AGNOS: An 18-month, Open-label, Multi-Center Phase IV Study to Assess the Effect of Ofatumumab 20mg SC Monthly in Treatment Naïve, Very Early Relapsing Remitting Multiple Sclerosis Patients Benchmarked Against Healthy Controls on Select Outcomes.
Phase: PHASE4
Conditions: Relapse Remitting Multiple Sclerosis
Sponsor: Novartis Pharmaceuticals

 
Novartis Research and Development 
Ofatumumab 
Clinical Trial Protocol COMB157GUS10 / NCT05084638
AGNOS: An 18-month, Open-label, Multi-Center Phase IV 
Study to Assess the Effect of Ofatumumab 20mg SC 
Monthly in Treatment Naïve, Very Early Relapsing 
Remitting Multiple Sclerosis Patients Benchmarked 
Against Healthy Controls on Select Outcomes. 
Document type: 
Amended Protocol 
EUDRACT number: 
Not applicable 
Version number: 
03 (Clean) 
Clinical Trial Phase: 
IV 
Release date: 
14-Sep-2023
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 

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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ......................................................................................................................... 6 
List of figures ....................................................................................................................... 7 
List of abbreviations ............................................................................................................. 8 
Glossary of terms ............................................................................................................... 11 
Amendment 03 ................................................................................................................... 14 
Amendment 02.01.............................................................................................................. 15 
Amendment 02 ................................................................................................................... 16 
Amendment 01................................................................................................................... 17 
Protocol summary .............................................................................................................. 18 
1 
Introduction ........................................................................................................................ 24 
1.1 
Background ............................................................................................................ 24 
1.2 
Purpose ................................................................................................................... 26 
2 
Objectives, endpoints and estimands ................................................................................. 27 
2.1 
Primary estimands .................................................................................................. 29 
2.2 
Secondary estimands .............................................................................................. 29 
3 
Study design ....................................................................................................................... 29 
4 
Rationale ............................................................................................................................ 32 
4.1 
Rationale for study design ...................................................................................... 32 
4.2 
Rationale for dose/regimen and duration of treatment ........................................... 33 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ....................................................................................................................... 33 
4.4 
Purpose and timing of interim analyses/design adaptations ................................... 33 
4.5 
Risks and benefits .................................................................................................. 33 
4.5.1 
Blood sample volume ............................................................................ 35 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................. 35 
5 
Study Population ................................................................................................................ 35 
5.1 
Inclusion criteria ..................................................................................................... 35 
5.2 
Exclusion criteria ................................................................................................... 36 
6 
Treatment ........................................................................................................................... 38 
6.1 
Study treatment ...................................................................................................... 38 
6.1.1 
Investigational and control drugs ........................................................... 38 
6.1.2 
Additional study treatments ................................................................... 39 
6.1.3 
Treatment arms/group ............................................................................ 39 
6.1.4 
Treatment duration ................................................................................ 39 
6.1.5 
Post-Trial Access ................................................................................... 39 

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6.2 
Other treatment(s) .................................................................................................. 40 
6.2.1 
Concomitant therapy.............................................................................. 40 
6.2.2 
Prohibited medication ............................................................................ 41 
6.2.3 
Recommended treatment of MS Relapse .............................................. 41 
6.3 
Preparation and dispensation .................................................................................. 42 
6.3.1 
Handling of study treatment and other treatment .................................. 42 
6.3.2 
Instruction for prescribing and taking study treatment .......................... 42 
6.4 
Participant numbering, treatment assignment, randomization ............................... 44 
6.4.1 
Participant numbering ........................................................................... 44 
6.4.2 
Treatment assignment, randomization ................................................... 45 
6.5 
Dose escalation and dose modification .................................................................. 45 
6.5.1 
Dose escalation guidelines ..................................................................... 45 
6.5.2 
Follow-up for toxicities ......................................................................... 45 
6.5.3 
Drug Interruptions ................................................................................. 45 
6.6 
Additional treatment guidance ............................................................................... 45 
6.6.1 
Treatment compliance ........................................................................... 45 
6.6.2 
Recommended treatment of adverse events ........................................... 46 
6.6.3 
Emergency breaking of assigned treatment code .................................. 46 
7 
Informed consent procedures ............................................................................................. 46 
8 
Assessment schedule and assessments ............................................................................... 47 
8.1 
Screening ................................................................................................................ 55 
8.1.1 
Eligibility screening ............................................................................... 55 
8.1.2 
Information to be collected on screening failures .................................. 55 
8.2 
Participant demographics/other baseline characteristics ........................................ 55 
8.3 
Efficacy .................................................................................................................. 56 
8.3.1 
MS Relapse Assessment ........................................................................ 56 
 
 58 
 
 58 
 
 58 
 
 58 
8.3.6 
Magnetic Resonance Imaging (MRI) .................................................... 59 
 
 60 
8.3.8 
Quality of Life in Neurological Disorders (NeuroQOLTM) ................... 61 
8.3.9 
Patient Determined Disease Steps (PDDS) ........................................... 62 
 
 62 
8.3.11 
Appropriateness of efficacy assessments ............................................... 62 

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8.4 
Safety ..................................................................................................................... 62 
8.4.1 
Laboratory evaluations .......................................................................... 63 
8.4.2 
Pregnancy and assessments of fertility .................................................. 64 
8.4.3 
Columbia Suicide Severity Rating Scale (C-SSRS) .............................. 65 
8.4.4 
Appropriateness of safety measurements .............................................. 65 
8.5 
Additional assessments .......................................................................................... 66 
8.5.1 
Clinical Outcome Assessments (COAs) ................................................ 66 
 
 66 
 
 67 
8.6 
Remote visits in case of Public Health Emergency ............................................... 68 
9 
Study discontinuation and completion ............................................................................... 68 
9.1 
Discontinuation from study treatment and from study .......................................... 68 
9.1.1 
Discontinuation from study treatment ................................................... 68 
9.1.2 
Discontinuation from study ................................................................... 69 
9.1.3 
Lost to follow-up ................................................................................... 69 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples........ 70 
9.3 
Study completion and post-study treatment ........................................................... 70 
9.4 
Early study termination by the sponsor .................................................................. 71 
10 Safety monitoring, reporting and committees .................................................................... 71 
10.1 
Definition of adverse events and reporting requirements ...................................... 71 
10.1.1 
Adverse events ....................................................................................... 71 
10.1.2 
Serious adverse events ........................................................................... 73 
10.1.3 
SAE reporting ........................................................................................ 74 
10.1.4 
Pregnancy reporting ............................................................................... 75 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................. 75 
10.2 
Additional Safety Monitoring ................................................................................ 76 
10.2.1 
Prospective suicidality assessment ........................................................ 76 
10.3 
Committees ............................................................................................................ 76 
10.3.1 
Data Monitoring Committee .................................................................. 76 
10.3.2 
Steering Committee ............................................................................... 76 
11 Data Collection and Database management ....................................................................... 77 
11.1 
Data collection ....................................................................................................... 77 
11.2 
Database management and quality control ............................................................ 77 
11.3 
Site monitoring ....................................................................................................... 77 
12 Data analysis and statistical methods ................................................................................. 78 
12.1 
Analysis sets ........................................................................................................... 78 

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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 27 
Table 6-1 
Investigational drug ............................................................................... 38 
Table 6-2 
Treatment arms/group ............................................................................ 39 
Table 6-3 
Prohibited medication ............................................................................ 41 
Table 6-4 
Arm 1 treatment schedule ...................................................................... 44 
Table 6-5 
Extension treatment schedule ................................................................ 44 
Table 8-1 
Assessment Schedule............................................................................. 49 
Table 8-2 
Severity of MS relapse .......................................................................... 57 
Table 8-3 
Safety assessments and specifications ................................................... 63 
Table 8-4 
Laboratory Assessments ........................................................................ 64 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................... 76 

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List of figures 
Figure 3-1 
Study design .......................................................................................... 30 

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List of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
b.i.d. 
bis in die/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C-SSRS 
Columbia Suicide Severity Rating Scale 
 
 
CD-ROM 
Compact Disc – Read Only Memory 
CDP 
Clinical Development Plan 
CDS 
Core Data Sheet 
CK 
Creatine Kinase 
ClinRO 
Clinician Reported Outcomes 
CMO&PS 
Chief Medical Office and Patient Safety 
CO 
Country Organization 
CO2 
carbon dioxide 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSF 
Cerebral Spinal Fluid 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DIN 
Drug Inducted Nephrotoxicity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DMT 
Disease Modifying Therapy 
DQF 
Data Query Form 
DSMB 
Data Safety Monitoring Board 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
ELISA 
Enzyme-linked immunosorbent assay 
EOI 
End of Infusion 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 

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FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
h 
Hour 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HC 
Healthy controls 
HED 
Human Equivalent Dose 
HEOR 
Health Economics & Outcomes Research 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest Non-Severely Toxic Dose 
HRQoL 
Health-Related Quality of Life 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
Nab 
Neutralizing antibody 
NCDS 
Novartis Clinical Data Standards 
NEDA 
No Evidence of Disease Activity 
NOVDD 
Novartis Data Dictionary 
ObsRO 
Observer Reported Outcomes 
OMB 
Ofatumumab 
p.o. 
oral(ly) 
PA 
posteroanterior 
PD 
Pharmacodynamic(s) 
PDDS 
Patient Determine Disease Steps 

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PerfO 
Performance Outcomes 
PK 
Pharmacokinetic(s) 
PPD 
Premature Participant Discontinuation 
PRO 
Patient Reported Outcomes 
PSD 
Premature Subject Discontinuation 
PT 
prothrombin time 
QD 
Once a day 
QMS 
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RAP 
The Report and Analysis Plan 
RBC 
red blood cell(s) 
RDC 
Remote Data Capture 
REB 
Research Ethics Board 
RoW 
Rest of World 
RU 
Resource Utilization 
sc 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
sCR 
serum creatinine 
SD 
standard deviation 
 
 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TD 
Study Treatment Discontinuation 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 

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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 group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over 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 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g. q28 days) 
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 source 
data/documents 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 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
combines source documents and case report forms (eCRFs) into one 
application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is 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 

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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 or the participant allocated to 
an invalid stratification factor 
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 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in 
data collection 
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. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else 
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 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
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 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size 
of the tumor, whether lymph nodes contain cancer, and whether the 
cancer has spread from the original site to other parts of the body 
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 

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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 
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or videoconference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial 
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 
Victim drug 
The drug that is affected by the drug-drug interaction 
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/ biological samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different 
legal reason than consent 

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Amendment 02.01 
Rationale for Amendment 
Administrative change on the protocol cover page 1 and the protocol summary page 17, to 
update the protocol title to reflect the trial phase (Phase IV): 
• “An 18 month, Open-label, Multi-Center Phase IV Study to Assess the Effect of 
Ofatumumab 20mg SC Monthly in Treatment Naïve, Very Early Relapsing Remitting 
Multiple Sclerosis Patients Benchmarked Against Healthy Controls on Select Outcomes.” 

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Amendment 01 
Rationale for Amendment 
 
The purpose of Amendment 1 is to amend items that were not clear in the assessment 
schedule and study design. 
 
Changes in Table 8-1 
• PROs will be captured at on-site visits only, not monthly as per previous footnote in 
Table 8-1 
• C-SSRS will now be captured at every screening or baseline, and every on-site visit 
thereafter, up until EOS 
• Study Design has been updated to show 100-day Safety Follow-up visit separate from 
M21 visit for clarification 
• Clarified assessments for Healthy Control participants 
Change in Section 6.3.2 
• Updated language regarding timing of assessment and drug administration if occurring 
on same day 
Changes throughout protocol 
• Clarified the period for NEDA-3 measurement is month 6-18 
• Clarified that month 18 will have an interim analysis conducted as the primary 
endpoint will be measured at this time 
• Clarified 100-day Safety Follow-up data will only be captured in the Source 
Document, not the EDC 

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5.
Diagnosis of RRMS per McDonald Criteria (2010/2017)
6.
Within 6 months of diagnosis of clinically definite MS (CDMS)
7.
EDSS 0-3.0 (Inclusive) at both screening and baseline
8.
Treatment-naïve to MS DMT
9.
Able to obtain MRI and attend study visits at sites
10. Able to use wearable device
11. Able to provide blood sample (and CSF for sub-group n=15)
12. If a participant is receiving dalfampridine
(Ampyra®/Fampyra®) concomitantly with study treatment, the participant
should have been on a stable dose at least 30 days prior to first study
drug administration and remain on that dose throughout the study
wherever possible
Key Exclusion 
criteria 
Participants in the healthy control arm meeting any of the following criteria are not 
eligible for inclusion in this study: 
1.
Confounding medical condition as determined by the investigator
RRMS patients fulfilling any of the following exclusion criteria are not eligible for 
inclusion in this study: 
2.
Diseases other than multiple sclerosis responsible for the clinical or MRI
presentation
3.
Patients with neuromyelitis optica, Radiologic/Clinically Isolated
Syndrome, Secondary Progressive or Primary Progressive MS diagnosis
4.
Use of experimental or investigational drugs for MS
5.
Previous use of Disease Modifying Therapy (DMT) or chemotherapeutic
medications for MS
6.
Relapse between screening and Baseline visits
7.
Known sensitivity to gadolinium; patients with chronic, severe kidney
disease (GFR < 30 mL/min/1.73m2) or acute kidney injury
(contraindicated with use of gadolinium)
8.
Known history of hypersensitivity to any of the study treatments or its
excipients or to drugs of similar chemical classes
9.
CNS anomalies that are better accounted for by another disease process
(e.g., traumatic brain injury) or MRI anomalies causing clinically apparent
impairments in social, occupational, or generalized areas of functioning,
due to the direct physiologic effects of substances (recreational drug
abuse, toxic exposure, etc) or a medical condition
10. Known active malignancies
11. 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
12. Females of childbearing potential (all women physiologically capable of
becoming pregnant) should use effective contraception while receiving
ofatumumab and for 6 months after the last treatment of ofatumumab
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,

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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 
• 
Single barrier methods of contraception: male or female condom or 
occlusive cap, diaphragm, or cervical/vault caps. 
• 
For female participants on the study, the vasectomized male partner 
should be the sole male 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. Oral contraceptive may be switched 
during the trial, if participant is able to maintain stable dose during 
course of participation 
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 childbearing 
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 
13. Patients with an active chronic disease (or stable but treated with immune 
therapy) of the immune system other than MS (e.g. rheumatoid arthritis, 
scleroderma, Sjögren’s syndrome, Crohn’s disease, ulcerative colitis, etc.) 
or with immunodeficiency syndrome (e.g., hereditary immune deficiency, 
drug-induced immune deficiency) 
14. Patients with active infections including systemic bacterial, viral (including 
SARS-CoV-2/COVID-19) or fungal infections, or known to have AIDS or 
to test positive for HIV antibody at Screening 
15. Patients with neurological findings consistent with Progressive Multifocal 
Leukoencephalopathy (PML), or confirmed PML 
16. Patients with IgG or IgM levels below LLN at Screening 
17. Patients that have received any live or live-attenuated vaccines within 4 
weeks prior to first dose of study drug administration 
18. Patients at risk of developing or having reactivation of hepatitis: Positive 
results at Screening for serological markers for hepatitis (H) B indicating 
acute or chronic infection: 

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1 
Introduction 
1.1 
Background 
Multiple sclerosis (MS), one of the most common causes of neurological disability in young 
adults, is the prototypic inflammatory demyelinating condition of the central nervous system 
(CNS), characterized by inflammation, demyelination and axonal/neuronal destruction, 
ultimately leading to disability in many patients. 
The McDonald Criteria (McDonald et al., 2001) was the first diagnostic criteria for MS to 
employ MRI measures alongside clinical assessments. As more data and experience with MRI 
were acquired (Tintore et al., 2000; Swanton et al., 2006, 2007; Montalban et al., 2010), the 
criteria evolved further with two subsequent revisions (Polman et al., 2005, 2011). Currently, 
the 2010 revision of the McDonald Criteria is utilized to characterize the patients’ clinical stage 
and determine the patients’ eligibility to participate in the trial. 
Several disease modifying treatments have been approved for relapsing MS over the past decade, 
which has led to improved outcomes over the short term. However, many individual patients do 
not tolerate these (newer) approved drugs which forces them to discontinue the treatment 
(Merkel et al., 2017). Further, long term disability resulting from relapse independent 
progression, even in patients thought to have relapsing MS, demonstrates that an underlying 
progression occurs in most MS patients from disease onset (Cree et al., 2019). For example, in 
a study by (Cree et al., 2016), follow-up data from 471 patients over 10 years demonstrated 
clinically significant disability accrued in 59% of the patients. This illustrates that an unmet need 
remains for highly effective disease-modifying therapies (DMTs) with acceptable safety profiles 
in early relapsing MS patients and that those treatments should be used at first diagnosis to reduce 
the burden of long-term accrual of disability as there are no limitations based on the prescribing 
information and decisions are generally made based on HCP preference. 
While traditional research has focused on the role of T cells for MS, pathogenic B cells are 
known to play an early role in the immune-mediated pathogenesis of MS (Archelos et al., 2000, 
Frohman et al., 2006, McFarland, 2008). B cells, acting in concert with T cells, have been found 
to be required for full disease expression (Genain and Hauser, 1996) and have been shown to 
be essential in regulating immune response. B cells may contribute to disease pathogenesis by 
self-antigen presentation, promoting CD4+ T-cell activation (Bouaziz et al., 2007), regulating 
T-cell function/inflammation via cytokine production (Lund, 2008) and producing 
autoantibodies. B-cells are present in chronic MS plaques, areas of demyelination, and in the 
cerebrospinal fluid of MS patients (Lehmann-Horn et al., 2013). These observations have 
provided a new framework for the importance of B cells in MS pathogenesis and validate the 
use of B□cell□based therapeutics in the disease. 
 
Ofatumumab (also known as Kesimpta®, OMB157, GSK1841157 and HuMax-CD20) is a 
human type 1 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) which targets 
the CD20 molecule on cell surfaces. Ofatumumab (20mg subcutaneous [sc]) is available for 
commercial use in the US with an indication of “the treatment of relapsing forms of multiple 
sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active 
secondary progressive disease, in adults” (Kesimpta®, PI). 

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Ofatumumab binds specifically to two distinct epitopes on the receptor, encompassing both the 
small and large extracellular loops of the CD20 molecule. The CD20 molecule is a 
transmembrane phosphoprotein expressed on B lymphocytes from the late pre-B to mature B 
lymphocyte stage but is not expressed in stem cells or in plasma cells. Once bound to cell 
surface CD20, ofatumumab induces B-cell lysis via complement dependent cytotoxicity (CDC) 
and antibody dependent T-cell-mediated cytotoxicity (ADCC). The pharmacokinetics (PK) of 
ofatumumab are typical of a mAb with low clearance, a small volume of distribution, and a 
relatively long half-life (T1/2). Since ofatumumab is a mAb, conventional studies to investigate 
protein binding, whole body distribution, metabolism, excretion, and the potential for 
pharmacokinetic drug-drug interactions, are not appropriate and have therefore not been 
conducted. 
 
A comprehensive package of nonclinical toxicology studies with toxicokinetic evaluation has 
been conducted to support the intravenous (iv) and sc administration of ofatumumab in humans. 
Intravenous administration for up to 7 months duration and a repeat dose toxicity study of 2 
weeks duration by the sc route in cynomolgus monkeys resulted in the expected depletion of 
peripheral and lymphoid tissue B-cells with no associated toxicological findings. Studies 
conducted to investigate human tissue cross reactivity in vitro, inflammatory and coagulation 
parameters in cynomolgus monkeys, and local tolerance evaluation as part of repeat dose 
toxicity studies in cynomolgus monkeys revealed no adverse or unexpected findings. No 
maternal toxicity or adverse effects on embryo fetal development effects were noted in 
cynomolgus monkeys (refer to Kesimpta®, PI, COMB157G2301 and COMB157G2302-- 
clinical-study-report here and below for further information on the pivotal trial program). 
 
Efficacy data for ofatumumab in MS was obtained from two completed Phase 2 studies in 
patients with RRMS: one study with iv administration (OMS115102) and one study with sc 
administration (OMS112831). Ofatumumab administered iv (100, 300, 700mg) and sc (3mg, 
30mg, 60mg every 12 weeks [q12w], 60mg every 4 weeks [q4w]) demonstrated profound, dose- 
dependent B-cell depletion and beneficial clinical effects compared to placebo (Sorensen et al., 
2014, Bar-Or et al., 2018). Analysis of peripheral B-cell counts in the iv Phase 2 study showed 
that ofatumumab caused CD19+ and CD20+ cells at all dose levels studied to decrease below 
the detectable limit within one week (Sorensen et al 2014). Analysis of peripheral B-cell counts 
in the sc Phase 2 also demonstrated a rapid, dose and dose frequency dependent reduction in B- 
cell counts, the effect being less pronounced with the 3mg q12w regimen compared to the higher 
dose regimens studied. In the sc Phase 2 study, dosing every 4 weeks showed no signs of B-cell 
repletion during the inter-dosing interval. Both 30mg and 60mg q12w showed approximately 
75% decrease of B-cell counts compared to baseline prior to re-dosing. Once dosing was ceased, 
all treatments showed a similar rate of B-cell repletion over up to 60 weeks of follow up (Bar- 
Or et al., 2018). 
 
Ofatumumab also demonstrated strong suppression of inflammatory activity on magnetic 
resonance imaging (MRI). Only one of three subjects in the iv Phase 2 study dosed with 
ofatumumab (active/placebo treatment in the 100mg dose cohort) had a single new Gd- 
enhancing lesion detected up to Week 24 (Sorensen et al., 2014). In the sc Phase 2 study, 
ofatumumab reduced the mean cumulative number of new Gd-enhancing lesions by 65% vs 
placebo during weeks 0-12 (p<0.001) (Bar-Or et al., 2018). Disease activity that occurred before 

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onset of action of ofatumumab was captured in this analysis, and therefore a post hoc analysis 
of cumulative ofatumumab doses of 30mg and 60mg dose groups during weeks 4-12 was done; 
it demonstrated a reduction in the mean cumulative number of new Gd-enhancing lesions 
by >90% vs placebo. Reductions were maintained up to the last observation at week 48, even 
though last dosing of ofatumumab was at week 20 (Bar-Or et al., 2018). 
 
Based on the promising Phase 2 results, Novartis continued the development of ofatumumab 
for the treatment of patients with relapsing MS using a large Phase 3 pivotal trial program 
named ASCLEPIOS. This clinical program comprised of two worldwide, randomized, double- 
blind, double-dummy, active comparator-controlled, parallel-group studies of identical design 
(COMB157G2301 and COMB157G2302; also referred to as ASCLEPIOS I and II). The 
ofatumumab Phase III studies (ASCLEPIOS I and II) were designed in accordance with the 
recommendations from the FDA and EMA during end-of-Phase 2 meetings. The purpose of 
ASCLEPIOS I and II were to provide efficacy, safety and tolerability data for ofatumumab sc 
compared to oral (po) teriflunomide (Aubagio®) in patients with relapsing MS. 
 
In ASCLEPIOS I and II, monthly subcutaneous ofatumumab 20mg demonstrated superiority 
over once daily oral teriflunomide 14mg in participants with relapsing forms of MS (Hauser et 
al., 2020, Kesimpta®, PI). Both studies met the primary endpoints where ofatumumab showed 
a highly significant and clinically meaningful reduction in the number of confirmed relapses, 
evaluated as the annualized relapse rate (ARR). Specifically, RMS participants on 
ofatumumab had a reduction in annualized relapse rate (ARR) by 50.5% (0.11 vs. 0.22) and 
58.5% (0.10 vs. 0.25) compared to teriflunomide (both studies p<0.001) in ASCLEPIOS I and 
II studies respectively (Hauser et al., 2020). Key secondary endpoints were also met, with 
ofatumumab showing a relative risk reduction of 34.4% in 3-month confirmed disability 
(CDW) (p=0.002) and 32.5% in 6-month CDW (p=0.012) versus teriflunomide in a pre- 
specified pooled analyses (Hauser et al., 2020). The results from the pooled safety analyses 
from the two pivotal Phase 3 studies showed no new or unexpected safety signals for 
ofatumumab, as compared to earlier MS clinical studies. 
 
Data from ASCLEPIOS I and II supported the US regulatory filing and approval of ofatumumab 
for the treatment of patients with relapsing MS. Ofatumumab was approved by the FDA with an 
indication of treatment of relapsing forms of MS, to include clinically isolated syndrome, 
relapsing-remitting disease, and active secondary progressive disease, in adults (Kesimpta®, PI). 
1.2 
Purpose 
This study is meant to complement the ofatumumab clinical development pivotal trials by 
demonstrating clinical and MRI efficacy (both conventional and non-conventional) in a young 
adult, treatment naïve, very early MS patient population. The focus will be on patients earlier 
in the MS disease continuum than the average patient studied in ASCLEPIOS I and II. The 
baseline characteristics for ASCLEPIOS I and II included: mean ages of 38.9 years and 38.0 
years, mean duration from first symptoms of 8.36 years and 8.2 years, and mean EDSS scores 
of 2.97 and 2.90 years, respectively. In the ASCLEPIOS I and II studies, only ~30% of 
ofatumumab patients were treatment-naïve and ~24% were under the age of 30, leading to an 

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identified data gap for ofatumumab in the United States for the treatment of young adult, 
treatment naïve and very early MS patients (Hauser et al., 2020). 
 
Because the ASCLEPIOS I and II studies had relatively small numbers of treatment-naïve 
patients compared to similar regulatory trials for competitor products and did not specifically 
address the very early MS patient population, the current proposed study intends to address 
these groups. The ASCLEPIOS I and II trials used an active comparator (as required by 
regulatory authorities) and therefore did not compare ofatumumab to healthy control (HC) 
patients. This type of HC comparator data can provide important information on safety 
outcomes (e.g., infections) and the ability of ofatumumab to normalize CNS pathology as 
measured by biomarkers and MRI. Additionally, there remains a data gap for patient reported 
outcomes (PRO), digital monitoring and biomarker work, which was either not or incompletely 
addressed in the ASCLEPIOS study program. 
 
The proposed study would provide rigorous clinical, MRI, digital and biomarker data 
demonstrating the effect of ofatumumab in a naïve RRMS population at first diagnosis and 
would provide the first data relative to healthy controls, identified data gaps in the US. The very 
early MS young adult population in this study will consist of treatment naïve RRMS patients 
that are within 6 months of diagnosis at the time of study entry. Detailed data will be collected 
within the first month to document a rapid response to therapy. Further, a HC group will be 
used to analyze select endpoints vs ofatumumab (e.g., brain atrophy) with the strategy of 
showing normalization of brain structural/functional changes. This would also highlight the 
need for high efficacy therapy very early in the course of the disease as the extension data of up 
to 30 months would potentially show stabilization long term. 
 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
The primary objective is to explore the 
impact of ofatumumab (OMB) on the ability 
to achieve No Evidence of Disease Activity 
(NEDA-3) status in treatment-naïve, very 
early RRMS patients over an 18 month, 
open-label study period after a re-baseline 
of MRI at 6 months 
Endpoint(s) for primary objective(s) 
• 
NEDA-3 (Relapse-free, 3-month clinical 
disability progression-free, MRI activity-free) 
in Months 6 to 18 (yes/no) 
 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
Evaluate the effect of ofatumumab on 
various clinical (NEDA, disability, relapse) 
metrics at 18 months 
 
 
• 
Evaluate the effect of ofatumumab on 
conventional MRI metrics, with MRIs at 
Baseline and months 6, 12, 18, 30 (T1 Gd 

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Objective(s) 
Endpoint(s) 
@ Baseline, month 6, 18 and T1/T2 @ every 
timepoint) 
 
 
• 
Evaluate the effect of ofatumumab on 
patient reported outcomes (PROs) 
(NeuroQOLTM, Patient Determined Disease 
Steps [PDDS]) 
• 
Evaluate the effect of ofatumumab vs 
healthy controls on 1) whole brain and 
regional atrophy measured at month 18/30 
after re-baseline at 6 months; and 2) 
regional atrophy measured 18/30 months 
from Baseline 
• 
Evaluate the safety and tolerability of 
ofatumumab 
number (Baseline), New/enlarging T2 lesion 
number (post-Baseline), T2 lesion volume, 
new unenhancing T1 lesion number, T1 
unenhancing lesion volume) 
• 
Change from Baseline in Patient Reported 
Outcomes (NeuroQOLTM, PDDS) (also 
obtained in HC) 
 
• 
Brain volume loss (BVL) assessment (whole 
brain and regional) (also obtained in HC) 
 
 
 
 
• 
Adverse events, laboratory data, physical 
examination, and vital signs (also obtained 
in HC) 
 
 
 
 
 

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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to 
address events occurring during the trial conduct which could impact the interpretation of the 
trial results (e.g. premature discontinuation of treatment). 
 
The primary clinical question of interest is: will treatment with ofatumumab allow young and 
very early RRMS patients to achieve No Evidence of Disease Activity (NEDA-3) at 18 
months and what changes occur in these patients as measured by innovative methods such as 
non-conventional MRI, patient reported outcomes (PRO), biomarker and digital monitoring 
technologies? 
 
The justification for the primary estimand is that it will capture the effect of ofatumumab on 
shutting down MS inflammatory and associated clinical disease activity within the CNS in a 
RRMS population that is at first diagnosis. 
 
The primary estimand is described by the following attributes: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. Young adult and very early RRMS (defined as within six months of 
diagnosis of clinically definite RRMS) patients that are disease modifying therapy 
treatment naïve. Further details about the population are provided in Section 5. 
• Variable: No evidence of Disease Activity (NEDA-3) [Relapse-free, clinical disability 
progression-free, MRI activity-free] in Months 6 to 18 (yes/no). 
• Treatment of interest: an initial dose regimen consisting of doses administered at 
Baseline/Week 0 (Day 1), followed by Week 1 (Day 7), Week 2 (Day 14), and then every 
month thereafter, beginning at Week 4 (Month 1) until Month 18 (see Figure 3-1). All 
doses of ofatumumab will be given subcutaneously via an auto-injector at a dose of 20mg. 
Further details about the investigational treatment are provided in Section 6. Healthy 
controls will be used for comparison purposes and will not receive study treatment. 
• Intercurrent event: Death or treatment/study discontinuation. 
• Summary measure: Proportion of participants achieving NEDA-3 in Months 6 to 18. 
 
 
2.2 
Secondary estimands 
Not applicable. 
 
3 
Study design 
This study is an open-label, multi-center, prospective eighteen-month study in a minimum of 

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definite RRMS) and who are disease modifying therapy (DMT) treatment naïve. RRMS 
patients will be benchmarked against age- and sex-matched healthy controls (n=50) for select 
secondary 
. A screening period of 4 weeks will be used to assess 
eligibility and the assessment to address the primary objective will be performed at the end of 
the maintenance period (Month 18). There will be one interim analysis after the last 
participant completes his/her Month 18 (primary analysis time point) visit. Participants who 
complete the treatment period or who prematurely discontinue study drug and the study, and 
do not continue on any MS DMT, will undergo a safety evaluation 100 days following last 
dose of study treatment (captured only in source documents and only for ofatumumab treated 
participants), and will be discharged from the study if they choose to not be included in the 
optional extension portion of the trial for an additional 12 months (up to 30 months total in 
trial). Healthy control participants will not have a safety evaluation post end of study. 
Additional efficacy and safety assessments will be evaluated during the optional open-label 
extension to further elucidate the long-term clinical and radiological effects of ofatumumab 
(Figure 3-1). Of note, MRI data will be re-baselined at month 6 to account for treatment- 
related pseudo atrophy. 
Eligible participants with RRMS will receive ofatumumab 20mg subcutaneous doses at 
Baseline/Week 0 (Day 1), followed by Week 1 (Day 7), Week 2 (Day 14) and then every month 
thereafter, beginning at Week 4 (Month 1) until Month 18 (see Figure 3-1). Additional efficacy 
and safety assessments will be evaluated up to 30 months, necessitating ofatumumab 
monotherapy over the course of up to 30 months. Ofatumumab will be administered according 
to the United States Prescribing Information (USPI). RRMS patients must remain on 
ofatumumab monotherapy to remain in the trial, with no DMT switching or combination DMT 
therapy allowed. Healthy controls will not be given a therapy. 
Assessments will be performed per the assessment schedule found in Table 8-1. 
Figure 3-1 
Study design 
There are 3 periods to this trial: Screening (up to 4 weeks), open-label active treatment (from 
Baseline to month 18), and optional 12-month open-label extension (from month 18 to 30). 

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For participants who discontinue study treatment and study participation prematurely for any 
reason before the end of the treatment phase, an End of Study visit must be performed within 7 
days of study discontinuation. 
Upon completing the trial, study patients can continue ofatumumab therapy on commercial drug. 
 
Safety follow-up: 
 
The Safety follow-up (FU) period will be applicable for the following participants: 
• participants who complete the Treatment period on the study drug and do not 
continue on any MS DMT. 
• participants who prematurely discontinue study drug and study participation, and 
do not continue on any MS DMT. 
All Safety FU visits must be scheduled relative to the End of Study (EOS) Visit. 
Any RRMS patient starting another MS DMT post-trial discontinuation will not have a FU visit 
performed. 
All patients who elect to not be included in the 12-month extension will be followed for an 
additional 100 days following the EOS timing for that individual patient. A shorter follow-up 
time is acceptable if patients select a different approved MS DMT (injectable, infusion or oral) 
treatment during this period. Patients who do not have access to commercial drug within one 
day of the EOS Visit must continue into the safety FU phase until they are able to access 
commercial drug or decline DMT therapy moving forward (up to 100 days maximum). 
Safety assessments will include standard clinical laboratory evaluations (hematology), 
, adverse event, and serious adverse event monitoring. 
Participants that elect to not continue on a DMT after study and have low levels of quantitative 

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serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent 
infections, should have immunoglobulins monitored by the trial site until B-cell repletion occurs. 
 
 
4 
Rationale 
4.1 
Rationale for study design 
This study is an open-label, multi-center, prospective eighteen-month study in a minimum of 
118 MS patients with early RRMS (defined as within 6 months of diagnosis of clinically definite 
RRMS) and who are DMT treatment naïve. RMS patients will be benchmarked against age- 
and sex-matched healthy controls (n=50) for select secondary 
. The 
concept herein will expand on previous ofatumumab studies and provide important clinical and 
safety data in an earlier RRMS population than studied in ASCLEPIOS I and II. Further, this 
study will investigate multiple secondary 
 (over the course of up to 
30 months; all patients are in trial for 18 months, but the optional extension period extends to 
30 months) to build the data sets on early use of ofatumumab using MRI metrics, patient 
reported outcomes (PRO), biomarker and digital monitoring technologies. Finally, the study 
will compare select endpoints vs age- and sex-matched HC patients to provide first evidence of 
safety and disease stabilization measured by MRI/
 vs non-MS patients. 
Due to the limited time from diagnosis and lack of experience with B cell depleting therapies 
that this population will have, an open-label, multi-center design was selected to facilitate 
recruitment. Further, the clinical trial space is very active with numerous therapies under 
development and therefore careful consideration was taken regarding impact on the patient 
when designing monitoring outcomes. The design limited the number of clinic visits and MRIs 
to minimum acceptable levels and focused on using “at home” digital technology for monitoring 
when available. 
Finally, the use of a HC group for comparison is novel in the clinical trial program for 
ofatumumab. In the Phase 2 APOLITOS trial, a Japanese/Russian population was studied to 
evaluate the efficacy and safety of ofatumumab versus placebo in RMS patients. Although this 
study included RMS placebo-treated patients, no study has compared ofatumumab treated 
patients to non-MS HCs. The HC comparator data can provide important information on safety 
outcomes (e.g., infections) and the ability of ofatumumab to normalize CNS pathology as 
measured by MRI and 
 of disease. 
Rationale of chosen endpoints: 
The proposed study endpoints are widely accepted as clinically relevant and have been used in 
numerous pivotal clinical trials in RRMS. The primary endpoint for the study will be no 
evidence of disease activity as defined by NEDA-3 criteria (relapse-free, clinical disability 
progression-free, MRI activity-free). Secondary endpoints will include relapse-related 
endpoints, conventional and non-conventional MRI-related endpoints, safety endpoints, digital 
biometric and physical/cognitive function endpoints, 
, and patient reported outcomes 
(PROs). In two large phase 3 studies, ofatumumab demonstrated significant reductions in 
disease activity (reductions in relapses, Gd T1 lesions and new and/or enlarging T2 lesions) 

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versus an active comparator. This study will expand on those data and focus on patient centric 
outcomes and novel ways of measuring changes in patients with early/mild disease. This 
evidence is highly relevant for patients, neurologists, treating healthcare practitioners in the 
real-world setting, and payers. 
4.2 
Rationale for dose/regimen and duration of treatment 
Ofatumumab dose 
The dose regimen for ofatumumab, for this study is an initial dose regimen of 20mg at 
Baseline/Week 0 (Day 1), followed by Week 1 (Day 7), Week 2 (Day 14) and every month 
thereafter, beginning at Week 4 (Month 1), until Month 18 (see Figure 3-1). 
This dosing regimen is consistent with the dose and regimen in the Phase 3 development 
program of ofatumumab in RMS and in the US prescribing information. 
Duration of treatment 
Treatment duration within the primary study will be 18 months. RRMS patients must remain 
on ofatumumab monotherapy to remain in trial, with no DMT switching or combination 
therapy allowed. Additional efficacy and safety assessments will be evaluated during an 
optional 12-month open-label extension necessitating ofatumumab monotherapy over the 
course of up to 30 months (see Figure 3-1). 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not Applicable 
 
 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not Applicable 
 
 
4.5 
Risks and benefits 
The risk to participants in this trial will be minimized by compliance with eligibility criteria, 
close clinical monitoring, avoidance of prohibited treatments, adherence to protocol 
requirements, and Investigator guidance regarding specific safety areas. In addition, the study 
has been designed to minimize site visits (during COVID pandemic) and reduce the number 
of MRI scans using gadolinium. Safety data from the pivotal Phase 3 program are available 
and the benefit/risk profile for ofatumumab treated patients with RMS is assessed as 
favorable. 
 
Clinical experience with ofatumumab in RRMS patients comes from four Phase 2 studies and 
the two Phase 3 clinical trials, where a total of 1537 RMS patients have been exposed to 
ofatumumab (Phase 2 studies: iv: N=38; and sc: N=553; Phase 3 studies sc N=946). No 
unexpected safety findings were observed in MS patients who received ofatumumab in the 
two completed Phase 2 studies and two ASCLEPIOS Phase 3 studies. 

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Briefly, in the 48-week, placebo-controlled, cross-over study (cross-over at 24 weeks) of iv 
doses of ofatumumab up to 700mg, adverse events reported more frequently on ofatumumab 
vs placebo included: rash, throat irritation, erythema, fatigue, viral infection and flushing 
(Sorensen et al., 2014). In the placebo-controlled, dose-ranging study of ofatumumab 
administered at sc doses up to 60mg every 4 weeks for up to 24 weeks, injection related 
reactions were observed more frequently in the overall ofatumumab group (Bar-Or et al 
2018). In the ASCLEPIOS I and II studies, ofatumumab demonstrated a favorable safety 
profile with no unexpected safety signals, no imbalance in adverse events or serious adverse 
events (SAEs), rates of infection (including serious infection), or malignancy when compared 
to teriflunomide. In these studies, systemic injection-related reactions were reported in 20.6% 
of patients on ofatumumab and in 15.3% of patients on teriflunomide. 99% of all reported 
systemic injection reactions were mild to moderate (Grade 1-2) and limited to the first 
injection (Hauser et al., 2020, Kesimpta®, PI). 
 
Ofatumumab sc has demonstrated benefit on disease activity in the pivotal trial program, with 
profound suppression of new MRI lesion activity (≥ 90% versus placebo over Weeks 4-12) in 
RMS patients in a Phase 2 study (Bar-Or et al., 2018). In the Phase 3 studies, ofatumumab has 
shown a highly significant and clinically meaningful reduction in the number of confirmed 
relapses, evaluated as the annualized relapse rate (ARR). Patients treated with ofatumumab 
had an ARR of 0.11 and 0.10 compared to teriflunomide (ARR of 0.22 and 0.25) in 
ASCLEPIOS I and II respectively, corresponding to a reduction in ARR by 50.5% and 58.8% 
with ofatumumab (p<0.001 in both studies). Ofatumumab showed highly significant 
suppression of both Gd+ T1 lesions and new or enlarging T2 lesions compared to 
teriflunomide, demonstrating a profound suppression of new inflammatory activity. 
Additionally, ofatumumab showed a relative risk reduction of 34.4% (p=0.002) in 3-month 
confirmed disability progression (CDP) and 32.5% (p=0.012) in 6-month CDP versus 
teriflunomide in a pre-specified pooled analyses (Hauser et al., 2020, Kesimpta®, PI). Taken 
together, available information of relevant clinical and MRI outcome supports the potential 
efficacy of ofatumumab in patients with RRMS. 
 
Overall, data acquired to date supports the rationale of this study to evaluate the efficacy and 
safety of ofatumumab sc to address the unmet medical need of early, treatment naïve RRMS 
patients. 
 
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. 
 
There is no benefit expected for healthy control participants in this study. Similar to 
ofatumumab treated patients, the study has been designed to minimize site visits (during 
COVID pandemic) and to reduce the number of MRI scans. 

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In the context of the COVID-19 pandemic, additional risks for participants taking part in any 
clinical trial cannot be excluded. Eligibility criteria for the study requires the investigator to 
evaluate infections and exclude patients with ongoing infection. The protocol also includes 
general guidance on immunization (see Section 16.1.4). 
 
 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over the period of the 
study with blood draws from each participant. Additional samples may be required for safety 
monitoring. Timings of blood sample collection are outlined in the assessment schedule (Table 
8-1). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual. 
See the Section 8.5.2 on the potential use of residual samples. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
 
5 
Study Population 
The study population will consist of adult participants with RRMS fulfilling all the eligibility 
criteria listed below. The study is planned to be conducted in approximately 40 centers within 
the United States. It is aimed to enroll a minimum of 168 (118 ofatumumab, 50 HC) participants. 
Participants who enroll and prematurely discontinue study will not be replaced. 
 
 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-35 years 
 
Patients in the healthy control arm eligible for inclusion must fulfill the following criteria: 
 
3. Able to obtain MRI (HC with abnormal MRI at Screening will be excluded) and use 
wearable device 
4. Able to provide blood sample (no CSF will be collected in HC) 

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Patients in the ofatumumab-treated arm eligible for inclusion must fulfill the following criteria: 
 
5. Diagnosis of RRMS per McDonald Criteria (2010/2017) 
6. Within 6 months of diagnosis of clinically definite MS (CDMS) 
7. EDSS 0-3.0 (Inclusive) at both screening and baseline 
8. Treatment-naïve to MS DMT 
9. Able to obtain MRI and attend study visits at sites 
10. Able to use wearable device 
11. Able to provide blood sample (and CSF for sub-group n=15) 
12. If a participant is receiving dalfampridine (Ampyra®/Fampyra®) concomitantly with 
study treatment, the participant should have been on a stable dose at least 30 days prior 
to first study drug administration and remain on that dose throughout the study 
wherever possible 
5.2 
Exclusion criteria 
Participants in the healthy control arm meeting any of the following criteria are not eligible for 
inclusion in this study: 
1. Confounding medical condition as determined by the investigator 
Participants in the ofatumumab-treated arm meeting any of the following criteria are not eligible 
for inclusion in this study: 
2. Diseases other than multiple sclerosis responsible for the clinical or MRI presentation 
3. Patients with neuromyelitis optica, Radiologic/Clinically Isolated Syndrome, Secondary 
Progressive or Primary Progressive MS diagnosis 
4. Use of experimental or investigational drugs for MS. Use of other investigational drugs 
within 5 half-lives of enrollment/initiation of study treatment (select as appropriate) 
within 30 days (e.g. small molecules) / or until the expected pharmacodynamic effect 
has returned to baseline (e.g. biologics), whichever is longer; or longer if required by 
local regulations 
5. Previous use of Disease Modifying Therapy (DMT) or chemotherapeutic medications 
for MS 
6. Relapse between screening and Baseline visits 
7. Known sensitivity to gadolinium; patients with chronic, severe kidney disease (GFR < 
30 mL/min/1.73m2) or acute kidney injury (contraindicated with use of gadolinium) 
8. Known history of hypersensitivity to any of the study treatments or its excipients or to 
drugs of similar chemical classes 
9. CNS anomalies that are better accounted for by another disease process (e.g. traumatic 
brain injury) or MRI anomalies causing clinically apparent impairments in social, 
occupational, or generalized areas of functioning, due to the direct physiologic effects 
of substances (recreational drug abuse, toxic exposure, etc) or a medical condition 

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10. Known active malignancies 
11. 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 
12. Females of childbearing potential (all women physiologically capable of becoming 
pregnant) unless they are using effective contraception while receiving ofatumumab, 
and for 6 months after the last treatment of ofatumumab 
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 
• Single barrier methods of contraception: male or female condom or occlusive cap, 
diaphragm, or cervical/vault caps 
• For female participants on the study, the vasectomized male partner should be the 
sole male 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. Oral 
contraceptive may be switched during the trial, if participant is able to maintain 
stable dose during course of participation 
 
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 childbearing 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. 
13. Patients with an active chronic disease (or stable but treated with immune therapy) of 
the immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjögren’s 
syndrome, Crohn’s disease, ulcerative colitis, etc.) or with immunodeficiency syndrome 
(e.g., hereditary immune deficiency, drug-induced immune deficiency) 

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14. Patients with active infections including systemic bacterial, viral (including SARS- 
CoV-2/COVID-19) or fungal infections, or known to have AIDS or to test positive for 
HIV antibody at Screening 
15. Patients with neurological findings consistent with Progressive Multifocal 
Leukoencephalopathy (PML), or confirmed PML 
16. Patients with IgG or IgM levels below LLN at Screening 
17. Patients that have received any live or live-attenuated vaccines within 4 weeks prior to 
first dose of study drug administration 
18. Patients at risk of developing or having reactivation of hepatitis: Positive results at 
Screening for serological markers for hepatitis (H) B indicating acute or chronic 
infection: 
a. HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA) 
b. anti-HBs negative and Anti-HBc positive 
NOTE: If the Investigator suspects false positive hepatitis serology results, such as an 
antibody pattern indicating acute hepatitis infection but no corresponding elevated liver 
enzymes and no signs or symptoms of liver disease, an infectious disease expert may be 
consulted. If the infectious disease expert finds no evidence of acute or chronic hepatitis 
infection and considers the serology results false positive and not clinically relevant, the 
Investigator must document (in source data) that the serology results are considered false 
positive and may then enroll the patient. 
 
 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Investigational drug will be provided in an auto-injector pen for subcutaneous administration 
containing 20mg ofatumumab (20mg/0.4 ml). Study drug will be supplied by Novartis. 
Table 6-1 
Investigational drug 
 
Investigational/ 
Control Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
(Name and 
Strength) 
Ofatumumab 
Solution for 
Subcutaneous 
Commercial 
Sponsor (local) 
20mg 
injection 
pen 
 
6.1.1.1 
Decentralized Clinical Trial Model 
The study medication and all required clinical study supplies could possibly be distributed via 

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study visit options may be available and need to be discussed with Novartis prior to 
implementation. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
6.1.3 
Treatment arms/group 
This study is an open-label, multi-center, prospective eighteen-month study in a minimum of 
118 MS patients with early RRMS (defined as within 6 months of diagnosis of clinically definite 
RRMS) and who are treatment naïve. 
Participants with RRMS will be assigned at Baseline visit to ofatumumab. The dose regimen 
for ofatumumab for this study is an initial dose regimen of 20mg at Baseline/Week 0 (Day 1), 
followed by Week 1 (Day 7), Week 2 (Day 14) and every month thereafter, beginning at 
Week 4 (Month 1) until Month 18 (see Figure 3-1). Additional efficacy and safety 
assessments will be evaluated during an optional 12-month open-label extension, 
necessitating ofatumumab monotherapy over the course of up to 30 months. 
Table 6-2 
Treatment arms/group 
 
Treatment 
Arm 
# of 
Patients 
Entered 
Treatment 
Type of 
Study Drug 
Compound 
Min Dose 
Max 
Dose 
Frequency 
Admin. Route 
Generic 
Acceptable? 
(applies 
only for 
comparator) 
Arm 1 
118 
Commercial 
Ofatumumab 
20mg 
20mg 
Monthly 
Subcutaneous 
pen 
NA 
Arm 2 
50 
N/A 
Healthy 
Control 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
 
 
6.1.4 
Treatment duration 
The planned duration of treatment is 18 months and participants will continue on ofatumumab 
treatment arm for 18 months. Once a participant is started on ofatumumab, they must remain 
on ofatumumab throughout the duration of the study and switching to a different DMT therapy 
will not be permitted. Participants may be discontinued from treatment earlier due to 
unacceptable adverse events, disease progression and/or at the discretion of the Investigator or 
the participant. Additional efficacy and safety assessments will be evaluated during an optional 
12-month open-label extension, necessitating ofatumumab monotherapy over the course of up 
to 30 months in patients that choose to enter the extension. 
6.1.5 
Post-Trial Access 
Participants who have completed the treatment period successfully will be given the option to 
terminate from the study or will be referred to the ofatumumab commercial patient services 
hub for post-trial continuity of treatment programs, where the benefit/risk is acceptable and 
discussed with the participant and investigator. Participants who terminate prior to the end of 

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the treatment period or who withdraw permanently due to an ofatumumab related AE or SAE 
should follow up with their primary neurologist or treating physician for continued treatment 
options as quickly as possible. 
 
 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The Investigator should instruct the participant to notify the study site about any new 
medications he/she takes after study enrollment. 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. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact the Novartis medical monitor 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. 
If a participant is receiving dalfampridine (Ampyra®/Fampyra®) concomitantly with study 
treatment, the participant should have been on a stable dose at least 30 days prior to first study 
drug administration and remain on that dose throughout the study wherever possible. 
Premedication prior to subcutaneous injection 
Premedication is not required in this study. Premedication with acetaminophen and/or 
antihistamines (or equivalent) is optional for ofatumumab treated patients and may be 
administered at the discretion of the Investigator. 
Any administrations of premedication must be recorded in the appropriate CRF. 
After the initial dose of study medication, which should be given under the guidance of a 
healthcare professional, participants may inject study medication at home at Week 1 (Day 7) 
and onwards if they have demonstrated the ability to self-inject (refer to Section 6.3.2). Based 
on the experience with the injection(s) administered at the site and with the use of any 
premedication, the Investigator will evaluate whether or not premedication (such as 
acetaminophen and/or antihistamines) should be used before injections administered at home. 
If premedication is prescribed, the study staff must ensure that the participant will receive a 
sufficient supply of premedication for home-use (i.e., to last at least until the next study office 
visit) and clear instructions (oral and written) about type and dose of premedication, and when 
to take it (i.e., 30-60 min before the injection). The Investigator will evaluate the need for 
premedication, or a change in the prescription, at each visit (scheduled and unscheduled) 
including at the participant contacts during the study (contact should include specific questions 
about any injection-related symptoms and the use of premedication). If, based on the remote 
contacts, a change in premedication is needed, the participant should be asked to return to the 
site for an unscheduled visit. 
The participants must be informed (through the participant information and consent process) 
about the possibility that injection related reactions might occur despite use of premedications 

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and about the possible symptoms of a systemic injection reaction and their management. 
Participants must be reminded to always carry their Participant Card, which includes the 
Investigator and site telephone contact numbers in case of an emergency. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in Table 6-1 is NOT allowed in combination with study drug, 
due to increased risk of immunosuppression and confounding of efficacy evaluations. 
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. 
Table 6-3 
Prohibited medication 
 
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 
Monoclonal antibodies targeting the immune 
system, including but not limited to natalizumab, 
alemtuzumab, daclizumab ocrelizumab and 
rituximab and B-cell depleting agents under 
investigation, such as but not limited to 
ublituximab and obinutuzumab 
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) 
Administration of any live or live- 
attenuated (does not apply to non-live, 
inactivated, mRNA, adenovirus vector vaccines) 
vaccine (including for measles) is prohibited 
while participants are exposed to study drug 
(long lasting effects of the study drugs should be 
Discontinue study drug, increase 
vigilance regarding infections. 
NOTE: Restarting study drug in 
participants exposed to these medications is not 
permitted. 
 
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 Novartis. 
 
Discontinue study drug, increase vigilance 
regarding infections. 
NOTE: Restarting study drug in 
participants exposed to these medications is not 
permitted. 
 
 
They may be administered 4 weeks prior to first 
administration of ofatumumab in the study or 
when participants are no longer exposed to 
study drug with documented B cell repletion. 
Consider risk/benefit and follow local labels. 
 taken into consideration) 
 
 
 
6.2.3 
Recommended treatment of MS Relapse 
Prior to screening and study entry, use of corticosteroids or plasmapheresis is allowed to treat 
relapses per Investigator's judgement and/or local clinical practice, however there is a minimum 
time from last treatment to screening MRI of ≥30 days. The decision to treat MS relapses during 
the study should be based on the Investigator's judgement and/or local clinical practice. If 

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corticosteroids of 3-5 days and up to 1000mg methylprednisolone/day or equivalent on an 
inpatient or outpatient basis. 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 or plasmapheresis for treatment of MS attack/relapse must be recorded on the 
Concomitant Medications eCRF. Please refer to restrictions for MRI in Section 8.3.6 
concerning the use of steroids and performing the MRI. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
drug 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). 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study drug 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 drug must be stored according to the instructions 
specified on the labels and in the Investigator’s Brochure. 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. 
The Investigator must maintain an accurate record of the shipment and dispensing of study drug 
in a drug accountability log. Monitoring of drug accountability will be performed by field 
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 drug, packaging, drug labels, and a copy of the completed drug 
accountability log according to the instructions provided by Novartis or its agents. 
6.3.2 
Instruction for prescribing and taking study treatment 
All eligible RRMS participants will receive treatment with open label ofatumumab; no 
randomization will be performed in this study. In general, administration instructions contained 
within the USPI for Kesimpta® should be followed. Administration of ofatumumab (at study 
site or at home) should occur after the study visit assessments are performed, if on the same day 
of the study visit. 

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Drug will be dispensed at scheduled visits throughout the treatment period. Ofatumumab 
injection will be administered via an initial dose regimen of 20mg at Baseline/Week 0 (Day 1), 
followed by Week 1 (Day 7), Week 2 (Day 14) and every month thereafter, beginning at Week 
4 (Month 1) until Month 18. Additional efficacy and safety assessments will be evaluated during 
an optional 12-month open-label extension, necessitating ofatumumab monotherapy over the 
course of up to 30 months (see Figure 3-1). 
At the Baseline/Week 0 visit, participants will receive the subcutaneous injection at the study 
site. Site personnel will provide training to the participants on the correct procedure for self- 
administration of the subcutaneous injections. The participant or a caregiver may inject the 
study medication under supervision of a healthcare professional. Documentation of injection 
procedure understanding by the participant and/or the caregiver must be documented in the 
source document. Participants should remain at study site under observation for approximately 
1 hour following dosing at the Baseline/Week 0 visit, where post-dose vital signs will be 
collected. A longer observation period may be required if these vital signs are not within 
reasonable limits of the participant’s baseline values. 
Site staff should remove the study treatment from the refrigerator and allow the AI pen to reach 
room temperature in the unopened box (approximately 15-30 minutes) before self-injection by 
the participant. Used AI pens 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. 
Following the Baseline/Week 0 visit, sufficient study drug will be supplied to the participant to 
cover all home administrations. Participants may inject the study medication at home, if they 
demonstrated ability to self-administer injections. If a participant is unable/unwilling to self- 
administer injections, another individual (e.g. partner, caregiver, relative or a healthcare 
professional) may perform home-administration who has accompanied the participant to the site 
and has been trained on and demonstrated ability to correctly administer the subcutaneous 
injections. The participant may also continue to have injections at the site if this is the 
participant's preference. 
If a participant is unable to travel to the investigative site for their study visit, shipment of study 
treatment from the site to the participant’s home may be available in cases of a pandemic or a 
national and/or global emergency. 
Doses on Week 1 (dose #2) and Week 2 (dose #3) should be administered no more than +/- 1 
day. If the dose on Week 1 (dose #2) is missed, the dose due on Week 2 (dose #3) should be 
adjusted to 7 days after dose #2 was given. 
If a monthly injection of ofatumumab is missed, it should be administered as soon as possible 
without waiting until the next scheduled dose. Subsequent doses should be administered at the 
recommended intervals (+/- 3 days). 

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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. 
Participants will be provided with the following items to facilitate the at-home injections of study 
treatment: an insulated bag with cool gel packs to transport the study treatment from the site to 
the participant’s home; alcohol swabs and gauze pads; a sharps container for immediate disposal 
of the used syringes; monthly home urine pregnancy test; ofatumumab dose administration and 
pregnancy test diaries; and a copy of the AI instruction leaflet will be provided which includes 
detailed information, precautions and instructions for administering subcutaneous injections 
using the AI pen. This information should be reviewed with the participant (and his/her 
partner/relative as applicable) to ensure that they understand the correct procedure for self/home 
administration. 
All kits of study medication assigned by the IRT will be databased in the IRT system. 
Table 6-4 
Arm 1 treatment schedule 
 
Ofatumumab 
20mg 
BL 
D 
7 
D 
14 
M 
1 
M 
2 
M 
3 
M 
4 
M 
5 
M 
6 
M 
7 
M 
8 
M 
9 
M 
10 
M 
11 
M 
12 
M 
13 
M 
14 
M 
15 
M 
16 
M 
17 
Key 
BL = 
Baseline 
D = Day 
M = Month 
 
Table 6-5 
Extension treatment schedule 
 
Ofatumumab 
20mg 
M 
18 
M 
19 
M 
20 
M 
21 
M 
22 
M 
23 
M 
24 
M 
25 
M 
26 
M 
27 
M 
28 
M 
29 
M 
30 
Key 
 
 
 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The participant 
no. consists of the Center Number (Center No.) (assigned by Novartis to the investigative site) 
with a sequential participant number suffixed to it, so that each participant 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. The Investigator or his/her 
staff will contact the IRT 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. 
M = Month 

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If an enrolled participant fails to be assigned to treatment for any reason, the IRT must be 
notified within 2 days that the participant was not assigned to treatment. The reason for not 
being assigned to treatment will be entered into the appropriate eCRFs. If the participant is re- 
screened at a later date, a new Participant No. will be assigned. 
6.4.2 
Treatment assignment, randomization 
This is an open label study. There will be no treatment blinding. 
6.5 
Dose escalation and dose modification 
Dose escalation and modifications are not permitted in this study. 
6.5.1 
Dose escalation guidelines 
Not applicable. 
6.5.2 
Follow-up for toxicities 
Not applicable. 
6.5.3 
Drug Interruptions 
Conditions/events that may lead to study drug interruptions based on Investigator judgment and 
overall clinical assessment include: 
• reported serious adverse event; 
• emergency medical condition, unplanned hospitalization involving use of excluded 
concomitant medications; 
• abnormal laboratory value(s) or abnormal test or examination result(s) 
Should the participant interrupt the study drug for whatever reason, the re-start decision should 
be made on a case-by-case basis (refer to Section 6.6.1). Should the Investigator decide, after 
informing the Sponsor, to re-initiate treatment with study drug, depending on the duration of 
the interruption, the first dose at re-start may need to take place at the study site to ensure 
observation in a similar manner as on Baseline/Week 0 (Day 1). 
The reason for interruption of treatment and date of interruption should be appropriately 
documented in the source documents as well as in the appropriate eCRF. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The Investigator must promote compliance by instructing the participant to take the study drug 
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 drug as prescribed. Compliance will be assessed 
by the Investigator and/or study personnel at each visit. Participant compliance should be at 
least 80%. The Investigator and/or study personnel will counsel the participant if compliance is 
below 80% and will determine (in consultation with Novartis) if the participant will be removed 

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from the study due to lack of compliance with study drug. Study drug accountability will also 
be determined by the site monitor while performing routine site/virtual visits and at the 
completion of the study. This information should be captured in the source document at each 
visit. All study drug dispensed and returned must be recorded in the Drug Accountability Log. 
6.6.2 
Recommended treatment of adverse events 
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs) beyond standard clinical care. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.6.3 
Emergency breaking of assigned treatment code. 
Not applicable. 
 
 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-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 
possible given his/her level of 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 ICH E6 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/IEC. 
Information about common side effects already known about the investigational treatment 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 includes: 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples (e.g. additional new 
, MRI scans) collected during this study 

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• Potential for additional efficacy and safety assessments that will be evaluated during 
the optional 12-month open-label extension for up to 30 months 
• An Optional Biomarker Consent for those participants who opt into additional biomarker 
sample analysis provided from cerebral spinal fluid (CSF) 
• As applicable, Pregnancy Outcomes Reporting Consent for female subjects who took 
study treatment 
• As applicable, Pregnancy Outcomes Reporting Consent for the female partners of male 
participants who took study treatment 
Women of childbearing 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/IEC 
approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
 
8 
Assessment schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
Participants who discontinue from study treatment and study participation, and do not continue 
on any MS DMT, are to return for the end of study visit as soon as possible and attend safety 
follow-up visits as indicated in the Assessment Schedule (Table 8-1). Healthy control 
participants will not have a safety evaluation post end of study. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF. 

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The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 

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Table 8-1 
Assessment Schedule 
 
Name 
Scr 
BSL/ 
Wk0 
Wk 1 
Wk 
2 
Wk 
4 
M3 
M6 
M96 
M12 
M156 
M18 
M216 
M246 
M276 
M30/ 
EOS 
100- 
day 
Safety 
Follow 
-up12 
USV4 
Days: 
Window: 
-28 
1 
(+3) 
7 
(+1) 
14 
(+1) 
28 
(+3) 
90 
(+3) 
180 
(+3) 
270 
(+3) 
360 
(+3) 
450 
(+3) 
540 
(+3) 
630 
(+3) 
720 
(+3) 
810 
(+3) 
900 
(+3) 
Informed 
ConsentX 
O,H 
O,H13 
Patient 
DemographicsX 
O,H 
Medical HistoryX 
O,H 
Smoking Status 
O,H 
O,H 
O,H 
MS HistoryX 
O 
Inclusion/ 
Exclusion 
CriteriaX 
O,H 
O 
Height/ 
WeightX 
O,H 
O 
Dispense Study 
DrugX 
O7 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Collect Study 
Drug/ Drug 
Account-ability 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 

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Name 
Scr 
BSL/ 
Wk0 
Wk 1 
Wk 
2 
Wk 
4 
M3 
M6 
M96 
M12 
M156 
M18 
M216 
M246 
M276 
M30/ 
EOS 
100- 
day 
Safety 
Follow 
-up12 
USV4 
Days: 
Window: 
-28 
1 
(+3) 
7 
(+1) 
14 
(+1) 
28 
(+3) 
90 
(+3) 
180 
(+3) 
270 
(+3) 
360 
(+3) 
450 
(+3) 
540 
(+3) 
630 
(+3) 
720 
(+3) 
810 
(+3) 
900 
(+3) 
Sc Self-injection 
Training 
(participant 
and/or 
caregiver)S 
O 
Study drug self- 
injection (at- 
home or at site)X, 
16, 17 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Prior and 
Concomitant 
MedsX 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O 
O,H 
Non-drug 
therapiesX 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O 
O,H 
Vital SignsX, 7 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
Physical ExamS 
O3,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
Adverse 
EventsX, 4 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O 
O,H 

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Name 
Scr 
BSL/ 
Wk0 
Wk 1 
Wk 
2 
Wk 
4 
M3 
M6 
M96 
M12 
M156 
M18 
M216 
M246 
M276 
M30/ 
EOS 
100- 
day 
Safety 
Follow 
-up12 
USV4 
Days: 
Window: 
-28 
1 
(+3) 
7 
(+1) 
14 
(+1) 
28 
(+3) 
90 
(+3) 
180 
(+3) 
270 
(+3) 
360 
(+3) 
450 
(+3) 
540 
(+3) 
630 
(+3) 
720 
(+3) 
810 
(+3) 
900 
(+3) 
MS Relapse 
AssessmentX, 2 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Labs 
(hematology, 
biochemistry) X 
O 
O 
O 
O 
O 

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Name 
Scr 
BSL/ 
Wk0 
Wk 1 
Wk 
2 
Wk 
4 
M3 
M6 
M96 
M12 
M156 
M18 
M216 
M246 
M276 
M30/ 
EOS 
100- 
day 
Safety 
Follow 
-up12 
USV4 
Days: 
Window: 
-28 
1 
(+3) 
7 
(+1) 
14 
(+1) 
28 
(+3) 
90 
(+3) 
180 
(+3) 
270 
(+3) 
360 
(+3) 
450 
(+3) 
540 
(+3) 
630 
(+3) 
720 
(+3) 
810 
(+3) 
900 
(+3) 
Hepatitis BS, 9 
O 
HIVS, 9 
O 
CoagulationS, 9 
O 
O 
O 
O 
O 
Dipstick 
urinalysisX, 10 
O 
O 
O 
O 
O 
Serum β-hCG in 
women of 
childbearing 
potentialS, 3 
O 
O 
O 
Urine β-hCG in 
women of 
childbearing 
potentialS, 3 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
MRIX, 14, 18 
O,H 
O,H 
O,H 
O,H 
O,H 
O 
Columbia 
Suicide Severity 
Scale (C- 
SSRS)X, 15 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
PROsX 
(NeuroQOLTM, 
PDDS) 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 
O,H 

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Name 
Scr 
BSL/ 
Wk0 
Wk 1 
Wk 
2 
Wk 
4 
M3 
M6 
M96 
M12 
M156 
M18 
M216 
M246 
M276 
M30/ 
EOS 
100- 
day 
Safety 
Follow 
-up12 
USV4 
Days: 
Window: 
-28 
1 
(+3) 
7 
(+1) 
14 
(+1) 
28 
(+3) 
90 
(+3) 
180 
(+3) 
270 
(+3) 
360 
(+3) 
450 
(+3) 
540 
(+3) 
630 
(+3) 
720 
(+3) 
810 
(+3) 
900 
(+3) 
Optional Trial 
Feedback 
QuestionnaireS 
O,H 
O,H 
O,H 
O,H 
Participant 
Thank You 
LetterS 
O,H 
O,H 
O,H 
 
O = Ofatumumab participant 
H = Healthy Control 
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 
 
2 Relapse assessment will be performed in scheduled, as well as unscheduled visits as deemed necessary by the Investigator or designee. Assessment can be done on 
site or via remote procedures 
3 Urine β-hCG will be conducted monthly, at home, as well as, at defined clinical visits (scheduled and unscheduled) 

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8.1 
Screening 
Screening 
A participant who enters screening but is determined not to be eligible will be considered a 
screen failure. The Investigator may consider re-screening the participant later if he/she believes 
that the participant’s condition has changed, and he/she may potentially be eligible. In this case, 
a new participant number will be allocated to the participant and he/she will need to re-perform 
all screening procedures except for MRI. The original MRI may be used during rescreening if 
the rescreening occurs within 3 months of the original MRI date. Requests from the 
investigator/site staff to rescreen patients will be handled on a case-by-case basis, with Clinical 
Trial Lead approval required, prior to rescreening. A participant may be re-screened only once. 
A minimum of 24 hours must elapse between screen failure and re-screening. If a participant is 
re-screened, a new ICF must be obtained, and a new participant number issued prior to 
conducting any screening assessments. This must be documented in the participant's source 
documents with the new participant number assigned. 
8.1.1 
Eligibility screening 
8.1.1.1 
Hepatitis screen, HIV screen 
All ofatumumab treated participants will be screened for Hepatitis B surface antigen (HBsAg) 
and, if standard local practice, Hepatitis B core antigen (HBcAg). 
Evaluation for HIV seropositivity will be performed in ofatumumab treated participants, and, if 
positive, confirmation by a second technique available at the laboratory site (e.g. Western blot). 
Appropriate counseling will be made available by the Investigator in the event of a positive 
confirmatory test. Notification of state and federal authorities, as required by law, will be the 
responsibility of the Investigator. This will be recorded as source data only by the use of an 
“S” for the corresponding criteria in Table 8-1 (Assessment Schedule) of the protocol. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
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). 
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form. 
8.2 
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 

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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. 
8.3 
Efficacy 
The study includes the following efficacy assessments which are conducted at visits as shown 
in Assessment Schedule, Table 8-1: 
Clinical 
• MS Relapse Assessment 
 
 
 
 
 
 
• Vitals 
 
 
 
 
 
 
 
 
Laboratory 
 
 
Patient Reported Outcomes 
• NeuroQOLTM 
• PDDS 
An overview of each of these assessments is provided in the sections below and the details of 
these assessments will be provided in the appropriate site manuals. 
8.3.1 
MS Relapse Assessment 
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 a relapse, an unscheduled visit to the Investigator must be scheduled as 
soon as possible (whenever possible within 7 days of onset of the symptoms). 
The assessment, management and reporting of MS relapse is made by the Investigator. 
Confirmation of MS relapse and severity grading is based on the
 
 
 
MS relapse definition 

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Table 8-1, and will be in addition to the regular monthly telephone interview between scheduled 
visits detailed in the assessment schedule Table 8-1. 
 
Table 8-3 
Safety assessments and specifications 
 
Assessment 
Specification 
 
Physical examination 
A complete physical examination will be performed at the visits 
indicated in assessment schedule, Table 8-1 and will include an 
assessment of skin, head and neck, lymph nodes, heart, lungs, 
abdomen, back, neurological function and comments on general 
appearance. A complete neurological examination will be part of the 
initial physical examination at Screening. 
Information for all physical examinations (including skin 
examination) must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate 
CRF that captures medical history. Significant findings made after 
signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event. 
Vital signs 
Vital signs will include the collection of sitting pulse rate, sitting 
systolic and diastolic blood pressure, and body temperature (oral, 
or per local practice; recorded in °C). 
After the subject has been sitting for 5 minutes, with back 
supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured using an automated validated 
device, with an appropriately sized cuff. In case the cuff sizes 
available are not large enough for the participant’s arm 
circumference, a sphygmomanometer with an appropriately sized 
cuff may be used. 
For the first injection, vital signs should be obtained 30-60 minutes 
before sc injection and again approximately 60 minutes post- 
injection. If premedication is administered, the vital signs should 
be taken prior to pre-medication administration. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 
kilogram (kg) in indoor clothing, but without shoes) will be 
measured as specified in Table 8-1. 
 
 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator (in 

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consultation with the sponsor) and shall be based, in part, upon the nature and degree of the 
observed abnormality. The assessment may be repeated once prior to randomization. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
Table 8-4 
Laboratory Assessments 
 
Test Category 
Test Name 
 
Hematology 
Hematocrit, hemoglobin, platelets, red blood cell count, total white 
blood cell count and differential counts (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils). 
Chemistry 
Albumin, ALP, ALT, AST, gamma-glutamyl transferase (GGT), lactate 
dehydrogenase (LDH), calcium, magnesium, phosphorus, sodium, 
potassium, creatinine, total and conjugated bilirubin (BIL), blood urea 
nitrogen (BUN), uric acid, amylase, lipase, glucose (non-fasting). 
 
Urinalysis 
Dipstick parameters assessed will include pH, blood, glucose, specific 
gravity, WBC, Nitrite, Bilirubin, Ketones and protein. In case of an 
abnormal dipstick test, a urine sample will be sent to the central 
laboratory for testing including additional parameters such as 
microscopy and white blood cell and red blood cell sediments. 
Coagulation 
Prothrombin time (PT), international normalized ratio [INR]), activated 
partial thromboplastin time (APTT). 
 
 
 
 
 
 
Hepatitis markers 
HBV screening is required in all participants, including Hepatitis B 
surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) 
testing. 
Participants with positive hepatitis B serology (either HBsAg or HBcAb) 
should consult a liver disease expert before the start of treatment and 
should be monitored and managed following local medical standards to 
prevent HBV infection or reactivation. 
NOTE: If the infectious disease expert finds no evidence of acute or 
chronic hepatitis infection and considers the serology results false 
positive and not clinically relevant, the Investigator must document (in 
source data) that the serology results are considered false positive and 
may then enroll the participant. 
Pregnancy Test 
Serum / Urine pregnancy test (refer to Section 8.4.2). 
 
 
 
8.4.2 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
Serum pregnancy tests will be conducted at Screening and Baseline visits. Urine pregnancy 
tests will be conducted for all women who are of childbearing potential at all other planned 
clinic visits prior to study drug administration. In addition, participants will be provided with 
urinary pregnancy test kits for monthly home pregnancy testing required between the scheduled 

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clinic visits prior to study drug administration. The participants will document the date and 
result of each home pregnancy test in a diary provided for the study. In case of a positive test 
result, the participant must contact the Investigator immediately for confirmatory testing at the 
Investigator's discretion. 
In addition, the Investigator will review the contraception status with the participant at each 
visit to ascertain that the participant continues to comply with protocol requirements for highly 
effective contraception as applicable. 
Contraception must be used during the study and for at least 6 months after stopping study drug. 
If participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g. following country specific measures). 
8.4.3 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal 
behavior. The C-SSRS must be administered at either Screening or Baseline/week 0 (day 1), 
then at every on-site visit thereafter until end of study (EOS). 
The electronic version of the C-SSRS (eC-SSRS) will be administered by the Investigator. A 
completed pC-SSRS must be filed in the participant’s source documents. 
If, at any time after Screening, the score is “yes” on item 4 or item 5 of the suicidal ideation 
section of the C-SSRS or “yes” on any item of the suicidal behavior section, the participant 
must be referred to a mental healthcare professional for further assessment and/or treatment. 
The decision on whether the study drug should be discontinued is to be taken by the Investigator 
in consultation with the mental health professional to whom the participant is referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a participant 
answers “yes” to one of the questions in the suicidal behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” (question 
also included in the suicidal behavior section) should be reported as AEs and assigned the 
appropriate severity grade. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments included in this study (see Table 8-1, Table 8-3 and Table 8-4) are 
standard for the MS indication and study participant population and appropriate based on the 
current safety profile of ofatumumab as seen in both Phase 2 and Phase 3 studies, see 
Investigator's Brochure (IB) or Kesimpta® USPI for more information. 
The use of C-SSRS to detect suicidal ideation behavior is currently mandated in studies of CNS 
active drugs. 

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• Laboratory abnormalities requiring the action of study drug discontinuation as defined in 
Appendix 16.1 and abnormal test procedure as defined in Appendix 16.1.3 
• Any laboratory abnormalities that in the judgment of the Investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Non-compliance with study drug or study procedures 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from 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 9.2). Where possible, they should return for the assessments indicated 
in the visit assessment schedule (Table 8-1). If they fail to return for these assessments for 
unknown reasons, every effort (e.g. telephone, e-mail, certified letter) should be made to contact 
the participant/pre-designated contact as specified in the ‘Lost to Follow-up’ Section 9.1.3. This 
contact should preferably be done according to the study visit assessment schedule. 
If the participant cannot or is unwilling to attend any visit(s), and has not withdrawn consent to 
participate, 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 assessment schedule. 
After discontinuation from study treatment, 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. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
Discontinued patients will not be replaced in this trial. 
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 from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 

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dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
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 their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their 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. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
schedule Table 8-1. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion or End of 
Study visit and any repeat assessments associated with this End of Study visit have been 
documented and followed-up appropriately by the Investigator, or in the event of an early study 
termination decision, the date of that decision. 
Subject is considered to have completed the study when they fulfill the following criteria: 
1. Subject has completed the study in its entirety according to the approved duration of the study 

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2. Subject is eligible for commercially available ofatumumab after completing the minimum 
duration of 18 months in the study 
3. The subject has not stopped the study due to one or more of the following reasons: 
• Study discontinuation (Section 9.1.1) 
• Withdrawal of informed consent (Section 9.2) 
• Lost to follow-up (Section 9.1.3) 
End of Study (EOS) visit is mandatory for all subjects. The EOS visit is conducted at the end 
of the Open-label Treatment at Month 18 unless the patient continues into the extension period 
(as stipulated above). EOS will be done for all subjects. For subjects that complete the study, 
the next (and last) scheduled visit is the EOS visit and should align with the overall assessment 
schedule rhythm. Subjects who prematurely discontinue study treatment, and study 
participation, will have their EOS visit as soon as possible and continue into the Safety Follow- 
up for 100 days according to assessment schedule Table 8-1. The Investigator must provide 
follow-up medical care for all subjects who are prematurely withdrawn from the study or must 
refer them for appropriate ongoing care. 
At the end of the study, the study team will provide a plan on how subjects will have access 
to ongoing treatment. Furthermore, if the treatment’s risk-benefit ratio has turned negative 
and/or Novartis discontinues the development of the study treatment due to lack of efficacy 
and/or safety reasons, then Novartis will work with the investigators to transition the subjects 
onto locally available treatment or alternative treatment. 
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. 
This may include reasons related to the benefit/risk assessment of participating in the study, 
practical reasons (including slow enrollment), or for regulatory or medical reasons. 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible 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 Novartis depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
 
10 
Safety monitoring, reporting and committees 
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. 

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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. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. Clinically notable laboratory findings are defined according to the 
Common Terminology Criteria for Adverse Events (CTCAE; the most current version will be 
used and can be found on the following website: ctep.cancer.gov). 
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 CTCAE grade (based on most current version) 
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 
• 4 = life-threatening 
• 5 = death 
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 study 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 

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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 
• Recovering/resolving 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown 
• Conditions that were already present at the time of informed consent should be recorded 
in medical history of the participant. 
• Adverse events (including lab abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. 
• Adverse event monitoring should be continued for at least 100 days following the last 
dose of study treatment or until End of Post-Treatment Follow-up for premature 
withdrawals. 
• Once an adverse event is detected, it must be followed until its resolution or until it is 
judged to be permanent (e.g. continuing at the end of the study), and assessment must 
be made at each visit (or more frequently, if necessary) of any changes in severity, the 
suspected relationship to the interventions required to treat it, and the outcome. 
• Information about adverse drug reactions for the investigational drug can be found in 
the Investigator's Brochure (IB) or Kesimpta® USPI. 
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). 

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• 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 (e.g. hospitalization for treatment of a clinical event/attack 
as defined in Section 8.3.1) 
• 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 
• 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. 
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. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 100 days following the last dose of study treatment for 
study completers or until End of Safety Follow-up for premature withdrawals must be reported 
to Novartis safety immediately, without undue delay, under no circumstances later than 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. 

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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the Investigator folder provided to each site. 
If the SAE is not previously documented in the Investigator’s Brochure or Kesimpta® USPI 
(new occurrence) and is thought to be related to the study treatment, a Chief Medical Office & 
Patient Safety (CMO & PS) Department 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. 
Clinical events/attacks as defined in Section 8.3.1 are one of the effectiveness endpoints in this 
study; hence, they are exempt from SAE reporting although they may meet the SAE definition 
on the basis that they are considered medically significant and are frequently associated with 
hospitalization. These events will therefore be reported on the corresponding eCRF instead of 
the SAE form. However, if, in the judgment of the Investigator, a clinical event/attack is 
unusually severe or medically unexpected and warrants specific notification, then an SAE form 
must be completed and submitted according to SAE reporting procedures outlined above. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the 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 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. 
Pregnancy should be recorded and reported by the Investigator to the Novartis CMO & PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and 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). 

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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 eCRF 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. 
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 (Section 10.1). 
10.2 
Additional Safety Monitoring 
10.2.1 
Prospective suicidality assessment 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is described in Section 8.4.3. 
10.3 
Committees 
10.3.1 
Data Monitoring Committee 
No data monitoring committee will be implemented given that the study is open label. Data will 
be reviewed on an ongoing basis by the medical monitor and the clinical study team including 
safety data scientist and statistician. 
10.3.2 
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being Novartis representatives. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 

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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 and non-drug therapies will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. 
Enrollment and data about all study treatment (s) dispensed to the participant and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis (or a designated CRO) 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 

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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. Study personnel, at minimum, should include the principal investigator or sub- 
investigator and the study coordinator. 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 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, minimum, 25th percentiles, median, 75th percentiles, and maximum will be 
presented. 
12.1 
Analysis sets 
 
The Full Analysis Set (FAS) will include all participants that received any study drug. 
The Safety analysis set (Safety set) will be the same as the FAS. 
The healthy-control analysis set will include all participants with at least one valid assessment 
of variables of interest. This analysis set will be used in the analysis of data collected from 
healthy-control participants. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS. 

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Relevant medical histories and current medical conditions at baseline will be summarized 
system organ class and preferred term. 
12.3 
Treatments 
The Safety set will be used for the analyses below. 
The duration of exposure in days will be summarized by means of descriptive statistics. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system (if applicable) and preferred term. 
12.4 
Analysis supporting primary objectives 
The primary objective is to explore the impact of ofatumumab (OMB) on the ability to 
achieve No Evidence of Disease Activity (NEDA) status in treatment naïve, very early 
RRMS patients over an 18 month, open-label study period after a re-baseline of MRI at 6 
months. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint will be NEDA-3 (Relapse-free, 3-month clinical disability 
progression-free, MRI activity-free) in Months 6 to 18 (yes/no). 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The number (and percentage) of participants achieving NEDA-3 will be presented. The 95% 
confidence interval for the proportion of NEDA-3 will be calculated by using exact method. 
The full analysis set will used for those analyses. 
12.4.3 
Handling of intercurrent events of primary estimand 
Observed case approach (completers) will be used for the analyses of primary endpoint. 
12.4.4 
Handling of missing values not related to intercurrent event 
Observed case approach (completers) will be used for the analyses of primary endpoint. 
12.4.5 
Sensitivity analyses 
Not applicable. 
12.4.6 
Supplementary analysis 
Non-response imputation will be applied to missing data regardless of intercurrent events. 
The number (and percentage) of participants achieving NEDA-3 will be presented. The 95% 
confidence interval for the proportion of NEDA-3 will be calculated by using exact method. 
The full analysis set will used for those analyses. 

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12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy endpoint(s) 
For all efficacy analyses, the FAS will be used. The healthy control set will be used if 
applicable. 
Descriptive statistics will be provided for the following variables: 
• Number of relapses during the study 
• 3-month disability worsening-free (yes/no) during the study 
• NEDA clinical in Months 6 to 18 (yes/no) 
• NEDA radiological in Months 6 to 18 (yes/no) 
• Change from Baseline in conventional MRI metrics (Gd+ lesion number, new Gd+ 
lesion number, Gd+ lesion volume, T2 lesion number (Baseline), New/enlarging T2 
lesion number (post-Baseline), T2 lesion volume, new unenhancing T1 lesion number, 
T1 unenhancing lesion volume) by visit/time 
• Brain volume loss (BVL) assessment (whole brain and regional) (also obtained in HC 
for normalization purpose) by visit/time 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety set will be used. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate listing of death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
Adverse events 
All information obtained on adverse events will be displayed by 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 treatment but 
increased in severity based on preferred term) will be summarized in the following ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity. 
• by preferred term. 
Separate summaries will be provided for study medication related adverse events, serious 
adverse events, other significant adverse events leading to discontinuation. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 

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13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 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/IECs, 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. 
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. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter (beginning and end of study) 
• Plain language trial summary - after CSR publication 
• Individual study results - after CSR publication 

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• Trial Feedback Questionnaires (TFQ) – Baseline (week 0), Month 6 and End of Study 
(EOS) 
 
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/IEC 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/IEC 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/IEC 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/IEC at the study site should be informed according to 
local regulations. 

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15 
References 
References are available upon request 
Abdelhak A, Huss A, Kassubek J, et al (2018) Serum GFAP as a biomarker for disease severity 
in multiple sclerosis. Sci Rep; 8:14798. 
Abdelhak A, Hottenrott T, Moreanas-Rodríguez E, et al (2019) Glial Activation Markers in 
CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum 
GFAP as Disease Severity Marker? Front Neurol; 10:280. 
Archelos JJ, Storch MK, and Hartung HP (2000) The role of B cells and autoantibodies in 
multiple sclerosis. Ann Neurol; 47:694-706. 
Agarwal S, Cunningham-Rundles C (2007) Assessment and clinical interpretation of reduced 
IgG values. Ann Allergy Asthma Immunol;99:281-3. 
Bar-Or A, Grove RA, Austin DJ, et al (2018) Subcutaneous ofatumumab in participants with 
relapsing-remitting multiple sclerosis: The MIRROR study. Neurology p. e1805-e1814. 
Barro C, Benkert P, Disanto G, et al (2018) Serum neurofilament as a predictor of disease 
worsening and brain and spinal cord atrophy in multiple sclerosis. Brain; 141:2382-2391. 
Bazarian JJ, Biberthaler P, Welch RD, et al (2018) Serum GFAP and UCH-L1 for 
prediction of absence of intracranial injuries on head CT (ALERT-TBI): A multicentre 
observational study. Lancet Neurol; 17:782–9. 
Bouaziz JD, Yanaba K, Venturi GM, et al (2007) Therapeutic B cell depletion impairs adaptive 
and autoreactive CD4+ T cell activation in mice. PNAS; 104:20878-20883. 
Comabella M, Fernández M, Martin R, et al (2010) Cerebrospinal fluid chitinase 3-like 1 levels 
are associated with conversion to multiple sclerosis. Brain; 133:1082-93. 
Comini-Frota ER, Rodrigues DH, Miranda EC, et al (2012) Serum levels of brain-derived 
neurotrophic factor correlate with the number of T2 MRI lesions in multiple sclerosis. Braz J 
Med Biol Res; 45:68-71. 
Cree BA, Gourraud PA, Oksenberg JR, et al (2016) Long-Term Evolution of Multiple Sclerosis 
Disability in the Treatment Era. Ann Neural; 80:499-510. 
Cree BAC, Hollenbach JA, Bove R, et al (2019) Silent progression in disease activity- 
free relapsing multiple sclerosis. Ann Neurol; 85:653-66. 
Disanto G, Barro C, Benkert P, et al (2017) Serum Neurofilament light: A biomarker of 
neuronal damage in multiple sclerosis. Ann. Neurol; 81:857-870. 
DiSano KD, Gilli F, Pachner AR (2020) Intrathecally produced CXCL13: A predictive 
biomarker in multiple sclerosis. Mult Scler J Exp Transl Clin; 6:1-12. 
Eliasson C, Sahlgren C, Berthold CH, et al (1999) Intermediate filament protein partnership in 
astrocytes. J Biol Chem;274:23996-4006. 
Frohman EM, Racke MK, Raine CS (2006) Multiple Sclerosis - the Plaque and Its Pathogenesis 
N Engl J Med; 354:942-55. 

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16 
Appendices 
 
16.1 
Appendix 1: Guidance on safety monitoring 
16.1.1 
Guidance on monitoring of participants with symptoms of 
neurological deterioration suggestive of PML 
Should a participant develop any unexpected neurological or psychiatric symptom/signs in the 
opinion of Investigator (e.g. cognitive deficit, behavioral changes, cortical visual disturbances 
or any other neurological cortical symptoms/signs any symptom/sign suggestive of an increase 
of intracranial pressure) or accelerated neurological deterioration, the Investigator should 
schedule a complete physical and neurological examination and an MRI as soon as possible 
before beginning any steroid treatment. Conventional MRI, as defined in the protocol, as well 
as additional scanning such as Fluid-attenuated Inversion Recovery (FLAIR) and Diffusion- 
weighted imaging (DWI) sequences should be performed to aid in differential diagnosis. The 
MRI must be evaluated by the local neuroradiologist. The Investigator will contact the Medical 
Advisor at Novartis and/or a Global Study Team member to discuss findings and diagnostic 
possibilities as soon as possible. A copy of the unscheduled MRI should be sent to the MRI 
Evaluation Center designated by Novartis as soon as possible. AE/SAEs need to be filed as 
appropriate. 
If the MRI shows (new) lesions consistent with a clinical event/attack (as defined in Section 
8.3.1), assessment and treatment of the clinical event/attack will be performed as described in 
the protocol (Section 6.2.3 and Section 8.3.1). 
In case of new findings in the MRI images, in comparison with the previously available MRI, 
which are not compatible with lesions consistent with a clinical event/attack, the study drug will 
be interrupted, and other diagnostic evaluations need to be performed at the discretion of the 
Investigator. If new lesions are detected on the MRI, which may be infectious in origin, it is 
recommended to collect a cerebrospinal fluid (CSF) sample if indicated. Analysis of the CSF 
sample including cellular, biochemical, PCR, and microbiological analysis (e.g. herpes virus, 
JC virus, cryptococcus) to confirm/exclude an infection should be performed. In the event of 
suspected CNS infection (PML), a CSF aliquot should be sent to a central laboratory 
(designated by Novartis) for confirmatory testing. 
Only after the evaluations have excluded diagnoses other than MS and after discussion with the 
Medical Advisor at Novartis and a Global Study Team member, the study drug may be restarted. 
16.1.2 
Guidance on monitoring participants with infections 
All infections that develop during the study will be reported as adverse events on the respective 
eCRF pages. Treatment and additional evaluations will be performed at Investigator discretion. 
The Investigator should remind the participant of the risk of infections and instruct them to 
report any symptoms of infections promptly. The participants must also be reminded to always 
carry their Participant Information Card (with site contact information and which identifies 
them as participant in a clinical study with investigational and control agents with potential