mg sc ofatumumab will be administered at Week 
2, 3 and 4.  
Participants in Cohort 2: Will continue taking their prescribed ofatumumab as per their dosing 
schedule throughout the Investigational Period.  
Participants in Cohort 3: Will continue administration of their prescribed iDMT as per their 
dosing schedule in the Investigational Period.  
3. Optional, 6-month open-label Extension Period:
The optional, 6-month open-label extension is designed to continue to observe the immune 
response.
Participants in Cohort 1 will administer their first dose of ofatumumab in the open-label 
Extension Period at Week 6.  Thereinafter, they will continue monthly dosing until the final 
dose at Week 26. Novartis will supply ofatumumab to participants in Cohort 1 for the Extension 
Period.
Participants in Cohort 2 will continue to administer ofatumumab monthly until the final dose at 
Week 28. Novartis will supply ofatumumab to participants in Cohort 2 for the Extension Period.


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Cohort 2 participants may either remain on their commercially prescribed ofatumumab or 
switch to study supplied ofatumumab.  
Participants in Cohort 3 will not enter the open-label Extension Period.
Study design schematics for Cohorts 1, 2 and 3 are shown in Figure 3-1, Figure 3-2 and Figure 
3-3 respectively.
Figure 3-1
Study Design (Cohort 1)
Figure 3-2
Study Design (Cohort 2)


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Figure 3-3
Study Design (Cohort 3)
4
Rationale
4.1
Rationale for study design
A multicenter, multi-cohort, open-label, comparator design has been selected in order to render 
feasible recruitment before the end of the 2021-2022 or 2022-2023 , vaccine season and study 
completion. The study will address two questions:
1. Can participants treated with ofatumumab develop influenza antibodies if receiving 
influenza vaccine two weeks prior to ofatumumab start? 
2. If receiving influenza vaccine after introduction of ofatumumab treatment, can 
participants develop influenza antibodies?
A 3rd cohort of participants on iDMT is included to provide a comparison that would be useful 
to investigative sites since the influenza vaccine is in limited supply.  
Rationale of study population:
The included population is selected to be consistent with the phase 3 trial program and within 
the parameters of use specified by FDA approval and United States Prescribing Information 
(USPI). The population included is also within CDC recommendations to receive the influenza 
vaccine as part of routine clinical care.  Screening participants will be excluded if they possess 
contraindications to either receiving ofatumumab per prescribing information or they possess 
contraindications to receiving the influenza vaccine.  Participants will also be excluded if there 
is clinical or serologic evidence they have already contracted a 2020-2021, 2021-2022, or 2022-


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2023 influenza strain. This is appropriate because the aim of the study is to assess whether a 
non-vaccinated ofatumumab treated individual can mount a response after influenza vaccine.
Rationale of chosen endpoints:
The proposed study primary endpoints are widely accepted as measures of influenza vaccine 
efficacy and consistent with FDA and European guidelines establishing effect.  The endpoints 
will provide evidence addressing whether ofatumumab participants can mount an adequate 
immune response to the influenza vaccine.
4.2
Rationale for dose/regimen and duration of treatment
Ofatumumab dose
The dose regimen for ofatumumab in this study is consistent with the FDA approved regimen 
in the prescribing information.
In the Investigational Period, participants assigned to Cohort 1 will receive their first of three 
loading doses at Week 2.  The second and third loading doses will be administered at Week 3 
and Week 4. If participants in Cohort 1 opt to continue into the Extension Period, they will 
begin their monthly dose of ofatumumab starting at Week 6 and will continue receiving 
additional monthly doses until Week 26.
In the Investigational Period, participants assigned to Cohort 2 will continue to take 
ofatumumab as prescribed from their personal supply. Participants in Cohort 2 that continue 
into the Extension Period will continue taking ofatumumab monthly until Week 28 from a 
study-provided supply.
Vaccine Administration
Cohorts 1 – 3: Participants will need to receive an inactive influenza vaccine from their local 
pharmacy within 9 calendar days after the Screening Visit, before the Week 0 Visit occurs.  
Participants will obtain the quadrivalent influenza vaccine at no cost using a pharmacy card 
supplied by Novartis or will receive the vaccine from investigational site supply. Patients should 
be instructed to provide pharmacy documentation of vaccine administration to the Study Doctor 
at the next scheduled on-site study visit.
Duration of treatment:
Cohort 1: The treatment duration is 26 weeks (inclusive of a 6-month extension).  
Cohort 2: The treatment duration is 28 weeks (inclusive of a 6-month extension).  
Cohort 3: The treatment duration is 5 weeks.  Participants in Cohort 3 will not enter the 
extension.
4.3
Rationale for choice of control drugs (comparator/placebo)
Since the ability to mount an immune response varies depending on the influenza strain 
administered, a reference cohort of participants on iDMTs (interferon or glatiramer acetate) is 
included.  In a prior study, interferon and glatiramer acetate did not diminish influenza vaccine 
response (Olberg et al 2018.)


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4.4
Purpose and timing of interim analyses/design adaptations
For the purpose of earlier dissemination of results, an interim analysis will be performed after 
either all enrolled participants have completed or discontinued the Investigational Period or 
on/around March 31, 2022, whichever comes first. 
4.5
Risks and benefits
There is no benefit expected for participants in this study.  Their participation will help 
contribute to a better understanding of the immune response that occurs when participants 
receiving ofatumumab are given the influenza vaccine. The ability to mount an immune 
response on ofatumumab will also be important to understand in response to any potential 
COVID vaccine.  Though this study will not directly address COVID or potential COVID 
vaccines, it will provide some basic information about response to inactivated vaccine in 
ofatumumab treated participants.
Participants will obtain the quadrivalent influenza vaccine at no cost to them from their local 
pharmacy using a pharmacy card supplied by Novartis or will receive the vaccine from
investigational site supply.  
Novartis will supply participants in Cohort 1 with ofatumumab treatment in the Investigational 
Period and the optional Extension Period as per the assessment schedule (Table 8-1).  Novartis 
will provide participants in Cohort 2 with ofatumumab treatment from study supplies in the 
optional Extension Period as per the assessment schedule or they may remain on their prescribed 
supply (Table 8-2).  
Ocrelizumab safety data has been previously published (Hauser et al 2020) demonstrating 
infusion related reactions occur in 34.3%, serious infections occurred in 1.3%, and neoplasms 
occurred in 0.5% of participants.  The risk to participants in this trial may be minimized by 
compliance with the eligibility criteria and study procedures, as well as close clinical monitoring.
Over 1500 RMS participants have been exposed to ofatumumab across phase 2 and phase 3 
studies.  No unexpected safety findings were observed in MS participants who received 
ofatumumab in the completed studies (Hauser et al 2020). 
Men and women of child-bearing potential must use a highly-effective method of birth control 
method during the study.  Women of child-bearing potential must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study.
5
Study Population
The study population will consist of male and female participants, ≥ 18 years of age to 55 years 
of age inclusive, with a diagnosis of relapsing MS.  
The study aims to enroll up to 66 participants (up to 22 participants per cohort) at approximately 
12 centers in the United States.  Since a 25% screen failure rate is expected, approximately 88 
participants will be screened.


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The last day to screen a patient for this study will be when Cohort 1 and Cohort 3 each have 22 
participants enrolled, or at the end of Q1 2023, whichever comes first.
5.1
Inclusion criteria
Participants eligible for inclusion in Cohorts 1 and 2 must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Age 18-55 years old
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria
4. Must be willing to comply with the study schedule
5. Willing to receive a 2020-2021, 2021-2022, or 2022-2023 inactivated influenza vaccine
6. Planning to start treatment with ofatumumab or already on commercially prescribed 
ofatumumab for at least 2 weeks prior to the screening visit
Participants in Cohort 3 must fulfill criteria 1-5 above in addition to the following:
7. Participant must currently be receiving iDMT
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Already has received the 2020-2021, 2021-2022 or 2022-2023 season influenza vaccine
2. Known hypersensitivity to any component of the influenza vaccine
3. Any safety finding including low IgG and/or low IgM levels requiring an ofatumumab 
treatment interruption within the 12 weeks immediately prior to Week 0
4. Any major episode of infection requiring hospitalization or treatment with intravenous 
antibiotics within 4 weeks prior to or oral antibiotics within two weeks prior to Week 0
5. Known clinical diagnosis of influenza infection during the 2020-2021, 2021-2022 or 2022-
2023 influenza season prior to starting the study based on investigator’s or subject’s 
personal physician’s judgement (laboratory report of confirmed influenza infection is not 
required)
6. Prior treatment with B-cell targeted therapies (e.g., rituximab or ocrelizumab), lymphocyte-
trafficking blockers, alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone, 
azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, 
bone marrow transplantation.  Treatment with a natalizumab within 6 months of week 0
7. Treatment with an S1P modulator within 60 days prior to Week 0
8. Participants with any known active systemic bacterial, fungal or viral or fungal infections 
(such as hepatitis, progressive multifocal leukocencephalopathy, COVID-19 or HIV), or 
known to have acquired immunodeficiency syndrome (AIDS)
9. Participation in another interventional clinical trial within 14 days prior to the screening 
visit


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10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test
11. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for at least 6 months after stopping study medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant, if accepted by the local regulation). NOTE: Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal ARE 
NOT acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

For female participants on the study, the vasectomized male partner should be the sole 
partner

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF. Note: Women are considered post-
menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history 
of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child-bearing potential.
12. Patients with a history of Guillain-Barre syndrome within 6 weeks of receiving the influenza 
vaccination.
6
Treatment
6.1
Study Treatment
6.1.1
Investigational and control drugs
Novartis will supply the following study treatments:


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
Open-label ofatumumab will be provided in an auto-injector containing 20 mg sc
ofatumumab (20 mg/0.4ml) for subcutaneous administration.  

Novartis will supply participants in Cohort 1 with ofatumumab treatment in the 
Investigational Period and the optional 6-month Extension Period as per the 
assessment schedule in Table 8-1.  

Participants in Cohort 2 will continue on their commercially prescribed ofatumumab
treatment during the Investigational Period.  Novartis will supply participants in 
Cohort 2 with ofatumumab treatment in the optional 6-month Extension Period as per 
the assessment schedule in Table 8-2.  Cohort 2 participants may either remain on 
their prescribed ofatumumab or switch to study supplied ofatumumab.  

Participants will obtain the quadrivalent influenza vaccine at no cost to them from their local 
pharmacy using a pharmacy card supplied by Novartis or will receive the vaccine from
investigational site supply.  
Participants enrolled in Cohort 3 will continue on their commercially prescribed iDMT.
Table 6-1
Investigational and control drugs
Investigational/ 
Control Drug
Route of 
Administration
Supply Type
Supplied by
OMB157 
20mg/0.4mL
Subcutaneous Use
Open-label 
commercial supply; 
vials
Sponsor or commercially 
prescribed 
iDMT 
Subcutaneous or 
intramuscular use
Commercially 
prescribed
NA
Quadrivalent 
influenza vaccine
Intramuscular 
Commercially 
supplied
Participants to obtain 
from their local pharmacy 
via pharmacy card or from 
investigational site supply
6.1.1.1
Decentralized Clinical Trial Model 
The study medication and all required clinical study supplies may be distributed via direct-to-
participant shipment utilizing an extension of the IND for compliance purposes.
6.1.2
Treatment cohorts/group

Cohort 1:  RMS participants receiving a 2020-2021, 2021-2022, or 2022-2023 inactivated 
influenza vaccine at least two week prior to ofatumumab start.

Cohort 2:  RMS participants receiving a 2020-2021, 2021-2022, or 2022-2023 inactivated 
influenza vaccine at least 4 weeks after ofatumumab start. 

Cohort 3:  RMS participants currently on a prescribed iDMT receiving a 2020-2021, 
2021-2022, or 2022-2023 inactivated influenza vaccine.


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6.1.3
Post-Trial Access
Participants in Cohort 1 and 2 that successfully complete the Investigational Period may either 
continue into the optional, 6-month open-label Extension Period or will be referred to the 
commercial participant services hub for post-trial continuity of treatment, where the benefit/risk 
is acceptable and discussed with the participant, investigator and if applicable, the participant’s 
treating physician.  Participants who do not complete the study or withdraw due to an 
ofatumumab related AE or SAE should follow-up with their treating physician for continued 
treatment options.
6.2
Other treatments
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms.
Premedication prior to subcutaneous injection
Premedication is not required. Premedication with acetaminophen and/or antihistamines (or
equivalent) is optional and may be administered at the discretion of the Investigator. For 
participants in Cohort 1, the addition of premedication per normal clinical practice is an 
additional consideration for the first injection of the Investigational Period (Week 2). If 
Investigators choose to administer premedication, it should be administered 30 to 60 minutes 
prior to study drug injection.
Any administrations of premedication must be recorded in the appropriate CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis before enrolling a 
participant or allowing a new medication to be started. If the participant is already enrolled, 
contact Novartis to determine if the participant should continue participation in the study.
6.2.2
Prohibited medication
Exclusionary medications for study eligibility are listed in the exclusion criteria (Section 5.2). 
Use of excluded medications is not allowed while the participant is on study medication.
Use of the treatments displayed in Table 6-2 is NOT allowed in combination with study drug,
due to increased risk of immunosuppression and confounding of efficacy evaluations. 


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Table 6-2
Prohibited medication at enrollment
Medication
Action taken
Immunosuppressive/chemotherapeutic
medications (including herbal) or procedures, 
including but not limited to cyclosporine, 
azathioprine, 
leflunomide, 
methotrexate, 
cyclophosphamide, mitoxantrone, lymphoid 
irradiation and hematopoietic stem cell 
transplantation
Discontinue study drug, increase 
vigilance regarding infections. 
NOTE: Restarting study drug in 
participants exposed to these 
medications is not permitted.
Monoclonal antibodies targeting the immune 
system, 
including 
but 
not 
limited 
to 
natalizumab, alemtuzumab, daclizumab and 
B-cell depleting agents under investigation, 
such as but not limited to ublituximab and 
obinutuzumab
Discontinue study drug, increase 
vigilance regarding infections. 
NOTE: Restarting study drug after 
exposure to B-cell depleting agents is 
not permitted. For others only after 
consultation with the Sponsor.
Any other immunomodulatory or disease
modifying MS treatment, including but not
limited 
to 
fingolimod, 
interferon 
beta, 
glatiramer 
acetate, 
dimethyl 
fumarate, 
intravenous immunoglobulin, plasmapheresis 
or systemic corticosteroids (except for when 
given for MS relapse treatment as defined in
Section 6.2.3)
Interrupt or discontinue study drug, 
increase vigilance regarding infections.
NOTE: Restarting study drug in 
participants exposed to these 
medications is not permitted.
Administration of any live or live attenuated 
vaccine (including for measles) is prohibited 
while participants are exposed to study drug 
(long lasting effects of the study drugs should 
be taken into  consideration)
They may be administered when 
participants are no longer exposed to 
study drug. Consider risk/benefit and 
follow local labels.
6.2.3
Recommended treatment of MS Relapse
The decision to treat MS relapses should be based on the Investigator's judgement and/or local 
clinical practice. Standard of care will be followed during treatment as per local clinical practice. 
Taper with oral steroids is not permitted. Plasmapheresis may be used only if participant does 
not respond to standard treatment with corticosteroids.
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration. Use of steroids for treatment of MS attack/relapse must be recorded on the
Concomitant Medications eCRF. 


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6.3
Participant numbering, treatment assignment
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the Participant is assigned to the next 
sequential participant No. available by the Investigator. At the Screening Visit 
(Visit 1/Week -1), the Investigator or his/her staff will contact the Interactive Response 
Technology (IRT) system and provide the assigned participant study identification number 
along with the requested identifying information to register the participant into IRT. The site 
must use the eCRF with the matching participant number from the electronic data capture (EDC) 
system to enter data.
Once assigned to a participant, a participant number will not be reused. If a participant fails to 
be enrolled for any reason, the IRT system must be notified within 2 days and the reason for 
not being enrolled will be entered on the Screening Phase Disposition Form and the appropriate 
eCRF(s) pages should also be completed.
6.3.2
Treatment assignment
An IRT system will be used to track patient visits, patient status and dispense open-label 
treatment to Cohort 1 when indicated in the assessment schedule (Table 8-1).  The system will 
also be used to dispense treatment to participants in both Cohort 1 and Cohort 2 during the 
optional, 6-month open-label Extension Period.
At dosing visits, the system will specify unique medication numbers that will correspond to 
open-label treatment to be dispensed.  
6.4
Treatment blinding
Not applicable.
6.5
Dose escalation and dose modification
Dose escalation and modifications are not permitted in this study.
6.6
Additional treatment guidance
Not applicable.
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 


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Compliance will be assessed by the investigator and/or study personnel at each visit using 
information provided by the participant. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log.
6.6.2
Emergency breaking of assigned treatment code
Since this study is open-label, emergency breaking of assigned treatment codes is not applicable.
6.7
Preparation and dispensation
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). 
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the treatment label. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Medication labels will be in English and comply with legal requirements in the U.S. They will 
include storage conditions for the study treatment but no information about the patient except 
for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a Drug Accountability Log. Monitoring of drug accountability will be performed 
by monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study drug and packaging at the end of the study or at the time of 
discontinuation of treatment. At the conclusion of the study, and as appropriate during the 
course of the study, the investigator will return all unused study treatment, packaging, drug 
labels, and a copy of the completed drug accountability log to Novartis or its agents. 
Destruction of the unused drug should be done according to local requirements and after 
approval by Novartis clinical team.
6.7.2
Instruction for prescribing and taking study treatment
All investigational medication will be provided by Novartis. Ofatumumab treatment should be 
administered after study assessments have been completed for the visit.


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Influenza Vaccine
The quadrivalent vaccine should be obtained at the patient’s preferred pharmacy using the 
Novartis supplied pharmacy card or will receive the vaccine from the investigational site supply 
within 9 days of the screening visit. 
Ofatumumab
Site staff should remove the study treatment from the refrigerator and allow the auto injector 
pen to reach room temperature in their unopened box (approximately 15-30 minutes) before 
self-injection by the participant. Used syringes should be disposed of immediately after use in 
a sharps container. 
A different body site (front of thighs, lower abdomen) should be chosen each time a dose is 
administered to reduce the risk of an injection-site reaction; investigator/qualified site 
staff/caregiver can also inject the study treatment in the outer upper arms. Each new injection 
should be given at least one inch from the previously used site. If administration is in the 
abdomen, the 2-inch area around navel should be avoided. Study treatment should also not be 
injected into areas where the skin is tender, bruised, red, or hard, or where the participant has 
scars or stretch marks.
Participants in Cohort 1
The patients in Cohort 1 will receive their first loading dose of ofatumumab at the study site at 
Week 2 (2 weeks after receiving the influenza vaccine). The next loading dose of study drug 
will be dispensed to the participant at this visit to take home for administration at Week 3.  The 
Week 4 dose will be administered in the clinic after the post-vaccine titer is drawn.  Doses at
Week 3 (dose #2) and Week 4 (dose #3) should be administered +/- 1 day from when they are 
scheduled to be administered. If the dose on Week 3 (dose #2) is missed, the dose due on Week 
4 (dose #3) should be adjusted to 7 days after dose #2 was given.
If participants in Cohort 1 opt to participate in the Extension Period, at Week 4, sufficient study 
drug will be supplied to the participant to cover monthly home administrations of study drug 
until the Week 18 clinic visit which should take place in the clinic. At Week 18, sufficient study 
drug will be supplied to the participant to cover the Week 22 dose.  The Week 26 dose will be 
administered in-clinic. Note: At Week 26, sites must perform a study drug dispensation 
transaction in IRT before the transaction to register study completion is performed.  
Participants will be asked to complete a patient diary to record doses of study treatment 
administered at home study visits.
Participants in Cohort 2
Upon enrollment, participants already receiving prescribed ofatumumab will continue to take 
prescribed treatment as per their current dosing schedule during the Investigational Period.  If 
participants in Cohort 2 opt to participate in the Extension Period, at Week 4, the participant 
will be supplied with study drug to cover monthly administrations in the Extension Period of 
the study until the Week 16 clinic visit.   At Week 16, sufficient study drug will be supplied to 
the participant to cover monthly doses up to and including Week 24. The Week 28 dose will be 


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administered in-clinic. Note: At Week 28, sites must be sure to perform a study drug 
dispensation transaction in IRT before the transaction to register study completion is 
performed.
Participants will be asked to complete a patient diary to record doses of ofatumumab taken 
during the Investigational Period and during the Extension Period, if applicable.
Participants in Cohort 3
Upon enrollment, participants in Cohort 3 will continue to take their iDMT as per their current 
dosing schedule.
Participants will be asked to complete a patient diary to record doses of their iDMT taken during 
the Investigational Period.
Table 6-3
Dose and treatment schedule 
Investigational Drug
Frequency and/or Regimen
Cohort 1
OMB157 20mg/0.4mL
Week 2, Week 3, Week 4, 
Week 6, and then monthly
Cohort 2
OMB157 20mg/0.4mL
Monthly as prescribed
Cohort 3
iDMT
As prescribed
As patients must administer ofatumumab from home at certain visits, site personnel will provide 
training on the correct procedure for self-administration of the ofatumumab subcutaneous 
injections to enable the participant and/or a caregiver to administer treatment on the day of 
home visits. Documentation of the participant or caregiver understanding the correct 
administration procedure must be documented in the source document.  
Participants will be instructed to contact the investigator/site staff prior to self-administration 
at home if they are experiencing any AE/SAEs or have any concerns. Participants will record 
the dates of all at-home study treatment doses in a Participant Diary.
Site personnel will make remote contact with participants on/around the time of the 2nd loading 
dose to query about any new or worsening symptoms warranting an unscheduled visit, 
compliance with study treatment, injection reactions, and compliance with contraception 
requirements when applicable. Additional remote contacts should be conducted on/around the 
time patients are due to administer treatment at home. The method of contact with each 
participant can be the personal preference of the individual between telephone contacts, email 
contact or text messages, however, the site staff must be able to provide suitable source 
documentation of each contact regardless of the method of contact.  
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) approved informed consent.
If applicable, in cases where the participant’s representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 


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possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the IRB.
Information about common side effects already known about the investigational drug can be 
found in the USPI and Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
The following informed consents are included in this study:

Main study consent, which also included: 

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB 
approval.
8
Visit schedule and assessments
The below Assessment Schedules (Table 8-1, Table 8-2, Table 8-3) list all assessments with an 
X when they are performed. Assessments that will only be reported in the source documentation 
are marked with an ‘S’.
Participants should be seen for all visits/assessments as outlined in the assessment schedules or 
as close to the designated day/time as possible with an allowed visit window of ±3 days. The 
Investigator should promote compliance by instructing the subject to attend the study visits as 
scheduled and by stating that compliance is necessary for the subject’s safety and the validity 
of the study. Missed or rescheduled visits should not lead to automatic discontinuation. The 
subject should be instructed to contact the Investigator if he/she is unable for any reason to 


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attend a study visit as scheduled or if he/she is unable for any reason to take the study treatment 
as prescribed. 
Cohort 1:  At Week 0, the study site will perform a Vaccine Status Check-in via remote contact 
to confirm participant has received the influenza vaccine. At-home study visits will be 
performed at Week 2, 3, 6, 10, 14, and Week 22. Patients and/or caregivers trained to administer 
the ofatumumab subcutaneous injections will need to administer treatment at home study visits. 
At Week 4, sufficient study drug will be supplied to the participant to cover all home 
administrations of study drug until the Week 18 clinic visit.  At Week 18, sufficient study drug 
will be supplied to the participant to cover dosing up at Week 22. The last dose of study drug 
will be administered at the Week 26 visit at the site.  Refer to Table 8-1.
Cohort 2:  At Week 0, the study site will perform a Vaccine Status Check-in via remote contact 
to confirm participant has received the influenza vaccine. At-home study visits will be 
performed at Week 1, 2, 8, 12, 20, and Week 24. At Week 4, sufficient study drug will be 
supplied to the participant to cover all home until the next clinic visit (Week 16).  At Week 16, 
sufficient study drug will be supplied to the participant to cover dosing up to and including the 
Week 24 dose. The last dispensation of ofatumumab supplied in the study will occur at the 
Week 28 visit at the site.  Refer to Table 8-2.
Cohort 3:  At Week 0, the study site will perform a Vaccine Status Check-in via remote contact 
to confirm participant has received the influenza vaccine. At-home study visits will be 
performed at Week 1, 2 and 3.  Refer to Table 8-3.
Cohort 1 and 2 participants who prematurely discontinue the study while in the Investigational 
Period should be scheduled for the End of Study (EOS1) visit within 7 days. At this final visit, 
all the assessments mentioned under EOS1 visit should be performed except for study drug 
administration. Cohort 3 participants who prematurely discontinue the study while in the 
Investigational Period should be scheduled for the End of Study (EOS) visit within 7 days. 
Cohort 1 and 2 participants who prematurely discontinue the study while in the Extension 
Period should be scheduled for the final visit of the Extension Period (EOS2) within 7 days.  
All EOS2 assessments should be performed except study drug administration.
In addition to the scheduled visits, participants may have unscheduled visits due to a MS relapse, 
an acute illness of undetermined cause, for other reasons, or at the discretion of the Investigator. 
Data collected during unscheduled visits will be recorded in the unscheduled visits CRF.


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Table 8-1
Assessment schedule for participants (cohort 1)
Period
Screening
Investigational Period
6-month Extension Period
Unscheduled
Visit Name
Visit 1
Screening
Visit 2
(vaccine 
status 
check-in)
Visit 3
Visit 4
(home 
visit)
Visit 5
EOS1
Visit 6
(home 
visit)
Visit 7
(home 
visit)
Visit 8
(home visit)
Visit 9
Visit 10
(home 
visit)
Visit 11
EOS2
Unscheduled
Day/Week/Month
Week
-1
Week 0
Week 
2
Week 
3
Week 
4
Week 
6
Week 
10
Week 
14
Week
18
Week
22
Week
26
Visit Window Days (d)
± 1d
± 1d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
Obtain informed consent
X
Inclusion/exclusion 
criteria
X
Demography
X
Relevant medical 
history/current medical 
history
X
Prior/Concomitant 
Medications
X
X
X 
X
X
X
X
X 
X
X
X
MS Relapse
X
X
X
X
X
X
X
X
X
X
X
Hepatitis B virus (HBV) 
X1
Serum immunoglobulins
X1
Local Serum Pregnancy 
Test
S
Screening / Pre-vaccine 
HI titer
X
Dispense pharmacy card
S2
Self-injection training
S
IRT transaction
X
X
X
X 
X
X
X
X
X
X
X


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Period
Screening
Investigational Period
6-month Extension Period
Unscheduled
Visit Name
Visit 1
Screening
Visit 2
(vaccine 
status 
check-in)
Visit 3
Visit 4
(home 
visit)
Visit 5
EOS1
Visit 6
(home 
visit)
Visit 7
(home 
visit)
Visit 8
(home visit)
Visit 9
Visit 10
(home 
visit)
Visit 11
EOS2
Unscheduled
Day/Week/Month
Week
-1
Week 0
Week 
2
Week 
3
Week 
4
Week 
6
Week 
10
Week 
14
Week
18
Week
22
Week
26
Visit Window Days (d)
± 1d
± 1d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
Post vaccine Serum HI 
titers
X3
Administration of study 
drug 
X
X
X
X
X
X
X
X
X
Drug Accountability
S
S
S
S
Adverse Events / Serious 
Adverse Events
X
X
X
X 
X
X
X
X
X
X
X
X
Subject disposition
X
X
X
Remote Contact
X4
S5
S5
S5
S5
S5
S5
S5
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit. Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database.
2 Participants will use the pharmacy card to cover the cost of the influenza vaccine.  Participants administered the vaccine from investigator site supply will not receive a 
pharmacy card.  All participants should receive the vaccine within 9 calendar days after the Screening Visit, before the Week 0 visit occurs. 
3 Post vaccine titer to be drawn before administration of ofatumumab.
4 Remote contact to perform a Vaccine Status Check-in by site staff to confirm participant has received the influenza vaccine and to collect any AEs/SAEs.
5 Remote contact with participants by site staff. The contact should query about any new AEs or SAEs, changes in con meds and compliance with current treatment.
Method of contact can be via telephone, email or text message depending on the preference of each participant.


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Table 8-2
Assessment schedule for participants (cohort 2)
Period
Screening
Investigational Period
6-month Extension Period
Unscheduled
Visit Name
Visit 1
Screening
Visit 2
(vaccine 
status 
check-
in)
Visit 3
(home 
visit)
Visit 4
(home 
visit)
Visit 5
EOS1
Visit 6
(home 
visit)
Visit 7
(home 
visit)
Visit 8
Visit 9
(home 
visit)
Visit 10
(home 
visit)
Visit 11 
EOS2
Unscheduled
Day/Week/Month
Week 
-1
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week
12
Week
16
Week
20
Week
24
Week
28
Visit Window Days (d)
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
Obtain informed consent
X
Inclusion/exclusion criteria
X
Demography
X
Relevant medical 
history/current medical history
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
MS Relapse
X
X
X
X
X
X
X
X
X
X
X
Local Serum Pregnancy Test
S
Screening / Pre-vaccine HI 
titer
X
Dispense pharmacy card
S1
IRT transaction
X
X
X
X 
X
X
X
X
X
X
X
Administration of study drug 
X
X
X
X
X
X
Post vaccine Serum HI titers 
X2
Drug Accountability Log
S
S
S
S
Adverse Events / Serious 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Subject disposition
X
X
X


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Period
Screening
Investigational Period
6-month Extension Period
Unscheduled
Visit Name
Visit 1
Screening
Visit 2
(vaccine 
status 
check-
in)
Visit 3
(home 
visit)
Visit 4
(home 
visit)
Visit 5
EOS1
Visit 6
(home 
visit)
Visit 7
(home 
visit)
Visit 8
Visit 9
(home 
visit)
Visit 10
(home 
visit)
Visit 11 
EOS2
Unscheduled
Day/Week/Month
Week 
-1
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week
12
Week
16
Week
20
Week
24
Week
28
Visit Window Days (d)
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
± 3d
Remote Contact
X3
S4
S4
S4
S4
S4
S4
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1 Participants will use the pharmacy card to cover the cost of the influenza vaccine.  Participants administered the vaccine from investigator site supply will not receive a 
pharmacy card.  All participants should receive the vaccine within 9 calendar days after the Screening Visit, before the Week 0 visit occurs. 
2 Post vaccine titer to be drawn before administration of ofatumumab. 
3 Remote contact to perform Vaccine Status Check-in by site staff to confirm participant has received the influenza vaccine and to collect any AEs/SAEs.
4 Remote contact with participants by site staff. The contact should query about any new AEs or SAEs, changes in con meds and compliance with current treatment.
Method of contact can be via telephone, email or text message depending on the preference of each participant


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Table 8-3
Assessment schedule for participants (cohort 3)
Period
Screening
Investigational Period
Unscheduled
Visit Name
Visit 1
Screening
Visit 2
(vaccine 
status 
check-in)
Visit 3
(home visit)
Visit 4
(home 
visit)
Visit 5
(home visit)
Visit 6
EOS
Unscheduled
Day/Week/Month
Week -1
Week 0
Week 1
Week 2
Week 3
Week 4
Visit Window Days (d)
± 3d
± 3d
± 3d
± 3d
Obtain informed consent
X
Inclusion/exclusion criteria
X
Demography
X
Relevant medical history/current medical history
X
Prior/Concomitant Medications
X
X
X 
X
X
X
MS Relapse
X
X
X
X
X
X
Local Serum Pregnancy Test
S
Screening / Pre-vaccine HI titer
X
Dispense pharmacy card
S1
IRT Transaction
X
X
X
X 
X
X
iDMT administration log
X
X
Post vaccine Serum HI titers 
X
Drug Accountability log
S
S
Adverse Events / Serious Adverse Events
X
X
X
X
X
X
X
Subject disposition
X
X
Remote Contact
X2
S3
S3
S3
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1 Participants will use the pharmacy card to cover the cost of the influenza vaccine.  Participants administered the vaccine from investigator site supply will not receive a 
pharmacy card.  All participants should receive the vaccine within 9 calendar days after the Screening Visit, before the Week 0 visit occurs. 
2 Remote contact to perform a Vaccine Status Check-in by site staff to confirm participant has received the influenza vaccine and to collect any AEs/SAEs.
3 Remote contact with participants by site staff. The contact should query about any new AEs or SAEs, changes in con meds and compliance with current treatment.
Method of contact can be via telephone, email or text message depending on the preference of each participant.


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8.1
Rescreening
Rescreening is not permitted.
8.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to enrollment will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
section for reporting details). If the participant fails to be enrolled, the IRT must be notified 
within 2 days of the screen fail that the participant was not enrolled.
Participants who are enrolled and fail to start treatment, e.g. participants enrolled in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form.
8.3
Participant demographics/other baseline characteristics
Participant demographic data and baseline characteristics to be collected on the participants 
include: age, sex, race and ethnicity. Relevant medical history/current medical condition data 
includes data collected up to the point in which informed consent is signed. Where possible, 
diagnoses, and not symptoms will be recorded. Investigators will have the discretion to record 
abnormal test findings on the CRF capturing medical history whenever in their judgment, the 
test abnormality occurred prior to the informed consent signature.
8.4
Efficacy
Not applicable.
8.5
MS Relapse
Participants must be instructed to immediately report new neurological symptoms, re-occurring 
or worsening of previous symptoms to the Investigator. If a participant reports symptoms that 
may be consistent with relapse, an unscheduled visit to the Investigator must be scheduled as 
soon as possible (whenever possible within 7 days of onset of the symptoms). Confirmed 
relapses should be recorded on the Summary of MS Relapse eCRF.
MS relapse definition
An MS relapse is defined as an appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 30 
days from onset of a preceding clinical demyelinating event (Polman et al 2011). The 
abnormality must have been present for at least 24 hours and occurred in the absence of fever 
(< 37.5°C) or a known infection.


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8.5.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected listed below with the 
exception of the serum pregnancy test. Details on the collection, shipment of samples and 
reporting of results by the central laboratory are provided in the laboratory manual.
8.5.1.1
Hepatitis B virus (HBV)
Hepatitis B virus (HBV) will be performed at Visit 1/Screening for participants in Cohort 1 that 
do not have test results in their medical history within 6 months prior to the Screening 
Visit/Week -1.
8.5.1.2
Serum Immunoglobulins
Serum immunoglobulins will be performed at Visit 1/Screening for participants in Cohort 1 that 
do not have test results in their medical history within 6 months prior to the Screening 
Visit/Week -1.
8.5.2
Pregnancy and assessments of fertility
A local, serum pregnancy test will be performed for all women of child-bearing potential at 
Screening Visit/Week -1.  
The Investigator should review the contraception status with the participant at the Screening 
Visit/Week -1 to ascertain if the participant will comply with protocol requirements for highly 
effective contraception.
All pre-menopausal women who are not surgically sterile will have pregnancy testing.
8.6
Additional assessments
No additional tests will be performed on participants entered into this study.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Use of prohibited treatment as per the USPI


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
Any situation in which study participation might result in a safety risk to the participant

Diagnosis of PML

Participants with active serious infections or reactivation

Skin and/or mucosal reactions which raise the suspicion of severe generalized major skin 
reactions (Stevens-Johnson syndrome, or toxic epidermal necrolysis-Lyell's syndrome)

Hypersensitivity to the study medication

Protocol violation that results in a significant risk to the participant's safety

Emergence of certain adverse events, such as malignancy (except successfully treated 
basal cell carcinoma, in situ squamous cell carcinoma and in situ carcinoma of cervix of 
uterus), liver failure or serious chronic infection (such as human immunodeficiency 
virus(HIV))

Severe hypoproteinemia

Non-compliance with study drug or study procedures
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2 'Withdrawal of Informed Consent' section). Where possible, 
they should return for the EOS Visit applicable to the period in which the patient is 
currently in.  Participants in Cohort 1 that discontinue in the Investigational Period, 
should return for all assessments indicated for the EOS1 Visit except for study drug 
administration. Participants in Cohort 1 and 2 that discontinue in the Extension Period, 
should return for all assessments indicated for the EOS2 Visit except for study drug 
administration. At EOS visits all dispensed study drug to participants in Cohort 1 and Cohort 
2 should be reconciled and the adverse event and concomitant medications should be recorded 
on the CRF (for participants in both arms). If they fail to return for these assessments for 
unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.


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9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed.
9.1.4
Study stopping rules
Not applicable.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination may include:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Inability to complete enrollment by the end of the vaccination season

Practical reasons


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
Regulatory or medical reasons
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible for an end 
of study visit within 7 calendar days and treated as a prematurely withdrawn participant. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the participant’s interests. The investigator 
or sponsor depending on local regulation will be responsible for informing IRBs of the early 
termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant completes the EOS1 Visit if the 
participant will not continue into the Extension Period, or the EOS2 visit of the Extension Period 
if the participant continues into the extension.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (1-4)
If CTCAE grading does not exist for an adverse event, use:

1 = mild: usually transient in nature and generally not interfering with normal 
activities

2 = moderate: sufficiently discomforting to interfere with normal activities

3 = severe: prevents normal activities


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
4 = life threatening
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. Its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown).
Conditions that were already present at the time of informed consent should be recorded in the 
source medical history of the participant.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent


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
social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are 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 dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred as per Section 10.1. 
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.


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Any SAEs experienced > 30 days after the last study visit should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment.
Please note: The time of 30 days in the standard text above is the recommended minimum and 
the SAE form should be submitted to   Novartis Safety. A longer duration may be appropriate 
for drugs with particularly long elimination half-lives or from drug classes with known late 
occurring effects, or when risk assessment/management objectives require prolonged safety 
monitoring. Please ensure the Informed Consent Form reflects this 30 day/Post Study Safety 
Contact.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up on until after the Expected Due Date (EDD) 
to determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.  Additional follow up will be completed at EDD +1 month, EDD +2 
months (in case no answer is received after request at EDD +1 month) and at EDD +3 months. 
Information on the status of the baby after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected.
Pregnancy should be recorded and reported on the Pregnancy Form by the investigator to the 
Novartis Chief Medical Office and Participant Safety (CMO&PS). Pregnancy follow-up should 
be recorded on the same form and should include an assessment of the possible relationship to 
the any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.


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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.


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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
Enrollment and data about all study treatment(s) dispensed to the participant will be tracked 
using an IRT. The system will be supplied by a vendor, who will also manage the database. 
Novartis may request to receive the IRT data electronically at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for analysis. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / 
data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
The analysis will be conducted on all participant data at the time the trial ends. Any data analysis 
carried out independently by the Investigator should be submitted to Novartis before publication 
or presentation.


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Categorical variables will be presented as counts and percentages. For continuous variable, 
mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum 
will be presented.
All summaries will be presented by study arm.
12.1
Analysis sets
The Safety Set comprises all participants who received at least one dose of study drug. 
The Safety Set will be used for the summary of demography and baseline characteristics as well 
as for all safety analyses.
12.2
Participant demographics and other baseline characteristics
Demographics and other baseline characteristics will be summarized descriptively.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
12.3
Treatment
The duration of exposure in days will be summarized descriptively.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
12.4
Analysis of primary endpoint(s)/estimand(s)
The primary objective of this study is to characterize those achieving seroprotection after 
receiving the 2020-2021, 2021-2022, or 2022-2023 seasonal quadrivalent influenza vaccine in 
subjects treated with ofatumumab 20 mg sc once every 4 weeks.  This will be achieved by 
estimating the seroprotection response rate.  
A seroprotection responder is a participant achieving seroprotection as defined by a 
postvaccination antibody titer ≥ 40.
The seroprotection response rate is defined as the proportion of subjects with seroprotection. 
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary endpoint is achieving seroprotection as defined by a postvaccination antibody titer 
≥ 40 (yes/no) at Week 4.
12.4.2
Statistical model, hypothesis, and method of analysis
The number and percentage of responders by year of enrolment in study and overall will be 
presented. The 95% confidence interval for the proportion of responders will be calculated by 
using exact method.


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12.4.3
Handling of remaining intercurrent events of primary estimand
Not applicable. 
12.4.4
Handling of missing values not related to intercurrent event
Non-responder imputation approach will be applied to missing postvaccination antibody titer.
12.4.5
Sensitivity analyses for primary endpoint/estimand
Not applicable.
12.4.6
Supplementary analysis
12.4.7
Similar analyses will be performed by using observed data.Supportive 
analyses
Not applicable.
12.5
Analysis of secondary endpoint(s)/estimand(s)
The secondary endpoint is achieving seroconversion defined as meeting one of the following 
two criteria:

≥ 4-fold increase in HI titers after vaccination (in participants with prevaccination 
HI titers ≥10) (yes/no) or

postvaccination HI titers ≥40 (in participants with prevaccination HI titers < 10) 
(yes/no)
Proportion of participants achieved seroconversion at Week 4 will be estimated and the 
corresponding 95% confidence interval will be calculated using exact method.
Both non-responder imputation and observed case approaches will be applied in the analyses 
of seroconversion.
To assess the change in HI titers, geometric means will be calculated for pre- and post-
vaccination HI titers.
To meet European Medicines Agency guidelines for protection for the Cohort, at least one of 
the following criteria has to be met:
1. Seroprotection rate is better than 70%;
2. Seroconversion rate is higher than 40%;
3. Ratio of geometric mean of post- to pre-vaccination HI titers ≥ 2.5.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Not applicable.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment arm. 


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In particular, summary tables for adverse events (AEs) will summarize only on-treatment events, 
which started or worsened during the on-treatment period (treatment-emergent AEs). 
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment.
In addition, a separate listing of death including on treatment and post treatment deaths will be 
provided.
Clinical laboratory evaluations
All laboratory data will be listed by treatment arm, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment arm and overall. Shift tables using the low/normal/high/ (low and high) classification 
will be used to compare baseline to the worst on-treatment value.
12.6
Analysis of exploratory endpoints
Not applicable. 
12.7
Interim analyses
For the purpose of early dissemination of results, two interim analyses will be performed after:

on/around April 12, 2021, whichever comes first.

on/around March 31, 2022, whichever comes first.
At the time of each interim analysis, methods proposed in Sections 12.5 and 12.6 for data 
summary and analyses will be performed.  Since there will be no hypothesis testing involved, 
statistical adjustment for the interim analyses will not be made at the stage of final analyses of 
efficacy and safety.


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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The sample size of 20 participants per arm is selected based on budget and need for early 
availability of results for the current influenza season. This sample size of 20 subjects will 
provide estimates of proportion responded with margin of error (half-width of a 95% confidence 
interval) of 20.1%, 19%, and 17.5% corresponding to response rates of 70%, 75%, and 80%, 
respectively. Adjusting for 10% drop-out, 22 subjects will be enrolled in each arm.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB for the trial protocol, written informed consent form, consent form updates, participant 
recruitment procedures (e.g., advertisements) and any other written information to be provided 
to participants. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs, and regulatory authorities as required. If an inspection of 
the clinical site is requested by a regulatory authority, the investigator must inform Novartis
immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.


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13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis
and approved by the IRB and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB at the study site should be informed according to local 
regulations.


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15
References
References are available upon request.
Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in 
participants 
with 
multiple 
sclerosis: 
The 
VELOCE 
study 
Neurology. 
2020;10.1212/WNL.0000000000010380
Farez MF, Correale J, Armstrong MJ, et al. Practice guideline update summary: Vaccine-
preventable infections and immunization in multiple sclerosis: Report of the Guideline 
Development, Dissemination, and Implementation Subcommittee of the American Academy of 
Neurology. Neurology. 2019;93(13):584-594
Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. 
N Engl J Med. 2020;383(6):546-557. 
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing 
Multiple Sclerosis. N Engl J Med. 2017;376(3):221-234.
Olberg HK, Eide GE, et al. Antibody response to seasonal influenza vaccination in patients with 
multiple sclerosis receiving immunomodulatory therapy. Eur J Neurol. 2018 Mar;25:527-534. 

SAP_001.pdf: 


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SAP
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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
11-
Dec-
2020
Prior 
to 
CDBL
Creation of 
final 
version
N/A – First version
NA


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................11
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................12
2.3.1
Patient disposition.................................................................................12
2.3.2
Demographics .......................................................................................12
2.3.3
Medical history......................................................................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................13
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................16
2.5.4
Supportive analyses...............................................................................17
2.6
Analysis of the key secondary objective ...............................................................17
2.7
Analysis of secondary objective(s)........................................................................17
2.7.1
Secondary endpoints .............................................................................17
2.7.2
Statistical hypothesis, model, and method of analysis..........................17
2.7.3
Handling of missing values/censoring/discontinuations.......................17
2.8
Safety analyses.......................................................................................................18
2.8.1
Adverse events (AEs)............................................................................18
2.8.2
Deaths....................................................................................................18
2.8.3
Laboratory data .....................................................................................18
2.8.4
Other safety data ...................................................................................18
2.9
Pharmacokinetic endpoints....................................................................................19
2.10
PD and PK/PD analyses.........................................................................................19
2.11
Patient-reported outcomes .....................................................................................19


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2.12
Biomarkers.............................................................................................................19
2.13
Other analyses........................................................................................................19
2.14
Interim analysis......................................................................................................19
3
Sample size calculation .....................................................................................................19
4
Change to protocol specified analyses ..............................................................................19
5
Appendix ...........................................................................................................................20
5.1
Imputation rules.....................................................................................................20
5.1.1
Study drug.............................................................................................20
5.1.2
AE date imputation ...............................................................................20
5.1.3
Concomitant medication date imputation .............................................21
5.2
AEs coding/grading ...............................................................................................23
5.3
Laboratory parameters derivations ........................................................................23
5.4
Statistical models...................................................................................................23
Primary analysis.....................................................................................................23
Key secondary analysis..........................................................................................23
Rule of exclusion criteria of analysis sets .........................................................................23
6
Reference...........................................................................................................................24


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List of abbreviations
AE
AESI
BMI
CDBL
CRF
CRO
CSP
CSR
CTCAE
DMS
EMA
EOS
Adverse Event
Adverse Event of Special Interest
Body Mass Index
Clinical Database Lock
Case Report Form
Contract Research Organization
Clinical Study Protocol
Clinical Study Report
Common Terminology Criteria for Adverse Events
Document Management System
European Medicines Agency
End of Study
FAS
GPS
HI
IA
MS
Full Analysis Set
Global Statistical and Programming Environment
Hemagluttination Inhibition
Interim Analyses
Multiple Sclerosis
MedDRA
NRI
Medical Dictionary for Drug Regulatory Affairs
Non-responder Imputation
PK
Pharmacokinetics
PRO
PT
QIV
Patient-reported Outcomes
Preferred Term
Quadrivalent inactivated influenza vaccine
RAP
RMS
SAE
SAF
Reporting & Analysis Process
Relapsing Multiple Sclerosis
Serious Adverse Event
Safety Analysis Set
SAP
SAS
sc
SOC
TEAE
Statistical Analysis Plan
Statistical Analysis System
Subcutaneous
System Organ Class
Treatment Emergent Adverse Events
TFLs
iDMT
Tables, Figures, Listings
Injectable Disease Modifying Therapy


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the statistical methods planned 
in Section 12 of the Clinical Study Protocol (CSP) version 00 (release date 10 November 2020) 
for the clinical trial COMB157GUS12 and any additional analyses, specifications or deviations 
from this planned protocol before clinical database lock (CDBL).
This SAP will be used to draft the Clinical Study Report (CSR) Section 9.7: Statistical methods 
and IA plans. 
1.1
Study design
This is a three-cohort, multicenter prospective study in up to 66 participants with relapsing 
multiple sclerosis (RMS).
Cohorts 1 and 2 will include up to 44 participants who will either begin treatment with 
ofatumumab (Cohort 1) or who are already treated with commercial ofatumumab (Cohort 2).
Participants in Cohort 1 will receive the inactivated influenza vaccine two weeks prior to 
starting treatment with ofatumumab, while participants in Cohort 2 will receive the inactivated 
influenza vaccine after at least 4 weeks of commercial ofatumumab treatment. 
Cohort 3 will include the remaining 22 participants who are already treated with commercial
injectable disease modifying therapy (iDMT) and who will receive the inactivated influenza 
vaccine after at least 4 weeks of commercial iDMT treatment. 
The study consists of three periods:

Screening Period (1 week);

Investigational Period (4 weeks);

Optional, 6-month open-label Extension Period
Screening Period 
Participants will enter a Screening Period of up to 1 week to assess eligibility requirements.    
Participants in Cohort 1 without Hepatitis B virus (HBV) and serum immunoglobulin results 
within the past 6 months prior to screening will require central labs drawn.  Participants with 
Hepatitis B virus (HBV) and serum immunoglobulin results within the past 6 months prior to 
screening will not require the labs to be drawn.  
Investigational Period
All participants will receive the inactivated influenza vaccine before or during the Week 0 visit, 
but within 9 calendar days after their screening visit. 

Participants in Cohort 1:  Loading doses of ofatumumab will be administered at Week 2, 
3 and 4.  

Participants in Cohort 2 will continue taking their prescribed ofatumumab as per their 
dosing schedule throughout the investigational period.

Participants in Cohort 3 will continue administration of their prescribed iDMT as per their 
dosing schedule throughout the investigational period.


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Optional, 6-month open-label Extension Period

Participants in Cohort 1 will administer their first dose of ofatumumab in the open-label 
Extension Period at Week 6.  Thereinafter, they will continue monthly dosing until the 
final dose at Week 26. Novartis will supply ofatumumab to participants in Cohort 1 for the 
Extension Period.

Participants in Cohort 2 will continue to administer ofatumumab monthly until the final 
dose at Week 28. Novartis will supply ofatumumab to participants in Cohort 2 for the 
open-label Extension Period.

Participants in Cohort 3 will not have the option to enter this Extension Period.
Study completion
For participants completing the trial, the total duration of the trial will be a minimum of 5 weeks. 
This accounts for the mandatory 1 week Screening Period and 4 week Investigational Period
starting at Week 0. Upon completing the Investigational Period, participants in Cohorts 1 and 2 
will have the option to enter a 6 month open-label Extension Period, where they will continue 
monthly dosing of ofatumumab. Participants in cohort 3 will not enter the Extension Period. 
Cohort 1 and 2 participants who prematurely discontinue the study while in the Investigational 
Period should be scheduled for the End of Study (EOS1) visit within 7 days. Cohort 3 
participants who prematurely discontinue the study while in the Investigational Period should 
be scheduled for the End of Study (EOS) visit within 7 days. Cohort 1 and 2 participants who 
prematurely discontinue the study while in the Extension Period should be scheduled for the 
final visit of the extension period (EOS2) within 7 days. All EOS assessments should be 
performed except study drug administration.
Study design schematics for Cohorts 1, 2 and 3 are shown in Figure 1-1, Figure 1-2 and Figure 
1-3 and respectively. 
Primary analysis time point
The primary analysis time point will be Week 4. 
Interim analysis
An interim analysis (IA) will be performed after all participants complete the Investigational 
Period or discontinue the Investigational Period prematurely, or on/around March 29, 2021, 
whichever comes first.


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Figure 1-1
Study Design (Cohort 1)
Figure 1-2
Study Design (Cohort 2)


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Figure 1-3
Study Design (Cohort 3)
1.2
Study objectives and endpoints
Study objectives and associated endpoints are shown in Table 1-1.
Table 1-1
Study objectives and endpoints
Objective(s)
Endpoint(s)
Primary objectives(s)
Endpoint(s) for primary objective(s)

To characterize those achieving 
seroprotection after receiving the 2020-
2021 seasonal quadrivalent influenza 
vaccine in participants treated with 
ofatumumab 20 mg sc once every 4 
weeks

Achieving seroprotection as defined by a 
post-vaccination antibody titer ≥40 at 
Week 4 (yes/no)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To characterize those achieving 
seroconversion after receiving the 2020-
2021 seasonal quadrivalent influenza 
vaccine in participants treated with 
ofatumumab 20 mg sc once every 4 
weeks

Safety

Achieving seroconversion at Week 4 as 
defined by either:
a.
a ≥4-fold increase in HI titers 
after vaccination (in participants
with pre-vaccination HI titers 
≥10) or


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Objective(s)
Endpoint(s)
b.
post-vaccination HI titers ≥40 (in 
participants with pre-vaccination 
HI titers <10) (yes/no)

Change in HI titers

AEs, SAEs, AEs leading to 
discontinuation
2
Statistical methods
2.1
Data analysis general information
The statistical analysis outlined in this SAP will be performed by Novartis or a designated 
Contract Research Organization (CRO), using SAS® version 9.4 or higher and stored in the 
Novartis Global Programming and Statistical Environment (GPS). 
For continuous variables, summary statistics will include number of participants (n), mean, 
standard deviation, minimum, maximum, median and 25th and 75th percentiles (optional). For 
categorical variables, frequency counts and percentages will be reported.   
Unless otherwise stated, all data summaries will be presented by cohort and on all participants 
in the respective analysis set. 
The CSR analysis cut-off date will be the EOS1/EOS visit for participants who do not continue 
to the Extension Period, or the EOS2 visit for participants who continue into the Extension 
Period. All data collected prior to this date will be used for analysis.
All data (collected or derived) will be listed appropriately.
2.1.1
General definitions
Treatment of interest
The investigational treatment or treatment of interest will refer to a once-off administration of 
the 2020-2021 quadrivalent inactivated influenza vaccine (QIV) via 0.5-mL single-dose 
prefilled syringe to participants in all three cohorts.
Additional treatment

Ofatumumab provided by Novartis in an auto-injector containing 20 mg sc ofatumumab 
(20 mg/0.4ml) for subcutaneous administration to participants in Cohort 1 in the 
Investigational and optional Extension Periods and to participants in Cohort 2 entering the 
optional open-label extension period as per the assessment schedule.

Ofatumumab as commercially prescribed in the course of medical practice for participants 
in Cohort 2 for the Investigational Period.  

Any MS iDMT as commercially prescribed in the course of medical practice for 
participants in Cohort 3.


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Study day
The day of Week 0 visit is defined as Study Day 1 or Day 1. All other study days will be labeled 
relative to Day 1.
For event dates on or after Day 1, study day for a particular event date is calculated as:
(Date of event − date Week 0 visit) + 1
I.e. Day 2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively.
For dates before Day 1, study day for an event date is calculated as:
(Date of event − date Week 0 visit)
Duration of an event will be calculated as (event end date − event start date + 1).
The descriptor “Day 0” will not be used.
Screening, baseline and post-baseline definitions
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to vaccination. Per protocol, participant informed consent must be obtained prior to 
performing any study related activity. The date of signing of informed consent is the start date 
of the screening period. Any assessment obtained during the screening period will be labelled 
screening assessment.
Baseline is the last assessment (including unscheduled visits) obtained before the date of 
vaccination. No visit windows will be needed for the identification of baseline assessment. All 
assessments obtained after the date of vaccination are considered as post-baseline unless 
otherwise specified.
Nominal visits
Nominal visits are defined as all scheduled visits as per the clinical study protocol including 
the EOS visits. The definition of nominal visit excludes unscheduled visits.
Change from baseline
Change from baseline will be calculated as:
(Post-baseline value − baseline value)
Change from baseline will only be calculated and summarized for participants with both 
baseline and post-baseline values.
2.2
Analysis sets
Safety set
The Safety Set (SAF) comprises all participants who have received the 2020-2021 inactivated 
influenza vaccine.


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Unless stated otherwise, the SAF will be used for all summary tables and listings. 
2.2.1
Subgroup of interest
There is no subgroup analysis planned for this study.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Patient disposition will be summarized for the following study periods: screening, treatment, 
extension treatment and treatment assigned. 
Patient disposition for each period will be summarized for all participants who entered that 
period. Participants who have entered any study period but have discontinued from the study 
will be listed as appropriate along with the primary reason for discontinuation. 
The number and percentage of screening failures and the reason for screening failure will be 
presented for all screened participants. 
For each protocol deviation, the number and percentage of participants for whom the deviation 
applies will be tabulated. 
2.3.2
Demographics
The following demographic variables will summarized descriptively by cohort:
Continuous variables

Age (years)
Categorical variables

Sex (Male, Female)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown)

Race (White, Black or African American, Asian (Chinese, Indian, Japanese, Korean, 
Vietnamese), Native Hawaiian or Pacific Islander, American Indian or Alaska Native, 
Multiple)
2.3.3
Medical history
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class (SOC) and preferred term (PT). 
Medical histories will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The latest version of which will be used for the reporting activity.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Participants in all cohorts are expected to receive a single dose of the 2020-2021 quadrivalent
inactivated influenza vaccine. 
Participants in Cohort 1 are expected to take a total of 3 ofatumumab 20 mg injections at Week 
2, 3, 4 and once every 4 weeks starting at Week 6 if they chose to continue to the 6-month 
Extension Period. 
Participants in Cohort 2 are expected to continue on their commercially prescribed 
ofatumumab during the Investigational Period and take study supplied ofatumumab 20 mg 
injections once every 4 weeks thereafter if they chose to continue to the 6-month Extension 
Period. 
Participants in Cohort 3 are expected to continue on their commercially prescribed iDMT 
throughout the Investigational Period. 
The number of injections of either ofatumumab 20 mg, ofatumumab as prescribed or iDMT as 
prescribed actually taken will be summarized descriptively by cohort and period (i.e. 
Investigational Period and Extension Period). 
The summaries by cohort will be performed by the actual treatment received (as follows).
Treatment sequence:

QIV + OMB 20mg

QIV + OMB as prescribed

QIV + iDMT as prescribed
Study duration
Study duration will be summarized by cohort and duration category (i.e. ≥1 week, ≥2 weeks, 
≥3 weeks, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥24 weeks).
2.4.1.1
Visit windows
Visit windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows are created to cover 
the complete range of days within the study. 
The visit windows for Cohorts 1, 2 and 3 are shown in Table 2-2, Table 2-2 and Table 2-3
respectively. These windows apply to measurements taken at every visit. For assessments 
collected less often different visit windows will be applied as detailed below. 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of
the visit windows. In the case of major deviations from the visit schedule, or due to unscheduled 
visits, several assessments of a participant may fall in a particular visit window (either 


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scheduled or unscheduled). Statistical approaches to handle multiple assessments in a given 
visit window are specified below. 
As a rule, the following steps are followed to determine the cut-offs for post-baseline time 
windows:

Transform all scheduled assessment time points into study days, assuming 1 month is equal 
to 30.4375 days. Middle points of scheduled assessments are determined.

The time window associated with the previous assessment ends prior to the middle point; 
the time window associated with the latter assessment begins after the middle point. In case 
the middle point is an exact study day, it will belong to the previous assessment.

The time window of first post-baseline assessment starts with Study Day 2, unless otherwise 
indicated.

For parameters, which are not collected at every visit, visit windows will be combined. For
example, if a parameter is measured at Week 2 and Week 4 only, Week 2 visit window will 
extend from Week 2 to Week 4 (combining Week 2 and Week 4 visit windows).
Table 2-1
Visit windows for Cohort 1
Analysis visit
Time point
Scheduled visit day
(study days)
Visit window (study 
days)
Visit 2/Baseline
Week 0
1
-7 to 1*
Visit 3
Week 2
14
2 to 17
Visit 4
Week 3
21
18 to 24
Visit 5/EOS1
Week 4
28
25 to 35
Visit 6
Week 6
42
36 to 56
Visit 7
Week 10
70
57 to 84
Visit 8
Week 14
98
85 to 112
Visit 9
Week 18
126
113 to 140
Visit 10
Week 22
154
141 to 168
Visit 11/EOS2
Week 26
182
169 to 196
*Baseline measurement before vaccine administration for safety assessments. 
Table 2-2
Visit windows for Cohort 2
Analysis visit
Time point
Scheduled visit day 
(study days)
Visit window (study 
days)
Visit 2/Baseline
Week 0
1
-7 to 1*
Visit 3
Week 1
7
2 to 10
Visit 4
Week 2
14
11 to 21
Visit 5/EOS1
Week 4
28
22 to 42
Visit 6
Week 8
56
43 to 70
Visit 7
Week 12
84
71 to 98
Visit 8
Week 16
112
99 to 126
Visit 9
Week 20
140
127 to 154
Visit 10
Week 24
168
155 to 182
Visit 11/EOS2
Week 28
196
183 to 210


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* Baseline measurement before vaccine administration for safety assessments. 
Table 2-3
Visit windows for Cohort 3
Analysis visit
Time point
Scheduled visit day 
(study days)
Visit windows (study 
days)
Visit 2/Baseline
Week 0
1
-7 to 1*
Visit 3
Week 1
7
2 to 10
Visit 4
Week 2
14
11 to 17
Visit 5
Week 3
21
18 to 24 
Visit 6/EOS
Week 4
28
25 to 31
* Baseline measurement before vaccine administration for safety assessments. 
Multiple assessments
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the participant in summary statistics in a visit window

Baseline: The last non-missing measurement made prior to or on the date of administration 
of vaccine administration (the reference start date / Day 1). Only date part is considered if 
just one assessment on Day 1. If there are multiple assessments on Day 1, the following 
rules will apply:
a. If assessment time exists,

select the last available measurement prior to reference start date/time 
considering time;

If no measurement prior to reference start date/time considering time, select 
the earliest measurement post reference start date/time considering time.
b. If assessment time does not exist, select the available measurement from the lowest 
CRF visit number.

Post-baseline: The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 day after), the 
earlier one will be used. Cases where the same parameter is recorded more than once on the 
same date will be handled as follows:
a.
If time of completion exists, the earliest measurement will be used;
b. If time does not exist, the measurement from the lowest CRF visit number will be 
used.
For post-baseline visit windows, the following applies (unless otherwise specified):

For continuous variables, the closest to the target study day is chosen (if two assessments 
have the same distance, than the earlier one will be chosen).

For categorical variables, identifying notable abnormalities, the record with the worst result 
is selected. It is noted that in the analyses performed, the worst case is clearly defined.
In case categorical variables are based on continuous variables, the visit will be assigned to 
the continuous variable, and this visit will be used for the derived categorical variable. 
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications will be summarized separately by cohort. 


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Medications will be classified as prior or concomitant as follows:

Prior medications are defined as drugs taken and stopped prior to the Week 0 visit.

Concomitant medications are defined as drugs taken at least once between Week 0 visit 
and the date of study completion (including those which were started prior to the Week 0 
visit and continued into the Investigational Period).
Medications will be categorized into one (and only one) of above classes based on recorded or 
imputed start and end dates.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and
percentage of participants receiving at least one treatment of a particular ATC code and at least
one treatment in a particular anatomical main group.
2.5
Analysis of the primary objective
The primary objective of this study is to characterize those achieving seroprotection after 
receiving the 2020-2021 inactivated influenza vaccine in participants in all three cohorts. This 
will be achieved by estimating the seroprotection response rate. 
A seroprotection responder is a participant achieving seroprotection as defined by a post-
vaccination hemagluttination inhibition (HI) titer ≥40.
The seroprotection response rate is defined as the proportion of participants with seroprotection.
2.5.1
Primary endpoint
The primary endpoint variable is achieving seroprotection as defined by a post vaccination HI
titer ≥40 (Yes/No) at Week 4. 
The primary estimand is described by the following attributes:

Treatment: 2020-2021 inactivated influenza vaccine in participants treated with 
ofatumumab 20 mg (Cohort 1), ofatumumab as commercially prescribed (Cohort 2) or 
iDMT as commercially prescribed (Cohort 3). 

Population: Relapsing MS participants subdivided into three cohorts as defined in Section 
1.1

Variable: Achieving seroprotection as defined by a post-vaccination HI titer ≥40 (Yes/No)

Other intercurrent events: None

Population-level summary: Proportion of participants who achieve seroprotection at Week 
4
2.5.2
Statistical hypothesis, model, and method of analysis
The number and percentage of responders will be presented. A 95% confidence interval for the 
proportion of responders will be calculated using an exact method.
2.5.3
Handling of missing values/censoring/discontinuations
Non-responder imputation (NRI) for missing data will be applied. NRI is a conservative 
imputation method for dichotomous variables. NRI assumes that a participant is a treatment 


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failure if they discontinue the study prematurely. Hence, for missing data the primary variable
outcome will be imputed to “No”. Please refer to Appendix Section 5.1.3.3.
2.5.4
Supportive analyses
No supportive analyses are planned. 
2.6
Analysis of the key secondary objective
There is not key secondary objective for this study. 
2.7
Analysis of secondary objective(s)
The secondary objective of this study is to characterize those achieving seroconversion after 
receiving the 2020-2021 inactivated influenza vaccine in participants in all three cohorts where 
seroconversion is defined as:

a ≥4-fold increase in HI titers after vaccination (in participants with pre vaccination HI 
titers ≥10) OR

post vaccination HI titers ≥40 (in participants with pre vaccination HI titers <10) 
The seroconversion response rate is defined as the proportion of participants with 
seroconversion.
To meet European Medicines Agency (EMA) guidelines for cohort protection, at least one of
the following criteria has to be met:

Seroprotection rate is better than 70%;

Seroconversion rate is higher than 40%;

Mean geometric increase of post- to pre-vaccination HI titers ≥ 2.5.
2.7.1
Secondary endpoints
The secondary endpoint variable is achieving seroconversion as defined in Section 2.7 above 
(Yes/No) at Week 4.  
2.7.2
Statistical hypothesis, model, and method of analysis
The number and percentage of responders will be presented. A 95% confidence interval for the 
proportion of responders will be calculated using an exact method. To assess the change in HI
titers, geometric means will be calculated and summarized for pre- and post-vaccination HI
titers.
2.7.3
Handling of missing values/censoring/discontinuations
Both NRI for missing data and observed data approaches will be applied. Result based on NRI 
will be used to meet the secondary endpoint. Other observed data approaches will be applied as 
sensitivity analyses. 


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2.8
Safety analyses
2.8.1
Adverse events (AEs)
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant
or clinical investigation of a participant after providing written informed consent for
participation in the study. That means that a participant can report AEs before having started 
study medication. For reporting purposes, the main focus will be on any adverse event which 
started on or after the Week 0 visit.
The number (and percentage) of participants with AEs will be summarized by cohort in the 
following ways:

by primary SOC and PT

by primary SOC, PT and maximum severity

by Standardized MedDRA Query (SMQ) and PT
Separate summaries will be provided for:

serious adverse events (SAEs)

AEs leading study discontinuation
Separate summaries will be presented for data collected during the Extension Period.
The MedDRA version used for reporting the study will be described in a footnote. If a particular 
Missing CTCAE grade will not be imputed. If a participant reported more than one AE with the 
same PT, the AE with the greatest severity will be presented. A participant with multiple AEs 
within a primary SOC is only counted once towards the total of the primary SOC.
All AEs will be listed by cohort.
2.8.2
Deaths
If a meaningful number of cases of death is reported (i.e., 5 or more cases), deaths will be 
summarized. All deaths will be listed. Deaths occurring during the Extension Period will be 
flagged.
2.8.3
Laboratory data
For participants in Cohort 1 that do not have relevant laboratory test results in their medical 
history within 6 months prior to the Screening Visit, all laboratory data collected will be listed 
by participant and if normal ranges are available, abnormalities will be flagged.
2.8.4
Other safety data
2.8.4.1
MS Relapse
An MS relapse is defined as an appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 30 
days from onset of a preceding clinical demyelinating event (Polman et al 2011). The 
abnormality must have been present for at least 24 hours and occurred in the absence of fever 
(< 37.5°C) or a known infection.


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If a meaningful number of cases of MS relapse is reported (i.e., 5 or more cases), MS relapse 
during the study will be summarized by cohort. All occurrence of MS relapse will be listed. 
Incidence of MS relapse during the Extension Period will be flagged.
2.9
Pharmacokinetic endpoints
There are no pharmacokinetic endpoints planned for this study.
2.10
PD and PK/PD analyses
There are no PD and PK/PD analyses planned for this study.
2.11
Patient-reported outcomes
There are no patient-reported outcome analyses planned for this study. 
2.12
Biomarkers
There are no biomarker analyses planned for this study.
2.13
Other analyses
No other analyses are planned for this study. 
2.14
Interim analysis
For the purpose of earlier dissemination of results, an interim analysis will be performed after:

all enrolled participants have completed the Investigational Period or discontinued the 
Investigational Period prematurely OR

On/around March 29, 2021, whichever comes first.
Since there will be no hypothesis testing involved, statistical adjustment for the interim analysis 
will not be made at the stage of final analyses.
3
Sample size calculation
Sample size calculations were based on the proportion of participants who responded to 
influenza vaccination.
The sample size of 20 participants per arm is selected based on budget and need for early
availability of results. The sample size of 20 subjects will provide estimates with margin of 
error (half-width of a 95% confidence interval) of 20.1%, 19%, and 17.5% corresponding to 
response rates of 70%, 75%, and 80%, respectively. Adjusting for 10% drop-out, 22 subjects 
will be enrolled in each arm.
4
Change to protocol specified analyses
There are no changes to protocol specified analyses.








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5.1.3.3
Other imputations
Non-responder imputation
Non-responder imputation (NRI) assumes that a participant is a treatment failure if they 
discontinue the study prematurely. Hence, for missing data the primary variable outcome of 
achieving seroprotection as defined by a post vaccination HI titer ≥40 (Yes/No) at Week 4 will 
be imputed to “No”. 
5.2
AEs coding/grading
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
The latest MedDRA version will be used and will be described in the footnote of relevant 
outputs. 
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
Primary analysis
There is no hypothesis testing planned for this study.
Key secondary analysis
There is no key secondary analysis planned for this study.
Rule of exclusion criteria of analysis sets 
Deviation 
ID
Description of deviation
Exclusion in analyses
INCL01A
No informed consent obtained or 
missing. 
Exclude from the SAF.
INCL05
Not Planning to receive a 2020-2021 
inactivated influenza vaccine
Exclude from the SAF
INCL06A
Not Planning to start treatment with 
ofatumumab for Cohort 1
Exclude from the SAF
INCL06B
Not already on commercially prescribed 
ofatumumab for Cohort 2 with minimum 
4 weeks
Exclude from the SAF
INCL07
Currently not be receiving iDMT for 
Cohort 3
Exclude from the SAF
Analysis set
PD ID that cause participants 
to be excluded
Non-PD criteria that cause participants to be 
excluded
SAF
INCL01A
Influenza vaccine not taken 
SAF
INCL05
Influenza vaccine not taken


Novartis
For business use only
Page 24 of 24
SAP
COMB157GUS12
Analysis set
PD ID that cause participants 
to be excluded
Non-PD criteria that cause participants to be 
excluded
SAF
INCL06A
Study treatment not taken
SAF
INCL06B
Study treatment not taken
SAF
INCL07
Study treatment not taken
6
Reference
Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., Fujihara, K., 
Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F.D., Montalban, X., O'Connor, P., 
Sandberg‐Wollheim, M., Thompson, A.J., Waubant, E., Weinshenker, B. and Wolinsky, J.S. 
(2011), Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. 
Ann Neurol., 69: 292-302.