A 12 Week Randomized Open Label Parallel Group Multicenter Study to Evaluate Bioequivalence of 20 mg Subcutaneous Ofatumumab Injected by Pre-filled Syringe or Autoinjector in Adult RMS Patients
Phase: PHASE2
Conditions: Multiple Sclerosis
Sponsor: Novartis Pharmaceuticals

Global Clinical Development - General Medicine 
OMB157
Protocol COMB157G2102 / NCT03560739
A 12 week randomized open label parallel group 
multicenter study to evaluate bioequivalence of 20 mg 
subcutaneous ofatumumab injected by pre-filled syringe or 
autoinjector in adult RMS patients.
Document type:
Protocol
EUDRACT number:
2017-004702-17
Version number:
00
Clinical trial phase:
II
Release date:
30-March-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 2017)

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................17
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale for study design .....................................................................................21
3.3
Rationale for dose/regimen, route of administration and duration of treatment....21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................23
4.1
Inclusion criteria ....................................................................................................23
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................28
5.1
Study treatment......................................................................................................28
5.1.1
Investigational and control drugs..........................................................28
5.1.2
Additional treatment..............................................................................28
5.2
Treatment arms......................................................................................................28
5.3
Treatment assignment and randomization.............................................................28
5.4
Treatment blinding.................................................................................................29
5.5
Treating the patient................................................................................................29
5.5.1
Patient numbering .................................................................................29
5.5.2
Dispensing the study drug.....................................................................29
5.5.3
Handling of study and additional treatment..........................................30
5.5.4
Instructions for prescribing and taking study treatment........................30
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31

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5.5.6
Recommendations for the treatment of MS relapses ............................31
5.5.7
Concomitant medication .......................................................................31
Premedication prior to sc injection........................................................................31
5.5.8
Prohibited medication ...........................................................................32
5.5.9
Emergency breaking of assigned treatment code..................................32
5.6
Study completion and discontinuation...................................................................33
5.6.1
Study completion and post-study treatment..........................................33
5.6.2
Discontinuation of study treatment .......................................................33
5.6.3
Withdrawal of informed consent...........................................................34
5.6.4
Loss to follow-up ..................................................................................35
5.6.5
Early study termination by the sponsor.................................................35
5.6.6
Role of Key site personnel ....................................................................35
6
Visit schedule and assessments .........................................................................................37
6.1
Information to be collected on screening failures..................................................42
6.2
Pharmacokinetics sampling ...................................................................................42
6.3
Patient demographics/other baseline characteristics .............................................42
6.4
Treatment exposure and compliance .....................................................................42
6.5
Efficacy..................................................................................................................43
43
.44
45
46
6.5.5
Appropriateness of efficacy assessments..............................................46
6.6
Safety.....................................................................................................................46
6.6.1
Physical examination ............................................................................47
6.6.2
Vital signs..............................................................................................47
6.6.3
Height and weight .................................................................................47
6.6.4
Laboratory evaluations..........................................................................47
6.6.5
Electrocardiogram (ECG) .....................................................................49
6.6.6
Pregnancy and assessments of fertility .................................................49
6.6.7
Appropriateness of safety measurements..............................................49
6.7
Other assessments..................................................................................................50
6.7.1
Clinical Outcome Assessments (COAs) ...............................................50
6.7.2
Pharmacokinetics ..................................................................................50
6.7.3
Immunogenicity ....................................................................................51
51

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7
Safety monitoring..............................................................................................................51
7.1
Adverse events.......................................................................................................51
7.2
Serious adverse events...........................................................................................53
7.2.1
Definition of SAE .................................................................................53
7.2.2
SAE reporting........................................................................................54
7.3
Liver safety monitoring .........................................................................................55
7.4
Renal safety monitoring.........................................................................................56
7.5
Reporting of study treatment errors including misuse/abuse ................................56
7.6
Pregnancy reporting...............................................................................................57
7.7
Prospective suicidality assessment ........................................................................57
8
Data review and database management.............................................................................58
8.1
Site monitoring ......................................................................................................58
8.2
Data collection.......................................................................................................58
8.3
Database management and quality control............................................................59
8.4
Data Monitoring Committee..................................................................................59
8.5        Adjudication Committee ......................................................................................59
9
Data analysis......................................................................................................................59
9.1
Analysis sets ..........................................................................................................59
9.2
Patient demographics and other baseline characteristics.......................................60
9.3
Treatments .............................................................................................................60
9.4
Analysis of the primary variable(s) .......................................................................60
9.4.1
Primary Variable(s)...............................................................................60
9.4.2
Statistical model, hypothesis, and method of analysis..........................60
9.4.3
Handling of missing values/censoring/discontinuations.......................61
9.4.4
Sensitivity analyses ...............................................................................61
9.5
Analysis of secondary variables ............................................................................61
9.5.1
Efficacy variables..................................................................................61
9.5.2
Safety variables .....................................................................................62
9.5.3
Resource utilization...............................................................................62
9.5.4
Pharmacokinetics ..................................................................................62
9.5.5
DNA......................................................................................................62
9.5.6
PK/PD ...................................................................................................62
62
9.7
Interim analyses.....................................................................................................62
9.8
Sample size calculation..........................................................................................63
9.8.1
Sample size calculation for PFS (abdomen) and AI (abdomen)...........63

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9.8.2
Sample size calculation for PFS (thigh) and AI (thigh)........................64
10 Ethical considerations........................................................................................................65
10.1
Regulatory and ethical compliance........................................................................65
10.2
Informed consent procedures.................................................................................65
10.3
Responsibilities of the investigator and IRB/IEC..................................................65
10.4
Publication of study protocol and results...............................................................66
10.5
Quality Control and Quality Assurance.................................................................66
11 Protocol adherence ............................................................................................................66
11.1
Protocol amendments.............................................................................................66
12 References .........................................................................................................................67
13 Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................69
14 Appendix 2: Specific Renal Alert Criteria and Actions....................................................72
15 Appendix 3: Safety monitoring Guidance.........................................................................73
15.1
Guidance on monitoring of patients with symptoms of neurological 
deterioration suggestive of PML ...........................................................................73
15.2
Guidance on monitoring of patients with infections..............................................73
15.3
Guidance on immunization....................................................................................74
15.4
Guidance on monitoring of patients with low immunoglobulin levels .................74

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List of tables
Table 2-1
Objectives and related endpoints.......................................................................... 18
Table 5-1
Prohibited medication........................................................................................... 32
Table 6-1
Assessment schedule ............................................................................................ 38
Table 6-2
Assessment schedule for Safety Follow-up period............................................... 41
44
Table 7-1 
Guidance for capturing the study treatment errors including misuse/abuse ......... 56
Table 13-1
Liver Event and Laboratory Trigger Definitions.................................................. 69
Table 13-2
Follow-Up Requirements for Liver Events and Laboratory Triggers................... 69
Table 14-1
Specific Renal Alert Criteria and Actions ............................................................ 72
List of figures
Figure 3-1
Study design – Part 2.............................................................................19
22
Figure 5-1
Alternation of injection areas for abdomen and thigh...........................31

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List of abbreviations
γ-GT
Gamma-glutamyl transferase
ABE
Average bioequivalence
ACR
Albumin/creatinine ration
ADA
Anti-drug antibodies
ADCC
Anitbody dependent cell-mediated cytotoxicity
AE
Adverse event
AI
Autoinjector
AIDS
Acquired immunodeficiency syndrome
Alb
Albumin
ALT
Alanine Aminotransferase
ALP
Alkaline Phosphatase
AST
Aspartate Aminotransferase
AUC
Area under the curve
BE
Bioequivalence
BUN
Blood Urea Nitrogen
CFR
Code of Federal Regulation
CI
Confidence interval
CLL
Chronic Lymphocytic Leukemia
CNS
Central Nervous System
CPO
Country Pharma Organization
CRF
Case Report/Record Form (paper or electronic)
CRP
C-Reactive protein
CRO
Contract Research Organization
CSF
Cerebrospinal fluid
CSR
Clinical Study report
CTCAE
CTC
Common Terminology Criteria for Adverse 
Events
Common Toxicity Criteria
CV
Coefficient of variation
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DTPA
DWI                                                     
Diethylenetriamine pentaacetic acid
Diffusion-weighted imaging
EC
Ethics committee
ECG
Electrocardiogram
eCSSRS
Electronic Columbia Suicide Severity Rating 
Scale
EDC
Electronic Data Capture
EDSS
Expanded Disability Status scale
EMA
European Medicines Agency
EOS
End of Study
EU
European Union
FDA
Food and Drug Administration

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FLAIR
Fluid-Attenuated Inversion Recovery
FSs
FU
Functional scores
Follow up
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HA
HBV
hCG
HCP
HCV
HDL
HEV
Health Authority
Hepatitis B virus
Human chorionic gonadotropin
Health Care provider
Hepatitis C Virus 
high density lipoprotein
Hepatitis E Virus 
HIV
human immunodeficiency virus
IB
Investigator Brochure
Ig
Immunoglobulins
IN
IRT
Investigator Notification
Interactive Response Technology
iv
Intravenous
ICH
International Council  of Harmonization
IEC
Independent Ethics Committee
IRB
LDL
Institutional Review Board
low density lipoprotein
LFT
Liver Function Test
LLN
lower limit of normal
MedDRA
Medical dictionary for regulatory activities
MRI
Magnetic Resonance Imaging
MS
NCA
Multiple Sclerosis
Non- Compartmental Analysis
NYHA
New York Heart Association
PCR
protein-creatinine ratio
PD
pharmacodynamic(s)
PFS
prefilled syringe
PK
pharmacokinetic(s)
PML
Progressive Multifocal Leukoencephalopathy
QM
Quality Managmenet
QTcF
QT correction formula
RBC
Red blood cells
RNA
Ribonucleic Acid
RRMS
Relapsing-remitting Multiple Sclerosis
RSABE
Reference scaled average bioequivalence
SAE
sc
Serious Adverse Event
Subcutaneous

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SOP
Standard operating procedure
SPMS
Secondary progressive Multiple Sclerosis
SUSAR
Suspected Unexpected Serious Adverse 
Reactions
TOST
Test one sided test
ULN
upper limit of normal
US
United States
WBC
white blood cell(s)
WHO
World Health Organization

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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from time zero 
to time 't' where t is a defined time point after administration (mass x time/volume)
AUClast
The area under the plasma (or serum or blood) concentration-time curve from time zero 
to the time of the last quantifiable concentration (mass x time/volume)
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from time zero 
to the end of the dosing interval tau (mass x time/volume)
Cmax
The observed maximum plasma (or serum or blood) concentration following drug 
administration (mass/volume)
Tmax
The time to reach the maximum concentration after drug administration (time)

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Dosage
Dose of the study treatment given to the subject in a time unit (eg 100 mg once 
a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study; the point at which informed consent 
must be obtained (ie prior to starting any of the procedures described in the 
protocol).
Healthy subject
A person with no known significant health problems who volunteers to be a 
study participant 
Induction
Initial treatment regimen to ensure b cell depletion.
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”.
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.
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 patients with established disease and in 
those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Period
The subdivisions of the trial design (eg Screening, Treatment, Follow-up) which 
are described in the Protocol. Periods define the study phases and will be used 
in clinical trial database setup and eventually in analysis
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Premature 
subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion 
of all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
A subject who is screened and didn’t pass the screening criteria and is not 
treated or randomized
Study disposition
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.

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Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points.
Withdrawal
Withdrawal of study consent: Withdrawal of consent from the study occurs only 
when a subject does not want to participate in the study any longer, and does 
not allow any further collection of personal data

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Protocol summary
Protocol number
COMB157G2102
Full Title
A 12 week randomized open label parallel group multicenter study to 
evaluate bioequivalence of 20 mg subcutaneous ofatumumab injected by 
pre-filled syringe or autoinjector in adult RMS patients.
Brief title
An open label study evaluating bioequivalence of ofatumumab using a 
prefilled syringe or autoinjector.
Sponsor and Clinical 
Phase
Novartis
Phase 2
Investigation type
Biological
Study type
Interventional
Purpose and rationale
The primary objective of this study is to demonstrate pharmacokinetic 
bioequivalence of ofatumumab injected by PFS versus AI devices and 
thereby establish a bridge between the ongoing Phase 3 program and the 
.
Primary Objective(s) 
To demonstrate pharmacokinetic bioequivalence of 20 mg ofatumumab 
injected by the PFS or AI devices
Secondary Objectives
To characterize the pharmacokinetics following subcutaneous 
administration of ofatumumab to either the abdominal region or the thigh
Assessment of immunogenicity
Assess the safety and tolerability of ofatumumab
Study design
This is a randomized, open-label, multi-center, parallel group 12-week 
study to evaluate the pharmacokinetic bioequivalence of ofatumumab 
injected by PFS or AI devices. The study design includes four parallel 
groups of RMS patients. Assessment of the primary and secondary 
endpoints are performed based on data collected through the dosing 
interval between Week 8 and Week 12 where approximate steady-state 
pharmacokinetics are anticipated.
Population
Adult patients with RMS
Key Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.

Male or female patients aged 18 to 55 years (inclusive) at screening.

Diagnosis of MS

Relapsing MS: relapsing-remitting course (RRMS), or Secondary 
progressive (SPMS) course with disease activity

Disability status at Screening with an EDSS score of 0 to 5.5 
(inclusive)

Documentation of at least: 1 relapse during the previous year OR 2 
relapses during the previous 2 years prior to Screening OR a positive 
Gd-enhancing MRI scan during the year prior to randomization. 

Neurologically stable within 1 month prior to randomization
Key Exclusion criteria

Patients with primary progressive MS or SPMS without disease 
activity 

Patients meeting criteria for neuromyelitis optica 

Disease duration of more than 10 years in patients with EDSS score 
of 2 or less

Pregnant or nursing (lactating) women

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
Women of child-bearing potential unless they are using highly 
effective methods of contraception.

Patients with an active chronic disease (or stable but treated with 
immune therapy) of the immune system other than MS (eg
rheumatoid arthritis, scleroderma, Sjögren’s syndrome, Crohn’s 
disease, ulcerative colitis, etc.) or with immunodeficiency syndrome 
(hereditary immune deficiency, drug-induced immune deficiency)

Patients with active systemic bacterial, viral or fungal infections, or 
known to have AIDS or to test positive for HIV antibody at Screening

Patients with neurological findings consistent with Progressive 
Multifocal Leukoencephalopathy (PML), or confirmed PML

Patients at risk of developing or having reactivation of syphilis or 
tuberculosis

Patients at risk of developing or having reactivation of hepatitis
Study treatment
Investigational drug will be provided in pre-filled syringes containing 
20 mg ofatumumab (50 mg/ml, 0.4 ml content) or autoinjector containing 
20 mg ofatumumab (50 mg/ml, 0.4 ml content) for subcutaneous 
administration. Ofatumumab is a clear to opalescent, colorless to pale 
yellow, essentially particle-free liquid. 
Efficacy assessments
Key safety 
assessments

Adverse events

Physical examination (including skin)

Vital signs

Laboratory Evaluations

Pregnancy testing (females of childbearing potential) 

ECG

Electronic Columbia Suicide Severity Rating Scale (eCSSRS)
Other assessments
 PK, B-cells, ADA 
Data analysis
The analysis will be conducted per statistical analysis plan. Any data 
analysis carried out independently by the investigator should be 
submitted to Novartis before publication or presentation.
Key words
Open label, Bioequivalence, autoinjector, pre-filled syringe, 

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1
Introduction
1.1
Background
Multiple Sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system 
(CNS) characterized by inflammation, demyelination and axonal/neuronal destruction, 
ultimately leading to severe disability. MS affects ~ 2.5 million individuals worldwide.
For the patients with relapsing MS (RMS), interferon-β and glatiramer acetate have long been 
used as first-line drugs. These drugs require frequent self-injections which may become an 
increasing burden for patients over time. In the recent years, oral drugs such as fingolimod, 
dimethyl fumarate and teriflunomide have become available and enhanced the convenience of 
treatment for the patients. In addition, treatment with more potent drugs including natalizumab, 
alemtuzumab and ocrelizumab have been put into practice. Despite the increased options 
available, there are patients whose disease activity cannot be fully controlled by the existing 
drugs, or are experiencing intolerable side effects from current available drugs. The need 
therefore remains to develop drugs with alternative mechanisms of action, convenient dosing, 
and a favorable safety profile.
There is accumulating evidence that the immune-mediated damage in MS involves more than 
just T cells. Specifically, the early role of B-cells in the contribution to the immune-mediated 
histopathology in MS (Archelos et al 2000; Frohman et al 2006; McFarland 2008), has become 
clearer. B-cells have essential functions in regulating immune response and may contribute to 
disease pathogenesis in MS by self-antigen presentation, serving as cellular adjuvants for CD4+
T-cell activation (Bouaziz et al 200712 References) and by regulating T-cell function and 
inflammation via cytokine production (Lund 2008), in addition to producing autoantibodies. B-
cells are present in the chronic plaques, areas of demyelination, and in the cerebrospinal fluid 
of MS patients (Lehmann-Horn et al 2013). Recently, it has been recognized that CD20 
expression is not restricted to B-cells, but it also present in a subset of T-cells. Anti-CD20 
therapy eliminates these T-cells.
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 relapsing MS 
patients. Recently the efficacy of ocrelizumab was confirmed in 2 Phase 3 trials in patients with 
relapsing MS (Hauser et al 2017). These studies showed that ocrelizumab significantly reduced 
relapse rates, reduced MRI disease activity and, delayed the time to disability worsening vs 
interferon beta 1a over 2 years. 
Both rituximab and ocrelizumab are delivered in an outpatient setting by intravenous (iv) 
infusion. However, self-administrated treatment at home with a B-cell targeting therapy with 
high efficacy, and safety profile, as approached with sc ofatumumab, is highly desirable.
Ofatumumab
Ofatumumab is a fully human anti-CD20 monoclonal antibody (mAb), depleting B-cells similar 
to rituximab and ocrelizumab. Ofatumumab recognizes a unique epitope localized close to the 
cell membrane on the two extracellular domains of the CD20 molecule, N-proximal to the 

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epitopes for the anti-CD20 mAbs rituximab and ocrelizumab. CD20 binding of ofatumumab 
induces B-cell lysis primarily through complement-dependent cytotoxicity (CDC) and 
antibody-dependent cell-mediated cytotoxicity (ADCC) (Klein et al 2013, Teeling et al 2004). 
Ofatumumab iv, Phase II data: OMS115102 was a double-blind, randomized, placebo-
controlled, multicenter, dose-escalation study of intravenous ofatumumab in RRMS patients. 
This trial showed a dose-dependent B-cell depletion and a reduction of MRI lesion activity of
99% compared to placebo, and an acceptable safety profile of ofatumumab in MS (Sorensen et 
al 2014). 
Ofatumumab sc, Phase II data: OMS112831 (MIRROR study) was a double-blind, placebo-
controlled, parallel-group, dose-ranging study evaluating the safety and MRI efficacy of sc
ofatumumab in subjects with RRMS. The objective of OMS112831 was to evaluate efficacy as 
assessed by MRI, and the tolerability and safety of a range of doses of ofatumumab (3, 30, or 
60 mg) to enable selection of a dosing regimen for further study in Phase III. Cumulative doses >
30 mg showed a reduction of MRI lesion activity of > 90% compared with placebo during 
weeks 4-12 and reduction was maintained up to the last observation at Week 48. In addition, 
analysis of peripheral B-cell counts demonstrated a rapid, dose and dose frequency dependent 
B-cell depletion. 
Overall, ofatumumab was safe and well tolerated in patients with RRMS. The safety profile of 
ofatumumab was consistent with previous data; no new safety signals were reported. For 
detailed safety information, please refer to the current version of the investigator’s Brochure.
PK/PD modelling of the ofatumumab sc Phase 2 clinical trial data in RRMS patients indicate 
that an induction regimen (3 weekly doses of 20 mg) followed by a maintenance dose regimen 
of ofatumumab 20 mg every 4 weeks, will achieve and maintain effective tissue depletion of 
circulating CD20+ B-cells. This dosing scheme was chosen for the Phase 3 studies in relapsing 
MS.
Novartis initiated a Phase 3 clinical program in relapsing MS (RMS) which completed 
recruitment in March 2018, enrolling a total of 1884 patients. Two worldwide, double-blind, 
double-dummy, active-controlled trials of identical design, are being conducted in parallel in 
RMS patients (OMG157G2301, aka ASCLEPIOS I and OMB157G2302, aka ASCLEPIOS II). 
These trials evaluate the efficacy and safety of ofatumumab 20 mg subcutaneously (sc) vs 
teriflunomide 14 mg orally. Ofatumumab is administered starting with a loading dose regimen 
of three doses of 20 mg every week for the first three doses (Day 1, Day 7 and Day 14) followed 
by a maintenance dose of 20 mg every 4 weeks starting at Day 28.
Ofatumumab administration
This study will use the same treatment regimen as the Phase 3 program that is described above.
The induction regimen was chosen to ensure a fast and effective depletion of CD20-positive B-
cells without the need for administration of high doses. Thereafter, the maintenance regimen 
starting at week 4 is subcutaneous administration of 20 mg every 4 weeks. Subcutaneous 
administration in the Phase 3 studies is provided via a pre-filled syringe (PFS) whereas the 
 
 
 

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In order to demonstrate that administration of ofatumumab via the AI leads to equivalent drug 
concentration profiles compared to administration via the PFS, bioequivalence endpoints 
(Cmax and AUCtau) will be determined in the study and compared statistically according to 
health authority requirements. 
1.2
Purpose
The primary objective of this study is to demonstrate pharmacokinetic bioequivalence of 
ofatumumab injected by PFS versus AI devices and thereby establish a bridge between the 
ongoing Phase 3 program 
.
Characterization of the pharmacokinetics of ofatumumab administered via the PFS used in 
clinical trials
 at the clinical dose of 20 mg will be conducted 
after an initial depletion of CD20 positive B-cells. Comparing the ofatumumab 
pharmacokinetics between the two drug-device combinations only after the induction period is 
expected to reduce initial high variability due to target-mediated clearance. This ensures a more 
stable baseline for PK comparison in a parallel group study design and reflects the clinical 
situation where systemic concentrations are at steady-state. In order to justify the resulting long-
term B-cell depletion, a PK comparability study between the PFS and the AI can only be 
conducted in MS patients rather than in healthy subjects to balance the risk/benefit and to obtain 
PK data from the relevant patient population. In order for patients to obtain a clinical benefit 
from participation in the study, continued treatment with ofatumumab will be offered to all 
eligible patients through enrollment into the open-label Phase 3 extension study (separate 
protocol, COMB157G2399). 
A secondary objective of the study is to characterize the pharmacokinetics following 
subcutaneous administration of ofatumumab to either the abdominal region or the thigh which 
are two injections sites allowed in the Phase 3 study and planned for inclusion in the label. 
Another secondary objective is assessment of immunogenicity during the 12 weeks duration of 
the study addressing potential differences in ofatumumab anti-drug antibody formation between 
the PFS and AI devices as well as between abdomen and thigh injection sites.
 
 
 
 
 
 
2
Study objectives and endpoints

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2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 
To demonstrate pharmacokinetic bioequivalence 
of 20 mg ofatumumab injected by the PFS or AI 
devices
AUCtau
Cmax
Secondary Objective(s)
Endpoint(s) for secondary objective(s)
To characterize the pharmacokinetics following 
subcutaneous administration of ofatumumab to 
either the abdominal region or the thigh
Assessment of immunogenicity
Assess the safety and tolerability of ofatumumab
AUCtau
Cmax
Proportion of patients with anti-ofatumumab 
antibodies
Adverse events including injection related 
reaction, lab, vital signs, ECG, and eCSSRS
3
Investigational plan
3.1
Study design
This is a randomized, open-label, multi-center, parallel group 12-week study to evaluate the 
pharmacokinetic bioequivalence of ofatumumab injected by PFS or AI devices. The study 
design includes four parallel groups of RMS patients. Assessment of the primary and secondary 
endpoints are performed based on data collected through the dosing interval between Week 8 
and Week 12 where approximate steady-state pharmacokinetics are anticipated.
Randomization: A total of approximately 150 eligible patients will receive open-label 
ofatumumab 20 mg sc every 4 weeks (after an initial loading regimen of three weekly 20 mg 
doses in the first 14 days). Patients will be randomized in a 5:5:1:1 ratio into the following 4 
groups dependent on what type of injection device they will use and the location of their 
injection (62 subjects for groups 1 and 2, and 13 subjects for groups 3 and 4). Randomization 
will be stratified by body weight (< 60 kg, 60-90 kg, > 90 kg) to ensure a balance between 
covariates with potential impact on the primary endpoint. Randomization will not be blinded as 

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the endpoints of the study are primarily related to pharmacokinetics and all patients will be 
receiving active treatment at identical dosing regimens.  

Group 1: PFS, abdomen

Group 2: AI, abdomen

Group 3: PFS, thigh

Group 4: AI, thigh
Interim analyses: The study will feature one interim analysis that will be conducted when 
approximately 36 patients have completed Week 12 (Section 3.5). 
The study has 3 Parts: 

Part 1 – Screening 

Part 2 - Treatment 

Part 3 - Safety follow-up
Part 1 – Screening

The Screening period can last up to 30 days and consists of Screening and Baseline 
assessments. Patient eligibility will be determined based on the Screening and/or Baseline 
assessments.

Patients may be rescreened if they do not initially meet eligibility criteria. All assessments 
must be repeated, 
 
Part 2 – Treatment
Graphical outline of Part 2, Treatment period study design with four parallel groups. Evaluation 
of primary and secondary end-points are performed between Week 8 and Week 12.
Figure 3-1
Study design – Part 2
The study Part 2 Treatment period will consist of an initial induction phase (Week 0 to Week 
4) and a pharmacokinetics phase (Week 8 to Week 12) at approximate steady-state conditions. 

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Week 4 to Week 8 ensures that approximate steady-state conditions are reached prior to the 
pharmacokinetics phase. A schematic presentation of the study design is provided in           
Figure 3-1.
 
 
 
 
 
 
 
 
The pharmacokinetics will be assessed for primary objectives during Week 8 to Week 12 at 
approximate steady-state conditions. The rationale for this is to avoid the expected larger inter-
individual variation in exposure at treatment initiation due to the potentially different levels of 
target expression between patients. This would result in high variability in the pharmacokinetics 
parameter leading to an increased sample size of the study. Further, the approximate steady-
state condition is a clinically relevant situation as full target depletion would be expected in 
contrast to the situation after administration of a single dose typically used for bioequivalence 
assessment. During the study, ofatumumab will be administered to the respective groups of 
patients by a health care provider and according to specified instructions. 
No clinically significant difference in ofatumumab exposure is expected between the two 
administration sites (abdomen vs thigh) (Xu et al 2010). Groups 3 and 4 will enable an 
assessment of the pharmacokinetics of ofatumumab injected to the thigh which can then be 
compared to abdominal administration using the PFS and AI, respectively. The aim of 
assessment of the injection site influence on ofatumumab pharmacokinetics is not to 
demonstrate bioequivalence but to enable an evaluation of the potential clinical significance of 
differences in pharmacokinetic parameters. Potentially, the absorption rate may vary between 
different injection sites for subcutaneous single dose administration of ofatumumab possibly 
resulting in different Tmax and Cmax values. However, under steady-state conditions and with 
the primary target being depletion of CD20-positive B-cells, the comparison of AUCs over the 
dosing period would be the most relevant parameter to evaluate. In order for patients to obtain 
a clinical benefit from participation in the study, continued treatment with ofatumumab will be 
offered to the eligible patients through enrollment into the umbrella open-label Phase 3 
extension study (COMB157G2399). Patients waiting for open label extension study to open can 
continue to receive study drug. Patients should return every 12 weeks and complete assessments 
per Table 6.1.
Part 3 – Safety follow-up/Extension study

The Safety FU period Table 6-2 will be applicable for the following patients:  
a. Patients who complete the Treatment period on study drug and do not enter the 
planned Extension study

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b. Patients who prematurely discontinue study treatment 

All Safety FU visits must be scheduled relative to the EOS Visit.

All patients will be followed for a total of at least 9 months after study drug 
discontinuation (by 9 months the vast majority of patients are expected to have repleted 
their circulating B-cells, see IB). 

A longer than 9 months of post-treatment follow up in the Safety FU period will be 
required for patients who have not repleted their B-cells (ie  B-cells not back to baseline 
value or to lower limit of normal (LLN) whichever comes first as determined by central 
lab) at 9 months. These patients will continue to be followed with 3-monthly assessments 
until their B-cell counts have repleted. Patients who have initiated therapy with another 
disease modifying/immunosuppressive therapy before the end of the 9-month follow up 
will not be monitored beyond 9 months.
3.2
Rationale for study design
The study is a parallel-group design with four groups (PFS (abdomen), AI (abdomen), PFS 
(thigh), and AI (thigh)). The two main groups are designed to address the primary objective of 
demonstrating bioequivalence. The two additional groups are designed to address the secondary 
objective of evaluating potential difference in the pharmacokinetic parameters with different 
administration sites. The parallel-groups design is chosen to avoid potential carryover treatment 
effect which is difficult to control with a cross-over study design. The primary and secondary 
objective will be evaluated during approximate pharmacokinetic steady-state conditions 
anticipated during Week 8 and Week 12. This will contribute to a reduction of variability 
between subjects compared to an assessment after a single dose. Further, an evaluation at 
steady-state will be more clinically relevant.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment 
The dosing regimen for ofatumumab in this study comprises an initial induction phase with 
20 mg subcutaneous administration on treatment initiation (Day 1) and on Day 7, and Day 14. 
Thereafter, the maintenance regimen will be subcutaneous administration of 20 mg every 4 
weeks starting at week 4. Subcutaneous injection is the route of administration used in the Phase 
3 program, 
. 
 
 
 
The duration of the study is planned to be 12 weeks.

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3.4
Rationale for choice of comparator
There is no comparator in this study.
3.5
Purpose and timing of interim analyses/design adaptations
An interim analysis of the variability of Cmax and AUCtau is planned to enable a re-estimation 
and potential increase of the final sample size in case the observed variability is higher than 
initially predicted. This interim analysis is to be conducted when approximately 36 patients total 
completed Week 12 in the PFS (abdomen) and AI (abdomen) treatment groups.  
3.6
Risks and benefits
The risk to subjects in this trial will be minimized by compliance with eligibility criteria, close 
clinical monitoring, avoidance of prohibited treatments and adherence to protocol contraception 
requirements and Investigator guidance regarding specific safety areas.
Ofatumumab is approved for treatment of CLL and is administered via iv infusion at doses up 
to 2000 mg. Risks in this population include: infusion reactions, tumor lysis syndrome, 
cytopenia, progressive multifocal leukoencephalopathy (PML), hepatitis B virus (HBV) 
infection and reactivation, and bowel obstruction (please refer to locally available Arzerra®
Prescribing Information). The dose of ofatumumab in this study in MS patients is 20 mg; ie, 
100 times lower than the dose used in CLL. 267 RRMS patients have been exposed to 

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ofatumumab (i.v. N=38 and sc N=229 in 2 Phase 2 studies (Study OMS115102 and 
OMS112831). No unexpected safety findings were observed in MS patients who received 
ofatumumab in the completed studies. In the 48-week, placebo-controlled, cross-over study 
(cross-over at 24 weeks) of iv. doses of ofatumumab up to 700 mg (OMS115102), adverse 
events reported more frequently on ofatumumab vs placebo included: rash, throat irritation, 
erythema, fatigue, viral infection and flushing. In the placebo-controlled, dose-ranging study of 
ofatumumab (OMS112831) administered at sc 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. Safety and tolerability of ofatumumab is currently being further investigated in two large 
global Phase 3 studies (COMB157G2301 and G2302), with a planned total sample size of 1800 
randomized patients. A DMC is monitoring the safety and risk/benefit for the Ofatumumab 
controlled, blinded studies 
Ofatumumab sc has demonstrated profound suppression of MRI lesion activity (≥90% versus 
placebo over Weeks 4-12) in relapsing MS patients in the Phase 2 studies. Confirmation of 
clinical efficacy will be evaluated in the Phase 3 studies (Study COMB157G2301 and G2302).
The efficacy of ocrelizumab, another intravenously administered B-cell depleting compound on 
clinical and MRI disease activity has been reported in 2 Phase 3 trials in relapsing MS patients 
(Hauser et al 2017). Taken together, available information of relevant clinical and MRI outcome 
supports the potential efficacy of ofatumumab in patients with relapsing MS.
The OMB157G2102 study involves dosing for 12 weeks which is a short treatment period for 
MS patients. Therefore, in order to provide a clinical benefit and balance the potential risks 
associated with B cell depletion, all patients eligible will be offered enrollment in the umbrella 
open-label extension trial (OMB157G2399) in direct continuation of the G2102 study.
Overall, the balance of benefit and risk supports the rationale of COMB157G2102 study to 
evaluate the bioequivalence, pharmacokinetics, and immunogenicity in combination with 
additional safety and efficacy data obtained from the open-label extension study (G2399) of 
ofatumumab sc to address the unmet medical need of patients with RMS.
4
Population
The study population will consist of adult patients with RMS fulfilling all the eligibility criteria 
listed below. The study is planned to be conducted in approximately 30 centers worldwide. It 
is aimed to randomize a total of 150 patients. To reach this number it is anticipated that the total 
number of patients to be screened is approximately 200 depending on the screen failure rate. 
Patients, who have been randomized and prematurely discontinue study, will not be replaced. 
In the event that sample size is to be increased after the planned interim analysis, the number of 
sites and patients to be screened may be increased to accommodate the increase of up to 284 
total randomized patients.
4.1
Inclusion criteria
MS Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.

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2. Male or Female patients aged 18 to 55 years (inclusive) at screening.
3. Diagnosis of MS according to the 2010 Revised McDonald criteria (Polman et al 2011)
4. Relapsing MS: relapsing-remitting course (RRMS), or Secondary progressive (SPMS) 
course with disease activity, as defined by (Lublin et al 2014)
5. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive)
6. Documentation of at least: 1 relapse during the previous year OR 2 relapses during the 
previous 2 years prior to Screening OR a positive Gd-enhancing MRI scan during the year 
prior to randomization. Note: Screening MRI scan may be used if no positive Gd 
enhancing scan exist from prior year.
7. Neurologically stable within 1 month prior to randomization
4.2
Exclusion criteria
MS Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Patients suspected of not being able or willing to cooperate or comply with study protocol 
requirements in the opinion of the Investigator
2. Patients with primary progressive MS (Polman et al 2011) or SPMS without disease 
activity (Lublin et al 2014)
3. Patients meeting criteria for neuromyelitis optica (Wingerchuk et al 2006)
4. Disease duration of more than 10 years in patients with EDSS score of 2 or less
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 12 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 
subject, if accepted by the local regulation). Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 

Male partner sterilization (at least 6 months prior to Screening). For female 
patients 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 or intrauterine system 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 study drug. 

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
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 (eg 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 ago. 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. Patients with an active chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (eg rheumatoid arthritis, scleroderma, Sjögren’s syndrome, 
Crohn’s disease, ulcerative colitis, etc.) or with immunodeficiency syndrome (hereditary 
immune deficiency, drug-induced immune deficiency)
8. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS 
or to test positive for HIV antibody at Screening
9. Patients with neurological findings consistent with Progressive Multifocal 
Leukoencephalopathy (PML), or confirmed PML
10. Patients at risk of developing or having reactivation of syphilis or tuberculosis (eg patients 
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 unless 
such testing has been performed in the past 6 months prior to Screening with documented 
negative result. For tuberculosis testing, QuantiFERON®-TB Gold test can be done 
locally or by the central lab to assess patient’s eligibility at Screening.
NOTE:

Patients with an indeterminate QuantiFERON®-TB Gold test may be enrolled if the 
repeat QuantiFERON®-TB Gold test is negative prior to randomization.

Patients with positive QuantiFERON®-TB Gold test are not eligible.
11. Patients 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 or 
chronic infection: 

anti-HA Immunoglobulin (Ig) 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, 
patient can be randomized)

anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative, 
patient can be randomized) 
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 CRF) that the serology results are considered false positive and may then 
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12. Have received any live or live-attenuated vaccines (including for varicella-zoster virus or 
measles) within 2 months prior to randomization
13. Have been treated with any of the medications listed below (Note: no wash-out period is 
required in the case of prior treatment with interferon-β or glatiramer acetate):
Medication
Exclusionary if used/used within required 
wash-out period
Systemic corticosteroids, adrenocorticotropic 
hormone
30 days prior to Screening MRI scan
Dimethylfumarate
1 month prior to randomization
Intravenous immunoglobulin, plasmapheresis, 
fingolimod, siponimod, ozanimod
2 months prior to randomization
Daclizumab
4 months prior to randomization
Teriflunomide
3.5 months prior to randomization or 1 month 
prior to randomization if patient undergoes 
accelerated elimination procedure and has 
documented teriflunomide plasma level below 
0.02 mg/L before randomization
Natalizumab
Laquinimod
Mildly to moderately 
immunosuppressive/chemotherapeutic 
medications (eg azathioprine, methotrexate)
6 months prior to randomization
Highly immunosuppressive/chemotherapeutic 
medications (mitoxantrone, cyclophosphamide, 
cladribine)
B-cell targeted therapies such as rituximab or 
ocrelizumab, ublituximab, or obinutuzumab
2 years prior to randomization
Mitoxantrone (with evidence of cardiotoxicity 
following treatment or cumulative life-time 
dose > 60 mg/m2)
Alemtuzumab
Lymphoid irradiation; bone marrow 
transplantation, stem cell therapy
Other strongly immunosuppressive treatments 
(with effects potentially lasting over 6 months)
Ofatumumab
Any time
14. Use of other investigational drugs at the time of enrolment (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 of the uterus that have 
been radically treated eg 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 patient:

History of, or current, significant cardiac disease including cardiac failure (NYHA 
functional class II-IV), myocardial infarction (within 6 months), unstable 

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angina(within 6 months), transient ischemic attack (within 6 months), stroke, cardiac 
arrhythmias requiring treatment or uncontrolled arterial hypertension. 

Concomitant clinically significant cardiac arrhythmias, eg, sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker on screening electrocardiogram (ECG). 

History of familial long QT syndrome or known family history of Torsades de Pointe. 

History of or active severe respiratory disease, including Chronic Obstructive 
Pulmonary Disease, interstitial lung disease or pulmonary fibrosis. 

Patients with asthma requiring regular treatment with oral steroids. 

Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary 
disease. 

Patients with severe renal impairment (Glomerular Filtration Rate < 30 
ml/min/1.73m2). 

Any medically unstable condition as determined by the Investigator
17. Any of the following abnormal laboratory values prior to randomization

Total or conjugated bilirubin (BIL) greater than 1.5 times upper limit of normal 
(ULN) range, unless in the context of Gilbert’s syndrome.

Alkaline phosphatase (ALP) greater than 1.5 times the ULN range.

AST or ALT greater than 1.5 times ULN or gamma-glutamyl transferase (GGT) 
greater than 2 times ULN range. 

White blood cell (WBC) count < 3500/mm3 (< 3.5 x 109/L) Lymphocyte count < 
800/mm3 (< 0.8 x 109/L)

Serum IgG and/or serum IgM < lower limit of normal (according to central laboratory 
range)

Any other clinically significant laboratory assessment as determined by the 
Investigator (eg significant anemia, neutropenia, thrombocytopenia, signs of impaired 
bone marrow function)
18. Patients with severe hypoproteinaemia eg in nephrotic syndrome
19. Patients with any of the following neurologic/psychiatric disorders prior to randomization: 
Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Columbia -Suicide 
Severity Rating Scale (eCSSRS), 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. Ongoing substance abuse (drug or alcohol) or any other factor (ie
serious psychiatric condition, recurrent substance abuse) that may interfere with the 
subject’s ability to cooperate and comply with the study procedures. History of clinically 
significant CNS disease (eg stroke, traumatic brain or spinal injury, history or presence of 
myelopathy) or neurological disorders which may mimic MS
20. Patients unable or unwilling to undergo MRI scans
21. History of hypersensitivity to the study drug or excipients or to drugs of similar chemical 
classes 

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Note: If a patient fails on one or more laboratory (or other) assessment criteria, as part of the 
Screening process, the assessment(s) may be repeated at the discretion of the Investigator, and 
the patient may be included if criteria are then met, provided the assessments are completed 
within the Screening or Baseline time window. 
*If additional restrictions and/or assessments are required in order to comply with the local legal 
(eg in regards to a higher legal age for study participation) or regulatory (eg in regards to 
compliance with local prescribing information) requirements, the local requirements must be 
followed. No additional exclusions may be applied by the investigator, in order to ensure that 
the study population will be representative of all eligible patients.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Investigational drug will be provided in pre-filled syringes containing 20 mg ofatumumab 
(50 mg/ml, 0.4 ml content) or autoinjector containing 20 mg ofatumumab (50 mg/ml, 0.4 ml 
content) for subcutaneous administration. Ofatumumab is a clear to opalescent, colorless to pale 
yellow, essentially particle-free liquid. 
Study drug will be supplied by Novartis.
5.1.2
Additional treatment
No additional treatment beyond investigational drug is included in this trial.
5.2
Treatment arms
Subjects will be assigned at visit Day 1 to one of the following 4 treatment arms in a ratio of 
5:5:1:1

PFS (abdomen): ofatumumab 20 mg sc. injection with PFS administrated on abdomen

AI (abdomen): ofatumumab 20 mg sc. injection with AI administrated on abdomen

PFS (thigh): ofatumumab 20 mg sc. injection with PFS administrated on thigh

AI (thigh): ofatumumab 20 mg sc. injection with AI administrated on thigh
5.3
Treatment assignment and randomization
On Day 1 all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the patient.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the IRT 

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provider using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Drug Supply Management using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational devices as well as the assigned injection location. 
Randomization will be stratified by body weight (< 60 kg, 60-90 kg, > 90 kg).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding
Not applicable for this trial.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number assigned by Novartis. The subject 
number is composed of a site number and a sequential number. Once assigned to a patient, the 
Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in the electronic data capture (EDC) system. 
If an enrolled patient fails to be randomized or treated for any reason, the reason will be entered 
on the appropriate screening period CRF. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in the electronic data capture (EDC) system. The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. The site must select the CRF book with a matching Subject Number in the 
EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
Screening period CRF.
5.5.2
Dispensing the study drug
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 4 treatment arms and a specific visit. 
Investigator staff will identify the study drug package(s) to dispense to the patient by contacting 
the IRT and obtaining the medication number(s). Investigator staff will detach the outer part of 
the label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique subject number. 

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5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment
Not applicable to this trial.
5.5.4
Instructions for prescribing and taking study treatment
The study medication (ofatumumab injections) will be dispensed starting at the Randomization
Visit (Day 1). Drug will then be dispensed at planned visits throughout the treatment period 
according to Table 6-1. On Day 7 and Day 14, the same time-window (+/− 1 day) as for study 
visit applies. Starting at Week 4, the subcutaneous injections should be administered at 4-Week
(28 days) intervals (+/− 3 days).
All investigational drugs will be administered at site by a HCP/study nurse. The study 
medication will be administered as subcutaneous injections either to the abdomen or to the thigh 
depending on the randomization. For each of the two injection areas, study medication should 
be administered in an alternating fashion in accordance with the graphics in Figure 5-1
Alternation of injection areas for abdomen and thigh.
In order to assess tolerability of the initial dose of study medication patients will be closely 
monitored following administration for any reactions including injection related. Patients must 
remain at the site under observation for a minimum of approximately 5 hours following dosing 
on Day 1. Vital signs should be obtained 30-60 minute before sc injection (if premedication is 
administered, pre-injection vital signs should be obtained before premedication is administered), 
and again approximately 60 min post-injection on Day 1, 7, 14 and Week 4 and 8. 

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Figure 5-1
Alternation of injection areas for abdomen and thigh
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments and interruptions are not permitted during the study. 
Should the patient interrupt the study drug for whatever reason, re-start decision should be made 
on a case-by-case basis. 
5.5.6
Recommendations for the treatment of MS relapses
MS relapses may be treated with a standard short course of corticosteroids (eg
methylprednisolone) on an inpatient or outpatient basis. Steroid treatment should consist of       
3-5 days and up to 1,000 mg methylprednisolone/day or equivalent. The decision to treat should 
be based on Investigator’s judgment and/or local clinical practice. Standard of care will be 
followed during treatment.
Taper with oral steroids is not permitted.
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 relapse must be recorded on the appropriate 
CRF. 
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the appropriate CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
Premedication prior to sc injection
Premedication with acetaminophen and/or antihistamines (or equivalent) is recommended and 
may be administered at the discretion of the Investigator. Only for the first injection of treatment 
period (Day 1), the addition of premedication with steroids (methylprednisolone 100 mg iv or 

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equivalent) is recommended. Premedication should be administered 30 to 60 min prior to study 
drug injection.
Any administration of premedication must be recorded in the appropriate CRF.
The patients must be comprehensively informed (through the patient information and consent 
process) about the possibility that injection-related reactions may occur despite use of pre-
medications and about the possible symptoms of a systemic injection reaction and their 
management. Furthermore, patients must be reminded to always carry their Patient Card which 
includes the Investigator and site telephone contact numbers in case of an emergency.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 is NOT allowed in combination with study 
treatment, due to increased risk of immunosuppression and confounding of efficacy evaluations.
Exclusionary medications and washout periods for study eligibility are listed in the exclusion 
criteria (Section 4.2). Use of excluded medications is not allowed after randomization while the 
patient is on study medication.
Table 5-1
Prohibited medication
Medication
Action taken
Immunosuppressive/chemotherapeutic 
medications (including herbal) or procedures, 
including but not limited to cyclosporine, 
azathioprine, methotrexate, cyclophosphamide, 
mitoxantrone, cladribine, lymphoid irradiation and
hematopoietic/other stem cell transplantation
Discontinue study treatment, increase vigilance 
regarding infections.
NOTE: Restarting study treatment in patients 
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 such as but not limited to rituximab, 
ocrelizumab, ublituximab and obinutuzumab
Discontinue study treatment, increase vigilance 
regarding infections. 
NOTE: Restarting study treatment 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, siponimod, ozanimod, laquinimod, 
interferon beta, glatiramer acetate, dimethyl 
fumarate, teriflunomide, leflunomide, intravenous 
immunoglobulin, plasmapheresis or systemic 
corticosteroids (except for when given for MS 
relapse treatment as defined in Section 5.5.6).
Interrupt or discontinue study treatment, 
increase vigilance regarding infections.
Administration of any live or live-attenuated 
vaccine (including for measles) is prohibited while 
patients are exposed to study drug (long-lasting 
effects of the study drugs should be taken into 
consideration)
They may be administered when patients are 
no longer exposed to study drug. Consider 
risk/benefit and follow local labels
5.5.9
Emergency breaking of assigned treatment code
Not applicable for this trial. 

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5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
A patient will complete this study when the patient has completed the End of Study (EOS) visit.
Patients, who complete the EOS visit (Table 6-1) on study drug, may be eligible for inclusion 
in the planned umbrella extension study (under separate protocol).
Either patients who complete their EOS visits on study drug and do not enter the umbrella 
extension study (planned) or patients who prematurely discontinue study drug and complete 
their EOS visits will enter the Safety FU period (Table 6-2) for continued follow-up.
The Safety FU will complete when all patients who entered have been followed for the 
stipulated period of time (for at least 9 months after study drug discontinuation) (see Section 3.3) 
or have withdrawn participation prematurely.
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the Investigator.
The Investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Discontinuation of study treatment does not mean discontinuation from study. The patient 
should return to the site as soon as possible, after discontinuation of study drug, for EOS visit. 
EOS visit assessments (Table 6-1) should be completed and results recorded in the CRF. The 
Investigator must determine the primary reason for the patient’s premature discontinuation of 
study treatment and record this information on the appropriate CRF. 
Study treatment must be permanently discontinued under the following circumstances: 

Patient wish (withdrawal of consent Section 5.6.3)

Pregnancy (see Section 6.6.6 and Section 7.6)

Use of prohibited treatment (Table 5-1)

Diagnosis of PML

Patient with active serious infections or reactivation (eg 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 study participation might result in a safety risk to the patient

Protocol violation that results in a significant risk to the patient’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 HIV)

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
Laboratory abnormalities (eg liver function tests (LFT)) and abnormal test procedure as 
defined in Appendix 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 treatment
If the patient cannot attend any further study visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient, unless the 
patient has withdrawn informed consent (see Section 5.6.3). This telephone contact should 
preferably be done according to the study visit schedule
The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
Note: Patients who prematurely discontinue study drug and complete their EOS visits will enter 
the Safety FU period (Table 6-2) for continued follow-up (See Section 3.1, Section 5.6.1). The 
Investigator should consider the benefit/risk of initiation of alternative MS therapy in terms of 
the patient's clinical status, local regulations, treatment guidelines and local prescribing 
information.
5.6.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (eg telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US and Japan: 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. 

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For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
5.6.4
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her planned end of study visit has passed.
5.6.5
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, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. 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 patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
5.6.6
Role of Key site personnel
Key site personnel include (but are not limited to) the following individuals:
Investigator
The Investigator will be responsible for:

Overall conduct of the study at the study site including assigning per protocol required 
study staff

Management of the routine clinical care of the study patients

Administration and supervision of sc injections. The Investigator may delegate this 
responsibility to the Study Nurse/Study Coordinator as appropriate and permissible by 
local regulation

Confirmation of patient’s eligibility for randomization

Administration of EDSS

Management of adverse events and MS relapses

Ensuring that all site personnel are informed of concomitant medications excluded per 
protocol (eg the use of systemic steroids other than for the treatment of MS relapses or as 
pre-medication before injection)
It is strongly recommended that the Investigator remain unchanged throughout the entire course 
of the study. Occasionally, the Investigator may designate other medical personnel/health care 
professionals (eg, a back-up physician or Study Nurse/Study Coordinator) at the study site to 

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perform some of the tests and evaluations listed above. The Investigator is also responsible for 
ensuring access to appropriate expertise for consultation (eg infectious disease, ECG 
interpretation, mental health care) during the study as needed.
EDSS Rater – Investigator or delegate
The EDSS Rater will be responsible for:

Obtaining an EDSS score based on detailed neurological examination of patients with 
neurological symptoms consistent with MS relapse as referred by the Investigator at 
planned or unplanned visits

Obtaining an EDSS score based on detailed neurological examination at planned visits

EDSS is not blinded and therefore the investigator can serve as the EDSS rater
The EDSS Rater is a physician, or other trained healthcare professional who is qualified to 
perform the neurological examination and has been trained and certified as an EDSS rater.
To ensure consistency in the EDSS scoring across Raters, the EDSS Rater must participate in 
the standardized training and certification session on EDSS scoring (unless already certified at 
required level in past 12 months) prior to enrollment of patients at their site and will need to 
obtain recertification on a yearly basis. The EDSS Rater should remain the same throughout the 
study, whenever possible.
Study Nurse/Study Coordinator
The Study Nurse/Study Coordinator’s responsibilities may include:

Assisting the Investigator in patient management, including the assessment and treatment 
of adverse events, MS relapses and the recording of adverse events, concomitant 
medications and monitoring of compliance 

Administration of injections 
 

Scheduling visits and assessments as outlined in the protocol, maintaining proper source 
documentation and transcription of the data to the CRFs

Coordination with and between the study selected central labs, drawing and processing lab 
samples

Providing patient with a Patient Information Card identifying patients as study participant 
in a clinical trial with pertinent information and site contact information. 
MRI technician
The MRI technician will be responsible for:

Familiarization with the MRI manual procedures and the study specific MRI protocol

Performance of a “dry” or “dummy” run using the MRI parameters outlined by the MRI 
protocol

Performance of high-quality MRI scans using the study specific parameters stored in the 
designated MRI scanner for the duration of the study

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
Submission of the MRIs in the appropriate format to the central MRI reader immediately 
upon completion
Radiologist/Neurologist
The local radiologist/Neurologist will be responsible for:

Reviewing each MRI scan performed for the study patients and contacting the Investigator 
in case of unexpected or safety-related findings detected on the MRI scan
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Subjects must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. In case a visit is performed 
outside the schedule, subsequent visits shall be performed in keeping with the original visit 
schedule. In addition to the scheduled visits, patients may have unplanned 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 unplanned visits will be recorded in the unplanned visit 
CRFs. Patients who prematurely discontinue the study for any reason should be scheduled for 
a visit as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled and the 
adverse event and concomitant medications reconciled on the CRF.

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Table 6-1
Assessment schedule
Period
Screening/Pretreatment
Induction
Pharmacokinetics
Visit
SCR 
D-30 to D-8
BL 
D-7 to D1
D11
D4
D7
D14
W4
D28
W6
D42
W8
D56
W8
D57
W8
D59
W9
D63
W10
D70
W11
D77
EOS2/W12
D84
Visit No.
1
20
110
120
130
140
150
160
170
180
190
200
210
220
1999
Visit Window (hours or days)
n.a.
n.a.
n.a.
±1d
±1d
±1d
±1d
±3d
±1d
±1d
±1d
±2d
±2d
±2d
±2d
Informed consent
X
Demography, Height
X
Medical history
X
MS History/Treatments
X
Incl/Excl
X3
X
IRT contact
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
Premedication4
X
X
X
X
X
X
Vital signs5
X
X
X5
X5
X5
X5
X5
X
Weight
X
Routine lab samples including urine
X
X13
X
X
Physical Exam6
X9a
X9a
ECG
X9a
X9a
X
Sample for CD19+ B-cells and 
CD3+CD20+ T-cells
X
X
X
X
X
X
X
X
X
Pregnancy test7
X
X
X
X
X
Contraception status8
X
X
X
X
X
X
PK sampling prior to dosing
X
X
X10
X
X
X
X
X
X10
X10
X10
X10
X10
X
ADA sampling prior to dosing
X
X
X
X
Total IgM, IgG levels
X9a
X9a13
X
X
Serological markers for hepatitis A, B, 
C, and E
X

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Period
Screening/Pretreatment
Induction
Pharmacokinetics
Visit
SCR 
D-30 to D-8
BL 
D-7 to D1
D11
D4
D7
D14
W4
D28
W6
D42
W8
D56
W8
D57
W8
D59
W9
D63
W10
D70
W11
D77
EOS2/W12
D84
Visit No.
1
20
110
120
130
140
150
160
170
180
190
200
210
220
1999
Visit Window (hours or days)
n.a.
n.a.
n.a.
±1d
±1d
±1d
±1d
±3d
±1d
±1d
±1d
±2d
±2d
±2d
±2d
HIV test
X
eCSSRS
X9a
X9a
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/Con Meds12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Disposition
X
1.
Randomization and first dose (usually expected on the same day). If first dose occurs on a different day after randomization, the day of first dose 
should be considered to be Day 1. Patients must remain at the site under observation for a minimum of 5 hours following dosing on Day 1.
2.
EOS visit will be required for all patients (Patients who permanently discontinue study drug and patients who complete the study). Patients waiting for 
open label extension study to open can continue to receive study drug. Patients should return every 12 Weeks and complete all EOS assessments 
with the exception of PK, 
and ECG.
3.
Syphilis and Tuberculosis testing must be done as part of eligibility check (Exclusion criterion #10) unless completed in the last 6 months prior to 
screening with documented negative results. For tuberculosis testing, QuantiFERON®-TB Gold test can be done by the local lab to assess patient's 
eligibility at Screening.
4.
For the first injection (Day 1), the addition of premedication with steroids (methylprednisolone 100 mg iv. or equivalent) is recommended. 
Premedication with acetaminophen and/or antihistamines (or equivalent) is recommended and may be administered at the discretion of the 
Investigator. Premedication should be administered 30 to 60 min prior to study drug injection.
5.
Vital signs should be obtained 30-60 min before sc injection (if premedication is administered, pre-injection vital signs should be obtained before 
premedication is administered), and again approximately 60 min post-injection on Day 1, 7, 14 and Week 4 and 8.
6.
A complete physical examination will be performed at the visits indicated in Table 6-1 and will include an assessment of skin, head and neck, lymph 
nodes, heart, lungs, abdomen, back, neurological function and comments on general appearance. A complete neurological examination will be part 
of the initial physical examination at Screening.

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7.
Pregnancy test is conducted on female patients only: Serum pregnancy tests will be conducted at Screening and EOS visit. Urine pregnancy tests 
will be conducted at all other scheduled visits as indicated in Table 6-1 prior to dosing. The results will be captured in source documents.
8.
Patient’s contraception status must be reviewed and documented in source to ensure method of contraception continues to be appropriate per 
protocol requirement for highly effective contraception.
9.
a) Assessment can be conducted either at Screening OR Baseline visit. b) Assessment can be conducted at either the Baseline OR the Day 1 visit 
(they must be conducted before the first dose of investigational treatment. Labs must be drawn to allow adequate time for results to be obtained 
before randomization to ensure patient's eligibility
10. On non-injection visits the PK (Plasma) 
 samples can be drawn at any time during the visit.
 
12. Including corticosteroids used to treat MS relapse.
13. Labs must be drawn to allow adequate time for results to be obtained before randomization to ensure patient's eligibility.

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Table 6-2
Assessment schedule for Safety Follow-up period
Visit Week1
(relative to EOS)
+W12
+W24
+W36
Every 
12 Weeks2
End of Safety-FU3
Visit Number
410
420
430
440/4XX
2999
Visit window (days)
±14
±14
±14
±14
AEs
X
X
X
X
X
Concomitant Meds*
X
X
X
X
X
Vital Signs
X
X
X
X
X
eCSSRS
X
X
X
X
X
Urine pregnancy test4
X
X
X
X
X
Contraception status
X
X
X
X
X
Sample for Total IgG, IgM
X
X
X
X
X
Routine Labs
X
X
X
X
X
Follow up Disposition
X
W=week.
1.
Time measured from the EOS visit
2.
As needed for the patients requiring 
 (Section 3.1)
3.
If planned visit and End of Safety-FU occur at the same time only End of Safety-FU visit should be done. If patient is prematurely withdrawn 
from the Safety-FU period, the End of Safety-FU assessments should be done at the time of withdrawal
4.
Female patients only: monthly urine home pregnancy testing will be conducted between clinic visits. The patient must contact the Investigator 
immediately in the case of a positive test for confirmatory testing at the Investigator’s discretion
* including steroids for MS relapse and newly started disease modifying therapy as applicable

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6.1
Information to be collected on screening failures
For sites using RAVE for data collection, all patients who have signed informed consent and 
who have agreed to participate in the trial will fully complete Screening CRFs. Additionally all 
adverse events occurring after informed consent is signed will be recorded on the AE form. 
Investigators will have the discretion to record abnormal test findings on the medical history 
form whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature.
All subjects who have signed informed consent but not entered into the next period will have 
the disposition, demographics, inclusion/exclusion, informed consent, rescreening (only in case 
it is applicable for OMB study) withdrawal of consent (if subject withdrew consent) and serious 
adverse event (SAE) data collected. Adverse events that are not SAEs will be followed by the 
investigator or primary care physician and collected only in the source data.
6.2
Pharmacokinetics sampling
The primary objectives of this trial are depending upon the pharmacokinetics assessment of the 
study drug. Bioequivalence will be evaluated statistically based on AUCtau and Cmax values 
from individual patient time-concentration profiles of ofatumumab. Data from patients 
randomized to group 1 and 2 will be used for the bioequivalence assessment. Hence, it is of key 
importance that the dosing instructions, samples collection procedures and timing of visits 
during the study are followed closely. The dosing interval between Week 8 and Week 12 is of 
particular importance to obtaining accurately assessed bioequivalence data. Pharmacokinetics 
sampling has been scheduled prior to dosing on all dosing visits. The time window in which the 
respective visits should occur, is also specified in the assessment schedule (see Table 6-1). If, 
for some reason, the visit cannot be completed within the specified time window, the planned 
dose administration and associated blood sampling should still be carried out as close as 
possible to the originally planning time points. In all cases, the PK sample collection date and 
time must be recorded as instructed in the lab manual and entered in the appropriate CRF.
6.3
Patient demographics/other baseline characteristics
Patient demographic data and baseline characteristics to be collected on the appropriate CRF 
will include age, sex, race and ethnicity. Alcohol and smoking history and relevant medical 
history/current medical condition present before signing informed consent and any medications 
taken to treat these conditions will also be captured on the corresponding CRFs. Where possible, 
diagnoses, and not symptoms should 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), 
and previous MS treatment and will also be collected on the corresponding CRFs.
6.4
Treatment exposure and compliance
In order to collect accurate information about the study drug exposure, the following records 
should be maintained for each randomized patient: records of study medication dosages 

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administered and intervals between visits. These data should be transcribed on the appropriate 
CRFs. 
All study treatment dispensed must be recorded in the Drug Accountability Log.
6.5
Efficacy
The primary objective of this study is to demonstrate pharmacokinetic bioequivalence of 20 mg 
ofatumumab injected by the PFS or AI devices, as assessed by AUCtau and Cmax. MS efficacy 
assessments 
 will not be included in the CSR, but reported in a separate 
document at a later date. This data will be used to inform the Open-label Extension study for 
patients who continue into that study. This study includes the following efficacy assessments 
conducted at visits as shown in Table 6-1:
An overview of each of these assessments is provided in the sections below. Details of the 
administration of each of these assessments will be provided in the site manuals.

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6.5.5
Appropriateness of efficacy assessments
The 
, 
 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 patient population in terms 
of their MS disease status.
 
6.6
Safety
Safety assessments will include:

Adverse events

Physical examination (including skin)

Vital signs

Laboratory Evaluations

Pregnancy testing (females of childbearing potential)

ECG

Columbia Suicide Severity Rating Scale (eCSSRS) (Section 7.7)
Additional safety assessments may be conducted should these be requested by the local 
regulatory authority. Any new or worsening clinically relevant findings from such additional 
assessments meeting definition of an adverse event (AE) or serious AE should be recorded as 
AE/SAE (refer to Section 7).

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Medical history, including MS history and prior MS treatments will be assessed during the 
Screening. Concomitant medications will be assessed at every visit following informed consent. 
6.6.1
Physical examination
A complete physical examination will be performed at the visits indicated in the Study 
Assessments (Table 6-1) and will include an assessment of skin, head and neck, lymph nodes, 
heart, lungs, abdomen, back, neurological function and comments on general appearance. A
complete neurological examination will be part of the initial physical examination at Screening. 
Information for all physical examinations (including skin exams) must be included in the source 
documentation at the study site. All significant findings that are present prior to signing 
informed consent must be reported on the relevant medical history/current medical conditions 
CRF. Significant findings seen after signing the informed consent and being randomized meet 
the definition of an AE and must be recorded on the adverse events CRF.
6.6.2
Vital signs
Vital signs will include sitting pulse rate (measured as radial pulse for 60 seconds), sitting 
systolic and diastolic blood pressure and body temperature (oral, or per local practice) which 
will be assessed at the visits indicated in Table 6-1.
Vital signs should be obtained 30-60 min before sc injection and again approximately 60 min 
post-injection on Day 1, Day 7, Day 14, Week 4 and 8. If pre-medication is administered, the 
vital signs should be taken prior to pre-medication administration.
After the patient has been sitting for five min, with their back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured 3 times using an automated 
validated device (manual sphygmomanometer may be used if automated device is not available 
at the study site). The repeat sitting measurements of blood pressure and pulse will be made at 
1-2 min intervals. If an automated blood pressure device is used, it will need to have been 
calibrated according to the manufacturer’s guidelines. In case the cuff sizes available are not 
large enough for the patient’s arm circumference, a manual sphygmomanometer with an 
appropriately sized cuff may be used.
6.6.3
Height and weight
Height will be assessed at the Screening visit only.
Weight will be assessed at the visits indicated in Table 6-1. Body weight (to the nearest 0.1 kg) 
in indoor clothing, but without shoes, will be measured.
6.6.4
Laboratory evaluations
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.

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6.6.4.1
Hematology
Blood samples will be collected at the planned visits indicated in Table 6-1. The parameters 
assessed will include: red blood cell (RBC) count, hemoglobin, hematocrit, platelets, total WBC 
count, WBC differential counts (neutrophils, lymphocytes, basophils, eosinophils, monocytes), 
CD19+ B-cell counts and CD3+CD20+ T-cell counts.
6.6.4.2
Clinical chemistry
Blood samples will be collected at the planned visits indicated in Table 6-1. The parameters 
assessed will include: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, P), random glucose, total 
protein, blood urea nitrogen (BUN), albumin (Alb), alkaline phosphatase, ALT, AST, GGT, 
total bilirubin (TBL), conjugated bilirubin, creatinine, amylase, total cholesterol, triglycerides, 
high density lipoprotein (HDL) and low density lipoprotein (LDL), C-Reactive protein (CRP).
All patients with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 
other than drug-related adverse events is identified, even after study medication has been 
discontinued. Appendix 1 refers to liver events and Appendix 2 refers to renal events. 
6.6.4.3
Urinalysis
Urine will be collected at the planned visits indicated in Table 6-1 and the dipstick parameters 
assessed will include: blood, glucose, specific gravity 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.
6.6.4.4
Other
Testing of lab samples will be conducted at Screening to determine the patient’s eligibility for 
inclusion in the study with respect to hepatitis and HIV viruses, total IgG and IgM serology 
status. Testing for syphilis and tuberculosis at Screening is needed unless such testing has been 
done in the past 6 months with documented negative results (see Exclusion criterion 10, 
Section 4.2). QuantiFERON®-TB Gold test can be done locally or by the central lab to assess 
patient’s eligibility at Screening
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 (Ig) 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, patient 
can be randomized)

anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative, patient 
can be randomized) 

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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 CRF) that the serology results are considered false 
positive and may then randomize the patient.
Samples will additionally be collected during the study according to Table 6-1 and Table 6-2
for total IgM and IgG levels.
Additional samples for ADA, 
 will be taken 
(Section 6.6.1, Section 6.6.2, and Section 6.6.3).
6.6.5
Electrocardiogram (ECG)
An ECG will be performed at Screening or Baseline and EOS visits. Additional unplanned 
ECGs may be performed at Investigator’s discretion if clinically indicated.
Single 12 lead ECGs are collected. The ECG should be recorded (after 10 min rest in the supine 
position to ensure a stable reading) according to the local site practice. Clinically significant 
ECG findings at Baseline must be discussed with the Sponsor before administration of study 
treatment.
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF)
should be used for clinical decisions.
The original ECGs on non-heat-sensitive paper/and a certified copy on non-heat sensitive 
paper), appropriately signed, must be collected and archived at the study site. Each ECG tracing 
must be labeled with study number, subject number, date and time, and filed in the study site 
source documents.
Findings and clinically significant abnormalities must be recorded on the relevant section of the 
CRFs capturing medical history/current medical conditions and AEs.
6.6.6
Pregnancy and assessments of fertility
Serum pregnancy tests will be conducted for all women who are of child bearing potential at 
the Screening and EOS Visits. Urinary pregnancy tests will be conducted for all women who 
are of child bearing potential at all other planned clinic visits as indicated in Table 6-1.
In addition, the Investigator will review the contraception status with the patient at each visit 
per Table 6-1 to ascertain that the patient continues to comply with protocol requirements for 
highly effective contraception as applicable.
6.6.7
Appropriateness of safety measurements
The safety assessments included in this study (Table 6-1) are standard for the MS indication 
and study patient population and appropriate based on the current safety profile of ofatumumab 
iv. and sc (IB).

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The use of an instrument such as the eCSSRS to detect suicidal ideation or behavior is currently 
mandated in studies of CNS active drugs.
The safety assessments selected are standard for this indication/patient population.
6.7
Other assessments
6.7.1
Clinical Outcome Assessments (COAs)
Not applicable for this trial.
6.7.1.1
Clinician Reported Outcomes (ClinRO)
Not applicable for this trial.
6.7.1.2
Patient Reported Outcomes (PRO)
Not applicable for this trial.
6.7.1.3
Observer Reported Outcomes (ObsRO)
Not applicable for this trial.
6.7.1.4
Proxy Reported Outcomes
Not applicable for this trial.
6.7.1.5
Resource utilization
Not applicable for this trial.
6.7.2
Pharmacokinetics 
Subcutaneous administration of ofatumumab will occur on Day 1, Day 7, Day 14, Week 4, 
Week 8 and Week 12. 
 
 
 
 
 
 The secondary objectives include a pharmacokinetics evaluation of the two different 
injection areas also used in the Phase 3 studies (thigh and abdomen). Data from patients 
randomized to group 3 and 4 will be used for this assessment through comparison to data 
obtained from group 1 and 2, respectively (please refer to the study design overview in         
Figure 3-1). A description of the primary endpoints of the study can be found in Section 6.2. 
Further details on sample collection, numbering, processing and shipment will be provided in 
the Laboratory Manual provided to the sites.

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6.7.3
Immunogenicity
ADA will be assessed to evaluate the immunogenicity potential of ofatumumab. Sampling time 
points are provided in Table 6-1. Samples for ADA assessment should be taken prior to dosing 
at the visit. The ADA sample collection date and time must be entered on the appropriate CRF.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (eg, any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. 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 if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Clinically notable laboratory findings are defined 
according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03 will 
be used and can be found on the following web-site: http://ctep.cancer.gov). 
Adverse events must be recorded in the appropriate CRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information:

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
the [severity grade/Common Toxicity Criteria (CTC) AE grade]

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
If CTCAE grading does not exist for an adverse event, use 
1=mild
2=moderate
3=severe
4=life-threatening (see Section 7.2.1 for definition of SAE)

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 serious adverse event (SAE - See Section 7.2.1 or definition of 
SAE) and which seriousness criteria have been met.

action taken regarding (investigational) treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (eg further observation only) 

study treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2.1 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product 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 patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 

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source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
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:

is fatal or life-threatening 

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 (specify what this includes)

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

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 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, eg defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 Annex IV, ICH-E2D Guideline).
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 patient or might 
require intervention to prevent one of the other outcomes listed above. 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 Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.

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7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days (after the last study visit/ following the last 
administration of study treatment) if there are post-treatment follow-up visits with no required 
procedures must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Any SAEs experienced after the 30 day period (after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures) should only be reported to Novartis safety if the investigator suspects a causal 
relationship to study treatment. 
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. 
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 patient 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 Drug Safety and Epidemiology 
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.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.2.2.1
Reporting of 
 as SAE
 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 appropriate CRF capturing 
 instead of the SAE form. 
However, if, in the judgment of the Investigator, a 
 is unusually severe or medically 

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unexpected and warrants specific notification, then an SAE form must be completed and 
submitted according to SAE reporting procedures outlined above.
7.2.2.2
Reporting of Disability Worsening as SAE
Disability worsening is one of the efficacy endpoints in this study; hence it is exempt from SAE 
reporting although it may meet the SAE definition “results in persistent or significant 
disability/incapacity” (Section 7.2). However, if, in the judgment of the Investigator the 
disability worsening 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.
7.3
Liver safety monitoring
To ensure patient 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 (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring should be 
entered into the appropriate CRFs. Please refer to Table 13-1 in Appendix 1 for complete 
definitions of liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 1 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 1.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are associated 
with this event must be reported on the appropriate CRFs.
Repeat laboratory tests must be entered on the appropriate unplanned assessment CRFs.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (eg, disease, 
co-medications)

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
An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on the appropriate CRFs.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

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 
Every renal laboratory trigger or renal event as defined in Table 14-1 in Appendix 2 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 2.
7.5
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, 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 collected in 
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.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in CRF 
(Yes/No)
Document in AE 
CRF
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

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7.6
Pregnancy reporting
To ensure patient 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Patient Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
7.7
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (CSSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior. The CSSRS must be administered at each 
visit, including unplanned visits.
A validated version of the CSSRS will be used to capture self-reported CSSRS data via an 
interactive voice response telephone system (eCSSRS). The eCSSRS, which uses a semi-
structured interview to probe patient responses, will be administered by an individual who has 
received training and certification in its administration. At the first study visit, the 
“Baseline/screening” version of the eCSSRS will be administered. This version assesses 
Suicidal Ideation and Suicidal Behavior during the patient’s lifetime and during a predefined 
period. At subsequent visits, the “since last visit” version will be administered.
A validated version of the eCSSRS will be used to capture self-reported eCSSRS data via an 
interactive voice response telephone system (eCSSRS). The eCSSRS uses a detailed branched 
logic algorithm to perform the eCSSRS patient interview, evaluating each patient’s suicidality 
ideation and behavior in a consistent manner. At the conclusion of each assessment, the 
investigator will receive a detailed eCSSRS Findings Report via e-mail or fax. If the system 
assesses the patient as having positive suicidal signs, the investigator will be immediately 
notified by either fax, email and/or via telephone.
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the eCSSRS or “yes” on any item of the Suicidal Behavior section, 
the patient must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the patient is 
referred.
In addition, all life-threatening events must be reported as SAEs. For example, if a patient 
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. 

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All SAEs relating to suicidal behavior must be reviewed by the Novartis Safety Management 
team.
8
Data review and database management
8.1
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 (or CRFs) 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 patient 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.  
The investigator must maintain source documents for each patient 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 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
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 
subjects will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (CRFs) using fully validated secure web-enabled software that conforms to 
US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access to 
the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 

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8.3
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 is required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies 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 
Novartis.
ECG readings will be processed locally.
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis (or a designated CRO).
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed 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.
8.4
Data Monitoring Committee
A DMC is not required for this open label study
8.5        Adjudication Committee
Not applicable.
9
Data analysis
The analysis will be conducted on all subject 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.
9.1
Analysis sets 
BE analysis set: All patients randomized to PFS (Abdomen) or AI (Abdomen) treatment arms 
with PK data during dosing interval starting at Week 8.
PK analysis set: All patients randomized to PFS (Abdomen) or PFS (Thigh) or AI (Abdomen) 
or AI (Thigh) treatment arms with PK data during dose administrations.
Safety set: All patients randomized and have taken at least one dose of study drug.

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9.2
Patient demographics and other baseline characteristics
Demographics, MS disease history, 
, and MS medication history 
will be summarized based on the safety set.
9.3
Treatments
Patients are expected to take a total of 6 injections at Day 1, Day 7, Day 14, Day 28 (Week 4), 
Week 8 and Week 12. The number of injections actually taken will be summarized descriptively. 
Duration of exposure to ofatumumab study drug will be summarized by duration category (eg, 
number of patients exposed to study drug for at least 1 Week, 2 Weeks, 3 Weeks, 4 Weeks, 8 
Weeks and 12 Weeks will be provided). The number of patient-years is calculated as (the sum 
of the number of days of exposure for all patients in the group)/365.25 and will also be 
summarized. All summaries will be based on the safety set.
9.4
Analysis of the primary variable(s)
To address the primary objectives, comparisons on the primary endpoints from Week 8 to Week 
12 between PFS (abdomen) and AI (abdomen) will be made to test bioequivalence in these 2 
treatment groups.
9.4.1
Primary Variable(s)
The primary variables are pharmacokinetic endpoints, namely AUCtau and Cmax calculated 
from data collected in the dosing interval after Week 8 dose administration in accordance with 
the assessment schedule.
9.4.2
Statistical model, hypothesis, and method of analysis
To address the primary objective of testing bioequivalence at dosing interval after Week 8 
between PFS and AI, the primary analysis involves the two groups (PFS (abdomen) and AI 
(abdomen)). In the following, the PFS (abdomen) group will be referred to as the Reference (or 
R) group and the AI (abdomen) group as the Test group (or T).
The null hypothesis is that “Mean difference in ln (AUCtau) and/or ln (Cmax) greater than 
allowed-difference between these 2 groups” (H0:| −| > ∆). The alternative hypothesis is
that “Mean difference in ln (AUCtau) and ln (Cmax) less than allowed-difference between these 
2 groups” (Ha: | −| ≤∆). Ln refers to the natural log function. The testing procedure is 
described below.
As the testing for Average Bioequivalence (ABE) will be based on a between-groups 
comparison, the variabilities of the R and T groups are expected to be high, with a coefficient 
of variation (CV) greater than 0.3. Hence, the FDA recommended, Reference-scaled average 
bioequivalence (RSABE) bioequivalence approach for highly variable drugs is proposed.
As there is no FDA guidance for using RSABE in a parallel groups design, the current guidance 
for cross-over trials (Davit et al, 2012, Draft Guidance on Progesterone, 2011,) has been 
modified for application in a parallel groups design.
The between-subject variability for the R group will take the place of the within-subject 
variability for R.

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A mixed scaling approach will be used: (1) if the standard deviation of the R group data (on the 
log scale) exceeds 0.294, the traditional ABE limits of ln(0.8) and ln(1.25) will be scaled by the 
between-subject variability for the R group, (2) otherwise the standard TOST (two one-sided 
test) approach for (unscaled) ABE will be used. The regulatory constant used in the linearised 
criterion for the RSABE approach will be set to σ =0.25 (as in the recommended RSABE 
approach for cross-over trials).
The steps in the analysis will therefore be:
1. Calculate s the standard deviation of the R group subjects’ data on the log-scale (for 
AUCtau or Cmax).
2. If s < 0.294 then apply the standard ABE criteria, ie, determine if the 90% confidence 
interval for the mean difference between T and R on the log-scale, (μ −μ), lies within 
[-ln(1.25), ln(1.25)].
3. If s ≥0.294 then apply the reference scaled ABE criteria, ie, determine if, −θ ≤
( ! ")
"
≤θ where θ =
#$(%.&')
()
, and σ = 0.25 This is done by calculating an 
approximate 95% upper confidence bound for the linearised criterion, (μ −μ)& - θ
&
σ
&. If this upper bound is less than or equal to zero and the point estimate of the T/R 
geometric mean ratio (GMR) falls within (0.8, 1.25), then ABE is declared (ie, the null 
hypothesis is rejected). 
Testing will be performed as above for AUCtau and Cmax separately on the BE analysis set.
9.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed in general for any analyses. Only patients with non-missing 
data will be included in the relevant analyses. The BE analysis set is defined to include patients 
randomized to PFS (Abdomen) or AI (Abdomen) treatment arms with PK data during dosing 
interval starting at Week 8. Patients without PK data during that dosing interval will not be 
included in the BE analysis.
9.4.4
Sensitivity analyses
No sensitivity analysis is planned.
9.5
Analysis of secondary variables
Summary statistics of AUCtau and Cmax by time point will be provided for each of the four 
treatment groups on the PK analysis set.
Proportion of patients with positive ADA will be provided by time point and overall for each 
of the four treatment groups on the safety set. The proportion will be based on patients with 
non-missing ADA results at the evaluation time point.
9.5.1
Efficacy variables 
Efficacy variables include 
, 
, 
, 
 
Efficacy data are collected in order to evaluate long term treatment effect after patients continue 
into the open label long term study. Data analyses on efficacy variables are not planned for the 
CSR of this study.

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9.5.2
Safety variables
Safety variables include the number of patients with at least one AE or injection related reaction, 
the number of patients meeting abnormal criteria and change from baseline in all relevant 
parameters of lab, vital signs, and ECG evaluations, and the number of patients meeting 
predefined criteria as collected in eCSSRS. For all safety variables, descriptive statistics will be 
provided on the safety set.
9.5.3
Resource utilization
Not applicable for this trial.
9.5.4
Pharmacokinetics
The pharmacokinetics parameters will be calculated using the standard NCA module of 
Winnonlin.
9.5.5
DNA
Not applicable for this trial.
9.7
Interim analyses
As this is an open-label study with primary objective of pharmacokinetic endpoints and no 
interim analyses on which statistical comparisons will be made is planned, there is no relevance 
on blinding or alpha-adjustment.
Periodic interim safety analyses to support regulatory updates and interim reports may be 
warranted.
An interim analysis will be conducted to assess the variability of data as measured by coefficient 
of variation (CV) when approximately 36 patients total randomized in the PFS (abdomen) and 
AI (abdomen) treatment groups have completed Week 12. The purpose of this interim analysis 
is to provide an opportunity to increase the sample size so that sufficient power for the 
bioequivalence testing can still be achieved in case the estimated CV is larger than the assumed 
value of 85% at design stage. If deemed necessary, the sample size for the bioequivalence 
testing can be increased from 120 to a maximum of 250 completed patients.

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9.8
Sample size calculation
The grand total sample size of this study is estimated by sum of the estimated sample size in all 
4 treatment groups.
Section 9.8.1 provides sample size calculation for groups 1 and 2, which are used to address 
our primary objective. This sample size may be increased by the results of the interim analysis.
Section 9.8.2 provides sample size calculation for groups 3 and 4. This sample size will not be 
impacted by the results of the interim analysis.
9.8.1
Sample size calculation for PFS (abdomen) and AI (abdomen)
A total of 120 patients (60 per arm) will be required to achieve 90% power in the testing of 
bioequivalence between these two groups assuming their geometric mean ratio (GMR) = 1 and 
the coefficient of variation (CV) = 85%, which are considered reasonable and conservative 
assumptions according to previous experience with the variability of drug concentration 
pharmacokinetic parameters. To account for 3% dropout, a total of 124 patients (62 per arm) 
will be randomized. The dropout rate assumption is based on data observed in the on-going 
Phase III studies. 
Due to limited PK data in the existing databases, CV can’t be assessed accurately. Therefore, 
an interim analysis is planned to re-assess the CV of Cmax and AUCtau. Details are as described 
in Section 9.7. If deemed necessary, the sample size for the BE testing can be increased to a 
maximum of 250 (125 per arm), in which case, the total number of patients to be randomized 
will be is 258 (129 per arm) accounting for 3% dropout. The maximum sample size will provide 
approximately 80% power if the true CV is as high as 240%.
The sample size calculation is based on simulation for the testing procedure via a mixed scaling 
approach as described in Section 9.4.2. Specifically, for a given CV on the natural scale, which 
is assumed to be the same for the two groups, and an assumed value of the GMR, 10,000 parallel 
groups trials with a given total sample size n are simulated and the proportion of trials that lead 
to a decision to declare ABE are recorded. If this value of n does not give a power greater than 
or equal to 0.9 then the n is increased in steps of 2, until a power of 0.9 is first achieved or 
exceeded. This n is then taken as the sample size that gives 90% power for the chosen values 
of CV and GMR. The estimated sample sizes for a range of values of CV and three values 
assumed for the GMR are given in below table.

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As a comparison, the sample sizes required to achieve a power of 0.9, when the standard test 
(TOST) for ABE is used with a parallel groups design, are given in below table.
For true CV values larger than 0.30, the Type I error rate is controlled at true mean difference 
values equal to the FDA implied limits [+/- (log(1.25)/0.25)* σ ] on the log-transformed scale 
(see, Davit et. al 2012), where CV=+,-. −1.
9.8.2
Sample size calculation for PFS (thigh) and AI (thigh)
Sample size requirement is based on a conventional size of studies for an evaluation of 
pharmacokinetic endpoints in treatment groups with different administration sites (ie, 
comparing PFS (abdomen) vs. PFS (thigh) or comparing AI (abdomen) vs. AI (thigh)). No 
formal statistical testing is planned. 

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A total of 24 patients (12 per arm) will be required for PFS (thigh) and AI (thigh) groups. This 
is in alignment with sample size often applied to standard pharmacokinetic studies.
For an estimation of mean difference in the two groups of different administration sites 
(abdomen (n=60) vs. thigh (n=12)), the width of 90% CI will be 0.78 assuming the CV is 85%. 
To account for 3% dropout, a total of 26 patients (13 per arm) will be randomized.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and with the ethical 
principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such consent 
has been provided by a legally acceptable representative(s) of the patient. Informed consent 
must be obtained before conducting any study-specific procedures (eg all of the procedures 
described in the protocol). The process of obtaining informed consent must be documented in 
the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
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 requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study.
10.3
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, 
informed consent form, consent form updates, subject recruitment procedures (eg, 
advertisements) and any other written information to be provided to subjects. 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 

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requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
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 subjects 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, 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. 
11.1
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 intended to eliminate an apparent immediate hazard 
to subjects may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 

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need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
Archelos JJ, Storch MK, Hartung HP (2000) The role of B-cells and autoantibodies in 
multiple sclerosis. Ann Neurol; 47:694-706.
Arzerra® US prescribing information (1/2016). 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf.
Bouaziz JD, Yanaba K, Venturi GM, et al (2007) Therapeutic B-cell depletion impairs 
adaptive and autoreactive CD4+ T-cell activation in mice. Pro. Natl. Acad. Sci. USA; 
104:20878-83.
Davit et al (2012) FDA Draft Guidance on Progesterone. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm209294.pdf
Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis – the plaque and its 
pathogenesis. New Engl J Med; 354:942-55.
Hauser SL, Waubant E, Arnold DL, et al (2008) B-cell Depletion with Rituximab in 
Relapsing-Remitting Multiple Sclerosis. New Engl J Med; 358:676-88.
Hauser SL, Bar-Or A, Comi G, et al (2017) Ocrelizumab versus Interferon Beta-1a in 
Relapsing Multiple Sclerosis. New Engl J Med; 376(3):221-34.
Kappos L, Li D, Calabresi PA, et al (2011) Ocrelizumab in relapsing-remitting multiple 
sclerosis: a Phase 2, randomized, placebo-controlled, multicentre trial. Lancet; 378:1779-87.
Klein C, Lammens A, Schaefer W et al (2013) Epitope interactions of monoclonal antibodies 
targeting CD20 and their relationship to functional properties. mAbs; 5:1, 22-23.
Lehmann-Horn K, Kronsbein HC, Weber MS (2013) Targeting B-cells in the Treatment of 
Multiple Sclerosis. Ther Adv Neurol Disorders; 6(3):161-73.
Lublin FD, Reingold SC, Cohen JA, et al (2014) Defining the clinical course of multiple 
sclerosis. Neurology; 83:278-86.
Lund FE (2008) Cytokine-producing B lymphocytes – key regulators of immunity. Curr Opin 
Immunol; 20(3):332-8.
McDonald WI, Compston A, Edan G, et al (2001) Recommended diagnostic criteria for 
multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple 
sclerosis. Ann Neurol; 50:121-27.
McFarland HF (2008) The B-cell–old player, new position on the team. N Engl J Med; 
358:664-5.
Panitch H, Goodin DS, Francis G, et al (2002) Randomized, comparative study of interferon 
beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology; 59(10):1496-506.

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Polman CH, Reingold SC, Banwell B, et al (2011) Diagnostic criteria for multiple sclerosis: 
2010 revisions to the McDonald criteria. Ann Neurol; 69:292-302.
Soerensen PS, Lisby S, Grove R, et al (2014) Safety and efficacy of ofatumumab in relapsing-
remitting multiple sclerosis. Neurology; 82:573-81.
Teeling JL, French RR, Cragg MS et al (2004) Characterization of new human CD20 
monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 
104:1793-1800
Wingerchuk DM, Lennon VA, Pittock SJ, et al (2006) Revised diagnostic criteria for 
neuromyelitis optica. Neurology; 66:1485-9.
Xu, Z, Wang Q, Zhuang Y, et al Subcutaneous Bioavailability of Golimumab at 3 Different 
Injection Sites in Healthy Subjects. The Journal of Clinical Pharmacology, 50: 276–284. 
doi:10.1177/0091270009340782

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13
Appendix 1: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 13-1
Liver Event and Laboratory Trigger Definitions
Definition/threshold
LIVER LABORATORY TRIGGERS
3 × ULN < ALT/AST ≤5 × ULN
1.5 × ULN < TBL ≤2 × ULN
LIVER EVENTS
ALT or AST > 5 × ULN
AP > 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 AP 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
INR=International normalized ratio
Table 13-2
Follow-Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Discontinue the study treatment 
immediately
Hospitalize, if clinically appropriate
Establish causality 
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)
ALT or AST
> 8 × ULN
Discontinue the study treatment 
immediately
Hospitalize if clinically appropriate
Establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)

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Criteria
Actions required
Follow-up monitoring
> 3 × ULN and 
INR > 1.5
Discontinue the study treatment 
immediately
Hospitalize, if clinically appropriate
Establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs.
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT 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 AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)
> 3 × ULN 
accompanied by 
symptomsb
Discontinue the study treatment 
immediately
Hospitalize if clinically appropriate
Establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)
> 3 to ≤5 × ULN 
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)
Repeat LFT within 48 hours
If elevation persists, establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
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 AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)
Test for hemolysis (eg, reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)

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Criteria
Actions required
Follow-up monitoring
> 1.5 to ≤2 × ULN 
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice
Discontinue the study treatment 
immediately
Hospitalize the patient
Establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
ALT, AST, TBL, Alb, PT/INR, AP 
and GGT until resolutionc (frequency 
at Investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
Consider study treatment interruption or 
discontinuation
Hospitalization if clinically appropriate
Establish causality
Record AE/SAE and any contributing 
factors (concomitant medications, other 
co-morbid conditions/procedures) in the 
appropriate CRFs
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in AP 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.
PT=prothrombin time

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14
Appendix 2: Specific Renal Alert Criteria and Actions
Table 14-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25-49% compared to baseline
Confirm 25% increase after 24-48 hours
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 patient hospitalization/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 24-48 hours
Perform urine microscopy
Consider study treatment interruption/or 
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
For all renal events:
Record AE/SAE and any contributing factors (concomitant medications, other co-morbid 
conditions/procedures) in the appropriate CRFs.
Monitor patient regularly (frequency at Investigator’s discretion) until either: 
Event resolution: sCR within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCR level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.

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15
Appendix 3: Safety monitoring Guidance
15.1
Guidance on monitoring of patients with symptoms of 
neurological deterioration suggestive of PML
Should a patient develop any unexpected neurological or psychiatric symptom/signs in the 
opinion of Investigator (eg cognitive deficit, behavioral changes, cortical visual disturbances or 
any other neurological cortical symptoms/signs any symptom/sign suggestive of an increase of 
intracranial pressure) or accelerated neurological deterioration, the Investigator should schedule 
a complete physical and neurological examination and an MRI as soon as possible before 
beginning any steroid treatment. Conventional MRI as defined in the protocol as well as 
additional scanning such as Fluid-Attenuated Inversion Recovery (FLAIR) and Diffusion-
weighted imaging (DWI) sequences are recommended to aid in differential diagnosis. The MRI 
must be evaluated by the local radiologist/neurologist. The Investigator will contact the Medical 
Advisor at Novartis to discuss findings and diagnostic possibilities as soon as possible. A copy
of the unplanned MRI should be sent to the MRI Evaluation Center designated by the Sponsor 
as soon as possible. AE/SAEs need to be filed as appropriate.
If the MRI shows new MS lesions consistent with a
 
 
. 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, PCR, and microbiological analysis (eg herpes virus, JC 
virus) to confirm/exclude an infection should be performed. In the event of suspected CNS 
infection (PML), a CSF aliquot should be sent to a central laboratory (designated by the Sponsor) 
for confirmatory testing.
Only after the evaluations have excluded diagnoses other than MS and after discussion with the 
Medical Advisor at Novartis, the study drug may be restarted.
15.2
Guidance on monitoring of patients with infections
All infections that develop during the study will be reported as AEs on the appropriate CRF
capturing AEs. Treatment and additional evaluations will be performed at discretion of the 
Investigator.
The Investigator should remind the patient of the risk of infections and instruct them to promptly 
report any symptoms of infections to the Investigator. The patients must also be reminded to
always carry their Patient 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 Sponsor Medical 
Advisor of any such cases.

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When evaluating a patient with a suspected infection, the most sensitive tests available should 
be used (ie that directly detect the pathogen, as with PCR).
The Investigator should consider early treatment with specific antimicrobial therapy on the 
basis of clinical diagnosis or suspicion thereof in consultation with infectious disease experts, 
as appropriate. The Investigator should inform the Sponsor Medical Advisor 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 oncology patients treated with ofatumumab, cases of fatal HBV reactivation and fatal 
infection due to hepatitis B in patients who have not been previously infected have occurred 
(refer to local ARZERRA® prescribing information). This study excludes the patients who are 
at potential risk of HBV reactivation (See Section 4.2 Exclusion criterion 11). In patients with 
suspicion of HBV infection during the study, laboratory testing for HBV should be done. For 
patients who show new evidence of HBV infection [HBs antigen positive (regardless of 
antibody status) or HBs antigen negative but HBc IgM/IgG antibody positive], the Investigator 
is advised to consult with physicians with expertise in managing hepatitis B regarding 
monitoring and consideration for HBV antiviral therapy.
Patients with new active HBV infection should immediately discontinue study drug and 
institute appropriate treatment and follow-up.
15.3
Guidance on immunization
The safety of and ability to generate a primary or anamnestic response to immunization with 
live, live-attenuated or inactivated vaccines during ofatumumab treatment has not been 
investigated. The response to vaccination could be impaired due to B-cells depletion.
It is recommended that the Investigator review the patient's immunization history as part of the 
initial Screening procedure for a patient being considered for treatment with ofatumumab. 
Vaccination of the patient, in compliance with local area vaccination guidelines for the patient 
population being treated, is recommended prior to administration of ofatumumab. In particular, 
prior to administration of ofatumumab, hepatitis B vaccination, in patients with risk factors for 
hepatitis B infection or in areas with a high prevalence of hepatitis B, as per local area treatment 
guidelines should be considered.
Administration of live or live-attenuated vaccines must be avoided during and after 
treatment with ofatumumab and until B-cell counts are normalized.
15.4
Guidance on monitoring of patients with low immunoglobulin 
levels
After baseline, the immunoglobulin levels (IgM and IgG) will be measured at Week 4 and EOS 
by the central laboratory. They will only be communicated to the site after baseline in case of 
notably low levels. A notably low IgG level is defined as a level that is 20% below the LLN 
and a notably low IgM level is defined as a level 10% below the LLN. Following notification, 
the immunoglobulin level should be repeated within 2 weeks by the central lab to confirm the 
reading. If the repeated test confirms the immunoglobulin level to be below the threshold, the 

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study drug must be discontinued and the immunoglobulin levels needs to be monitored at the 
Investigator’s discretion until levels return back to normal limits. The patient should be 
evaluated and monitored for infections on a regular basis. Immunoglobulin substitution therapy 
as pert local medical practice is allowed. Re-initiation of the study drug can only be considered 
once the immunoglobulin levels are back within normal limits.