Clinical trial NCT04486716
Conditions: Relapsing Multiple Sclerosis
Keywords: Ofatumumab Relapsing multiple sclerosis MS RMS CIS RRMS SPM ocrelizumab MRI CD19 B adult, OMB157 open-label rituximab
Sponsor: Novartis Pharmaceuticals
Start date: 2020-10-19; Completion date: 2024-10-21
Enrollment: 111 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A single arm study evaluating the continued efficacy, safety and tolerability of ofatumumab in patients with relapsing multiple sclerosis who are transitioning from aCD20 mAb therapy

Detailed description:
This was a single-arm, multicenter, prospective, study in participants with relapsing multiple sclerosis (MS) who had been previously treated with intravenous (i.v.) anti-CD20 monoclonal antibody (aCD20 mAb) therapy and had received at least 2 consecutive courses of intravenously administered ocrelizumab or rituximab every 6 months, and the last dose was within 4 to 9 months before Baseline/Day 1. In this study, participants could have enrolled only if discontinuing i.v. aCD20 mAb therapy for reasons other than lack of efficacy or due to certain treatment-emergent adverse events (TEAEs). Reasons for switching could have included but were not limited to physician/participant preference, access to commercial drug (e.g. insurance coverage issues), or for other logistical reasons (e.g. geographical relocation, travel, etc.).

Eligible participants received open label ofatumumab 20 mg subcutaneous (s.c.) once monthly for 12 months following initial loading regimen of 20 mg s.c. doses on Days 1, 7, and 14. After the 12-Month Treatment Period there was a Telephone Safety Follow-up call 30 days after last dose of study treatment. The Core phase covered a 28-day Screening Period, 12-Month Treatment Period, and 30-Day Telephone Safety Follow-up.

Upon completing the study, participants could opt to continue ofatumumab therapy through commercial services. Participants who did not continue into the ofatumumab commercial patient services hub within 1 month of the end of study visit or who did not switch to another therapy had to continue into the Post-Treatment Safety Follow-up period, consisting of every 3 month visits including B cell monitoring, until they were able to start on commercial ofatumumab, until they switched to another therapy, or until their B cells were repleted (defined as a B cell concentration greater than the individual participant's baseline value prior to starting the i.v. aCD20 mAb or greater than the lower limit of normal).

Arms: arm 1: Investigational drug will be provided in an autoinjector for subcutaneous administration containing 20 mg ofatumumab (20 mg/0.4 ml) administered at baseline, Day 7, Day 14 and monthly thereafter
Interventions: intervention 1: Ofatumumab
Intervention descriptions: intervention 1: Investigational drug will be provided in an autoinjector for subcutaneous administration containing 20 mg ofatumumab (20 mg/0.4 ml)

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................17
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................22
2
Objectives, endpoints and estimands.................................................................................23
2.1
Primary estimands .................................................................................................24
2.2
Secondary estimands .............................................................................................24
3
Study design ......................................................................................................................25
3.1
Remote procedures ................................................................................................26
4
Rationale............................................................................................................................27
4.1
Rationale for study design .....................................................................................27
4.2
Rationale for dose/regimen and duration of treatment ..........................................28
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................28
4.4
Purpose and timing of interim analyses/design adaptations..................................28
4.5
Risks and benefits..................................................................................................28
4.6
Rationale for Public Health Emergency mitigation procedures ............................29
5
Population..........................................................................................................................30
5.1
Inclusion criteria ....................................................................................................30
5.2
Exclusion criteria...................................................................................................31
6
Treatment...........................................................................................................................35
6.1
Study treatment......................................................................................................35
6.1.1
Investigational drug...............................................................................35
6.1.2
Additional study treatments ..................................................................35
6.1.3
Treatment arms/group ...........................................................................35
6.1.4
Treatment duration................................................................................35
6.1.5
Post Trial Continuity.............................................................................35
6.2
Other treatment(s)..................................................................................................36
6.2.1
Concomitant therapy.............................................................................36
6.2.2
Prohibited medication ...........................................................................37
6.2.3
Recommended treatment of MS Relapse..............................................38


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6.3
Participant numbering, treatment assignment, randomization ..............................38
6.3.1
Participant numbering...........................................................................38
6.3.2
Treatment assignment, randomization ..................................................38
6.4
Treatment blinding.................................................................................................38
6.5
Dose escalation and dose modification..................................................................39
6.5.1
Dose modifications................................................................................39
6.5.2
Follow-up for toxicities.........................................................................39
6.5.3
Drug Interruptions.................................................................................39
6.6
Additional treatment guidance...............................................................................39
6.6.1
Transition period from previous aCD20 DMT .....................................39
6.6.2
Treatment compliance...........................................................................40
6.6.3
Emergency breaking of assigned treatment code..................................40
6.7
Preparation and dispensation.................................................................................40
6.7.2
Instruction for prescribing and taking study treatment .........................41
7
Informed consent procedures ............................................................................................42
8
Visit schedule and assessments .........................................................................................43
8.1
Screening ...............................................................................................................50
8.1.1
Eligibility screening ..............................................................................50
8.1.2
Site contact with participants during self/home drug administration....50
8.1.3
Information to be collected on screening failures.................................50
8.2
Participant demographics/other baseline characteristics .......................................51
8.3
Efficacy..................................................................................................................51
8.3.1
Magnetic Resonance Imaging (MRI)....................................................51
53
54
54
8.3.5
Treatment Satisfaction Questionnaire for Medication TSQM- 9..........55
55
55
8.3.8
Appropriateness of efficacy assessments..............................................55
56
8.4
Safety.....................................................................................................................56
8.4.1
Physical Examination............................................................................56
8.4.2
Electrocardiogram (ECG) .....................................................................57
8.4.3
Vital Signs.............................................................................................57
8.4.4
Height and Weight ................................................................................58
8.4.5
Laboratory evaluations..........................................................................58


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8.4.6
Pregnancy and assessments of fertility .................................................60
8.4.7
Appropriateness of safety measurements..............................................60
9
Discontinuation and completion........................................................................................61
9.1
Discontinuation from study treatment and study...................................................61
9.1.1
Discontinuation of study treatment .......................................................61
9.1.2
Discontinuation from study...................................................................62
9.1.3
Lost to follow-up...................................................................................62
9.2
Withdrawal of informed consent/Opposition to use..............................................63
9.3
Study completion and post-study treatment ..........................................................63
9.4
Early study termination by the sponsor .................................................................64
10 Safety monitoring and reporting........................................................................................64
10.1
Definition of adverse events and reporting requirements......................................64
10.1.1
Adverse events ......................................................................................64
10.1.2
Serious adverse events ..........................................................................66
10.1.3
SAE reporting........................................................................................67
10.1.4
Reporting MS relapse as a SAE............................................................68
10.1.5
Reporting of Disability Worsening as a SAE .......................................68
10.1.6
Pregnancy reporting ..............................................................................69
10.1.7
Pregnancies ...........................................................................................69
10.1.8
Reporting of study treatment errors including misuse/abuse................70
10.2
Additional Safety Monitoring................................................................................70
10.2.1
Liver safety monitoring.........................................................................70
10.2.2
Renal safety monitoring........................................................................71
10.2.3
Prospective suicidality assessment........................................................72
10.2.4
Data Monitoring Committee .................................................................72
10.2.5
Steering Committee...............................................................................72
11 Data Collection and Database management......................................................................72
11.1
Data collection.......................................................................................................72
11.2
Database management and quality control............................................................73
11.3
Site monitoring ......................................................................................................73
11.4
Potential Remote Study Visits...............................................................................74
12 Data analysis and statistical methods ................................................................................74
12.1
Analysis sets ..........................................................................................................74
12.2
Participant demographics and other baseline characteristics.................................75
12.3
Treatments .............................................................................................................75
12.4
Analysis of the primary endpoint(s) ......................................................................75
12.4.1
Definition of primary endpoint(s).........................................................75




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Table 8-4
Local ECG collection plan.....................................................................57
Table 8-5
Laboratory Assessments ........................................................................58
Table 10-1
Criterion for disability worsening based on change in EDSS score ......69
Table 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse ..........................................................................................70
Table 16-1
Liver event and laboratory trigger definitions .......................................84
Table 16-2
Follow up requirements for liver events and laboratory triggers...........84
Table 16-3
Specific Renal Alert Criteria and Actions..............................................88
Table 16-4
Renal Event Follow up...........................................................................89
List of figures
Figure 3-1
Study design..........................................................................................26


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List of abbreviations
aCD20
mAb
anti-CD20 monoclonal antibody
ADCC
Antibody-Dependent Cell-mediated Cytotoxicity
AE
adverse event
AESI
adverse event of special interest
AI
Autoinjector
AIDS
Acquired Immunodeficiency Syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARR
Annual Relapse Rate
AST
aspartate aminotransferase
BSL
Baseline
BUN
blood urea nitrogen
CDC
Complement-Dependent Cytotoxicity
CIS
Clinically isolated syndrome
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central Nervous System
CO
Country Organization
COA
Clinical Outcome Assessment
CRF
Case Report/Record Form (paper or electronic)
CSF
Cerebrospinal Fluid
C-SSRS
Columbia-Suicide Severity Rating Scale (paper)
CTC
Common Toxicity Criteria
CTT
Clinical Trial Team
DMC
Data Monitoring Committee
DMF
Dimethyl Fumarate
DMQ
Daily Mood Questions
DMT
Disease Modifying Therapy
DNA
Deoxyribonucleic Acid
DWI
Diffusion-weighted Imaging
EAE
Experimental Autoimmune Encephalomyelitis
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EDD
Expected Delivery Date
EDSS
Expanded Disability Status Scale
EMA
European Medicines Agency
EOS
End of Study
FACS
Fluorescence-activated cell sorting
FAS
Full Analysis Set
FDA
Food and Drug Administration


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FPFV
First patient first visit
FS
Functional Score
GCP
Good Clinical Practice
Gd
Gadolinium
h
Hour
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
INR
International Normalized Ratio
IPS
Information Processing Speed
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
iv
Intravenous
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver function test
LLN
lower limit of normal
mAb
Monoclonal Antibody
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
ml
milliliter(s)
MRI
Magnetic Resonance Imaging
MS
Multiple Sclerosis
NIH
National Institute of Health
OHP
Off-site Healthcare Professional
OMB
Ofatumumab
PCR
Protein-Creatinine Ratio
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
Progressive Multifocal Leukoencephalopathy


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PT
Prothrombin Time
PTA
Post-Trial Access
q4
Every 4
QMS
Quality Management System
RBC
red blood cell(s)
RPR
Rapid Plasma Reagin
RRMS
Relapsing Remitting Multiple Sclerosis
RMS
Relapsing Multiple Sclerosis
SAE
serious adverse event
SC
Steering Committee
sCR
serum creatinine
 
SPMS
Secondary Progressive Multiple Sclerosis
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin level
TSQM
Treatment Satisfaction Questionnaire for Medication
ULN
upper limit of normal
UPV
unplanned visit
UTI
Urinary Tract Infection
WBC
white blood cell(s)


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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Biologic Samples
Biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant.
Clinical Outcome
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, 
or survives.
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting 
of all clinical trial activities. Examples of team members include the 
Study Lead Medical Monitor Trial Statistician etc.
Coded data
Personal Data which has been de-identified by the investigative center 
team by replacing.
Cohort
A specific group of participants fulfilling certain criteria.
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their
samples.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the 
use of their samples or data.
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 Webbased 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms data/documents used at the point of care.
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in 
the protocol).  The action of enrolling one or more participants.
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.
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
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational medicinal 
product”.


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Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside of 
their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Off-site 
Describes trial activities that are performed at remote location by an off-
site healthcare professional, such as procedures performed at the 
participant's home.
Off-site healthcare 
professional (OHP) 
A qualified healthcare professional, such as include those used in the 
study e.g. Nurse, Phlebotomist, and/or Physician, who performs certain 
protocol procedures for the participant in an off-site location such as a 
participant's home.
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 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
An individual (trial participant) who has consented to participate in this 
study. The term Participant may be used to describe either a healthy 
volunteer or a Patient. “Participant” terminology is used in the protocol 
whereas term “Subject” is used in data collection.
Participant number
A number assigned to each Participant who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
Participant in the study and should be used to identify the participant 
throughout the study for all data collected, sample labels, etc.
Patient-Reported 
Outcome (PRO)
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
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Randomization
The method of assigning trial participants to investigational drug using a 
random process.
Re-screening
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol.
Remote
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location.
Screen Failure
A Participant who is screened but is not treated.
Study completion
Point/time at which the Participant came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug/treatment
Any drug (or combination of drugs) administered to the Participant as 
part of the required study procedures; includes investigational drug, 
active drug run-ins or background therapy.
Tele-visit
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial.


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Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study.
Withdrawal of 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
Rationale for Amendment
Although IgM and IgG are assessed at baseline, this does not indicate if participants’ values 
were declining, were stable or were inclining when entering the trial.  Collection of historical 
values will allow us to observe trends prior to initiating treatment with ofatumumab.
The purpose of the Amendment 2 is to amend the Schedule of Assessments to include:
Table 8-1:  Addition of “Historical IgM and IgG” collection to the screening visit

Footnote #25 added: Historical IgM and IgG results if available from pre-baseline of 
IV anti-CD20 treatment (one result pre-infusion) and then any testing done following 
IV anti-CD20 initiation.  This should be recorded once for all participants enrolled or 
completed and may be collected at any visit.

Footnote #14:  Addition of the word “safety” in front of assessments
Section 8.4.5: Added “If available, historical IgM and IgG values that have been collected 
prior to screening visit, include one pre-anti-CD20 infusion value, should be recorded 
including the collection date.  This should be recorded for all new, existing, and completed 
participants, and may be entered at any time-point during the study.
Section 12.5.2 under Clinical laboratory evaluations: Added “In addition, historical change of 
IgM and IgG will be summarized.”
Section 15: Added reference “Agarwal S and Cunningham-Rundles C (2007) Assessment and 
clinical interpretation of reduced IgG values. Annals of allergy, asthma & immunology. 99(3): 
281-283.”
All relevent section(s) of the protocol are updated to reflect all changes.
Additionally, other administrative changes include the following:

Under Table 8-3 (Severity of MS Relapse) removed “Byrne 2003”
Amendment 01
Rationale for Amendment
The purpose of Amendment 1 is to amend the inclusion and exclusion criteria.
Changes to the Inclusion criteria in protocol summary and section 5.1

Inclusion #2: Increased age limit to 60 years of age.

Inclusion #5:  Removed “no more than 5 courses” limit and updated to at least 1 fully 
infused ocrelizumab IV infusion every 6 months

Inclusion #7: Removed “Participants with CD19 B cells that are depleted to < 1%, as 
measured by the central laboratory”
Changes to the Exclusion criteria in protocol summary and section 5.2

Exclusion# 1:  Updated to include:
a.
Signs of MRI activity, defined as ≥ 2 active Gd+ T1 lesions, or any new or newly 
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Protocol summary
Protocol 
number
COMB157GUS07
Full Title
A single-arm, prospective, multi-center study to explore maintained efficacy with 
ofatumumab therapy in patients with relapsing multiple sclerosis who discontinue 
intravenously delivered anti-CD20 monoclonal antibody (aCD20 mAb) therapy
(OLIKOS)
Brief title
A single arm study evaluating the continued efficacy, safety and tolerability of 
ofatumumab in patients with relapsing multiple sclerosis who are transitioning 
from aCD20 mAb therapy
Sponsor and 
Clinical Phase
Novartis
Clinical Phase 3b
Investigation 
type
Drug
Study type
Interventional, Single-arm
Purpose and 
rationale
The objective of this study is to evaluate continued clinical efficacy, retention and 
satisfaction, as well as safety and tolerability for ofatumumab 20mg 
subcutaneous administered once monthly in participants with relapsing forms of
multiple sclerosis who transition from aCD20 mAb therapy. 
Primary 
Objective(s) 
To explore maintenance of efficacy evaluated by MRI lesions at twelve months 
after initiating ofatumumab therapy vs baseline in participants with relapsing 
multiple sclerosis who are transitioning to ofatumumab from aCD20 mAb therapy 
(for reasons other than suboptimal response or certain treatment-emergent 
adverse events). 
Secondary 
Objectives
Characterize participant retention, immune biomarkers, treatment satisfaction, 
and safety and tolerability at 6 and 12 months after transitioning to ofatumumab. 
Study design
This is a single-arm, multicenter, prospective study in approximately 100 
participants who are transitioning from aCD20 therapy to ofatumumab.  This 
study consists of three parts:  The 28 day screening period, the 12 month 
treatment period, plus a 30-day telephone safety follow-up and if required every
3 month post treatment safety follow-up visits until either another therapy is 
initiated or B cells are repleted, defined as a B cell concentration greater than the 
individual participant’s baseline value prior to starting the IV anti-CD20 mAb or 
greater than the lower limit of normal. The minimum duration of the study for 
participants that complete the study is 14 months.
Population
Adult (ages 18 to 60) relapsing multiple sclerosis participants
Key Inclusion 
criteria
Participants eligible for inclusion in this study must meet all of the following criteria:  
1.
Written informed consent must be obtained before any assessment is 
performed.
2.
Male or female participants aged 18 to 60 years (inclusive) at screening.
3.
Diagnosis of relapsing MS (RMS) according to the 2017 Revised McDonald 
criteria including CIS, RRMS or SPMS with disease activity as defined by 
Lublin et al. 2014.
4.
Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive).


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5.
Received at least 2 courses of intravenous aCD20 mAb (loading doses are 
considered 1 course):

participants
currently treated with ocrelizumab must have 
received (meet all three criteria below):
1.
2 fully infused initial 300 mg ocrelizumab iv infusions
2.
At least 1 fully infused 600 mg ocrelizumab iv infusions every 
6 months (+/- one month)
3.
Last fully infused ocrelizumab dose must have occurred within 
4-9 months prior to baseline.

participants currently treated with rituximab must have received 
(meet both criteria below):
1.
At least 2 fully infused courses of rituximab 500 mg – 1000 
mg iv every 6 months (+/- one month).
a.
Initial loading regimens of rituximab i.e. 500 mg – 1000 
mg on day 1 and on day 15, are allowed but this is 
considered a single course and must be followed by 
additional infusion(s) every 6 months (+/- one month)
2.
Last fully infused rituximab dose must have occurred within 4-
9 months prior to baseline.
6.
Participants currently stable on an intravenous aCD20 mAb therapy but are 
switching for reasons including physician/participant preference, access to 
commercial drug (e.g. insurance coverage issues) or for other logistical 
reasons (such as geographical relocation, travel, etc.) are eligible for this 
study.
7.
Neurologically stable within 1 month prior to first study drug administration.
8.
Must be able to use a smart device or have a care giver that can assist.
Key Exclusion 
criteria
Participants meeting any of the following criteria are not eligible for the inclusion 
of the study:
1.
Participants that have demonstrated suboptimal response to aCD20 therapy 
to include: 
a)
Signs of MRI activity, defined as ≥ 2 active Gd+ T1 lesions, or any 
new or newly enlarging T2 lesions, documented within the last 6 
months.

If a prior MRI within the last 6 months is not available, then new 
or newly enlarging T2 lesions should be considered “not 
documented” and the patient may continue screening.
b)
Documented relapse while on stable, previous aCD20 treatment

Relapses during the first 3 months of intravenous aCD20 
therapy are allowable if the participant is then relapse-free for 12 
months following the relapse while on intravenous aCD20 
therapy
c)
Any signs of clinical worsening as measured by EDSS or any 
clinical measure, documented within the last 6 months.
2.
Discontinuing aCD20 mAb therapy due to the following treatment-emergent 
adverse events:
a)
Severe infusion-related reactions (Grade 3 or above).


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b)
Recurrent infections defined as ≥2 severe infections or ≥3 respiratory 
infections or the need for ≥2 courses of antibiotics since starting aCD20 
therapy, if the Investigator believes this is related to therapy.
c)
Decreased IgG requiring treatment with Intravenous Immunoglobulin
3.
Participants with primary progressive MS or SPMS without disease activity.
4.
Participants meeting criteria for neuromyelitis optica.
5.
Pregnant or nursing (lactating) women.
6.
Women of child-bearing potential unless they are using highly effective forms 
of contraception during dosing and for at least 6 months after stopping study 
medication.
7.
Participants with active chronic disease of the immune system other than MS 
or with immunodeficiency syndrome.
8.
Participants with active systemic bacterial, viral or fungal infections, or known 
to have AIDS.
9.
Participants with neurological symptoms consistent with PML or with 
confirmed PML.
10. Participants at risk of developing or having reactivation of syphilis or 
tuberculosis.
11. Participants at risk of developing or having reactivation of hepatitis.
Study 
treatment
Following initial loading regimen of 20 mg subcutaneous dosed on Days 1, 7 and 
14, ofatumumab 20 mg subcutaneous injections once monthly.
Treatment of 
interest
The treatment of interest is ofatumumab and is the same as the study treatment. 
Following a loading dose regimen consisting of once daily doses on days 1, 7 
and 14, ofatumumab will be given to participants once monthly starting at Month 
1.  All doses of ofatumumab will be given subcutaneously via an autoinjector at a 
dose of 20mg.
Efficacy 
assessment

Magnetic Resonance Imaging (MRI)

Gadolinium enhancing T1 lesions

Gadolinium enhancing T1 upper cervical cord lesions
Key safety 
assessments

Adverse events

Laboratory evaluations (blood and urine)

Columbia Suicide Severity Rating Scale (C-SSRS)

Electrocardiogram (ECG)
Other 
assessments

Treatment Retention

Patient reported outcomes (PROs) 

Treatment Satisfaction Questionnaire for Medication (TSQM-9)
 
Data analysis
The primary aim of this study is to explore maintenance of efficacy evaluated by 
MRI lesions at Month 12 in participants with RMS who are transitioning to 
ofatumumab from aCD20 therapy.


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The primary endpoint will be no change or a reduction from Baseline (assessed 
at Screening Visit) in the number of gadolinium enhancing lesions observed by 
MRI at Month 12, a binary outcome (yes, no).
The number (and percentage) of participants with no change or a reduction will 
be presented. The 95% confidence interval for the proportion of participants with 
no change or a reduction will be calculated by using normal approximation 
method.
The above analyses will be conducted using the Full-Analysis-Set (FAS).
Sample size calculations were based on the proportion of participants with no 
change or a reduction from Baseline in the number of gadolinium-enhancing 
(GdE) MRI lesions 12 months after initiating ofatumumab therapy. Three 
precision estimates were considered for this study: 
A sample size of 100 participants will provide an 8.5% precision (half-width of 
95% confidence interval), a 7.8% precision, or a 7.0% precision corresponding to 
estimated proportions of 75%, 80%, and 85%, respectively, of participants
achieving the primary endpoint.
For the purpose of earlier dissemination of data, an interim analysis will be 
performed on all enrolled participants who either meet the criteria of at least 6 
months treatment or discontinued treatment prematurely. For this analysis, only 
primary variables, demographics, baseline characteristics, adverse events and 
serious adverse events will be summarized.
Since there will be no hypothesis testing involved, statistical adjustment for the 
interim analysis will not be made at the stage of final analyses of efficacy and 
safety.
Key words
Interventional, transitioning, clinical trial, effectiveness, safety, open-label, 
ofatumumab, relapsing multiple sclerosis, treatment satisfaction, patient reported 
outcomes


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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 acquired inflammatory demyelinating condition of the central nervous 
system (CNS), characterized by inflammation, demyelination and axonal/neuronal destruction, 
ultimately leading to severe disability in the majority of patients.
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), with essential functions in 
regulating immune response.  B cells may contribute to disease pathogenesis by self-antigen 
presentation, serving as cellular adjuvants for cluster of differentiation (CD) 4+ T-cell activation 
(Bouaziz et al 2007) and by regulating T-cell function and inflammation via cytokine 
production (Lund 2008), in addition to producing autoantibodies. B-cells are present in chronic 
plaques, areas of demyelination, and in the cerebrospinal fluid of MS patients (Lehmann-Horn 
et al 2013). These observations have provided a new theoretical framework for the use of B
cellbased therapeutics in MS.
Selectively targeting B cells with anti-CD20 monoclonal antibodies has been proven highly 
effective at limiting disease activity in patients with relapsing forms of MS1. Rituximab and 
ocrelizumab are anti-CD20-directed cytolytic antibodies that have been investigated in MS. 
Clinical evidence from randomized, placebo-controlled Phase 2 studies with the chimeric
mouse/human anti-CD20 monoclonal antibody (mAb) rituximab (Hauser et al 2008) and the
humanized anti-CD20 mAb ocrelizumab (Kappos et al 2011) showed B-cell depletion by these
agents lead to marked reductions in MRI-measured inflammatory activity in RMS participants.  
Recently, the efficacy of ocrelizumab was confirmed in two Phase 3 trials in participants with 
RMS (Hauser et al 2017). These studies showed that ocrelizumab significantly reduced relapse 
rates, reduced MRI disease activity and delayed the time to disability worsening versus 
interferon beta 1a over 2 years. Ocrelizumab was well tolerated with no major safety findings 
reported in these clinical trials.
While ocrelizumab has received FDA approval in 2017 (Ocrevus prescribing information; 
Hauser et al 2017) for the treatment of adult patients with relapsing or primary progressive 
forms of multiple sclerosis, rituximab has not.  Nonetheless, rituximab has been utilized in the 
real-world setting as off-label treatment for MS patients in the US. Both rituximab and 
ocrelizumab are delivered in a clinical setting by intravenous (iv) infusion. Rituximab is given 
off-label in a range of doses. A typical rituximab treatment for RMS may consist of 500-1,000 
mg infusions on Day 1 and Day 15 followed by a 1,000 mg infusion every six months. 
Ocrelizumab is initiated with 300 mg infusions on Day 1 and Day 15, and maintained with a 
600 mg infusion every six months. The real-world utilization of both rituximab and ocrelizumab 
in the US is common and ocrelizumab use has continued to increase since its 2017 approval for 
relapsing and primary progressive forms of MS. However, the real world safety, tolerability 
and continued access to these anti-CD20 (aCD20) therapies for MS patients in the clinical 
setting is not fully elucidated. Furthermore, clinical evidence demonstrating whether MS 
patients can be transitioned from IV aCD20 antibody therapy to ofatumumab is not yet available.


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Ofatumumab is a fully human aCD20 mAb that induces B cell lysis via complement-dependent 
cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (Teeling et al 
2006).  Ofatumumab recognizes an epitope localized close to the cell membrane on the 2 
extracellular domains of the CD20 molecule, N-proximal of the epitope for the anti–CD20mAb 
rituximab.  Preclinical differentiation between aCD20 mAb suggests a favorable profile of 
ofatumumab including higher CDC (Pacheco-Fernandez et al 2018), direct lymph node 
targeting (Torres et al 2019) and potential sparing of marginal zone B cells, which are relevant 
for host defense (Theil et al 2019).  The clinical correlates of these preclinical findings remain 
to be explored in Ph3b/4 studies. Ofatumumab has been evaluated in two Phase 2 studies in 
participants with RMS, one of which proved the positive effect on inflammatory lesions when 
given subcutaneously (Sorensen et al 2014, Bar-Or et al 2018). In the head-to-head phase III 
clinical trials, ASCLEPIOS I and II (COMB157G2301 and COMB157G2302, respectively), 
monthly subcutaneous ofatumumab 20mg demonstrated superiority over once daily oral 
teriflunomide 14mg in participants with relapsing forms of multiple sclerosis. 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 2019). Key 
secondary endpoints were also met, where ofatumumab showed 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.
In the ASCLEPIOS studies, ofatumumab was subcutaneously administered via pre-filled 
syringe (PFS). In the APLIOS Phase II study (COMB157G2102), the autoinjector (AI) pen was 
compared with the pre-filled syringe (PFS) in a 12 week randomized open label multicenter 
study to demonstrate bioequivalence (Bar-Or et al 2020). The current study will utilize the 
ofatumumab AI pen to facilitate improved self- and home-administration and hence reduce the 
participant burden of treatment.
Notably, the ASCLEPIOS trials enrolled participants that were either treatment exposed or 
naive (~60% and 40%, respectively), but excluded participants with prior aCD20 mAb exposure
(including rituximab and ocrelizumab) from study participation. Therefore, an evidence gap 
remains whether RMS participants discontinuing aCD20 mAb therapy might experience 
therapeutic benefit from treatment transition to ofatumumab. This study aims to explore 
whether ofatumumab is effective, safe, tolerable, and has better Participant satisfaction in these 
RMS participants.
1.2
Purpose
The purpose of the study is to complement the ofatumumab Phase 3 program by evaluating 
continued clinical efficacy, participant retention and satisfaction, as well as safety and 
tolerability for ofatumumab 20mg subcutaneous administered via the AI pen once monthly in 
participants with relapsing forms of MS who transition from aCD20 mAb therapy.
The primary outcome will be to explore maintenance of efficacy evaluated by MRI lesions
(gadolinium enhancing T1 lesions) at 12 months after initiating ofatumumab therapy vs baseline
in RMS participants transitioning to ofatumumab from aCD20 therapy (for reasons other than 




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2.1
Primary estimands
The primary clinical question of interest is whether ofatumumab can maintain efficacy in 
relapsing MS participants as measured by the presence of gadolinium enhancing lesions on MRI 
at 12 months after switching from an intravenous aCD20 mAb for reasons other than efficacy 
or safety.
The justification for the primary estimand is that it will capture whether or not participants can 
be maintained on subcutaneous ofatumumab after documented stable, effective treatment with 
an intravenous aCD20 mAb, a scenario that is a real life question in the MS community where 
continued access to an infusion suite may not be possible or desired.
The primary estimand is described by the following attributes:

Population: relapsing MS Participants currently treated with an infused aCD20 mAb, 
specifically ocrelizumab or rituximab, that have received at least 2 courses of therapy, that 
are switching due to reasons other than safety or efficacy. Further details about the 
population are provided in Section 5.

Variable: no change or a reduction in gadolinium enhancing lesions on MRI at Month 12
(yes/no).

Treatment of interest: following a loading dose regimen consisting of once daily doses
on days 1, 7 and 14, ofatumumab is given once monthly starting at Month 1. All doses of 
ofatumumab will be given subcutaneously via an autoinjector at a dose of 20mg. Further 
details about the investigational treatment are provided in Section 6.

Intercurrent event:  Death or treatment/study discontinuation.

Summary measure:  Proportion of subjects achieving no change or a reduction in 
gadolinium enhancing lesions on MRI at Month 12.
2.2
Secondary estimands
Not applicable


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3
Study design
This is a single-arm, multi-center, prospective, study in approximately 100 participants with 
relapsing multiple sclerosis who have been previously treated with aCD20 mAb therapy and 
have received at least 2 consecutive courses of intravenously administered ocrelizumab or 
rituximab every 6 months and the last dose is within 4 to 9 months before Baseline/Day 1.  In 
this study, participants may enroll only if discontinuing aCD20 therapy for reasons other than 
lack of efficacy or due to certain treatment-emergent adverse events. Reasons for switching 
may include but are not limited to physician/participant preference, access to commercial drug 
(e.g. insurance coverage issues) or for other logistical reasons (such as geographical relocation, 
travel, etc.) A total of approximately 100 eligible participants will receive open label 
ofatumumab 20 mg subcutaneous once monthly for 12 months following initial loading regimen 
of 20 mg subcutaneous doses on Days 1, 7 and 14.  
Assessments will be done per the assessment schedules (Table 8-1 and Table 8-2).
For participants who discontinue study treatment 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 study, participants may 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 do not continue on any 
MS DMT.

All Safety FU visits must be scheduled relative to the End of Study (EOS) Visit.
Participants that do not continue into the ofatumumab commercial patient services hub within 
one month of the EOS Visit or that do not switch to another therapy, must continue into the 
safety FU phase, consisting of every 3 month visits including B cell monitoring until they are 
able to start on commercial ofatumumab or until they switch to another therapy or until their B 
cells are repleted defined as a B cell concentration greater than the individual participant’s 
baseline value prior to starting the IV anti-CD20 mAb or greater than the lower limit of normal.  
All participants will have a safety follow-up phone call at 30 days post study.
A shortened follow-up time is acceptable if participants select different treatment during this 
period or show earlier repletion.  If participants are not fully repleted by the 6 month post-trial
safety follow-up visit, further follow up visits at a 3 monthly frequency are recommended until 
full repletion has occurred. (Table 8-2)
For participants completing the trial, the total duration of the trial will be a minimum of 14
months.  This accounts for the 28 day screening period, the 12 month treatment period, and a 
30 day telephone safety follow-up.  Safety follow-up may be longer if the participant has not 
switched to another therapy post-trial and B cell repletion has not occurred.




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4
Rationale
4.1
Rationale for study design
The single arm non-comparative design has been selected due to feasibility of recruitment and 
time to study completion.  The real-world varied dosing schedules associated with ocrelizumab 
and rituximab would not allow for standardization of a parallel arm. It is also designed to more 
closely reflect routine clinical setting and care, especially for RMS participants transitioning 
from intravenous aCD20 mAbs to ofatumumab.  To further elucidate the effectiveness of 
transitioning to ofatumumab, additional data from participant registries or other data sources 
may be utilized.
Rationale of study population:
The study includes RMS participants who are transitioning from rituximab or ocrelizumab for 
reasons other than lack of efficacy (defined as documented relapse while on previous aCD20 
treatment, or signs of MRI activity, defined as ≥ 2 active Gd+ T1 lesions, or any new or newly 
enlarging T2 lesions or change in EDSS) or due to certain treatment-emergent adverse events. 
These criteria have been implemented to further characterize the benefits of treatment with 
ofatumumab in a RMS population who already have achieved stable disease activity with other 
anti-CD20 mAbs which have demonstrated strong reductions in relapses and Gd T1 lesions and 
new and/or enlarging T2 lesions on MRI. 
Exclusion of participants who have breakthrough disease with rituximab or ocrelizumab
reduces the potential for enrolling participants who may not respond to aCD20 mAb therapy. 
Additional exclusion criteria, relating to certain treatment-emergent adverse events on 
rituximab or ocrelizumab, concomitant diseases, laboratory parameters, and previous 
medications help to ensure participants safety in the study.
Rationale of chosen endpoints:
The proposed study endpoints are widely accepted as clinically relevant and have been used in 
numerous pivotal clinical trials in relapsing MS. The primary endpoint for the study will be no 
change or a reduction in the number of gadolinium enhancing lesions observed by MRI at 12
months of ofatumumab treatment vs baseline. Key secondary endpoints will include participant
retention, immune biomarkers, treatment satisfaction, and safety and tolerability at 6 and 12 
months after transitioning to ofatumumab. In two large phase 3 studies, ofatumumab 
demonstrated a significant reduction in disease activity (reductions in relapses, Gd T1 lesions 
and new and/or enlarging T2 lesions) versus an active comparator.
This study aims to provide clinical evidence supplementing the phase 3 program by providing 
effectiveness and safety data of ofatumumab in a RMS participant population that is switching 
aCD20 treatment. This evidence is highly relevant for neurologists and treating healthcare 
practitioners in the real world setting.  A planned analysis for the primary endpoint at six months 
will provide early and important data to the health care community about the effectiveness and 
safety of ofatumumab in participants transitioning from other aCD20 therapies.


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4.2
Rationale for dose/regimen and duration of treatment
Ofatumumab dose
The dose regimen for ofatumumab for this study is a loading dose regimen of 20 mg at Day 1, 
Day 7 and Day 14, followed by a monthly maintenance dose regimen of 20 mg administered 
once monthly starting at Month 1. 
This dose regimen is consistent with the USPI and the dose and regimen in the Phase 3 
development program of ofatumumab in RMS.
Duration of treatment
Treatment duration within the study will be 12 months. 
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
No comparator arm will be implemented.
4.4
Purpose and timing of interim analyses/design adaptations
The sponsor will conduct an interim analysis once 100% of enrolled participants have reached 
approximately 6 months of ofatumumab treatment, or discontinued within 6 months of 
enrollment, to provide early effectiveness data for transitioning to ofatumumab from previous 
aCD20 therapy.
For this analysis, only primary variables, demographics, baseline 
characteristics, adverse events and serious adverse events will be summarized.
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, participants
will receive the benefit of being systematically monitored over a 12 month period at regular 
follow-ups for efficacy and safety outcomes. 
Clinical experience with ofatumumab in RMS participants has accumulated from four Phase 2 
studies and the two Phase 3 clinical trials. Approximately 2000 RMS participants have been 
exposed to ofatumumab in total. No unexpected safety findings were observed in MS 
participants who received ofatumumab in the completed studies. 
In the 48-week, placebo-controlled, cross-over study (cross-over at 24 weeks) of intravenous 
doses of ofatumumab up to 700 mg, 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 subcutaneous doses up to 60 mg 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).  A 12-week study performed to demonstrate bioequivalence between 
ofatumumab 20 mg administered subcutaneous via either pre-filled syringe or autoinjector pen
exposed 284 RMS participants to study drug. This study also showed that adverse events and 
serious adverse events were overall low in ofatumumab-treated participants and there were no 
unexpected safety signals (Bar-Or 2020). In the ASCLEPIOS I and II studies, ofatumumab 


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demonstrated a favorable safety profile with no unexpected safety signals, and no imbalance in 
adverse events or serious adverse events, rates of infection (including serious infection) or 
malignancy when compared to teriflunomide. In the studies, systemic injection-related 
reactions were reported in 20.6% of participants on ofatumumab and in 15.3% of participants
on teriflunomide. Nearly all (99%) reported systemic injection reactions were mild to moderate 
(Grade 1-2) and were generally limited to the first injection.
Ofatumumab subcutaneous has demonstrated profound suppression of new MRI lesion activity 
(≥ 90% versus placebo over Weeks 4-12) in relapsing MS participants in a Phase 2 study. In 
the Phase 3 studies, ofatumumab showed a highly significant and clinically meaningful 
reduction in the number of confirmed relapses, evaluated as the annualized relapse rate (ARR). 
Participants 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 worsening (CDW†) and 32.5% (p=0.012) in 6-month CDW versus 
teriflunomide in pre-specified pooled analyses (Hauser et al 2019). Taken together, available 
information of relevant clinical and MRI outcomes supports the potential efficacy of 
ofatumumab in participants with relapsing MS.
In the study described here, RMS participants transitioning to ofatumumab, will have been 
previously exposed to a minimum of 2 of rituximab or ocrelizumab. While rituximab is not a 
currently an FDA-approved disease-modifying therapy for RMS, large retrospective 
observational studies suggest that rituximab safety and efficacy in a heterogeneous RMS 
population are consistent with randomized controlled trials (Salzer et al 2016; Hauser et al 2008). 
The most common types of AEs and SAEs were infections; infusion-related reactions occurred 
in 7.8% of infusions and most commonly during the first 3 infusions (Salzer et al 2016).  In 
RRMS, rituxumab also demonstrated clinical efficacy in the form of a low ARR of (0.044), a 
low incidence of contrast-enhancing lesions (4.6%) and the median EDSS remained stable from 
baseline.
Ocrelizumab safety and efficacy has been previously published (Hauser et al 2017) 
demonstrating that infusion-related reactions occur in 34.3% of participants, serious infections 
occurred in 1.3% of participants and neoplasms occurred 0.5% of participants. Efficacy 
outcomes from the ocrelizumab pivotal studies demonstrated that the annualized relapse rate, 
risk of confirmed disability progression, and MRI lesions were significantly decreased 
compared to interferon beta-1a in the pivotal trials.
While RMS participants in this study must be discontinuing rituximab or ocrelizumab treatment 
for reasons other than safety, the potential safety risks associated with those therapies still exist.
There is currently no information about whether the transition from aCD20 mAbs to 
ofatumumab can be performed safely with acceptable efficacy outcomes for RMS participants. 
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 


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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
Population
The study population will consist of adult participants with RMS fulfilling all the eligibility 
criteria listed below. The study is planned to be conducted in approximately 10-20 centers 
within the United States. It is aimed to enroll approximately 100 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. Written informed consent must be obtained before any assessment is performed.
2. Male or female participants aged 18 to 60 years (inclusive) at screening.
3. Diagnosis of relapsing MS (RMS) according to the 2017 Revised McDonald criteria 
(Thompson et al. 2018), including CIS, RRMS or SPMS with disease activity as defined 
by (Lublin et al. 2014).
4. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive).
5. Received at least 2 courses of intravenous aCD20 mAb (loading doses are considered 1 
course):

Participants currently treated with ocrelizumab must have received (meet all 
three criteria below):
1. 2 fully infused initial 300 mg ocrelizumab iv infusions
2. At least 1 fully infused 600 mg ocrelizumab iv infusions every 6 
months (+/- one month)
3. Last fully infused ocrelizumab dose must have occurred within 4-9
months prior to baseline 

Participants currently treated with rituximab must have received (meet both 
criteria below):
1.
At least 2, fully infused courses of rituximab 500 mg – 1000 mg iv 
every 6 months (+/- one month). 
a.
Initial loading regimens of rituximab i.e. 500 mg – 1000 mg on 
day 1 and on day 15, are allowed but this is consider a single 
course and must be followed by additional infusion(s) every 6 
months (+/- one month)
2.
Last fully infused rituximab dose must have occurred within 4-9
months prior to baseline. 


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6. Participants discontinuing aCD20 therapy for reasons including, but not limited to:
physician/participant preference, access to commercial drug (e.g. insurance coverage 
issues) or for other logistical reasons (such as geographical relocation, travel, etc.) are 
eligible for this study.
7.   Neurologically stable within 1 month prior to first study drug administration.
8.  Must be able to use a smart device or have a caregiver that can assist.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study:
1. Participants that have demonstrated suboptimal response to aCD20 therapy to include: 
a.
Signs of MRI activity, defined as ≥2 active Gd+ T1 lesions, or any new or 
newly enlarging T2 lesions, documented within the past 6 months

If a prior MRI within the last 6 months is not available, then new or newly 
enlarging T2 lesions should be considered “not documented” and the patient may 
continue screening
b.
Documented relapse while on stable, previous aCD20 treatment.

Relapses during the first 3 months of intravenous aCD20 therapy are allowable 
if the participant is then relapse-free for the 12 months following the relapse 
while on intravenous aCD20 therapy
c.
Any signs of clinical worsening as measured by EDSS or any clinical measure 
documented within the last 6 months
2. Discontinuing aCD20 mAb therapy due to the following treatment-emergent adverse 
events: 
a.
Severe infusion-related reactions (Grade 3 or above)
b. Recurrent infections defined as ≥ 2 severe infections or ≥ 3 respiratory 
infections or the need for ≥ 2 courses of antibiotics since starting aCD20 
therapy, if the Investigator believes this is related to therapy.
c.
Decreased IgG requiring treatment with Intravenous Immunoglobulin
3. Participants with primary progressive MS (Polman et al 2011) or SPMS without
disease activity (Lublin et al 2014).
4. Participants meeting criteria for neuromyelitis optica (Wingerchuk et al 2015).
5. 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.
6. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for at least 6 months after stopping study medication. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant, if accepted by the local regulation). NOTE: Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
ARE NOT acceptable methods of contraception


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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

For female participants on the study, the vasectomized male partner should be the 
sole partner 

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods 
of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS) or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. In case of use of oral contraception, women should have 
been stable on the same pill for a minimum of 3 months before taking 
investigational drug.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
Note: Women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or 
tubal ligation at least six weeks. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential.
7. Participants with 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 
(hereditary immune deficiency, drug-induced immune deficiency).
8. Participants with active systemic bacterial, viral or fungal infections, or known to have 
acquired immunodeficiency syndrome (AIDS).
9. Participants with neurological symptoms consistent with PML or with confirmed PML.
10. Participants at risk of developing or having reactivation of syphilis or tuberculosis (eg.
Participants with known exposure to, or history of syphilis, or active or latent 
tuberculosis, even if previously treated). Testing for syphilis and tuberculosis will be 
done at Screening.
Testing must be done by the central lab (for syphilis e.g. by positive rapid plasma 
reagin (RPR); for tuberculosis testing, QuantiFERON®-TB Gold test to assess
participant's eligibility at Screening).
NOTE:

participants with an indeterminate QuantiFERON®-TB Gold test may be enrolled 
if the repeat QuantiFERON®-TB Gold test is negative prior to baseline visit.

participants with positive QuantiFERON®-TB Gold test are not eligible.
11. Participants at risk of developing or having reactivation of hepatitis: Positive results at 
Screening for serological markers for hepatitis (H) A, B, C, and E indicating acute 
orpchronic infection:

anti-HA Immunoglobulin M (IgM)


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
HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA)

anti-HBs negative and Anti-HBc positive

anti-HC IgG (if positive IgG, HCV-RNA PCR will be performed and if negative, 
participant can be enrolled)

anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative, 
participant can be enrolled)
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 and as a comment in the 
eCRF) that the serology results are considered false positive and may then enroll the 
participant.
12. Have received any live or live-attenuated vaccines (including for varicella-zoster virus 
or measles) within 4 weeks prior to first study drug administration.
a.
There is presently no contraindication for the use of an inactivated, viral-vector-, 
or mRNA based Sars-CoV-2 vaccine in patients who are immunocompromised. 
However, different Sars-CoV-2 vaccines may have various mechanisms of action 
and different associated potential risks. Please review local prescribing 
information of any specific Sars-CoV-2 vaccine and comply with local 
prescribing information requirements for specific contra-indications and special 
warnings and precautions for use
13. Have been treated with any of the medications listed below within the time specified
Medication
Exclusionary if used within the 
timeframe specified below
Intravenous, oral, intra-articular or 
intramuscular corticosteroids, 
adrenocorticotropic hormone
30 days prior to Screening MRI scan
Immunosuppressive, chemotherapeutic 
medications (e.g. natalizumab, 
mitoxantrone, cyclophosphamide, 
cladribine, S1P modulators)
2 years prior to first study drug 
administration
Mitoxantrone (with evidence of 
cardiotoxicity following treatment or 
cumulative life-time dose > 60mg/m2)
Alemtuzumab
Lymphoid irradiation; bone marrow 
transplantation
       Anytime


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Other strongly immunosuppressive 
treatments (with effects potentially 
lasting over 6 months)
Ofatumumab
aCD20+ monoclonal antibodies in 
development (e.g. ublituximab or
obinutuzumab)
Daclizumab
14. Use of other investigational drugs at the time of enrollment (Screening) or within the 
prior 30 days, or five elimination half-lives, or until the expected pharmacodynamic 
effect has returned to baseline, whichever is longer.
15. History of malignancy of any organ system (other than basal cell carcinoma, in situ 
squamous cell carcinoma of skin, or in situ carcinoma of cervix or the uterus that have 
been radically treated e.g. completely excised with clear margins), within the past 5 
years, regardless of whether or not there is evidence of local recurrence or metastases.
16. Any of the following conditions or treatments that may impact the safety of the 
participant:

History of, or current, significant cardiac disease including cardiac failure (NYHA 
functional class II-IV), myocardial infarction (within 6 months), unstable angina 
(within 6 months), transient ischemic attack (within 6 months), stroke, cardiac 
arrhythmias requiring treatment or uncontrolled arterial hypertension

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia and clinically significant second or third degree AV block without a 
pacemaker on screening electrocardiogram (ECG)

History of or active severe respiratory disease, including Chronic Obstructive 
Pulmonary Disease, interstitial lung disease or pulmonary fibrosis

Participants with asthma requiring regular treatment with oral steroids

Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary 
disease

Participants with severe renal impairment (Glomerular Filtration Rate < 30 
ml/min/1.73 m2)

Any medically unstable condition as determined by the Investigator
17. Any of the following abnormal laboratory values as confirmed by the central 
laboratory prior to first study drug administration:

Total or conjugated bilirubin (BIL) greater than 3 times upper limit of normal 
(ULN) range, unless in the context of Gilbert’s syndrome

Alkaline phosphatase (ALP) greater than 5 times the ULN range

ALT between 1.5 and 5 times the ULN range and an active infection with 
hepatotropic viruses (Herpes simplex virus, Cytomegalovirus and Epstein-Barr 
Virus)

Serum IgG < 300mg/dL (according to central laboratory range)


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
Any other clinically significant laboratory assessment as determined by the 
Investigator (e.g. significant anemia, neutropenia, thrombocytopenia, signs of 
impaired bone marrow function)
18. Participants with severe hypoproteinaemia e.g. in nephrotic syndrome.
19. Participants with any of the following neurologic/psychiatric disorders prior to first 
study drug administration:

Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Columbia-
Suicide Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6 
months, or “yes” on any item of the Suicidal Behavior section, except for the 
“Non-Suicidal Self-Injurious Behavior” (item also included in the Suicidal 
Behavior section), if this behavior occurred in the past 2 years.
20. Participants unable or unwilling to undergo MRI scans with gadolinium.
6
Treatment
6.1
Study treatment
6.1.1
Investigational drug
Investigational drug will be provided in an autoinjector for subcutaneous administration
containing 20 mg ofatumumab (20 mg/0.4 ml).  Study drug will be supplied by Novartis.
6.1.1.1
Decentralized Clinical Trial Model 
The study medication and all required clinical study supplies could possibly be distributed via 
direct-to-patient shipment utilizing an extension of the IND for compliance purposes in cases 
of a pandemic or a national and/or global emergency.  Remote study visit options may be 
available for participants unable to travel to the clinic for their study visit only under these 
circumstances.  
6.1.2
Additional study treatments
No other treatment beyond investigational drug are included in this trial.
6.1.3
Treatment arms/group
This is open label treatment study with one arm.
6.1.4
Treatment duration
The planned duration of treatment is 12 months. 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.
6.1.5
Post Trial Continuity
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 


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discussed with the participant and investigator. Participants who terminate prior to the end of 
the treatment period or who withdraw permanently due to ofatumumab related AE or SAE 
should follow up with their primary neurologist 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. Premedication with acetaminophen and/or antihistamines (or 
equivalent) is optional and may be administered at the discretion of the Investigator. For the 
first injection of treatment period (Day 1), the addition of premedication with steroids 
(methylprednisolone 100 mg iv or equivalent) is an additional consideration. If Investigators 
choose to administer premedication, it should be administered 30 to 60 minutes prior to study 
drug injection.
Any administrations of premedication must be recorded in the appropriate CRF.
After the initial dose of study medication, participants may inject study medication at home at 
Day 7 and onwards if they have demonstrated the ability to self-inject (refer to Section 6.7.2). 
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 monthly 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 pre-medication may be needed, the participant should be asked to 
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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 
and about the possible symptoms of a systemic injection reaction and their management. 
Furthermore, participants must be informed that the use of steroid premedication may increase 
the occurrence of premedication related adverse events i.e. flushing, chest discomfort, 
hypertension, tachycardia, and abdominal pain. 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 6-1
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
Discontinue study drug, increase 
vigilance regarding infections.
NOTE: Restarting study drug in 
participants exposed to these medications is 
not permitted.
Monoclonal antibodies targeting the immune 
system, including but not limited to 
natalizumab, alemtuzumab, daclizumab and 
B-cell depleting agents under investigation, 
such as but not limited to ublituximab and 
obinutuzumab
Discontinue study drug, increase vigilance 
regarding infections.
NOTE: Restarting study drug after exposure 
to B-cell depleting agents is not permitted. 
For others only after consultation with the 
Sponsor.
Any other immunomodulatory or disease-
modifying MS treatment, including but not 
limited to fingolimod, interferon beta, 
glatiramer acetate, dimethyl fumarate, 
intravenous immunoglobulin, 
plasmapheresis or systemic corticosteroids 
(except for when given for MS relapse 
treatment as defined in Section 6.2.3)
Interrupt or discontinue study drug, increase 
vigilance regarding infections.
NOTE: Restarting study drug in 
participants exposed to these medications is 
not permitted.
Administration of any live or live-
attenuated vaccine (including for measles) is 
prohibited while participants are exposed to 
study drug (long lasting effects of the study 
drugs should be taken into consideration)
They may be administered when 
participants are no longer exposed to study 
drug. Consider risk/benefit and follow local 
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6.2.3
Recommended treatment of MS Relapse
The decision to treat MS relapses should be based on the Investigator's judgement and/or local 
clinical practice. If MS relapses require treatment, the standard treatment should consist of a 
short course of 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 for treatment of MS attack/relapse must be recorded on the Concomitant 
Medications eCRF. Please refer to restrictions for MRI in Section 8.3.1 concerning the use of 
steroids and performing the MRI.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a participant Number (Participant No.), that is 
assigned when the participant is 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.) (as 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.
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 number will be assigned.
6.3.2
Treatment assignment, randomization
No randomization will be performed in this study.  All participants will receive a loading dose 
regimen of ofatumumab (OMB157) 20 mg subcutaneous on Day 1, Day 7 and Day 14 with 
maintenance doses once monthly starting at Month 1 for study duration of one year.
6.4
Treatment blinding
Not applicable.


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6.5
Dose escalation and dose modification
Dose escalation and modifications are not permitted in this study. 
6.5.1
Dose modifications
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 6.7.2).  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 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
Transition period from previous aCD20 DMT
Evidence-based recommendations on transitioning between DMTs are lacking. Hence, only 
general recommendations apply for sequential administration of immunosuppressive therapies. 
The risk of additive immune system effects when switching from drugs with immune effects 
such as rituximab or ocrelizumab must be considered and balanced with the time to transition 
to ofatumumab.
For the purpose of this study, we define the transitioning period as the time between the last 
aCD20 mAb therapy infusion and starting ofatumumab treatment. Participants should initiate 
ofatumumab within 9 months of the last aCD20 infusion but no sooner than 4 months after the 
last aCD20 infusion.
During this transition period, the participant may not receive any other DMT for the 
treatment of MS.
The transition period should be documented in the appropriate eCRF and any AEs reported 
during the procedure must be recorded on the AE eCRF.


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6.6.2
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%.  Study drug accountability will also be determined by the site monitor while 
performing routine site 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.
6.6.3
Emergency breaking of assigned treatment code
Emergency breaking of assigned treatment code is not applicable to this study as this is an open-
label study.
6.7
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). The study medication has a 2-part label (base plus tear-off 
label).  Immediately before dispensing the medication kit to the participant, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document.  
6.7.1.1
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. 


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6.7.2
Instruction for prescribing and taking study treatment
All medication for the duration of the study will be provided by Novartis.  All eligible 
Participants will receive ofatumumab open label treatment. The study drug (ofatumumab 
injection) will be administered starting at “Visit 1 (Baseline/Day 1)”. Drug will then be 
dispensed at scheduled visits throughout the treatment period. Starting at Month 1, the 
subcutaneous injections should be administered at monthly intervals (+/- 3 days).
At Visit 1/BSL, participants will receive the subcutaneous injection at the study site. Site 
personnel will provide training to the participants and view training video on the correct 
procedure for self- administration of the subcutaneous injections. The participant or a caregiver 
may inject the study medication under supervision of the study staff.
Documentation of 
injection procedure understanding by the participant and/or the caregiver must be documented 
in the source document. 
Site staff should remove the study treatment from the refrigerator and allow the AI pen to reach 
room temperature in their unopened box (approximately 15-30 minutes) before self-injection 
by the participant. Used syringes should be disposed of immediately after use in a sharps 
container.
A different body site (front of thighs, lower abdomen) should be chosen each time a dose
is administered to reduce the risk of an injection-site reaction; investigator/qualified site 
staff/caregiver can also inject the study treatment in the outer upper arms. Each new injection 
should be given at least one inch from the previously used site.  If administration is in the 
abdomen, the 2-inch area around navel should be avoided.  Study treatment should also not be
injected into areas where the skin is tender, bruised, red, or hard, or where the participant has 
scars or stretch marks.
Following Visit 1, 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. 
Participants with severe neurological deficits should not self-administer injections.
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 day 7 (dose #2) and day 14 (dose #3) should be administered +/- 1 day. If the dose on 
day 7 (dose #2) is missed, the dose due on day 14 (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.
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 


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the dates and time of all in office and at-home study treatment doses using the participant smart 
device through the Engage app (Clinical Ink).  Provisional devices are available for participants 
that do not have a smart device and/or refuses to use their own.
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 and a copy of the instructions for home 
administration use 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.
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 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 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 drug can be 
found in the 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.
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.


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8
Visit schedule and assessments
Assessment schedule (Table 8-1) lists all of the assessments and indicates with an "X" when 
they are performed. Assessments that will only be reported in the source documentation are 
marked with an “S”.  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, with an allowed visit window of 
±1 day for Days 7, 14 and an allowed visit window of ± 3 days for Months 1, 2, 3, 4, 5, 6 7, 8, 
9, 10, 11, 12 and an allowed visit window of ±7 days for 30 day telephone safety follow-up. 
Missed or rescheduled visits should not lead to automatic discontinuation. In case a visit is 
performed outside of the schedule, subsequent visits shall be performed in keeping with the 
original visit schedule. In addition to the scheduled visits, participants may have unscheduled 
visits due to a MS relapse, an acute illness of undetermined cause, for other reasons, or at the 
discretion of the Investigator. Data collected during unscheduled visits will be recorded in the 
unscheduled visits CRF.  Eligible participants may start study treatment once it is confirmed 
that they meet all inclusion criteria and none of the exclusion criteria.
Participants who prematurely discontinue the study for any reason should be scheduled for the 
EOS visit within 7 days and then enter the Safety Follow-up period according to the schedule 
in Table 8-2. At this final visit, all dispensed investigational product should be reconciled, and 
the adverse event and concomitant medications should be recorded on the CRF.












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Table 8-2
Assessment Schedule, Safety Follow-up
Period1
Post-Treatment Follow-Up
Visit Name
Safety Follow-up Visit 1
Safety Follow-up Visit 2
Additional Follow-up 
Visits2
Visit  (Month)
EOS + 3 Months
EOS + 6 Months
Every 3 months
Visit  Window (Day)
±14
±14
±14
Physical Exam,5
S
S
S
Vital Signs (including 
weight)
X
X
X
Routine lab samples 
including urine
X
X
X
Sample for CD19+ B-
cells and 
CD3+CD20+ T-cells
X
X
X
Total IgG, IgM levels
X
X
X
Urine Pregnancy 
Test3,5
S
S
S
Contraception 
Status4,5
S
S
S
Concomitant 
medications6
X
X
X
Adverse Events
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Visit structure given for internal programming purpose only
2 As needed for the Participants requiring prolonged B-cell plasma level monitoring
3 Pregnancy test is conducted on female Participants only. Urine pregnancy tests will be conducted at all 
scheduled visits as indicated in Table 8-2. The Participant must contact the Investigator immediately in the case 
of a positive test for confirmatory testing at the Investigator's discretion. 
4 Participant's contraception status must be reviewed and documented to ensure method of contraception 
continues to be appropriate per protocol requirement for highly effective contraception.
5 Assessments captured as source data
6 Including corticosteroids used to treat MS relapse; any newly started MS treatment as applicable.


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8.1
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 at a later time if he/she 
believes that the participant’s condition has changed and they 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 with the exception of MRI. The original MRI may be used 
during rescreening if the rescreening occurs within 3 months of the original MRI date. 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 prior to re-
screening the participant and re-screening must be documented in the participant's source 
documents. 
8.1.1
Eligibility screening
8.1.1.1
Hepatitis screen, HIV screen
All participants will be screened for Hepatitis B surface antigen (HBsAg) and, if standard local 
practice, Hepatitis B core antigen (HBcAg). Screening for Hepatitis C will be based in HCV 
antibodies and if positive, HCV RNA levels should be determined.
Evaluation for HIV seropositivity will be performed, 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.
8.1.2
Site contact with participants during self/home drug administration
Site personnel will make remote contact with participants starting at Day 7 and Day 14 and then 
on a monthly basis (months 2, 3, 4, 5, 7, 8, 9, 10, and 11) in between scheduled site visits starting 
at Month 1 and continuing for the remainder of the study. The contact should take place around 
time of the monthly subcutaneous self/home-administration to query about any new or 
worsening symptoms warranting an unscheduled visit, compliance with study treatment, 
injection reactions, and compliance with contraception requirements when applicable. The 
method of contact with each participant can be the personal preference of the individual between 
telephone contacts, email contact or text messages, however, the site staff must be able to 
provide suitable source documentation of each contact regardless of the method of contact.
8.1.3
Information to be collected on screening failures
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to treatment or fail to start the treatment for any reason will be considered a screen failure. 
The reason for screen failure should be recorded on the appropriate Case Report Form. The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event during the screening phase (Section 10.1.3).
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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 
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.
MS disease history (including date of onset and diagnosis, number of previous MS relapses), 
previous MS treatment and employment status will also be collected on the corresponding CRFs.
Reason for switching from previous intravenous aCD20 must be captured on the CRF i.e. 
Participant convenience, insurance issues, mild-moderate infusion reactions, etc.
8.3
Efficacy
The primary objective of this study is to evaluate the maintenance of efficacy of ofatumumab 
in participants with RMS transitioning from intravenous aCD20 mAb therapy, as assessed by 
change or reduction in the number of gadolinium enhancing lesions observed by MRI at 12
months of ofatumumab treatment versus study screening. The secondary objective of this study 
is to characterize participant retention, immune biomarkers, treatment satisfaction, as well as 
safety and tolerability at 6 and 12 months after transitioning to ofatumumab. The study includes 
the following efficacy assessments conducted at visits as shown in Table 8-1:
Imaging

Magnetic Resonance Imaging
Clinical
Laboratory
Patient Reported Outcomes

Treatment Satisfaction Questionnaire for Medication - 9 (TSQM-9)
An overview of each of these assessments is provided in the sections below and the details of 
these assessments will be provided in the site manuals.
8.3.1
Magnetic Resonance Imaging (MRI)
All participants will undergo MRI scanning of the brain and cervical spine according to the 
schedules in Table 8-1.


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MRI scans will be read by the central MRI reading center. Prior to the start of the study, MRI 
technician from each center will receive an MRI Manual, outlining technical implementation, 
image quality requirements and MRI administrative procedures.
The site will be asked to program the MRI scanner that is designated for evaluation of the study 
participants. Site will be asked to perform and submit a dummy scan (so called “dummy or dry 
run”) to the central MRI reading center to assess the image quality and to evaluate the 
compatibility of the electronic data carrier. Once the dummy run has been accepted, all the 
parameter settings for the study specific MRI sequences must remain unchanged for the 
duration of the study. Finally, if the site is already pre-approved for performing conventional 
MRI scan sequences by the imaging vendor the dummy or dry run may be skipped.
Each MRI scan performed for the study needs to be previewed by a local neuro radiologist. 
During the study, the quality of each scan performed will be assessed by the central MRI reading
center. The MRI scan should be sent to the central MRI reading center upon completion of each 
individual scan. As soon as the scan is received by the central MRI reading center, it will be 
evaluated for quality, completeness and adherence to the protocol. Confirmation of MRI quality 
or a description of the quality problems, if detected, will be communicated to the site. If a scan 
is incomplete or incorrectly performed, the study center will be asked to repeat it as soon as 
possible. After completion of the quality check, all scans will be analyzed according to the MRI 
protocol.
Restrictions to MRI schedule
To avoid interferences caused by steroids (in regards to Gd+-enhancing lesions) for the 
treatment of MS relapse, the following restrictions apply for this study:

In case of relapse, if an MRI has been scheduled within 30 days of the initiation of steroid 
treatment, MRI (with Gd+ enhancement) should be performed before steroid treatment is 
initiated.

No MRI should be performed while a participant is on steroid therapy and within the 
following 30 days upon termination of steroid treatment.
Because of these restrictions, MRI scheduling can be adjusted accordingly. In case a visit is 
performed outside the visit window, any subsequent visits should be performed according to 
the original visit schedule.
Scanning
All sequences/scans will be performed according to the study MRI manual.
MRI scan sequences, such as but not limited to, will include conventional MRI measures of T1 
hypointense images (with and without contrast medium, i.e., gadolinium-DTPA), and
 
 
The gadolinium contrast medium may occasionally cause nausea and vomiting. Allergic 
reactions may also occur very rarely and, in extremely rare instances, can be potentially serious 
and require immediate anti anaphylactic treatment. Any AE experience due to the contrast 
medium should be recorded on the AE eCRF.


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8.3.5
Treatment Satisfaction Questionnaire for Medication TSQM- 9
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used to evaluate 
the participants’ satisfaction with Ofatumumab.  The TSQM-9 is a psychometrically sound and 
valid participant reported outcome to measure participants’ satisfaction with medication and a 
good predictor of adherence across different types of medication and participant population.  
The TSQM-9 is a 9 item questionnaire having a global satisfaction score ranging from 0-100. 
The questionnaire consists of 3 domains: satisfaction, convenience and effectiveness (3 items 
each). The domain scores range from 0 to 100 with higher scores representing higher 
satisfaction on that domain. (Bharmal et al. 2009)
8.3.8
Appropriateness of efficacy assessments
The 
 MRI assessments to be performed in this study are 
standard and widely accepted efficacy assessments used in clinical MS studies to monitor 
disease activity and to evaluate treatment effects. They also serve to characterize the 
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history. Significant findings made after signing informed consent, which meet the definition of 
an Adverse Event must be recorded on the adverse events eCRF.
8.4.2
Electrocardiogram (ECG)
All ECGs will be locally collected and evaluated for the eligibility assessment at the Screening 
visit. Another ECG will be performed at the baseline and EOS visit.  Additional unplanned 
ECGs may be performed at the Investigator's discretion if clinically indicated. Interpretation of 
the tracing must be made by a qualified physician and documented on the appropriate CRF. 
Each ECG tracing should be labeled with the study number, participant initials (where 
regulations permit), participant number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the appropriate 
CRF. Clinically significant findings must be discussed with Novartis prior to enrolling the 
participant in the study. New or worsened clinically significant findings occurring after 
informed consent must be recorded as adverse events.
Single 12 lead ECGs are collected.  The ECG should be recorded (after 10 minutes rest in the 
supine position to ensure a stable reading) according to the local site practice. 
Clinically significant ECG findings at Screening must be discussed with the Novartis Medical 
Advisor before administration of study drug.  
The preferred sequence of cardiovascular data collection during study visits are ECG collection 
first, followed by vital signs and blood sampling.  The Fridericia's QT correction formula 
(QTcF) should be used for clinical decisions.
The original ECGs on non-heat-sensitive paper (or a certified copy on non-heat-sensitive paper), 
appropriately signed must be archived at the study site.  
Findings and clinically significant abnormalities must be recorded on the relevant section of the 
medical history form and AE eCRF page as appropriate.
Table 8-4
Local ECG collection plan
Visit 
Day 
Time
Number of ECG 
Replicates
Screening
0
Within the 28 day 
window
12 Lead Single
Baseline/V1
1
Pre-dose
12 Lead Single
V15/EOT/EOS
Month 12
Pre-dose
12 Lead Single
Unscheduled 
Unplanned
Anytime
12 Lead Single
8.4.3
Vital Signs
Vital signs will include siting pulse rate (measured as radial pulse for 60 seconds), sitting 
systolic and diastolic blood pressure and body temperature (oral, or per local practice and should 
be recorded in the relevant CRF page in Celsius) which will be assessed at the visits indicated 
in Table 8-1 and Table 8-2.


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After the participant has been sitting for five minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured three times using an 
automated validated device, e.g. OMRON, with an appropriately sized cuff. At the baseline
visit only, systolic and diastolic blood pressure should be measured 3 times. The repeat sitting 
measurements will be made at 1 - 2 minute intervals and the mean of the three measurements 
will be used.  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.
Vital signs should be obtained 30-60 (+/- 10min) minutes before the subcutaneous injection
(study drug).  If premedication is required, the vital signs should be taken prior to premedication 
administration.
8.4.4
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.
8.4.5
Laboratory evaluations
If available, historical IgM and IgG values that have been collected prior to the screening visit, 
including one pre-anti-CD20 infusion value, should be recorded including the collection date. 
This should be recorded for all new, existing, and completed participants, and may be entered 
at any time-point during the study.
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in the laboratory manual. 
Abnormal laboratory parameters, inconsistent with clinical presentation of MS, or which cause 
suspicion of an underlying medical condition should be repeated for confirmation. All abnormal 
lab results must be evaluated for criteria defining an adverse event and reported as such if the 
criteria are met.  For those lab adverse events, repeated evaluations are mandatory until 
normalization of the result(s) or until the result is no longer considered clinically significant.
Table 8-5
Laboratory Assessments
Test Category
Test Name
Hematology
Blood samples will be collected according 
to the schedule in Table 8-1 and Table 8-2. 
Hematocrit, Hemoglobin, Platelets, Red 
blood cell (RBC) count, Total WBC count 
and WBC differential counts (Basophils, 
Eosinophils, Lymphocytes, Monocytes, 
Neutrophils).
Chemistry
Blood samples will be collected according 
to the schedule in Table 8-1 and Table 8-2.


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Electrolytes (Sodium, potassium, chlorine, 
bicarbonate, calcium, magnesium, 
phosphorus), random glucose, total protein, 
urea nitrogen, albumin, alkaline 
phosphatase, ALT, AST, y-GT, total 
bilirubin, conjugated bilirubin, creatinine, 
amylase, total cholesterol, triglycerides, high 
density lipoprotein and low density 
lipoprotein, C-Reactive protein.
B-cell/T-cell sampling
CD19+ B-cell counts and CD3+CD20+ T-cell 
counts. Samples will be collected according 
to the schedule in Table 8-1 and Table 8-2.
Total IgG and IgM levels
Samples will be collected according to the 
schedule in Table 8-1 and Table 8-2. 
Urinalysis
Urine will be collected at the scheduled 
visits indicated in Table 8-1 and Table 8-
2. The 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.
Additional tests
Testing of lab samples will be conducted at 
screening to determine the participant’s 
eligibility for inclusion in the study with 
respect to hepatitis viruses. Testing for 
syphilis and tuberculosis at Screening is also 
needed.
A positive result for any of the following 
serological markers for hepatitis A, B, C and 
E as below is an exclusion criterion:

anti-HA Immunoglobulin M (IgM)

HBs Ag and/or anti-HBc IgM and/or HB 
virus deoxyribonucleic acid (DNA)

anti-HBs negative and anti-HBc positive

anti-HC IgG (if positive IgG, HCV 
RNA PCR will be performed and if 
negative, participant can be enrolled)


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
anti-HE IgM (if positive IgG and/or 
IgM, perform HE-RNA PCR and if 
negative, participant can be enrolled)
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 participant.
Pregnancy Test
Serum / Urine pregnancy test (refer to 
Section 8.4.7).
8.4.6
Pregnancy and assessments of fertility
Serum pregnancy tests will be conducted for all women of childbearing potential at each clinic 
visit including the EOS visit.  Urine pregnancy tests will be conducted for all women who are 
of child bearing potential at all other planned clinic visits as indicated in Table 8-1 and Table 
8-2 prior to study drug administration.  In addition, the participants will be provided with 
urinary pregnancy test kits for monthly home pregnancy testing required between the scheduled 
clinic visits prior to study drug administration.  The participants will document the date and 
result of each home pregnancy test.  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.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if required by local requirements.
8.4.7
Appropriateness of safety measurements
The safety assessments included in this study (Table 8-1 and Table 8-2) 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) 
for more information.
The use of C-SSRS to detect suicidal ideation behavior is currently mandated in studies of CNS 
active drugs, for further details, refer to Section 10.2.3.


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9
Discontinuation and completion
9.1
Discontinuation from study treatment and study
9.1.1
Discontinuation of study treatment
Discontinuation of study drug for a participant occurs when study drug is permanently stopped 
for any reason (prior to the planned completion of study drug administration, if any), and can 
be initiated by either the participant or the Investigator.
The Investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively affect the participant's well-being.
Discontinuation from study treatment is required under the following circumstances:

Participant/guardian decision (Section 9.2) 

Pregnancy (Section 10.1.6 and Section 10.1.7) 

Use of prohibited treatment (Section 6.2.2)

Diagnosis of PML

Participants with active serious infections or reactivation (e.g. tuberculosis, hepatitis B or 
C)

Skin and/or mucosal reactions which raise the suspicion of severe generalized major skin 
reactions (Stevens-Johnson syndrome, or toxic epidermal necrolysis-Lyell's syndrome)

Hypersensitivity to the study medication

Any situation in which continued study participation might result in a safety risk to the 
participant

Protocol violation that results in a significant risk to the participant's safety

Emergence of certain adverse events, such as malignancy (except successfully treated 
basal cell carcinoma, in situ squamous cell carcinoma and in situ carcinoma of cervix of 
uterus), liver failure or serious chronic infection (such as human immunodeficiency virus 
(HIV))

Laboratory abnormalities (e.g. liver functions tests (LFTs) and abnormal test procedure 
defined in Appendix 1 (Section 16.1)

Severe hypoproteinemia

Interstitial lung disease or new onset or worsening of pulmonary symptoms, such as 
persistent cough and dyspnea, with or without associated fever, suspicious of interstitial 
lung disease

Non-compliance with study drug or study procedures
Study treatment discontinuation should be considered under the following circumstances:

For participants who meet the criterion for 6-month confirmed disability worsening 
on EDSS (see Section 10.1.5) during the study, the Investigator must reassess the benefits 
and risks of continuing study treatment.  The Investigator will also discuss the further 
treatment with the participant, including any other MS treatment options that may be 
available to the participant.  The outcome of the discussion with the participant must be 
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
In case the Investigator deems the benefit-risk of continuing study treatment to be 
unfavorable or if the participant does not wish to continue study treatment and the 
participant does not initiate a commercial MS disease modifying therapy, the participant 
will be discontinued from the study and will enter the Safety Follow-up period           
(Table 8-2).  
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 from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (see Table 8-1). Participants that 
discontinue treatment and do not initiate a commercial MS disease modifying therapy should 
complete the EOS visit and move to the Safety Follow-up as per Table 8-2.  If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the participant/pre-designated contact as specified in Section 9.1.3.  This 
contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular contact with the participant, or with a person pre-designated by the participant.  This 
contact should preferably be done according to the study visit schedule for up to 6 months post 
last study drug administration.
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 drug.
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).
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. 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 
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9.2
Withdrawal of informed consent/Opposition to use
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore, and

Does not allow further visits or assessments, and 

Does not want any 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 his/her 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent.  However, they still retain the right to object to the further collection or use 
of personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. 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 
table (section 8)
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 the time of consent withdrawal/opposition.  No new Personal Data (including
biological samples) will be collected following withdrawal of consent/opposition according to 
applicable law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
9.3
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this 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.
A participant is considered to have completed the study when they fulfill the following criteria:

Participant has completed the study in its entirety according to the approved duration of 
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
The participant has not stopped the study due to one or more of the following reasons: 

Discontinuation of study treatment (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 participants. For participants that complete the 
study, the next (and last) scheduled visit is the EOS visit and should align with the overall visit 
schedule. Participants will then enter the Safety Follow-up according to the assessment 
schedule in Table 8-2 if they do not initiate a commercial MS disease modifying therapy.  
Participants who prematurely discontinue study treatment will have their EOS visit as soon as 
possible and continue into the Safety Follow-up for 6 months according to the assessment 
schedule in Table 8-2 if they do not initiate a commercial MS disease modifying therapy.
The Investigator must provide follow-up medical care for all Participants who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
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 sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective of if a clinical event has occurred.
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 


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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 event 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 non-typical in participants with 
the underlying disease. Investigators have the responsibility for managing the safety of 
individual participant and identifying adverse events. 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 web-site: 
http://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):

The Common Toxicity Criteria (CTC) AE grade (1-4)
If CTCAE grading does not exist for an adverse event, use:
1 = mild: usually transient in nature and generally not interfering with normal activities
2 = moderate: sufficiently discomforting to interfere with normal activities
3 = severe: prevents normal activities
4 = life-threatening

Its relationship to the study treatment.

Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported

Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met

Action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

No action taken (e.g. further observation only)

Drug interrupted/withdrawn

Concomitant medication or non-drug therapy given

Participant hospitalization/participant's hospitalization prolonged (see Section 10.1.2 for 
definition of SAE)

Its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved 
with sequelae; fatal; or unknown).


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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 following the last dose of study treatment until 
the participant starts a commercially available MS disease modifying therapy or until their B 
cells are repleted.  Repletion is defined as a concentration > the participant’s baseline value
prior to starting the IV anti-CD20 mAb or > the lower limit of normal, whichever is observed 
first.
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 (ofatumumab) can be 
found in the 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 ofatumumab 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 has then to be discussed with the participant.
The Investigator must also instruct each participant to report any new adverse event (beyond 
the protocol observation period) that the participant, or the participant's personal physician, 
believes might reasonably be related to study treatment. This information must be recorded in 
the Investigator’s source documents; however, if the AE meets the criteria of an SAE, it must 
be reported to Novartis.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. hospitalization for MS relapse treatment)


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
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 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, and are to be reported as appropriate 
according to Section 10.1.8.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant
has provided informed consent and until B cells are repleted after the final study drug 
administration for study completers or until they initiate a commercially available MS disease 
modifying therapy 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.
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 each specific 
component of study treatment (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 


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Detailed instructions regarding the submission process and requirements for signature are to be 
found in the Investigator folder provided to each site.
Follow-up information is submitted as instructed in the Investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated and whether the participant continued or 
withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a 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.
Any SAEs experienced after the B cells are repleted following final study drug administration 
or after the end of Safety Follow-up should only be reported to Novartis Safety if the 
Investigator suspects a causal relationship to study treatment unless otherwise specified by local 
law/regulations.
10.1.4
Reporting MS relapse as a SAE
MS relapses are one of the efficacy 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 MS relapse eCRF instead of the SAE form. However, if, in the 
judgment of the Investigator, a MS relapse 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.
10.1.5
Reporting of Disability Worsening as a SAE
Disability worsening is not one of the efficacy endpoints in this study and therefore should be 
reported as an AE. If, in the judgment of the Investigator the disability worsening is unusually 
severe or medically unexpected and warrants specific notification, then a SAE form must be 
completed and submitted according to SAE reporting procedures outlined above.
A 6-month confirmed disability worsening is defined as an increase from baseline in EDSS 
sustained for at least 6 months. This means that after a scheduled or unscheduled visit at which 
the patient fulfills the disability worsening criterion, all EDSS assessments (scheduled or 
unscheduled) need to also fulfill the worsening criteria until the worsening (“the event”) can be 
confirmed at the first scheduled visit that occurs 6 months after the onset of the worsening, or 
later.


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Table 10-1
Criterion for disability worsening based on change in EDSS score
Total EDSS at Baseline
“Disability worsening” criterion
0
1 to 5
≥5.5
≥ +1.5
≥ +1
≥ +0.5
EDSS=Expanded Disability Status Scale                                                   
A 6-month confirmed disability worsening (6-mCDW) can have an onset at any scheduled unscheduled visit if the disability 
worsening criterion is met. 
A disability worsening event can only be confirmed at a scheduled visit if, over a period of 6 months (≥ 166 days=6*30-14) time 
interval, all assessments meet the worsening criterion.
If a patients dies due to MS (EDSS=10 at any time), it will be considered a confirmed disability worsening regardless of the 
baseline EDSS or the change in EDSS.
* Baseline EDSS is defined as the last EDSS assessment prior to the first dose of study medication (protocol inclusion criterion is 
EDSS 0-5.5)
10.1.6
Pregnancy reporting
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 until after the Expected Delivery Date (EDD) to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. Additional 
follow up will be completed at EDD +1 month, EDD +2 months (in case no answer is received 
after request at EDD +1 month) and at EDD +3 months. Information on the status of the baby 
after delivery and information on any development issue or abnormality that would not be seen 
at birth must be collected.
10.1.7
Pregnancies
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 on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the Novartis Chief Medical Office and Patient Safety (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 any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on a SAE form.


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10.1.8
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, patient or 
consumer (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in 
Dosing CRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE 
form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 in Appendix 1 for complete definitions of liver laboratory triggers 
and liver events.


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Every liver event defined in Table 16-1 should be followed up by the Investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2.
For all liver event triggers, liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and y-GT) 
must be repeated within the next week to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant.

If a liver event is subsequently reported, any local liver chemistry tests previously 
conducted that are associated with this event should have results recorded on the 
appropriate CRF. Repeat laboratory examinations must then be performed at central 
laboratory as soon as possible.

If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum creatinine (sCR) increase ≥ 25% compared to baseline during normal hydration 
status, confirmed after 24 hours

new onset (≥ 1+) proteinuria; confirmed by doubling in the urinary albumin/creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥ 1+), hematuria or glycosuria
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the Investigator or designated personnel at the trial site as summarized in Table 16-4.


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10.2.3
Prospective suicidality assessment
The C-SSRS is a paper questionnaire that prospectively assesses suicidal ideation and suicidal 
behavior. The C-SSRS can be administered at each visit (as per Table 8-1), including unplanned 
visits.
At the screening visit, the “baseline/screening” version of the C-SSRS will be administered. 
This version assesses suicidal ideation and suicidal behavior during the participant’s lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered.
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 health care 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.
10.2.4
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.
10.2.5
Steering Committee
The Steering Committee (SC) will be established comprising Investigators participating in the 
trial, i.e. not being members of the Novartis/sponsor representative from the Clinical Trial Team.  
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”.  
A study steering committee will be appointed prior to first patient first visit (FPFV).
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 


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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.
All other data captured for this study will have either the eCRF as source or an external 
originating source (either written or electronic) with the CRF not being considered as source. 
In cases where electronic source data capture devices experience faults, for example, digital
device used for ePROs, paper back-up source will be permitted.
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Sponsor. MRI scans will be analyzed centrally the derived results will also be sent electronically 
to Sponsor.
Enrollment codes and data about all study treatment(s) dispensed to the participant will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. 
For electronic COAs, devices will be supplied by a vendor, data will be processed centrally, 
and both raw and processed data will be sent electronically to Novartis (or a designated CRO).
Once all the necessary actions have been completed, including determining the occurrence of 
relevant protocol deviations, and the database has been declared to be complete and accurate, it 
will be locked and made available for data 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. eSource 


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DDE or eCRFs) with the Investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The Investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The Investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
11.4
Potential Remote Study Visits
If a pandemic or a national and/or global emergency were to occur, remote study visits may be 
available for participants unable to travel to the clinic for their study visit.  This would allow 
the opportunity for participants, if desired, to continue their participation in the study.
12
Data analysis and statistical methods
The analysis will be conducted on all participant data at the time the trial ends. Any data analysis 
carried out independently by the Investigator should be submitted to Novartis before publication 
or presentation.
Categorical variables will be presented as counts and percentages. For continuous variable, 
mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum 
will be presented.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all participants who received at least one dose of study 
drug.
The FAS will be used for the summary of demography and baseline characteristics as well as 
for all efficacy analyses.


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The Safety Set is identical to FAS in this study.
12.2
Participant demographics and other baseline characteristics
Demographics, MS disease history, MRI baseline characteristics and MS medication history 
will be summarized for the FAS.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
12.3
Treatments
The duration of exposure in (days) to study medication will be summarized descriptively. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system and preferred term.
12.4
Analysis of the primary endpoint(s)
The primary aim of this study is to explore maintenance of efficacy evaluated by MRI lesions 
at twelve months after initiating ofatumumab therapy in RMS participants transitioning to 
ofatumumab from aCD20 therapy (for reasons other than suboptimal response or the occurrence 
of certain treatment-emergent adverse events). 
12.4.1
Definition of primary endpoint(s)
The primary endpoint will be no change or a reduction from Baseline (assessed at Screening 
Visit) in the number of gadolinium enhancing lesions observed by MRI at Month 12, a binary 
outcome (yes, no).
12.4.2
Statistical model, hypothesis, and method of analysis
The number and percentage of participants with no change or a reduction in number of 
gadolinium enhancing lesions at Month 12 will be presented. The 95% confidence interval for 
the proportion of participants with no change or a reduction will be calculated by using normal 
approximation method.
Both non-response imputation for missing data and observed data approaches will be applied. 
The above analyses will be conducted using the Full-Analysis-Set (FAS).
12.4.3
Handling of intercurrent events of primary estimand
Missing data will be handled using non-response imputation regardless of intercurrent event.
12.4.4
Handling of missing values/censoring/discontinuations
For participants with missing number of gadolinium enhancing lesions at Month 6 and Month 
12, non-response imputation method will be used. 
12.4.5
Sensitivity and Supportive analyses
Neither sensitivity nor supportive analysis is planned.


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12.5
Analysis of secondary endpoints
12.5.1
Efficacy endpoint(s)
Retention on ofatumumab treatment from baseline to Month 6, and to Month 12 (yes, no) will 
be summarized using frequency count and percentage for the FAS.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment. Unless explicitly otherwise stated, only data up to and until B cells are repleted after 
the final study drug administration for study completers or until the participant initiates a 
commercial MS disease modifying therapy or until the end of Safety Follow-up for premature 
withdrawals will be included in the analysis and data beyond this time point for a participant
will be excluded from safety analysis.  In addition, a separate summary for 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, which started or worsened during the 
on-treatment period (treatment-emergent AEs).
The on-treatment period for safety analysis lasts from the date of first administration of study 
drug until B cells are repleted after the date of the last actual administration of study drug for 
study completers or until the participant initiates a commercial MS disease modifying therapy 
or until the end of Safety Follow-up.
Adverse events
All information obtained on adverse events will be displayed by treatment and participant. The 
number and percentage of participants with AEs of special interest/related to identified and 
potential risks will be summarized in the following ways:

By treatment, primary system organ class and preferred term.

By treatment, primary system organ class, preferred term and maximum severity.

By treatment, pre-defined topic of interest, primary system organ class and preferred 
term.
Separate summaries will be provided for study medication related adverse events, serious 
adverse events, and other significant adverse events leading to discontinuation.
The number and percentage of participants with adverse events of special interest will be 
summarized by treatment, primary system organ class and preferred term. A participant with 
multiple AEs within a category is only counted once towards the total of that category.
Vital signs
All vital signs data may be listed by participant, and visit.  Abnormalities will be flagged. 
Descriptive statistics for change from baseline will be provided by visit.




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12.7
Interim analyses
For the purpose of earlier dissemination of results, an interim analysis will be performed after 
all enrolled participants have either meet the criteria of at least 6 months treatment or 
discontinued treatment prematurely. For this analysis, only primary variables, demographics, 
baseline characteristics, adverse events and serious adverse events will be summarized.
Since there will be no hypothesis testing involved, statistical adjustment for the interim analysis 
will not be made at the stage of final analyses of efficacy and safety.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Sample size calculations were based on the proportion of participants with no change or a 
reduction from Baseline (assessed at Screening Visit) in the number of gadolinium-enhancing 
(GdE) MRI lesions 12 months after initiating ofatumumab therapy. Three precision estimates 
were considered for this study: 
The sample size of 100 participants is selected based on budget and early availability of interim 
analysis results.  This sample size of 100 participants will provide us with an 8.5% precision 


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(half-width of 95% confidence interval), a 7.8% precision, or a 7.0% precision corresponding 
to estimated proportions of 75%, 80%, and 85% of participants achieving the primary endpoint.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
13.2
Responsibilities of the Investigator and IRB/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.


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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/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 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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16
Appendices
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN

1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known 
bone pathology)

TBL > 2 × ULN (in the absence of known 
Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase 
in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a 
liver toxicity*
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal.
Table 16-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)


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Criteria
Actions required
Follow-up monitoring
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
> 3 × ULN and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 
hours

If elevation persists, 
continue follow-up 
monitoring

If elevation persists for 
more than 2 weeks, 
discontinue the study drug

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
> 3 × ULN accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
> 3 to ≤ 5 × ULN 
(participant is 
asymptomatic)

Repeat LFT within the next 
week
Investigator discretion
Monitor LFT within 1 to 4 
weeks


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Criteria
Actions required
Follow-up monitoring

If elevation is confirmed, 
initiate close observation of 
the participant
ALP (isolated)
> 2 × ULN (in the absence 
of known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence 
of known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, 
haptoglobin, 
unconjugated 
[indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(participant is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the participant
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the participant

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and y-GT 
until resolutionc (frequency 
at Investigator discretion)
Any AE potentially 
indicative of a liver toxicity*

Consider study drug 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality
Investigator discretion


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Criteria
Actions required
Follow-up monitoring

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP 
to > 2 × ULN b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia cResolution is defined as an outcome of one of the following: (1) return to 
baseline values, (2) stable values at three subsequent monitoring visits at least 2 weeks 
apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death.
Based on Investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Serum Event
Actions
Serum creatinine increase 25-
49% compared to baseline
Confirm 25% increase after 24-
48h
Follow up within 2-5 days
Acute Kidney Injury: Serum 
creatinine increase ≥ 50 % 
compared to baseline
Follow up within 24-48h if 
possible
Consider study treatment 
interruption
Consider participant
hospitalization and specialized 
treatment
Urine Event
New dipstick proteinuria ≥ 1+
Albumin- or Protein-creatinine 
ratio increase ≥ 2-fold
Albumin-creatinine ratio (ACR) 
≥ 30 mg/g or ≥ 3
mg/mmol;
Protein-creatinine ratio (PCR ) 
≥ 150 mg/g or > 15
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment 
interruption/discontinuation
New dipstick glycosuria ≥ 1+ 
not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria ≥ 1+ 
not due to trauma or 
menstruation
Urine sediment microscopy
Perform serum creatinine, ACR
Additional specialized assessments are available to assess renal function or renal pathology.
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed participant history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephroptoxin administration, or other diseases or 
causes, e.g. dehydration due to delirium, tumor lysis


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Table 16-4
Renal Event Follow up
Follow-up of Renal Events
Assess, Document & Record in eCRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the eCRF
Monitor participant regularly (frequency at the Investigator's discretion) until:

Event resolution: (sCR within 10% of baseline or PCT < 1 g/g Cr, or ACR <300mg/g Cr)
or

Event stabilization: sCR within +/- 10% variability over last 6 months or PCR stabilization at a 
new level with +/- 50% variability over last 6 months

Analysis of urine markers collected over the course of the DIN event
16.3
Appendix 3: Safety Monitoring Guidance
16.3.1
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 FLAIR and Diffusion-weighted imaging (DWI) sequences are 
recommended to aid in differential diagnosis. The local neuro-radiologist must evaluate the 
MRI. The Investigator will contact the Medical Advisor at Novartis and a clinical trial team 
(CTT) 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 MS lesions consistent with an MS relapse, assessment and treatment of 
the relapse 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 previous available MRI, which 
are not compatible with MS lesions, the study drug will be discontinued 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 sample if indicated. Analysis of the Cerebrospinal Fluid (CSF) sample including cellular, 
biochemical, Polymerase Chain Reaction, and microbiological analysis (e.g. herpes virus, JC 
virus) to confirm/exclude an infection should be performed. In the event of suspected CNS 


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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 CTT member, the study drug may be restarted.
16.3.2
Guidance on monitoring Participants with infections
All infections that develop during the study will be reported as AEs on the respective AE eCRF 
pages. Treatment and additional evaluations will be performed at discretion of the Investigator.
The Investigator should remind the participant of the risk of infections and instruct them to 
report any symptoms of infections promptly to the Investigator. The participants must also be 
reminded to always carry their participant Information Card (with site contact information and 
which identifies them as participants in a clinical study with investigational and control agents 
with potential immunosuppressive effects) and to show this to any local healthcare provider 
they may consult and ask that the Investigator be contacted.
In the case of suspected or confirmed serious (CTCAE, Grade 3-4) or atypical infection, study 
drug interruption should be considered. The Investigator should inform the Novartis Medical 
Advisor and/or a CTT member of any such cases.
When evaluating a participant with a suspected infection, the most sensitive tests available 
should be used (i.e. that directly detect the pathogen, as with polymerase chain reaction).
The Investigator should consider early treatment with specific antimicrobial therapy based on 
clinical diagnosis or suspicion thereof in consultation with infectious disease experts, as 
appropriate. The Investigator should inform the Novartis Medical Advisor and CTT of any such 
cases.
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
for treatment of MS attack/relapse and increase vigilance regarding infections during such 
therapy and in the weeks following administration.
In participants with known malignancies treated with ofatumumab, cases of fatal hepatitis B 
virus (HBV) reactivation and fatal infection due to hepatitis B in participants who have not been 
previously infected have occurred (refer to local Arzerra® prescribing information). The MS 
participants enrolled in the study who are at potential risk of HBV reactivation (e.g. Participants
with evidence of prior HBV infection (antibody to hepatitis B surface antigen (anti-HBc) 
positive and Hepatitis B surface antigen (HBsAg) negative) and whose HBV deoxyribonucleic 
acid (DNA) test is negative at Screening, should be closely monitored for signs of active HBV 
infection or reactivation during the study. In participants with suspicion of HBV infection 
(active/reactivation), laboratory testing for HBV should be done. For participants who show 
evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg 
negative but anti-HBc positive), the Investigator is advised to consult with physicians with 
expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral 
therapy.
In participants who develop reactivation of HBV while receiving study drug, immediately 
discontinue study drug and institute appropriate treatment and follow-up.


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16.3.3
Guidance on immunization
The safety of and ability to generate a primary or anamnestic (recall) response to immunization 
with live, live-attenuated or inactivated vaccines during ofatumumab treatment has not been 
investigated. The response to vaccination could be impaired when B-cells are depleted.
It is recommended that the Investigator review the participant's immunization history as part of 
the initial Screening procedure for a participant being considered for treatment with 
ofatumumab. 
Administration of live or live-attenuated vaccines must be avoided during and after 
treatment with ofatumumab and until B-cell counts are normalized.
There is presently no contraindication for the use of an inactivated, viral-vector-, or mRNA 
based Sars-CoV-2 vaccine in patients who are immunocompromised. However, different Sars-
CoV-2 vaccines may have various mechanisms of action and different associated potential risks. 
Please review local prescribing information of any specific Sars-CoV-2 vaccine and comply 
with local prescribing information requirements for specific contraindications and special 
warnings and precautions for use. Vaccination against Sars-CoV-2 should be considered on a 
case-by-case basis at the discretion of the treating physician taking into account the individual 
benefit-risk assessment and local vaccination recommendations
16.3.4
Guidance on monitoring of Participants with low immunoglobulin 
levels
During the study, the immunoglobulin levels (IgG and IgM) will be measured according to the 
schedule in Table 8-1 and Table 8-2. If IgG levels were to drop below 300mg/dL 
(Agarwal and Cunningham-Rundles 2007), study drug treatment should be interrupted and the 
Investigator should evaluate participant for any potential infections and monitor on a regular 
basis. Immunoglobulin substitution therapy as per local medical practice is allowed. In case of 
treatment interruption, re-initiation of the study drug can only be considered once the 
immunoglobulin levels are back within normal limits.

SAP_001.pdf: 












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2.4.2
Visit windows........................................................................................19
2.4.3
Prior, concomitant and post therapies ...................................................22
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint ...................................................................................23
2.5.2
Statistical hypothesis, model, and method of analysis ..........................23
2.5.3
Handling of missing values/censoring/discontinuations .......................24
2.5.4
Supplementary analyses ........................................................................24
2.6
Analysis of the key secondary objective................................................................24
2.7
Analysis of secondary objective ............................................................................24
2.7.1
Secondary endpoints..............................................................................24
2.7.2
Statistical hypothesis, model, and method of analysis ..........................25
2.8
Safety analyses.......................................................................................................25
2.8.1
Adverse events (AEs)............................................................................25
2.8.2
Laboratory data......................................................................................26
2.8.3
Other safety data....................................................................................27
2.9
Pharmacokinetic endpoints ....................................................................................29
2.10
PD and PK/PD analyses.........................................................................................29
2.11
Patient-reported outcomes......................................................................................29
2.11.1
Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).....29
30
30
2.12
Biomarkers.............................................................................................................30
2.12.1
B and T cell counts................................................................................30
30
31
31
31
32
32
2.14
Interim analysis......................................................................................................32
3
Sample size calculation......................................................................................................32
4
Change to protocol specified analyses...............................................................................33
5
Appendix............................................................................................................................33
5.1
Imputation rules .....................................................................................................33
5.1.1
Study drug .............................................................................................33
5.1.2
AE date imputation................................................................................33


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5.1.3
Concomitant medication date imputation..............................................34
5.1.4
Other imputations..................................................................................36
5.2
AEs coding/grading................................................................................................37
5.3
Laboratory parameters derivations.........................................................................37
5.3.1
Laboratory test groups and subgroups...................................................37
5.3.2
Newly occurring liver enzyme abnormalities........................................39
5.4
Other derivations....................................................................................................40
5.4.1
The Columbia-Suicide Severity Rating Scale (C-SSRS)......................40
5.4.2
TSQM-9 scoring ...................................................................................41
42
42
5.5
Statistical models ...................................................................................................43
Primary analysis.....................................................................................................43
Key secondary analysis..........................................................................................43
Mixed model with repeated measures (MMRM) with baseline value retained 
in the outcome – Sample SAS code ......................................................43
Rule of exclusion criteria of analysis sets..........................................................................43
6
Reference ...........................................................................................................................44


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List of abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
BMI
Body mass index
CDBL
Clinical database lock
CMD
Concomitant medication
CRF
Case Report Form
CSR
Clinical Study report
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTT
Clinical Trial Team
DMT
Disease Modifying Therapy
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Sheet
EOS
End of study
FACS
Fluorescence activated cell sorting
FAS
Full analysis set
FDA
Food and Drug Administration
FU
Follow-up
GdE
Gadolinium enhancing lesion
GPS
Global Programming and Statistical Environment
LLN
Lower limit of normal
LPLV
Last patient last visit 
mAb
Monoclonal Antibody 
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic Resonance Imaging
MS
Multiple Sclerosis
NBS
Novartis Business Services
NRI
Non-responder imputation
PD
Protocol deviation
PK
Pharmacokinetics


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PT
Preferred term
RAP
Report and Analysis Process
RMS
Relapsing Multiple Sclerosis
RRMS
Relapsing-remitting Multiple Sclerosis
SAE
Serious adverse event
SAF
Safety set
SAP
Statistical Analysis Plan
SOC
System Organ Class
SPMS
Secondary Progressive Multiple Sclerosis
TEAE
Treatment emergent adverse event
TSQM-9
Treatment Satisfaction Questionnaire for Medication
WHO
World Health Organization
WHODD
WHO Drug Dictionary


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the statistical methods planned 
in Section 12 of the clinical study protocol version 02 (release date 28 June 2022) for the clinical 
trial COMB157GUS07 and any additional analyses, specifications or deviations from this 
protocol planned before clinical database lock (CDBL).
The SAP will be used to draft the Clinical Study Report (CSR) Section 9.7: Statistical methods 
and IA plans.
1.1
Study design
This is a single-arm, multi-center, prospective study in patients with relapsing multiple sclerosis 
(RMS) who have been previously treated with anti-CD20 (aCD20) monoclonal antibody (mAb) 
therapy and have received at least 2 consecutive courses of intravenously administered 
ocrelizumab or rituximab every 6 months and the last dose is within 4 to 9 months before 
Baseline/Day 1. 
In this study, participants may enroll only if discontinuing aCD20 therapy for reasons other than 
lack of efficacy or due to certain treatment-emergent adverse events. Reasons for switching 
may include but are not limited to physician/participant preference, access to commercial drug 
(e.g., insurance coverage issues) or for other logistical reasons (such as geographical relocation, 
travel, etc.).
A total of approximately 100 eligible participants will be enrolled as part of this study. 
Participants will receive open label ofatumumab 20 mg subcutaneous once monthly for 12 
months following initial loading regimen of 20 mg subcutaneous doses on Days 1, 7 and 14. 
For participants completing the trial, the total duration of the trial will be a minimum of 14 
months. This accounts for the:
•
28 day screening period
•
12 month treatment period 
•
30 day telephone safety follow-up 
Participants are considered as having completed the study after completing the 12 month 
treatment period and attending the End of Study (EOS) visit. For participants who discontinue 
study treatment prematurely for any reason before the end of the 12 month treatment period, an 
EOS visit will be performed within 7 days of study discontinuation.
Additional post-treatment safety follow-up will be applicable for participants who:
•
Complete the Treatment period and do not continue on any MS disease modifying therapy 
(DMT) 
•
Do not continue into the ofatumumab commercial patient services hub within one month of 
the End of Study (EOS) visit, where the EOS visit is defined as the last patient’s last visit 
(LPLV), which is the last patient’s Month 12 visit, or the visit scheduled at the time of study 
discontinuation.
•
Prematurely discontinue study drug and do not continue on an MS DMT.


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The post-treatment safety FU period will consist of visits every 3 months post EOS. 
Assessments will include B cell monitoring until participants are able to start on commercial 
ofatumumab or until they switch to another therapy or until their B cells are repleted, where B 
cell repletion is defined as a B cell concentration greater than the individual participant’s 
baseline value prior to starting the IV anti-CD20 mAb or greater than the lower limit of normal. 
All post-treatment safety FU visits will be scheduled relative to the EOS visit. 
The following Figure 1-1 describes the study design.
Figure 1-1
Study design 
1.2
Study objectives and endpoints
Table 1-1
Study objectives and endpoints
Objectives(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
Explore maintenance of efficacy of 
ofatumumab in participants with RMS 
transitioning from aCD20 therapy
•
No change or a reduction from baseline 
in the number of gadolinium enhancing 
lesions  observed by MRI at 12 months 
of ofatumumab treatment (yes, no)
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
Characterize participants retention, 
immune biomarkers, treatment 
satisfaction, and safety and tolerability at 
6 and 12 months after transitioning to 
ofatumumab
•
Retention on ofatumumab treatment 
from baseline to Month 6 and to Month 
12 (Yes, No)
•
Change from baseline in lymphocytes, 
including total CD19+ B cell counts and 
CD20+CD3+ T cell counts, obtained by 
fluorescence activated cell sorting 
(FACS) at Months 6 and 12
•
C-SSRS at Months 6 and 12


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Objectives(s)
Endpoint(s)
•
Treatment Satisfaction Questionnaire for 
Medication (TSQM-9) scores (including 
domains) at baseline vs Month 6 and vs 
Month 12
•
Treatment-emergent adverse events
2
Statistical methods
2.1
Data analysis general information
The statistical analysis outlined in this SAP will be performed by Novartis Business Services 
(NBS) CONEXTS, using SAS® version 9.4 or higher software, and stored in the Novartis 
Global Programming and Statistical Environment (GPS). 
It is planned that the data from all centers that participate in this protocol will be used for 
analysis.  
For continuous variables, summary statistics will include number of participants (n), mean, 
standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum.
For categorical variables, frequency counts and percentages will be reported.
Unless otherwise specified, summary statistics tables will include change from baseline. 
The study will be divided into two phases (the core and post-treatment safety FU phase) for the 
purpose of preparing the CSR. 


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•
Core phase: The core phase will cover the on-treatment period up Month 12 visit date, or 
EOS date plus the 30 day Safety Telephone FU for participants who discontinue 
prematurely. The primary objective will be analyzed for the core phase and will be 
reported in the analysis CSR. All data up to this date will be reported in the analysis CSR.
•
Post-treatment phase: The post-treatment phase will cover the post-treatment safety 
follow-up period which extends from the EOS (+ every 3 months) until the date of B cell 
repletion for study completers until the participant initiates a commercial MS disease 
modifying therapy or until the end of the safety follow-up for premature withdrawals. This 
overlaps with the 30 day Safety Telephone FU. All safety data from the EOS to 30 day 
Safety Telephone FU will be reported as part of the core phase. Post-treatment phase will 
be reported in the final CSR. Data collected during the post-treatment safety FU will be 
listed. 
2.1.1
General definitions 
2.1.1.1
Investigational treatment/investigational drug
The investigational treatment is open label ofatumumab 20 mg (20 mg/0.4 ml) provided in an 
auto injector for subcutaneous administration. The investigational drug will be supplied by 
Novartis. Throughout the remainder of this document the investigational treatment will be 
referred to as study treatment/study drug. 
2.1.1.2
Date of first/last administration of study treatment
The date of first administration of study treatment is defined as the first date when a non-
zero dose of study treatment is administered and recorded on the “Study Treatment - Injection” 
electronic Case Report Form (eCRF).
The date of last administration of study treatment is defined as the last date when a non-
zero dose of the study treatment is recorded on the “Study Treatment - Injection” eCRF. 
2.1.1.3
Study day 
The first day of administration of study treatment (first dose) is defined as Study Day 1 or Day 
1. All other study days will be labeled relative to Day 1.  
For event dates on or after Day 1, study day for a particular event date is calculated as:
(Date of event − date of first dose) + 1
I.e., Day 2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively.
For dates before Day 1, study day for an event date is calculated as:
(Date of event − date of first dose)
Duration of an event will be calculated as (event end date − event start date + 1).
The descriptor “Day 0” will not be used.


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2.1.1.4
1 month
For reporting of event durations and determining target days of scheduled visits, 1 month will 
be considered as 365.25∕12=30.4375 days.
Unless specified otherwise, study days will be reported to the nearest whole number. 
2.1.1.5
Screening, baseline and post-baseline definitions
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to the date of the first dose of study treatment. Per protocol, participant informed consent 
must be obtained prior to performing any study related activity. The date of signing of informed 
consent is the start date of the screening period. Any assessment obtained during the screening 
period will be labelled screening assessment. 
Baseline is the last assessment (including unscheduled visits) obtained before the first 
administration of the study treatment. No visit windows will be needed for the identification of 
baseline assessment. All assessments obtained after the first administration of study treatment 
are considered as post-baseline unless otherwise specified.
For blood pressure vital sign values, the baseline is the average of the non-missing values of 
the 3 measurements taken on the last visit prior to the first administration of study drug. 
2.1.1.6
On-treatment period (efficacy analyses)
The on-treatment period for efficacy analyses is defined as:
(Last study treatment administration date − first study treatment administration date) + 
31.4375
The on-treatment period definition applies to efficacy analyses only. This definition considers 
that participants are scheduled to administer the study drug once monthly. 
2.1.1.7
Post-treatment safety follow-up period 
The post-treatment safety follow-up period is defined as:
(Date of B cell repletion – last actual study treatment administration date) + 1, for study 
completers
Or
(Date of initiation of a commercial MS disease modifying therapy – last actual study 
treatment administration date) + 1
2.1.1.8
Efficacy analysis cut-off
The efficacy analysis cut-off date is 30.4375 days after the date of last study treatment 
administration.


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2.1.1.9
Safety analysis cut-off
The safety analysis cut-off is the same as the efficacy analysis cut-off.  The safety analysis cut-
off is 30 days after the treatment end date but for programming purposes 30.4375 days will be 
used. 
2.1.1.10 Change from baseline
Change from baseline will be calculated as:
 (Post-baseline value − baseline value)
Change from baseline will only be calculated and summarized for participants with both 
baseline and post-baseline values.
2.1.1.11 Discontinuation from study treatment
Discontinuation of study drug for a participant occurs when study drug is permanently stopped 
for any reason (prior to the planned completion of study drug administration, if any), and can 
be initiated by either the participant or the Investigator.
2.1.1.12 Discontinuation from study
Discontinuation from study for a participant occurs when they permanently stop receiving the 
study treatment, and further protocol-required assessments or follow-up, for any reason.
2.2
Analysis sets
Full analysis set
The Full Analysis Set (FAS) comprises all participants who have received at least one dose of 
the investigational drug.
Safety set
The Safety Set (SAF) is identical to the FAS in this study. 
2.2.1
Subgroup of interest
There is no subgroup analysis planned for this study.  
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless stated otherwise, all patient disposition, demographics, medical history and baseline 
characteristics data will be listed and summarized descriptively for the FAS. 
2.3.1
Patient disposition
Participant disposition will be summarized for the following study periods: screening, baseline, 
study and 30 day Telephone follow-up.  


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Patient disposition for each period will be summarized for all participants who entered that 
period. Participants who have entered any study period but have discontinued from the study 
will be listed as appropriate along with the primary reason for discontinuation. 
The number and percentage of screening failures and the reason for screening failure will be 
presented for all screened participants. 
For each protocol deviation, the number and percentage of participants for whom the deviation 
applies will be tabulated.
2.3.2
Demographics
The following demographic variables will be listed and summarized descriptively:
Continuous variables 
•
Age (years)
•
Height (cm)
•
Weight (kg)
•
Body mass index (BMI) (kg/m2) = (weight in kg) ∕ (height in meters)2
Weight and height will be reported as captured in the “Vital signs” eCRF page at baseline. If 
there is no weight recorded prior to taking of study treatment, BMI will be missing.
Categorical variables 
•
Sex (Male, female, unknown, undifferentiated)
•
Ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported, unknown)
•
Race (White, Black or African American, Asian (Chinese, Indian, Japanese, Korean, 
Vietnamese), Native Hawaiian or Pacific Islander, American Indian or Alaska Native, 
Multiple)
2.3.3
Baseline characteristics
Baseline disease characteristics will be summarized for the following variables:
•
MS baseline characteristics:
•
 
•
Baseline lymphocyte value, including reporting of lymphocyte abnormalities (CTCAE 
grade).
•
 Immunoglobulin G (IgG) and 
Immunoglobulin M (IgM) value.
•
MRI parameters including:
•
Number of GdE enhancing T1 lesions
•
Number of GdE enhancing T1 upper cervical cord lesions
 
 


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•
MS disease history:
•
Duration of Multiple Sclerosis (MS) since diagnosis (years) defined as: (first study 
treatment administration date − date of MS diagnosis + 1) ∕ 365.25
•
Duration of MS since first symptom (years) defined as: (first study treatment 
administration date − first MS symptom date + 1) ∕ 365.25
•
Number of relapses in the last 12 months prior to screening
•
Number of relapses in the 12 to 24 months prior to screening
•
Type of MS at study entry (Relapsing-remitting MS (RRMS), Secondary progressive 
MS (SPMS))
•
Time since onset of most recent relapse (months) prior to screening defined as: (first 
study treatment administration date − most recent relapse onset date + 1) ∕ (365.25/12)
•
Participants’ employment status (part-time, full-time, not employed)
2.3.4
Medical history
Relevant medical histories and current medical conditions at baseline (i.e., prior to the first dose 
of the study treatment) will be summarized by system organ class (SOC) and preferred term 
(PT) for the SAF.
Medical histories will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The latest version of which (at the time of the data cut-off) will be 
used for the reporting activity. 
2.4
Treatments (study treatment, rescue medication, prior and 
concomitant therapies, compliance)
Unless otherwise stated, the SAF will be used for all treatment summaries.
2.4.1
Study treatment / compliance
Exposure to study treatment 
Duration of exposure to the study treatment will be calculated as 
(date of last administration of study drug – date of first administration of study drug + 1 + 
30.4375 – Σ [(j + 1)th administration date – jth administration date – 33.4375]).
Where j and j + 1 refer to consecutive study drug administration dates more than 33.4375 days 
apart (as participants are scheduled to receive the study drug once monthly ± 3 days).
The duration of exposure will include any periods of temporary dose interruption. 
Duration of exposure to the study drug will be summarized by duration category (i.e., ≥1 week, 
≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, ≥12, weeks, ≥24 weeks, ≥36 weeks, and ≥48 
weeks, >=52 weeks).
A listing of the drug doses administered will be provided.


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Treatment compliance
Compliance to the study drug administration schedule will be calculated as:
(Duration of exposure to study drug in (days) ∕ duration of on-treatment period in (days)) × 100%
This rule means that compliance will be measured during the time interval the participant took 
study drug: premature discontinuation from study drug will not be considered non-compliance. 
Compliance to study drug administration will be summarized descriptively for the SAF. In 
addition, compliance will be summarized with cumulative number and percentage of 
participants in each compliance category (i.e., ≥ 20%, ≥ 30%, ≥ 40%, ≥50%, ≥60%, ≥70%, 
≥80%, ≥90%, ≥95%, ≥98%, =100%).
2.4.2
Visit windows
Visit windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows are created to cover 
the complete range of days within the study. 
The visit windows for the on-treatment period are shown in Table 2-1. In this table, the days 
are counted since the first dose of study treatment (study days) for safety and efficacy 
assessments. These windows apply to measurements taken at every visit. For assessments 
collected less often different visit windows will be applied as detailed below. Similarly, visit 
windows for the post-treatment safety follow-up period are shown in Table 2-2. Unless 
specified otherwise these windows will be applied for all assessments.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Visit 4 visit of a participant is delayed and occurs on Day 62 
instead of on Day 30, say, it will be re-aligned to visit window Visit 5. In the case of major 
deviations from the visit schedule, or due to unscheduled visits, several assessments of a 
participant may fall in a particular visit window (either scheduled or unscheduled). Statistical 
approaches to handle multiple assessments in a given visit window are specified below. 
Tables displaying summary statistics “by visit” will also use the term visit-window as column 
header; this is to remind the reviewer that multiple assessments of a patient might be 
summarized.
As a rule, the following steps are followed to determine the cut-offs for post-baseline time 
windows:
•
Transform all scheduled assessment time points into study days, assuming 1 month is equal 
to 30.4375 days. Middle points of scheduled assessments are determined.
•
The time window associated with the previous assessment ends prior to the middle point; 
the time window associated with the latter assessment begins after the middle point. In case 
the middle point is an exact study day, it will belong to the previous assessment.
•
The time window of first post-baseline assessment starts with Study Day 2, unless otherwise 
indicated.


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•
For parameters, which are not collected at every visit, visit windows will be combined. For 
example, if a parameter is measured at Month 2 and Month 12 only, Month 2 visit window 
will extend from Month 2 to Month 12 (combining Month 2 and Month 12 visit windows). 
Table 2-1
Visit windows for the on-treatment period 
Analysis visit
Time point
Scheduled visit day 
(study days)
Visit window (study 
days)
Baseline
Day 1
1
-28 to 1*
Visit 2
Day 7
7
2 to 10
Visit 3
Day 14
14
11 to 22
Visit 4
Month 1
31
23 to 46
Visit 5
Month 2
62
47 to 77
Visit 6
Month 3
92
78 to 107
Visit 7
Month 4
123
108 to 138
Visit 8
Month 5
153
139 to 168
Visit 9
Month 6
184
169 to 199
Visit 10
Month 7
214
200 to 229
Visit 11
Month 8
245
230 to 260
Visit 12
Month 9
275
261 to 290
Visit 13
Month 10
305
291 to 320
Visit 14
Month 11
336
321 to 351
EOS (Visit 15)
Month 12
366
352 to 381
30-day tel. safety FU
Month 13
396
382 to 427 
*Baseline measurement before the first study drug administration for safety and efficacy assessments. 
Table 2-2
Visit windows for the post-treatment safety follow-up period
Analysis visit
Time point
Scheduled visit day 
(study days)
Visit window (study 
days)
Safety FU visit 1
EOS + 3 months
458
428 to 503
Safety FU visit 2
EOS + 6 months
549
504 to 594
Safety FU visit 3
EOS + 9 months
640
595 to 685
Safety FU visit n (n>3)
EOS + n*3 months
640+91*(n-3)
595+91*(n-3) to 
685+91*(n-3)
2.4.2.1
Vital signs, laboratory, biomarker and questionnaire
Chemistry , Hematology, Sample for CD+19 B-cells & CD20+CD3+ T-cells,  
LBCAT=Immunophenotyping, Total IgG and IgM levels, Urinalysis, serology (only 
measured at baseline visit), vital signs, 
, and questionnaires (
) are to be 
carried out at Screening, Baseline Day 1, Month 1, Month 6, Month 12 (EOS) and any 
unplanned visits. These are measured at EOS + 3 Months, EOS + 6 Months, and if required, at 
every 3 months after the 6 Month follow up for the patients requiring prolonged B-cell plasma 
level monitoring. Weight is not measured at unplanned visits, and height is only measured at 
the baseline visit. C-SSRS, TSQM-9,
 are not measured at post-treatment Safety 
FU, 
.


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Based on this criteria, for the above information, the visit windows are shown in Table 2-3. 
The window is based on the visit day for the scheduled visit +/- the additional days based on 
the half mark between the next/previous scheduled visit.
Table 2-3
Visit windows for vital signs, laboratory, biomarker and questionnaire
Analysis Visit
Time Point
Scheduled visit day
(study days)
Visit window (study
days)
Baseline
Day 1
1
-28 to 1
Visit 4
Month 1
31
2 to 107
Visit 9
Month 6
184
108 to 275
(EOS) Visit 15
Month 12
366
276 to 427
Safety FU visit 1
EOS + 3 months
458
428 to 503
Safety FU visit 2
EOS + 6 months
549
504 to 594
Safety FU visit n (n>2)
EOS + n*3 months
549+91*(n-2)
504+91*(n-2) to 
594+91*(n-2)
2.4.2.2
Morphology
Morphology i.e. MRI assessments are to be carried out at Screening, Month 6, and Month 12 
(EOS).  However, the final assessment of subjects who discontinue early is recorded as Month 
12 (EOS). Based on this criteria, the visit windows for morphology are shown in Table 2-4. 
Table 2-4
Visit windows for morphology  
Analysis Visit
Time Point
Scheduled visit day
(study days)
Visit window (study
days)
Baseline
-28 days
-28
-28 to 1
Visit 9
Month 5 - 7
184
139 to 229
(EOS) Visit 15
Month 11 – 13
366
321 to 427
2.4.2.3
Treatment exposure and Electrocardiogram (ECG)
Treatment exposure and ECG data will be presented according to the visit schedule, no visit 
windows will be applied. 
Multiple assessments
It is possible that multiple assessments of a patient fall into the same visit-window (e.g., due 
to unscheduled visits). All results (scheduled and unscheduled) will be displayed in listings, 
but only one value (observed or derived) will be selected for summary statistics by visit-
window.
For quantitative variables, the assessment closest to the target day will be selected. If more 
than one assessment is at the same distance to the target day, the later one will be selected. 


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For tables displaying the worst case scenario, such as shift tables or notable abnormalities, all 
assessments within a visit window will be used to identify the worst (e.g. the maximum or the 
minimum depending on parameter). 
•
Baseline: The last non-missing measurement made prior to or on the date of administration 
of the first dose of study treatment (the reference start date / Day 1). Only date part is 
considered if just one assessment on Day 1. If there are multiple assessments on Day 1, the 
following rules will apply:
a. If assessment time exists,
▪
select the last available measurement prior to reference start date/time 
considering time;
b. If assessment time does not exist, select the available measurement from the lowest 
CRF visit number.
•
Post-baseline: The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 day after), the 
later one will be used. Cases where the same parameter is recorded more than once on the 
same date will be handled as follows:
a.
If time of completion exists, the latest measurement will be used;
b. If time does not exist, the measurement from the lowest CRF visit number will be 
used.
In case categorical variables are based on continuous variables, the visit will be assigned to 
the continuous variable, and this visit will be used for the derived categorical variable. 
2.4.3
Prior, concomitant and post therapies
Prior and concomitant medications will be summarized in separate tables for the SAF. 
Medications will be coded using the WHO Drug Dictionary (WHODD). The latest version of 
which (at the time of the data cut-off) will be used for the reporting activity.
Medications will be classified as prior, or concomitant as follows:
•
Prior medications are defined as drugs taken (including MS medication) and stopped prior 
to first study treatment administration.
•
Concomitant medications are defined as drugs taken at least once between first and last 
study treatment administration (including those which were started prior to first study 
treatment administration and continued into the treatment period).
Medications will be categorized into one (and only one) of above classes based on recorded or 
imputed start and end dates.
Medications will be presented in alphabetical order, by medication category, by Anatomical 
Therapeutic Classification (ATC) codes and grouped by anatomical main group. Tables will 
show the overall number and percentage of participants receiving at least one treatment of a 
particular ATC code and at least one treatment in a particular anatomical main group. 


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Non-drug therapies/procedures
Records on the concomitant non-drug therapies/procedures eCRF page will be coded using the 
MedDRA dictionary. All procedures will be classified as prior or concomitant in the same way 
as done for medications above. Non-drug therapies/procedures in each of these 2 categories will 
be summarized separately by primary SOC and MedDRA PT. 
Prior MS medication 
Previous aCD20 therapy (ocrelizumab or rituximab) and reason for discontinuation/switching 
will be summarized.
Injection-related premedication
Injection related premedication will be identified by subcategory “Injection related 
premedication” in concomitant medication dataset. Injection related premedication will be 
summarized separately. 
2.5
Analysis of the primary objective
The primary objective of this study is to explore the maintenance of efficacy of ofatumumab in 
participants with RMS transitioning from aCD20 mAb therapy, as assessed by no change or 
reduction in the number of gadolinium enhancing (GdE) lesions observed by MRI.  
The primary efficacy analysis will be conducted when all participants complete the 12 month 
on-treatment period or discontinue from the study.
2.5.1
Primary endpoint
The primary efficacy variable is no change or a reduction from baseline in the number of GdE 
T1 lesions observed by MRI at 12 months of treatment (Yes, No).
2.5.2
Statistical hypothesis, model, and method of analysis 
The primary analysis to address the primary objective will be based on the following estimand:
•
Treatment of interest:  Following a loading dose regimen consisting of once daily doses on 
days 1, 7 and 14, ofatumumab is given once monthly starting at Month 1. All doses of 
ofatumumab will be given subcutaneously via an auto injector at a dose of 20mg.  
•
Population: Relapsing MS participants currently treated with an infused aCD20 mAb, 
specifically ocrelizumab or rituximab, that have received at least 2 courses of therapy that 
are switching due to reasons other than safety or efficacy. Further defined through the 
appropriate inclusion/exclusion criteria to reflect the target population.
•
Variable: Reduction or no change from baseline in the number of GdE lesions as observed 
by MRI (Yes, No).
•
Other intercurrent events:  Death or treatment/study discontinuation.
•
Summary measure: Proportion of participants with no change or a reduction in the number 
of GdE T1 lesions at Month 12 and corresponding 95% confidence interval. 


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The 95% CI for the primary endpoint will be calculated using a normal approximation method. 
In addition, the change from baseline in the number of GdE T1 lesions will also be summarized 
descriptively by time point and graphically using a longitudinal plot.  
Both non-responder imputation (NRI) for missing data and observed data approaches will be 
applied. 
NRI is a conservative imputation method for dichotomous variables. NRI assumes that a 
participant is a treatment failure, i.e. non-responder, if they do not have a valid month 12 MRI 
assessment, or if they discontinue the study prematurely and do not have a valid month 12 MRI 
assessment. Hence, for missing data the primary variable outcome will be imputed to “No”. 
MRI assessments occurring after the efficacy cut-off will not be included in the analysis.
The primary analysis of the primary efficacy variable will be based on the FAS. 
2.5.3
Handling of missing values/censoring/discontinuations
For participants with missing number of GdE T1 lesions at Month 6 and Month 12, NRI method 
will be used. 
2.5.4
Sensitivity analyses
The primary analysis will be repeated to analyze no change or a reduction from baseline in the 
number of GdE T1 lesions observed by MRI at 12 months of treatment (Yes, No), based on 
observed data. MRI assessments occurring after the efficacy cut-off will not be included in the 
analysis.
2.5.4.1
Supplementary analysis:
The primary analysis will be repeated to analyze no change or a reduction from baseline in the 
number of GdE T1 lesions observed by MRI at 12 months of treatment (Yes, No), including 
any assessments after the efficacy analysis cut-off. Both NRI for missing data and observed 
data approaches will be applied. 
2.6
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.7
Analysis of secondary objective
Refer to Table 1-1 of Section 1.2 for the list of secondary objectives. 
The secondary efficacy analysis will be conducted after all participants complete the 12 month 
on-treatment period or discontinue from the study.
2.7.1
Secondary endpoints
The secondary endpoints are as follows: 
1. Retention on study treatment from baseline to Month 6, and to Month 12 (Yes, No)


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2. Change from baseline in lymphocytes, including total CD19+ B cell counts and 
CD20+CD3+ T cell counts, obtained by fluorescence activated cell sorting (FACS) at 
Months 6 and 12 
3. The Columbia Suicide Severity Rating Scale (C-SSRS) at Months 6 and 12 
4. Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores (including 
domains) at baseline vs Month 6 and vs Month 12 
5. Treatment-emergent adverse events (TEAEs)
2.7.2
Statistical hypothesis, model, and method of analysis
The following statistical analyses are planned for the secondary endpoints:
1. Retention on study treatment from baseline to Month 6, and to Month 12 (Yes, No) 
will be summarized using frequency counts and percentages for the FAS. Retention 
will be based on the number of study drug discontinuations. 
2. Biomarker analysis – See Section 2.12.1
3. C-SSRS analysis – See Section 2.8.3.1
4. TSQM-9 analysis – See Section 2.11.1
5. TEAEs analysis – See Section 2.8.1 
2.8
Safety analyses
Unless stated otherwise, all safety analyses will be summarized for the SAF. Only data captured 
prior to the safety cut-off will be used for safety analyses. 
2.8.1
Adverse events (AEs)
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation of a participant after providing written informed consent for 
participation in the study. That means that a participant can report AEs before having started 
study medication. For reporting purposes, the main focus will be on treatment emergent adverse 
event (TEAE), defined as any adverse event which started on or after the day of first dose of 
study drug, or before 30 days after treatment end date, if severity at baseline if missing or if 
post baseline severity is greater than baseline severity.
The number (and percentage) of participants with TEAEs will be summarized in the following 
ways:
•
by primary SOC and PT
•
by primary SOC, PT and maximum severity
Separate summaries will be provided for: 
•
study drug related TEAEs
•
serious adverse events (SAEs)
•
TEAEs leading to permanent study drug discontinuation
•
TEAEs leading to study drug interruption


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The MedDRA version used for reporting the study will be described in a footnote. Missing 
CTCAE grades will not be imputed. If a participant reported more than one AE with the same 
PT, the AE with the greatest severity will be presented. A participant with multiple AEs within 
a primary SOC is only counted once towards the total of the primary SOC.
All AEs will be listed.
2.8.1.1
Adverse events of special interest / grouping of AEs
Selected AEs will be considered under the heading of adverse events of special interest (AESI) 
and described in the electronic Case Retrieval Sheet (eCRS). The eCRS that is current at the 
time of the database lock will be used and AESIs will be identified where the flag Core safety 
topic risk (SP) = ‘Y’. The search criteria for the AESI will be included in the TFL shell 
document. 
AESI will be summarized by category and preferred term for the SAF, and will also be listed. 
2.8.1.2
Other adverse events analyses
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs 
which are not SAEs with an incidence greater than 5% and on treatment emergent SAEs and 
SAEs suspected to be related to study treatment will be provided by primary SOC and PT.
If for the same participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same primary SOC and PT:
•
A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE.
•
More than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
2.8.1.3
Deaths
All deaths including on-treatment and post-treatment deaths will be summarized by MedDRA 
SOC and PT. All deaths will be listed. Deaths occurring after the on-treatment period will be 
highlighted in the listing. 
2.8.2
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests: 
hematology, chemistry and urinalysis. Each group will be further subdivided into subgroups 
and presented as per Table 5-1. Summary statistics for the change from baseline to each time 
point will be tabulated for each laboratory parameter. Data summaries will be provided in SI 
units.
In addition, shift tables based on normal ranges will be provided for all parameters in Table 5-
1 to compare participants’ baseline laboratory evaluation relative to the visit’s observed value 
and to the worst post-baseline  value. 


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Number of participants with newly occurring liver enzyme abnormalities at any time post 
baseline will be summarized. Newly occurring liver enzyme abnormalities are defined in 
Section 5.3.2. 
All laboratory data will be listed by participant and visit/time point and if normal ranges are 
available, abnormalities will be flagged. 
2.8.2.1
Other special laboratory results
Number and percentage of participants meeting the notable low level criteria in IgG or IgM at 
least once will be provided. A notably low IgG level is defined as a level that is 20% below the 
lower limit of normal (LLN) and a notably low IgM level is defined as a level 10% below the 
LLN.  A summary of IgG and IgM less than LLN will be provided. Historical change of IgG 
and IgM will be summarized. Historical IgG and IgM will not be considered for baseline 
calculations.
2.8.3
Other safety data
2.8.3.1
Suicidality evaluations
The Columbia-Suicide Severity Rating Scale (C-SSRS data) will be mapped into 11 levels (see 
Section 5.4.1 of the Appendix for details) using the Columbia Classification Algorithm for 
Suicide assessment (C-CASA) as outlined in Food and Drug Administration (FDA) guidance 
on suicidality (FDA, 2012). 
Definition of ‘all prior history’ and ‘recent history’
Suicidality evaluations will be collected once pre-treatment, either at screening or at baseline 
visits. These assessments will be defined by two components: all prior history and recent history. 
All prior history will be defined as the assessment result obtained from the lifetime assessment, 
and recent history will be defined as the assessment result obtained from the recent past period 
assessment.
Data summaries 
The number and percentage of participants with suicidal ideation, suicidal behavior and self-
injurious behavior without suicidal intent will be presented. The following 14 events will be 
included in the summary table:
•
Each of the 11 categories listed in Table 5-2.
•
Any suicidal ideation or behavior (a ‘yes’ answer to at least one of the 10 suicidal ideation 
and behavior questions).
•
Any suicidal ideation (answered ‘yes’ to at least one of the 5 suicidal ideation questions).
•
Any suicidal behavior (answered ‘yes’ to at least one of the 5 suicidal behavior questions).
In addition, the number and percentage of participants with the following post-baseline events 
will be presented (Nilsson et al. 2013):


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•
Worsening suicidal ideation compared to recent history: An increase in the maximum 
suicidal ideation category at any time post-baseline from the maximum suicidal ideation 
category during pre-treatment recent history.
•
Worsening serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation category to 4 or 5 at any time post-baseline from not having 
serious suicidal ideation (categories of 0-3) during pre-treatment recent history. 
•
Emergence of serious suicidal ideation compared to baseline: A maximum suicidal 
ideation category of 4 or 5 at any time post-baseline from no suicidal ideation (category 0) 
during pre-treatment recent history. 
•
Improvement in suicidal ideation at last on-treatment measurement compared to recent 
history: A decrease in suicidal ideation score at last on-treatment measurement from pre-
treatment recent history.
•
Emergence of suicidal behavior compared to all prior history: The occurrence of suicidal 
behavior (Categories 6-10) at any time post-baseline from not having suicidal behavior 
(Categories 6-10) prior to treatment (includes “lifetime” and any other assessments prior 
to treatment taken prior to treatment).
Note: in these definitions, a category of 0 is assigned to a subject without suicidal ideation 
(i.e., a ‘no’ answer to all suicidal ideation categories).
For those analyses, each participant can only be counted once for each event. However, a 
participant can be counted in several different events.
Suicidal ideation and behavior data will be listed. Detailed answers to C-SSRS items will be 
listed separately for participants with any suicidal ideation at any time post-baseline (i.e., a 
‘yes’ answer to at least one of the five suicidal ideation questions at any time post-baseline) 
and for a participant with any suicidal behavior at any time post-baseline (i.e., a ‘yes’ answer 
to at least one of the five suicidal behavior questions at any time post baseline).
2.8.3.2
ECG and cardiac imaging data
ECG data will be collected at screening visit, Day 1 and EOS visit. Clinically significant 
findings from ECG evaluations will be reported as AEs and included in the analysis of AEs. 
ECG parameters include: mean heart rate, pulse rate (PR) interval aggregate, QRS duration, 
QT duration and QT corrected using Fridericia’s correction formula (QTcF). 
Descriptive statistics including change from baseline of each ECG parameter will be provided 
by time point. In addition, the number and percentage of participants meeting the criteria 
defined in Table 2-9 will be summarized by time point. 
Table 2-9
Criteria for relevant ECG absolute or change from baseline values
Absolute values criteria
Changes from baseline criteria
Heart rate: HR <40 or HR >120 beats/min
NA
Pulse rate: PR <110 or PR >200 msec
NA
QRS duration: <70 msec or >120 msec
QRS duration: increase >25% compared to 
baseline
QTcF <350 or >450 msec (males) 
QTcF <360 or >460 msec (females)
QTcF >500 msec and QTcF increase >60 msec


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There will be no cardiac imaging data collected for this study.
2.8.3.3
Vital signs
All vital signs data will be listed by participant and time point (including pre and post injection 
data points as applicable), and if reference ranges are available, abnormalities will be flagged. 
For vital signs data collected at Month 6 and Month 12, summary statistics for change from 
baseline will be provided. 
Pre-injection vital sign assessments will be defined as the assessment result obtained 30-60 
(+/- 10 min) minutes pre-injection of the study drug, and post-injection vital sign assessments 
will be defined as the assessment result obtained 60 minutes post-injection of the study drug.
Height will be collected at screening visit only and will be summarized in the baseline 
characteristics summary only.
Notable vital sign abnormalities will be summarized. Notable vital sign abnormalities are 
defined in Table 2-10.
Table 2-10
Criteria for notable vital sign abnormalities
Vital sign 
Criteria for notable abnormality
Pulse (bpm)
<50 or >120 bpm
Systolic blood pressure (BP) (mmHg)
<90 or >180 mmHg
Diastolic BP (mmHg)
<50 or >205 mmHg
Temperature (°C)
<35 or >40 °C
Body weight (kg)
<30 or >180 kg
2.9
Pharmacokinetic endpoints  
There are no pharmacokinetic endpoints planned for this study. 
2.10
PD and PK/PD analyses
There are no PD and PK/PD analyses planned for this study.
2.11
Patient-reported outcomes 
2.11.1
Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)
The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is a 9-item general 
instrument that measures the major dimensions of satisfaction with a medication (Bharmal et 
al. 2009). Scores will be calculated for the effectiveness (Items 1-3), convenience (Items 4-6) 
and global satisfaction scale (Items 7-9). See Appendix Section 5.4.2 for the scoring algorithm. 
Scores on the TSQM scale range from 0 (indicating poor satisfaction) to 100 (indicating perfect 
satisfaction). 
Change from baseline in TSQM-9 scores for all 3 domains (effectiveness, convenience and 
global satisfaction) to Month 6 and 12 will be summarized for the FAS.




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2.14
Interim analysis
For the purpose of earlier dissemination of results, an interim analysis will be performed after 
all enrolled participants have either met the criteria of at least 6 months treatment or 
discontinued treatment prematurely. For this analysis, only primary variables, demographics, 
baseline characteristics, adverse events and serious adverse events will be summarized. The 
cut-off for the interim analysis will be the Month 6 visit date. Data up to the cut-off date will 
be presented. 
Since there will be no hypothesis testing involved, statistical adjustment for the interim analysis 
will not be made at the stage of final analyses of efficacy and safety.
3
Sample size calculation
Sample size calculations were based on the proportion of participants with no change or a 
reduction from baseline in the number of GdE MRI lesions 12 months after initiating 
ofatumumab therapy. Three precision estimates were considered for this study:
The sample size of 100 participants is selected based on budget and early availability of interim 
analysis results. This sample size of 100 participants will provide us with an 8.5% precision 
(half-width of 95% confidence interval), a 7.8% precision, or a 7.0% precision corresponding 
to estimated proportions of 75%, 80%, and 85% of participants achieving the primary endpoint.


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4
Change to protocol specified analyses 
Please see Table 4-1 Change to protocol specified analyses below for a list of changes to 
protocol specified analyses are tabulated below.
Table 4-1
Change to protocol specified analyses  
Section(s) of the protocol
Change
No changes
Not Applicable 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
There will be no imputation rules for study drug detailed for this study. 
5.1.2
AE date imputation
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start 
Date
Not used
MON
YYYY
Treatment 
Start 
Date 
(TRTSTD)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSIN
MON<TRTM
MON=TRTM
MON>TRTM
YYYY
MISSIN
NC
Uncertain
NC
NC
NC
YYYY < TRTY
(D)
Before 
Treatment Start
(C)
(C)
(C)
YYYY = TRTY
(B)
Uncertain
(C)
Before 
Treatment
(A)
Uncertain
(A)
After Treatment
YYYY > TRTY
(E)
After Treatment 
Start
(A)
After Treatment
(A)
After Treatment
(A)
After Treatment
The following table is the legend to the logic matrix.


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If AE end date is complete and AE end date < Treatment start date or AE end date is partial and 
AE imputed end date < Treatment start date, then AE start reference = min (informed consent 
date, earliest visit date from SV) Else if AE end date is partial, AE end date > = Treatment start 
date or AE is ongoing, then AE start reference = treatment start date.
Relationship
Before AE start reference
Partial date indicates AE start date prior to 
AE start
After AE start reference
Partial date indicates AE start date after AE 
start
Uncertain
Partial 
date 
insufficient 
to determine 
relationship of AE start date to AE start
Imputation Calculation
NC/Blank
No convention
(A)
MAX(01MONYYYY, AE start reference+1 
day)
(B)
AE start reference+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
Complete date
No date imputation
Adverse Event End Date Imputation
Imputed date = date part of original date, if complete date
Imputed date = min (completion/discontinuation visit date, DEC 31, date of death), if
month is missing
Imputed date = min (completion/discontinuation visit date, last day of the month, date
of death), if day is missing
Imputed Date Flag
If year of the imputed date is not equal to YYYY then date flag = Y
else if month of the imputed date is not equal to MON then date flag = M
else if day of the imputed date is not equal to day of original date then date flag = D
else date flag = null.
5.1.3
Concomitant medication date imputation
This algorithm is used when event is the partial start date of the concomitant medication. The 
following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed. Please note that missing start and end dates were not imputed.
Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start/end Date 
(TRTSDT)
Not used
TRTM
TRTY


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The following the logic behind the imputation of CM end date.
1. If CM end day is missing and CM month and year are non-missing then CM end day 
was imputed as the minimum of treatment end date and the last day of the month
2. If CM end day and month are missing and CM end year is non-missing then CM end 
day was imputed as the minimum of treatment end date and the end of the year 
(31DECYYYY).
3. Missing CM end dates was not imputed.
4. If the imputed CM end date is less than CM start date then impute CM end date as 
CM start date.
5. Additional condition for Prior MS modifying therapies (CMSCAT = 'OTHER 
MULTIPLE SCLEROSIS DISEASE MODIFYING THERAPY'): If imputed date 
after treatment start date TRTSDT, impute as TRTSDT – 1.
The following matrix explains the logic behind the imputation of start date.
MON
MISSING
MON<TRTM
MON=TRTM
MON>TRTM
YYYY
MISSING
(1)
Uncertain
(1)
Uncertain
(1)
Uncertain
(1)
Uncertain
YYYY < TRTY
(2.a)
Before 
Treatment Start
(2.b)
Before 
Treatment Start
(2.b)
Before 
Treatment Start
(2.b)
Before 
Treatment Start
YYYY = TRTY
(4.a)
Uncertain
(4.b)
Before 
Treatment Start
(4.b)
Uncertain
(4.c)
After Treatment 
Start
YYYY > TRTY
(3.a)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start
1. If the CM start date year value is missing, the imputed CM start date was set to missing.
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date was set to the mid-year point 
(01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date was set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date was set to the year start 
point(01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date was set to the month 
start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:


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a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date was set to one day prior treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date was set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date was set to the month start point (01MONYYYY).
5. If the imputed CM start date is after CM end date then impute CM start date as CM end 
date.
Concomitant Medication Date Flag
If not a complete date then
Y – If year of the imputed date is not equal to YYYY else M – If month of the imputed date is 
not equal to MON else D.
5.1.3.1
Prior therapies date imputation
Same as above.
5.1.3.2
Post therapies date imputation
Same as above.
5.1.4
Other imputations
5.1.4.1
Time
If it is a start date or date/time of test done and date is not missing, then;
1. If seconds component is missing then seconds component is imputed as 00.
2. If minutes and seconds component is missing then minutes and seconds component 
are imputed as 00 and 00 respectively.
3. If whole time component is missing then Time component is imputed as 00:00:00.
If it is an end date and date is not missing, then;
1. If seconds component is missing then seconds component is imputed as 59.
2. If minutes and seconds component is missing then minutes and seconds component 
are imputed as 59 and 59 respectively.
3. If whole time component is missing then Time component is imputed as 23:59:59.
5.1.4.2
Medical History
For the calculation of duration or time since relevant history events in Section 2.3.3 (Baseline 
Characteristics), partial dates will be imputed for the MS diagnosis start data, the first MS 
symptom date, and the most recent relapse onset date via the below imputation rules.
•
If the year is missing or impossible (e.g., 12-Jan-1911), then the date will be imputed 
as missing.




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Table 5-1
Laboratory test groups and subgroups with SI units
Order
Laboratory Group
Subgroups
Tests (SI unit)
Hematology
Red blood cells
Hematocrit (ratio)
Hemoglobin (g/L)
Platelets (10E9/L)
Erythrocytes (Red cell count) (10E12/L)
White blood cell differential
Basophils (10E9/L)
Eosinophils (10E9/L)
Lymphocytes (10E9/L)
Monocytes (10E9/L)
Neutrophils (10E9/L)
Basophils/Leukocytes (%)
Eosinophils/Leukocytes (%)
Lymphocytes/Leukocytes (%)
Monocytes/Leukocytes (%)
Neutrophils/Leukocytes (%)
Leukocytes (White cell count)(10E9/L)
B cells
CD19+ B cell counts (10E6/L)
1
 
Chemistry
Renal function
Creatinine (umol/L)
Blood urea nitrogen (mmol/L)
Liver function
ALT (U/L)
Albumin (g/L)
Alkaline phosphatase (U/L)
AST (U/L)
Bilirubin (direct/conjugated) (umol/L)
GGT (U/L)
Total bilirubin (umol/L)
Total protein (g/L)
Other enzymes
Amylase (U/L)
2
Lipids
Cholesterol HDL (mmol/L)
Cholesterol LDL (mmol/L)
Triglycerides (mmol/L)
Total cholesterol (mmol/L)


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Order
Laboratory Group
Subgroups
Tests (SI unit)
Other
Random glucose (mmol/L)
C-reactive protein (CRP) (mg/L)
Electrolytes/Metabolism 
Immunoglobulin
Bicarbonate (mmol/L)
Calcium (mmol/L)
Chloride (mmol/L)
Magnesium (mmol/L)
Phosphate (mmol/L)
Potassium (mmol/L)
Sodium (mmol/L)
Total IgG (g/L)
Total IgM (g/L)
3
Urinalysis
Erythrocytes (Blood)
Specific gravity 
Specific gravity (Ratio)
Albumin 
Protein
pH
Leukocytes (White blood count)
4
Immunophenotyping
     T cells
CD3+CD20+ T cell counts (10E6/L)
5.3.2
Newly occurring liver enzyme abnormalities
 Below lists the criteria for “events” of newly occurring liver enzymes abnormalities:
•
ALT > 3, 5, 10, 20x ULN
•
AST > 3, 5, 10, 20x ULN
•
ALT or AST > 3, 5, 8, 10, 20x ULN
•
ALT or AST > 3x ULN & TBIL > 1.5x ULN
•
ALT or AST > 3x ULN & TBIL > 2x ULN
•
ALP > 1.5, 2, 5x ULN
•
TBIL > 1, 1.5, 2x ULN
•
ALP > 3, 5x ULN & TBL > 2x ULN
•
ALT or AST > 3x ULN & TBIL > 2x ULN & ALP ≤ 2x ULNALT or AST > 3x ULN
When a criterion contains multiple laboratory parameters (e.g., ALT > 3xULN & TBL > 
2xULN), unless otherwise requested by the project clinical team/Brand Safety Leader (BSL), 
the criterion should be only considered to be met when the elevation in both parameters 
occurs on the same sample day (as evidenced by the same date that the lab samples were 


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taken). The “events” are defined in the Novartis safety guideline on hepatotoxicity (Novartis: 
Philippe Close 2011), section: Safety parameters for special liver event analyses.
5.3.2.1
Definition of characteristics for liver event overview summary
Characteristics: Liver events are categorized based on ALT and ALP measurements using the 
closest lab assessment +/- 7 days from the onset of the liver event into the following 
characteristics ‘Hepatocellular’ (ALT > 2xULN or ALT/ULN:ALP/ULN > 5), ‘Cholestatic’ 
(ALP > 2xULN or ALT/ULN:ALP/ULN ≤ 2), ‘Mixed’ (ALT > 2xULN and ALP > ULN and 
2 < ALT/ULN:ALP/ULN ≤ 5), ‘None’ (if none of the three above qualifies), and ‘Unknown’ 
(in case of a missing ALT or ALP values). Note that the categories are not mutually exclusive. 
The definition is consistent with Novartis safety guideline on hepatotoxicity.
5.4
Other derivations
5.4.1
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) includes 11 levels considered as 
standard for classifying suicidal ideation and behavior events.
These include five levels of suicidal ideation, five levels of suicidal behavior, and the category 
self-injurious behavior, no suicidal intent.  
These categories and levels are defined in Table 5-2:
Table 5-2
Suicidal ideation and behavior categories and definitions
Category 
number 
C-SSRS category
Definition
Suicidal ideation
1
Wish to be dead
Patient has thoughts about a wish to be dead or 
not alive anymore or wish to fall asleep and not 
wake up.
2
Non-specific active suicidal 
thoughts
General nonspecific thoughts of wanting to end 
one’s life or commit suicide (e.g., “I’ve thought 
about killing myself”) without general thoughts of 
ways to kill oneself/associated methods, intent, 
or plan during the assessment period.
3
Active suicidal ideation with 
any methods (not plan) 
without intent to act
Patient has thoughts of suicide and has thought 
of at least one method during the assessment 
period.  This situation is different than a specific 
plan with time, place, or method details worked 
out (e.g., thought of method to kill self but not a 
specific plan).  Includes person who would say, 
“I thought about taking an overdose but I never 
made a specific plan as to when, where, or how I 
would actually do it . . . and I would never go 
through with it.”
4
Active suicidal ideation with 
some intent to act, without 
specific plan 
Active suicidal thoughts of killing oneself, and 
patient reports having some intent to act on such 
thoughts, as opposed to “I have the thoughts but 
I definitely will not do anything about them.”


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5
Active suicidal ideation with 
specific plan and intent
Thoughts of killing oneself with details of plan 
fully or partially worked out and patient has 
some intent to carry it out (i.e., some degree of 
intent is implicit in the concept of plan).
Suicidal behavior
6
Completed suicide
A self-injurious behavior that resulted in fatality 
and was associated with at least some intent to 
die as a result of the act.  Evidence that the 
individual intended to kill him- or herself, at least 
to some degree, can be explicit or inferred from 
the behavior or circumstance.  
7
Suicide attempt
A potentially self-injurious behavior, associated 
with at least some intent to die as a result of the 
act.  Evidence that the individual intended to kill 
him- or herself, at least to some degree, can be 
explicit or inferred from the behavior or 
circumstance.  A suicide attempt may or may not 
result in actual injury.
8
Interrupted suicide attempt 
When the person is interrupted (by an outside 
circumstance) from starting a potentially self-
injurious act (if not for that, actual attempt would 
have occurred).   
9
Aborted suicide attempt
When person begins to take steps toward 
making a suicide attempt, but stops before 
actually engaging in any self-destructive 
behavior.  Examples are similar to interrupted 
attempts, except that the individual stops before 
being stopped by something else.
10
Preparatory acts toward 
imminent suicidal behaviors
This category can include anything beyond a 
verbalization or thought, but it stops short of a 
suicide attempt, an interrupted suicide attempt, 
or an aborted suicide attempt.  This might 
include behaviors related to assembling a 
specific method (e.g., buying pills, purchasing a 
gun) or preparing for one’s death by suicide 
(e.g., giving things away, writing a suicide note).
Self-Injurious Behavior Without Suicidal Intent
11
Self-injurious behavior associated with no intent to die.  The behavior is 
intended purely for other reasons, either to relieve distress (often referred to as 
self-mutilation (e.g., superficial cuts or scratches, hitting or banging, or burns)) 
or to effect change in others or the environment.
5.4.2
TSQM-9 scoring 
TSQM-9 scale scores range from 0 to 100 and no computed score should be lower or higher 
than these limits. If more than 1 item score is missing, the scale score should not be computed, 
and set to missing. The TSQM-9 scale scoring algorithm as described by Atkinson et al. is 
tabulated in Table 5-3:
Table 5-3
TSQM-9 scale scoring algorithm
Domain
Scale score 


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Effectiveness
[(Item 1 + Item 2 + Item 3 – 3) / 18] × 100.
If one item is missing then [sum(available 
items)-2/12]*100
Convenience
[(Item 4 + Item 5 + Item 6 - 3) / 18] × 100.
If one item is missing then [sum(available 
items)-2/12]*100
Global satisfaction
First recode create Item 9_R: Item 9_R = (Item 9 
- 1) × 4/6 + 1 
Then the global satisfaction scale score is [(Item 
7 + Item 8 + Item 9_R - 3) / 12] × 100.
If one item is missing then [sum(available 
items)-2/8]*100


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5.5
Statistical models 
Primary analysis
Type is no hypothesis testing planned for this study. 
Key secondary analysis
There is no key secondary analysis planned for this study. 
Mixed model with repeated measures (MMRM) with baseline value retained in 
the outcome – Sample SAS code
The OM option is to ensure that the distribution of categorical variable is according to 
population included in analysis.
PROC MIXED DATA = dsn;
    CLASS avisitn usubjid &listCatCovar;
    MODEL aval = avisitn &listCovar/s ddfm =kr;
    LSMEANS avisitn/diff cl E OM;
    LSMESTIMATE avisitn ‘chg from baseline at Week 24’ -1 1 0 /OM;
    LSMESTIMATE avisitn ‘chg from baseline at Week 48’ -1 0 1 /OM;
    REPEATED avisitn/TYPE = UN subject = usubjid;
RUN;
Rule of exclusion criteria of analysis sets 
Table 5-4
Protocol deviations that cause participants to be excluded
Deviation ID
Description of deviation
Exclusion in analyses
INCL01A
No informed consent obtained 
or missing
Exclude from Safety set and 
FAS