Clinical trial NCT03249714
Conditions: Relapsing Multiple Sclerosis
Keywords: double-blind placebo controlled ofatumumab relapsing multiple sclerosis Japanese patients MS RMS adult OMB157
Sponsor: Novartis Pharmaceuticals
Start date: 2018-03-15; Completion date: 2020-07-29
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study provided efficacy, safety, and pharmacokinetics (PK) data for patients with relapsing multiple sclerosis (RMS) in Japan and the other countries

Detailed description:
This study had 2 parts: A controlled Core and an open-label Extension.

* Core part: A 24-week, randomized, double-blind, placebo controlled, parallel-group, multicenter study evaluated the efficacy, safety and tolerability and PK of ofatumumab in patients with RMS.
* Extension part: The Core part was followed by an Extension part in which all patients received open-label ofatumumab. In the Extension part, patients were treated for at least 24 weeks and no longer than 48 weeks.

Sixty-four patients were randomized in a 2:1 ratio to ofatumumab or placebo in the Core part; half of the study patients were from Japan and the other half from the other countries.

Arms: arm 1: Ofatumumab 20 mg subcutaneous injection on Days 1,7, 14 and every 4 weeks for 24 weeks in Core. Core placebo patients received loading dose at Weeks 25 and 26 and then all Extension patients received dose every 4 Weeks up to Week 48. arm 2: Placebo subcutaneous injection matching to ofatumumab every 4 weeks for 24 weeks in Core
Interventions: intervention 1: Ofatumumab intervention 2: Matching placebo of ofatumumab
Intervention descriptions: intervention 1: Provided in pre-filled syringes for subcutaneous injection (s.c.) administration containing 20 mg ofatumumab (50 mg/mL, 0.4 mL content) intervention 2: Matching placebo in pre-filled syringes

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine
OMB157/Ofatumumab
Clinical Trial Protocol COMB157G1301 / NCT03249714
A 24-week, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study to evaluate the efficacy, 
safety and pharmacokinetics of ofatumumab in patients 
with relapsing multiple sclerosis followed by an extended 
treatment of at least 24 weeks with open-label ofatumumab
Document type:
Amended Protocol Version
EUDRACT number:
2017-003231-10
Version number:
01 (Clean)
Clinical trial phase:
II
Release date:
03-Oct-2017
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 ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................12
Amendment 1 ....................................................................................................................15
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Objectives and related endpoints...........................................................................19
2.1.1
Primary objective(s)..............................................................................19
2.1.2
Secondary objective(s)..........................................................................20
20
3
Investigational plan ...........................................................................................................21
3.1
Study design...........................................................................................................21
3.1.1
Core part................................................................................................21
3.1.2
Extension part........................................................................................22
3.1.3
Safety FU period ...................................................................................22
3.2
Rationale for study design .....................................................................................23
3.3
Rationale for dose/regimen, route of administration and duration of treatment....24
3.4
Rationale for choice of comparator .......................................................................26
3.5
Purpose and timing of interim analyses/design adaptations..................................26
3.6
Risks and benefits..................................................................................................27
4
Population..........................................................................................................................28
4.1
Inclusion criteria ....................................................................................................28
4.2
Exclusion criteria...................................................................................................28
5
Treatment...........................................................................................................................33
5.1
Study treatment......................................................................................................33
5.1.1
Investigational and control drugs..........................................................33
5.1.2
Additional treatment..............................................................................33
5.2
Treatment arms......................................................................................................33
5.3
Treatment assignment and randomization.............................................................33
5.4
Treatment blinding.................................................................................................34


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5.5
Treating the patient................................................................................................35
5.5.1
Patient numbering .................................................................................35
5.5.2
Dispensing the study drug.....................................................................35
5.5.3
Handling of study and additional treatment..........................................35
5.5.4
Instructions for prescribing and taking study treatment........................36
5.5.5
Permitted dose adjustments and interruptions of study treatment ........37
5.5.6
Recommendations for the treatment of MS relapses ............................38
5.5.7
Concomitant medication .......................................................................38
5.5.8
Prohibited medication ...........................................................................39
5.5.9
Emergency breaking of assigned treatment code..................................40
5.6
Study completion and discontinuation...................................................................40
5.6.1
Study completion and post-study treatment..........................................40
5.6.2
Discontinuation of study treatment .......................................................41
5.6.3
Withdrawal of informed consent...........................................................42
5.6.4
Loss to follow-up ..................................................................................43
5.6.5
Early study termination by the sponsor.................................................43
5.6.6
Role of Key site personnel ....................................................................43
6
Visit schedule and assessments .........................................................................................45
6.1
Information to be collected on screening failures..................................................51
6.2
Patient demographics/other baseline characteristics .............................................51
6.3
Treatment exposure and compliance .....................................................................52
6.4
Efficacy..................................................................................................................52
6.4.1
MS Relapse ...........................................................................................52
6.4.2
Expanded Disability Status Scale (EDSS)............................................53
6.4.3
Magnetic Resonance Imaging (MRI)....................................................54
55
6.4.5
Appropriateness of efficacy assessments..............................................55
6.5
Safety.....................................................................................................................55
6.5.1
Physical examination ............................................................................56
6.5.2
Vital signs..............................................................................................56
6.5.3
Height and weight .................................................................................57
6.5.4
Laboratory evaluations..........................................................................57
6.5.5
Electrocardiogram (ECG) .....................................................................58
6.5.6
Pregnancy and assessments of fertility .................................................59
6.5.7
Appropriateness of safety measurements..............................................59
6.6
Other assessments..................................................................................................59
6.6.1
Pharmacokinetics ..................................................................................59


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6.6.2
Immunogenicity ....................................................................................60
60
7
Safety monitoring..............................................................................................................60
7.1
Adverse events.......................................................................................................60
7.2
Serious adverse events...........................................................................................62
7.2.1
Definition of SAE .................................................................................62
7.2.2
SAE reporting........................................................................................63
7.3
Liver safety monitoring .........................................................................................64
7.4
Renal safety monitoring.........................................................................................65
7.5
Reporting of study treatment errors including misuse/abuse ................................65
7.6
Pregnancy reporting...............................................................................................66
7.7
Prospective suicidality assessment ........................................................................66
8
Data review and database management.............................................................................67
8.1
Site monitoring ......................................................................................................67
8.2
Data collection.......................................................................................................67
8.3
Database management and quality control............................................................68
8.4
Data Monitoring Committee..................................................................................68
9
Data analysis......................................................................................................................69
9.1
Analysis sets ..........................................................................................................69
9.2
Patient demographics and other baseline characteristics.......................................70
9.3
Treatments .............................................................................................................70
9.4
Analysis of the primary variable(s) .......................................................................70
9.4.1
Primary Variable(s)...............................................................................70
9.4.2
Statistical model, hypothesis, and method of analysis..........................70
9.4.3
Handling of missing values/censoring/discontinuations.......................71
9.4.4
Sensitivity analyses ...............................................................................71
9.4.5
Consistency across regions ...................................................................71
9.5
Analysis of secondary variables ............................................................................71
9.5.1
Efficacy variables (Core part) ...............................................................71
9.5.2
Safety variables (Core part) ..................................................................72
9.5.3
DNA......................................................................................................74
9.5.4
PK/PD ...................................................................................................74
9.5.5
Immunogenicity assessment..................................................................74
75
75
9.7
Analysis of the Extension part...............................................................................75
9.8
Interim analyses.....................................................................................................75


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9.9
Sample size calculation..........................................................................................75
9.9.1
Evaluation of consistency in the treatment effect on the primary 
variable across regions..........................................................................76
9.9.2
Numerical comparison of annualized relapse rate (ARR) ....................76
10 Ethical considerations........................................................................................................77
10.1
Regulatory and ethical compliance........................................................................77
10.2
Informed consent procedures.................................................................................77
10.3
Responsibilities of the investigator and IRB/IEC..................................................77
10.4
Publication of study protocol and results...............................................................78
10.5
Quality Control and Quality Assurance.................................................................78
11 Protocol adherence ............................................................................................................78
11.1
Protocol amendments.............................................................................................78
12 References .........................................................................................................................79
13 Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................81
14 Appendix 2: Specific Renal Alert Criteria and Actions....................................................84
15 Appendix 3: Safety monitoring Guidance.........................................................................85
15.1
Guidance on monitoring of patients with symptoms of neurological 
deterioration suggestive of PML ...........................................................................85
15.2
Guidance on monitoring of patients with infections..............................................85
15.3
Guidance on immunization....................................................................................86
15.4
Guidance on monitoring of patients with low immunoglobulin levels .................86
List of tables
Table 5-1
Prohibited medication ...........................................................................39
Table 6-1
Assessment schedule.............................................................................47
Table 6-2
Assessment schedule for Safety Follow-up period ...............................51
Table 6-3
Severity of MS relapse..........................................................................53
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................66
Table 9-1
Probability to observe a difference in Gd-lesion reduction across 
regions of more than delta.....................................................................76
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................81
Table 13-2
Follow-Up Requirements for Liver Events and Laboratory Triggers...81
Table 14-1
Specific Renal Alert Criteria and Actions.............................................84


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List of figures
Figure 3-1
Study design..........................................................................................23


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List of abbreviations
ACR
Albumin/Creatinine Ratio
ADA
Anti-drug-antibody
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
Alb
Albumin
ALT
Alanine Aminotransferase
AP/ALP
Alkaline Phosphatase
ARR
Annualized Relapse Rate
AST
Aspartate Aminotransferase
AV
Atrioventricular
BIL
Bilirubin
BUN
Blood Urea Nitrogen
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CFR
Code of Federal Regulations
CLL
Chronic Lymphocytic Leukemia
CNS
Central Nervous System
CQA
Compliance Quality Assurance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSF
Cerebrospinal fluid
(e)CSSRS
(electronic) Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Forms
EDC
Electronic Data Capture
EDSS
Expanded Disability Status Scale
EMA
European Medicines Agency
EOS
End of Study
EU
European Union
FAS
Full Analysis Set
FS
Functional Score
FU
Follow-up
GCP
Good Clinical Practice
Gd
Gadolinium
GGT
Gamma-Glutamyl-Transferase
HA, HB, HC, HE
Hepatitis A, B, C, E


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HBc
Hepatitis B core
HBV, HCV, HEV
Hepatitis B Virus, Hepatitis C Virus, Hepatitis E Virus
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICH
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention-To-Treat
iv
Intravenous(ly)
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLQ
Lower Limit of Quantification
mAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Image
MS
Multiple Sclerosis
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PK
Pharmacokinetic
PML
Progressive Multifocal Leukoencephalopathy
PPS
Per-Protocol Set
q4, q12
Every 4, every 12
QM
Quality Management
QTcF
The Fridericia QT correction formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RPR
Rapid Plasma Reagin
RRMS
Relapsing-Remitting MS
SAE
Serious Adverse Event
SAF
Safety Set
sc
Subcutaneous(ly)
sCR
Serum Creatinine
SPMS
Secondary progressive MS
TBIL/TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
ULN
Upper Limit of Normal
US
United States


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WBC
White Blood Cell
WHO
World Health Organization


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Glossary of terms
Cohort
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits.
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures described 
in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with United States (US) Code of Federal Regulations
(CFR) 21 Section 312.3 and is synonymous with “investigational new 
drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
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/subjects 
with established disease and in those with newly-diagnosed disease.
Patient/subject ID
A unique number assigned to each patient upon signing the informed 
consent
Period
The subdivisions of the trial design (e.g. Screening, Treatment, 
Follow-up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
Study drug/treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
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Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
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Protocol summary
Protocol number
COMB157G1301
Full Title
A 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the efficacy, safety and pharmacokinetics of 
ofatumumab in patients with relapsing multiple sclerosis followed by an 
extended treatment of at least 24 weeks with open-label ofatumumab
Brief title
Study of efficacy and safety of ofatumumab compared to placebo in 
patients with relapsing multiple sclerosis followed by extended treatment 
with open-label ofatumumab
Sponsor and Clinical 
Phase
Novartis
Phase 2
Investigation type
Biological (human Immunoglobulin G (IgG) 1k lytic monoclonal antibody 
(mAb) to human CD20 antigen)
Study type
Interventional 
Purpose and rationale
This study is designed, in conjunction with the global Phase 3 studies 
(COMB157G2301 and COMB157G2302), to provide the necessary data to 
support registration of ofatumumab for the treatment of relapsing multiple 
sclerosis (MS) in Japan.
The study will provide efficacy, safety, tolerability and pharmacokinetics
(PKs) data for ofatumumab 20 mg subcutaneous (sc) injections every 4 
weeks (q4) compared with placebo for 24 weeks in patients from Japan
(neither Caucasian nor African) and the other countries (mainly 
Caucasian, not East Asian) and also provide the extended efficacy, safety, 
tolerability and pharmacokinetics data.
Primary Objective(s)
Demonstrate that ofatumumab is superior to placebo in reducing the
cumulative number of Gadolinium (Gd)-enhanced T1 lesions across 4 
Magnetic Resonance Image (MRI) scans at Week 12, 16, 20 and 24 in 
patients with relapsing MS
Secondary Objectives
Core part
Assess the consistency of the efficacy of ofatumumab versus placebo 
across regions (Japan vs other countries) in the cumulative number of 
Gd-enhanced T1 lesions on MRI scans at Week 12, 16, 20 and 24.
Assess the efficacy of ofatumumab versus placebo in the number of new 
or enlarging T2 lesions on MRI scans
Assess the efficacy of ofatumumab versus placebo in annualized relapse 
rate (ARR) and time to first relapse
Assess the safety and tolerability of ofatumumab versus placebo
Assess the similarity of the PK and B-cell count following the treatment 
with ofatumumab across regions (Japan vs other countries)
Extension part (including Core part)
Assess extended safety and tolerability of ofatumumab
Assess extended efficacy of ofatumumab in:

Number of Gd-enhanced T1 lesions

Number of new or enlarging T2 lesions

Annualized relapse rate

Time to first relapse


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Assess the PK and B-cell count following the extended treatment with 
ofatumumab
Study design
This study has 2 parts: A controlled Core and an open-label Extension.

Core part: A 24-week, randomized, double-blind, 
placebo-controlled, parallel-group, multicenter study to evaluate 
the efficacy, safety and tolerability and PK of ofatumumab in 
patients with relapsing MS.

Extension part: The Core part is followed by an Extension part in 
which all patients receive open-label ofatumumab. In the 
Extension part, patients are treated for at least 24 weeks and no 
longer than 48 weeks. Patients who complete the Extension part 
will be transferred into a planned open label ofatumumab 
umbrella extension study (under separate protocol).
All patients who prematurely discontinue study treatment or who do not 
enter the separate umbrella extension study, will be followed for a total of 
at least 36 weeks after study drug discontinuation in the Safety Follow-up
(FU) period.
It is planned that a total of 60 patients will be randomized in a 2:1 ratio to 
ofatumumab or placebo in the Core part; approximately half of the study 
patients will be from Japan (neither Caucasian nor African) and the other 
half from the other countries (mainly Caucasian, not East Asian). 
Randomization will be stratified by region (Japan or other countries) and 
baseline number of Gd-enhanced T1 weighted lesions (0 or ≥1).
Population
Adult patients with relapsing MS 
Key Inclusion criteria

Male or female patients aged 18 to 55 years (inclusive) at Screening

Diagnosis of MS according to the 2010 Revised McDonald criteria

Relapsing MS

At least 1 appearance of a new neurological abnormality or worsening 
of pre-existing neurological abnormality during the previous 2 years 
prior to Screening AND an MRI activity (Gd-enhanced T1 lesions or 
new or enlarging T2 lesions) in brain during the previous 1 year prior to 
randomization.

Disability status at Screening with an Expanded Disability Status Scale 
(EDSS) score of 0 to 5.5 (inclusive)

Neurologically stable within 1 month prior to randomization
Key Exclusion criteria

Patients with primary progressive MS or Secondary progressive MS
(SPMS) without disease activity

Patients meeting criteria for neuromyelitis optica

Pregnant or nursing (lactating) women

Women of child-bearing potential unless using highly effective methods 
of contraception during study drug dosing and for 12 months 
post-dosing

Patients with an active chronic disease of the immune system other 
than MS

Patients with neurological findings consistent with progressive 
multifocal leukoencephalopathy (PML) or confirmed PML

Patients at risk of developing or having reactivation of hepatitis: positive 
results at Screening for serology markers for hepatitis A, B, C and E 
(HA, HB, HC, and HE)

Patients with active systemic infections or known to have acquired 


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immune deficiency syndrome (AIDS) or to test positive for human 
immunodeficiency virus (HIV) antibody at Screening

Patients at risk of developing or having reactivation of syphilis or 
tuberculosis

Have received any live or live-attenuated vaccines within 2 months 
prior to randomization

Have been treated with medications as specified or within timeframes 
specified (e.g. corticosteroids, dimethyl fumarate, fingolimod, 
natalizumab, ofatumumab, rituximab, ocrelizumab, alemtuzumab, 
cyclophosphamide, teriflunomide etc.)

Any other disease or condition that could interfere with participation in 
the study according to the study protocol, or with the ability of the 
patients to cooperate and comply with the study procedures.
Study treatment
<Core part>
Double-blind treatment period:
Ofatumumab 20 mg sc injections or ofatumumab-matching placebo 
sc injections on Day 1, 7, 14, Week 4 and every 4 weeks thereafter
<Extension part>
Double-blind loading dose period:
Patients randomized to ofatumumab in Core part: Ofatumumab 20 mg 
sc injections at Week 24 and ofatumumab-matching placebo sc 
injections at Week 25 and 26.
Patients randomized to placebo in Core part: Ofatumumab 20 mg sc 
injections at Week 24, 25 and 26.
Open-label treatment period:
In all patients: Ofatumumab 20 mg sc injections at Week 28 and 
every 4 weeks thereafter
Efficacy assessments
MRI, MS relapse, EDSS, 
Key safety 
assessments
Adverse events, Physical examinations (including skin), Vital signs,
Laboratory evaluations (including total IgM and IgG levels), Pregnancy 
testing, Electrocardiogram (ECG), Columbia Suicide Severity Rating Scale 
(CSSRS)
Other assessments
Pharmacokinetics, B-cell and T-cell counts, Anti-human antibodies (ADAs)
Data analysis
The primary and secondary analyses will be conducted at the end of the 
Core part. All efficacy data will be analyzed according to the intent-to-treat 
principle.
The primary endpoint (Cumulative number of Gd-enhanced T1 lesions 
across 4 MRI scans at Week 12, 16, 20 and 24) will be analyzed in a 
negative binominal regression model.
Secondary analyses include MRI-(Number of new/enlarging T2 lesions) 
and Clinical (Annualized Relapse Rate) endpoints, both will be analyzed in 
a negative binominal regression model.
For the regulatory submission in Japan, a data cut-off at Week 48 will be 
used to analyze extended safety and efficacy data in the 48 week 
ofatumumab continuous treatment group.
Key words
Interventional, clinical trial, efficacy and safety, double-blind, 
placebo-controlled, ofatumumab, relapsing multiple sclerosis, Japanese 
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Amendment 1
---------------------------------------------------------------------------------------------------------------
Amendment rationale
Amendment 1 was created to clarify the exclusion criteria for patients at potential risk of 
HBV reactivation, based on inquiry from Japanese health authority. Changes were made to 
maintain consistency among Section 4.2, Section 6.5.4.4 and Section 15.2.
Additional small changes include revisions to match protocol to the new Novartis RaveX 
system or eCRFs, the addition of EUDRACT number to the cover page, and other non-
substantial changes to correct/clarify minor errors or omissions throughout the protocol.
No subject was included in this study as of 03-Oct-2017.
Changes to the protocol
The main changes and Sections affected are listed as follows:
Section 4.2: The exclusion criterion # 10 has been modified to clarify the exclusion of patients 
at potential risk of HBV reactivation.
Section 5.5.1 and Section 6.1: The sentence regarding the Screening disposition CRF was 
modified because Novartis revised clinical data collection standard does not have the CRF 
page.
Section 6.2: “Year of birth” was deleted and “age” was added as patient demographic data, 
based on the Novartis revised clinical data collection standard.
Section 6.5.4.4: This section was modified to clarify exclusion of patients who are at potential 
risk of HBV reactivation.
Section 7.1: The description of actions taken with study drug in response to AE in CRF was 
modified based on the Novartis revised clinical data collection standard. “No action taken” 
was changed to “study treatment dose not changed”, and “recovering/resolving” was deleted
from “its outcome”.
Section 7.3: The sentence regarding the liver events CRF was modified because the Novartis 
revised clinical data collection standard does not have a specific page for liver events.
Section 7.4: The sentence regarding the renal events CRF was modified because the Novartis 
revised clinical data collection standard does not have a specific page for renal events.
Table 13-2: “Complete liver CRF” was changed to “Record AE/SAE and any contributing 
factors (concomitant medications, other co-morbid conditions/procedures) in the appropriate 
CRFs” in the actions required column, in accordance with the Novartis revised clinical data 
collection standard for liver events.
Table 14-1: “Document contributing factors in the CRF: co-medication, other co-morbid 
conditions, and additional diagnostic procedures performed” was changed to “Record 
AE/SAE and any contributing factors (concomitant medications, other co-morbid 


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conditions/procedures) in the appropriate CRFs” in accordance with Novartis revised clinical 
data collection standard.
Section 15.2: This section was modified to clarify exclusion of patients at potential risk of 
HBV reactivation to keep consistency among Section 4.2 and Section 6.5.4.4.


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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.
Relapsing-remitting MS (RRMS) is the most frequent clinical presentation of the disease. 
Approximately 85% of patients present with RRMS, characterized by recurrent acute 
exacerbations (relapses) of neurological dysfunction followed by recovery. After 15 to 20 
years, ~50% of patients with RRMS have progressed to secondary progressive MS (SPMS), 
which is a stage of the disease characterized by continuous worsening of disability that occurs 
independently of relapses. The term of relapsing MS applies to those affected patients either 
with a RRMS or SPMS with superimposed relapses. Patients with relapsing MS constitute a 
common target for current treatment options. There are no clear criteria that mark the 
transition from RRMS to SPMS (EMA/CHMP/771815/2011, Rev. 2. 2015).
For the patients with relapsing MS, interferon-β and glatiramer acetate have long been used as 
first-line drugs. However, these drugs require frequent self-injections and increase the burden 
on patients. In the recent years, oral drugs such as fingolimod, dimethyl fumarate and 
teriflunomide (not approved in Japan) have become available and enhanced the convenience 
of treatment for the patients. In addition, treatment with more potent drugs including 
natalizumab, alemtuzumab (not approved in Japan) and ocrelizumab (not approved in Japan) 
have been put into practice. Despite the increased options available, patients whose disease 
activity cannot be fully controlled exist due to the heterogeneity of MS or patients who are
intolerable to the current available drugs exist. 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 by self-antigen presentation, serving as cellular adjuvants 
for CD4+ T-cell activation (Bouaziz et al 2007) and by regulating T-cell function and 
inflammation via cytokine production (Lund 2008), in addition to producing autoantibodies. 
B-cells are present in the chronic plaques, areas of demyelination, and in the cerebrospinal 
fluid of MS patients (Lehmann-Horn et al 2013).
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 


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disability worsening vs interferon beta 1a over 2 years. Ocrelizumab was well tolerated with 
no major safety findings reported in these clinical trials.
Both rituximab and ocrelizumab are delivered in a clinical setting by intravenous (iv) infusion. 
There is still unmet need for an advanced treatment targeting B-cell pathology with a similar 
mechanism of action with high efficacy, an acceptable safety profile and the convenience of 
self-administration.
Ofatumumab
Ofatumumab is a human anti-CD20 monoclonal antibody (mAb) approved for the treatment 
of patients with chronic lymphocytic leukemia (CLL) (Arzerra®). The actions of ofatumumab 
on B-cells are similar to rituximab and ocrelizumab. Ofatumumab recognizes a unique epitope 
localized close to the cell membrane on the 2 extracellular domains of the CD20+ molecule, 
N-proximal of the epitope for the anti-CD20 mAb rituximab. CD20-binding of ofatumumab 
induces B-cell lysis primarily through complement-dependent cytotoxicity (CDC) and 
antibody-dependent cell-mediated cytotoxicity (ADCC). As a fully human antibody, 
ofatumumab is predicted to have low potential for immunogenicity, as confirmed by the very 
low incidence of anti-drug antibodies (ADA) against ofatumumab observed in clinical studies 
(< 1% of patients in oncology studies, Arzerra® US prescribing information).
Ofatumumab has been evaluated in two Phase 2 studies in patients with RRMS (Studies 
OMS115102 and OMS112831). Study OMS115102 was a 48-week (24-week cross-over), 
double-blind, placebo-controlled study that evaluated the effects of ofatumumab administered 
iv in 38 patients with RRMS (Soerensen et al 2014). The study consisted of 3 dose cohorts 
(100 mg, 300 mg, 700 mg) with 12 patients randomized in each cohort to ofatumumab or 
placebo in a 2:1 ratio. After 24 weeks, patients on ofatumumab were switched to placebo and 
patients on placebo were switched to the ofatumumab dose of their cohort and followed for 
24 weeks (Week 24-48). The study showed that iv administration of ofatumumab resulted in a 
profound reduction in circulating B-cell counts and suppression of MRI lesion activity at each 
dose level evaluated in both treatment periods (Week 0-24 and Week 24-48).
Study OMS112831 was a randomized, placebo-controlled, dose-ranging, 48-week study 
(24-week double-blind treatment phase, then 24-week follow-up phase) that examined the 
efficacy and safety of repeat-dose subcutaneous ofatumumab in RRMS. Patients were 
randomized (2:1:1:1:2) to placebo, ofatumumab 3 mg, 30 mg, or 60 mg every 12 (q12) weeks, 
or ofatumumab 60 mg every 4 (q4) weeks. The primary endpoint was the cumulative number 
of new gadolinium-enhancing lesions during Weeks 0-12 on brain magnetic resonance 
imaging (MRI). Of 232 randomized patients, 231 received ≥1 study drug dose; 214 (92.6%) 
completed 24 weeks, 212 (91.8%) completed 48 weeks. Ofatumumab reduced the mean 
cumulative number of new gadolinium-enhancing lesions by 65% vs placebo during 
Weeks 0-12 (p < 0.001), and by ≥90% during Weeks 4-12 vs placebo in a post hoc analysis 
of cumulative ofatumumab doses ≥30 mg (p < 0.001). Dose-dependent decreases were 
maintained up to Week 48. Ofatumumab reduced cumulative new/newly enlarged T2 lesions 
vs placebo during Weeks 0-12 (60-72%; p ≤0.002). Between 24-48 weeks, new/newly 
enlarged T2 lesion counts were stable for all ofatumumab doses apart from the 3 mg dose 
group. The results also demonstrated a rapid, dose and dose frequency dependent reduction in 
B-cell counts, the effect being less pronounced with the 3 mg q12 regimen. Monthly dosing 
showed no signs of B-cell repletion during the inter-dosing interval. Both 30 mg and 60 mg 


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q12 weeks showed approximately 75% suppression of B-cells prior to re-dosing. Once dosing 
was ceased, all treatments showed similar rate of B-cell repopulation over 60 weeks of 
follow-up.
Overall, ofatumumab was safe and well tolerated in patients with RRMS. The safety profile of 
ofatumumab was consistent with previous data; no new signals were reported.
In Study OMS112831 of sc ofatumumab, the most commonly reported adverse events (AEs)
across the ofatumumab dose groups were injection-related reactions (52% for ofatumumab, 15% 
for placebo). Injection-related reactions occurred primarily post-first dose, diminished on 
subsequent dosing and were mostly mild/moderate in severity (97% of the events). There 
were no notable differences across treatment groups in the overall incidence of 
infection-related AEs, including urinary and respiratory tract infections. Few serious adverse 
events (SAEs) were reported. These were mainly systemic injection-related reactions 
(3 patients), all occurring on Day 1 and in the 60 mg ofatumumab dose groups. There were no 
cases of opportunistic infections reported during the study. For further details about 
ofatumumab, please refer to the Investigator Brochure (IB).
Two multinational Phase 3 studies of ofatumumab (COMB157G2301 and COMB157G2302) 
are ongoing to provide efficacy, safety and tolerability data for sc injection of ofatumumab 
20 mg every 4 weeks compared to oral teriflunomide in patients with relapsing MS, targeting 
900 patients to be randomized in each study. Japan has not joined the Phase 3 studies because 
teriflunomide is not approved for use in patients with MS in Japan. Therefore, this 
placebo-controlled COMB157G1301 study, using the same dosing regimen in the Phase 3 
studies, was planned to support registration of ofatumumab for treatment of relapsing MS in 
Japan.
1.2
Purpose
This study is designed, in conjunction with the global Phase 3 studies (COMB157G2301 and 
COMB157G2302), to provide the necessary data to support registration of ofatumumab for 
the treatment of relapsing MS in Japan.
The study will provide efficacy, safety, tolerability and pharmacokinetics data for 
ofatumumab 20 mg subcutaneous injections every 4 weeks compared with placebo for 
24 weeks in patients from Japan (neither Caucasian nor African) and the other countries
(mainly Caucasian, not East Asian) and also provide the extended efficacy, safety, tolerability 
and pharmacokinetics data.
2
Study objectives and endpoints
2.1
Objectives and related endpoints
2.1.1
Primary objective(s)
Demonstrate that ofatumumab is superior to placebo in reducing the cumulative number of 
Gd-enhanced T1 lesions across 4 MRI scans at Week 12, 16, 20 and 24 in patients with 
relapsing MS.


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2.1.2
Secondary objective(s)
Core part
Assess the consistency of the efficacy of ofatumumab versus placebo across regions (Japan vs 
other countries) in the cumulative number of Gd-enhanced T1 lesions on MRI scans at 
Week 12, 16, 20 and 24.
Assess the efficacy of ofatumumab versus placebo in the number of new or enlarging T2 
lesions on MRI scans.
Assess the efficacy of ofatumumab versus placebo in annualized relapse rate (ARR) and time 
to first relapse.
Assess the safety and tolerability of ofatumumab versus placebo.
Assess the similarity of the pharmacokinetics (PK) and B-cell count following the treatment 
with ofatumumab across regions (Japan vs other countries).
Extension part (including Core part)
Assess extended safety and tolerability of ofatumumab.
Assess extended efficacy of ofatumumab in:

Number of Gd-enhanced T1 lesions

Number of new or enlarging T2 lesions

Annualized relapse rate

Time to first relapse
Assess the PK and B-cell count following the extended treatment with ofatumumab.


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3
Investigational plan
3.1
Study design
This study has 2 parts: A randomized, double-blind, placebo controlled Core part, and an 
Extension part in which all patients receive open-label ofatumumab.

Core part: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the efficacy, safety and tolerability and PK of 
ofatumumab in patients with relapsing MS.

Extension part: The Core part is followed by an Extension part in which all patients 
receive open-label ofatumumab. In the Extension part, patients are treated for at least 
24 weeks and no longer than 48 weeks. Patients who complete the Extension part will 
be transferred into a planned open label ofatumumab umbrella extension study (under 
separate protocol).
All patients who prematurely discontinue study treatment or who do not enter the separate 
umbrella extension study, will be followed for a total of at least 36 weeks after study drug 
discontinuation in the Safety Follow-up (FU) period.
It is planned that a total of 60 patients will be randomized in a 2:1 ratio to ofatumumab or 
placebo in the Core part; approximately half of the study patients will be from Japan (neither 
Caucasian nor African) and the other half from the other countries (mainly Caucasian, not 
East Asian). Randomization will be stratified by region (Japan or other countries) and baseline 
number of Gd-enhanced T1 weighted lesions (0 or ≥1).
3.1.1
Core part
The Core part consists of 2 periods; Screening period and Double-blind treatment period
(Figure 3-1).
The Screening period can last up to 45 days and consists of 2 sections; Screening section and 
Baseline section. The Baseline section can last up to the point of first study drug 
administration (Day −7 to Day 1). Patient eligibility will be determined based on the 
Screening and Baseline assessments.
The Double-blind treatment period will start on Day 1 with randomization of the patient. 
Patients will be randomly assigned in a 2:1 ratio to receive either ofatumumab 20 mg sc or 
matching placebo sc in a double-blind fashion. Injectable study treatments (ofatumumab or 
placebo) will be administered on Day 1, Day 7, Day 14, Week 4 and every 4 weeks thereafter. 
The Double-blind treatment period will continue until the completion of all assessments 
required for the Core part at Week 24 (refer to Section 5.5.4 for further details).
Patients who prematurely discontinue double-blind study medication will have their end of 
Study (EOS) visit as soon as possible (Table 6-1) and will be followed up for safety in the 
Safety FU period (Section 3.1.3) for a minimum of 36 weeks (Table 6-2).


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3.1.2
Extension part
The Extension part consists of 2 periods; Double-blind loading dose period and Open-label 
treatment period.
The Double-blind loading dose period will be applicable for patients who complete the 
Double-blind treatment period. All patients will receive ofatumumab 20 mg sc at Week 24; 
the Extension part starts with the injection of the Week 24. Patients randomized to 
ofatumumab in the Double-blind treatment period will receive the matching placebo sc at 
Week 25 and 26. Patients randomized to placebo in the Double-blind treatment period will
receive ofatumumab 20 mg sc at Week 25 and 26. All patients will receive the study drug in a 
double-blind manner at Week 25 and 26.
The Open-label treatment period will begin at Week 28 and all patients will receive 
open-label ofatumumab 20 mg sc every 4 weeks in this period. This period will continue until 
the last patient is transferred to a planned umbrella extension study (under separate protocol 
requiring another informed consent).
Patients who prematurely discontinue study treatment will have their EOS visits as soon as 
possible and will be followed up for safety in the Safety FU period (Section 3.1.3) for a 
minimum of 36 weeks (Table 6-2). After study drug discontinuation, during Core or 
Extension parts, patients may initiate alternative MS therapy according to local standard of 
care if clinically indicated (see Section 5.6.2).
3.1.3
Safety FU period
The Safety FU period (Table 6-2) will be applicable for the following patients:

Patients who complete this study and do not enter the planned umbrella long-term 
extension study

Patients who prematurely discontinue study treatment in Core or Extension part
All Safety FU visits must be scheduled relative to the date of EOS visit.
These patients will be followed for a total of at least 36 weeks after study drug discontinuation 
(by 36 weeks the vast majority of patients are expected to have repleted their circulating 
B-cells, see Section 3.3).
A longer than 36 weeks of post-treatment Safety FU period will be required for patients who 
have not repleted their B-cells (i.e. B-cells not back to baseline value or to lower limit of 
normal (LLN) whichever comes first as determined by central lab) at 36 weeks.
These patients will continue to be followed with 12-weekly assessments until their B-cell 
counts have repleted. To protect the study blind, the assessment of B-cell counts will be 
performed centrally and the Investigators and Sponsor study team will only be informed of 
whether or not continued follow-up is necessary.
Patients who have initiated therapy with another disease modifying/immunosuppressive 
therapy before the end of the 36-week follow-up will not be monitored beyond 36 weeks.


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Figure 3-1
Study design
* Patients randomized to placebo in the Double-blind treatment period will receive ofatumumab 20 mg sc at 
Week 24, 25 and 26 as loading dose regimen. Patients randomized to ofatumumab in the Double-blind treatment 
period will receive ofatumumab 20 mg sc at Week 24 and the matching placebo sc at Week 25 and 26. In all 
patients, the extension part starts with the Week 24 injection.
** Patients who prematurely discontinue study drug or patients who do not enter the umbrella extension study will 
enter the Safety FU period following their EOS visits.
*** Umbrella extension study (planned) will be conducted under separate protocol.
Data cut-off 1 is defined as the date the last patient completes all the assessments for Week 24.
Data cut-off 2 is defined as the date the last patient completes all the assessments for Week 48.
3.2
Rationale for study design
The Core part is a randomized, double-blind, placebo-controlled, parallel-group design that is 
an established scientific method to assess safety and efficacy of a new therapy.
Placebo control and a parallel arm design are statistically efficient and minimize the number 
of patients required to demonstrate efficacy. A 2:1 randomization to ofatumumab or placebo 
minimizes the chance of placebo exposure.
Stratification by region (Japan vs other countries) allows to assess the consistency of the 
effect 
of 
ofatumumab 
20 mg 
sc 
every 
4 
weeks 
on 
MRI 
endpoint 
and 
pharmacokinetic/pharmacodynamic (PK/PD) across regions (Japan vs other countries). This 
information is required to support the registration of ofatumumab in Japan.
The Extension part of this study allows patients to start (original placebo patients) or continue 
treatment with open-label ofatumumab with the aim to provide data on extended safety, 
tolerability and efficacy measures.
Double-blind loading dose period in the Extension part allows the patients originally 
randomized to placebo in the Core part to undergo the loading regimen when starting 
ofatumumab treatment in the Extension part, without unnecessary reloading the patients 
Randomization
Ofatumumab 20 mg sc
Scree
ning
Placebo injections sc
Base
line
Week  
1 7 14 4
8
12
16
20
Ofatumumab 20 mg sc
32
36
40
44
48
52
Safety FU 
period** 
or 
Umbrella 
extension 
study***
EOS
Data cut-off 2
Double-blind 
Treatment period
Open-label 
Treatment period
Screening 
period
25 26
Double-
blind 
loading 
dose 
period*
24
28
Randomized in a 2:1 ratio
Data cut-off 1
Day  
MRI  
Core part
Extension part


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randomized to ofatumumab in the Core part. Patients randomized to ofatumumab in the Core 
part will receive placebo at Week 25 and 26 in the double-blinded manner. This procedure
will protect the blind of the Core assessments.
Patients, aged 18 to 55 years (inclusive), with relapsing MS with an Expanded Disability 
Status Scale (EDSS) score of 0 to 5.5 will be enrolled. Specific disease activity criteria define 
a population with active inflammatory disease based on recent relapse in the 2 years prior to 
Screening AND an MRI activity in brain during the year prior to Randomization. The defined 
trial population is typical for relapsing MS. Stratification by baseline number of Gd-enhanced 
T1 weighted lesions (0 or ≥1) allows to evaluate the effect of ofatumumab 20 mg sc on MRI 
endpoint appropriately.
Given the long-lasting effect of ofatumumab on B-cells, all patients who prematurely 
discontinue study drug or who complete both the Core and Extension parts while on study 
drug but do not enter the planned umbrella extension study will continue to be followed up for 
at least 36 weeks until B-cell repletion from the safety point of view (Section 3.1).
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose regimen for ofatumumab for this study is a loading dose regimen of 20 mg at Day 1, 
Day 7 and Day 14, followed by a maintenance dose regimen of 20 mg administered every 
4 weeks starting at Week 4. Patients randomized to placebo in the Core will receive the 
ofatumumab 20 mg loading dose regimen during the extension at Week 24, 25 and 26, 
followed by a maintenance dose regimen of 20 mg administered every 4 weeks starting at 
Week 28.
The dose selection relies on the clinical hypothesis that the depletion of B-cells in lymphatic 
tissues is key for efficacy (as measured by MRI and relapses), and that the depletion of brain 
parenchymal and meningeal B-cells may be an additional factor for the mode of action; blood 
B-cell count is an imperfect, epiphenomenal measure of tissue status. This hypothesis 
suggests that, in order to attain the desired efficacy, 2 conditions should be met:

A loading regimen with high enough initial PK for lymphatic depletion, and

A continued maintenance dose that would keep B-cell depletion levels below desired 
threshold.
The Phase 2 study of ofatumumab sc (3 mg, 30 mg, 60 mg every 12 (q12) weeks, 60 mg every 
4 (q4) weeks) in relapsing MS patients (Study OMS112831) provided important information 
regarding the relationship between peripheral B-cell depletion and efficacy as measured by 
MRI Gd-enhancing brain lesions. Clear dose-response relationship was detected using a 
quasi-Poisson regression model that related new Gd-enhancing lesion volumes, baseline 
lesion number and treatment group. The dose-response was fully explained by the extent of 
the CD19+ cell count drop. The model indicates that lower CD19+ cells levels lead to better 
control of lesion volumes and, subsequently, high level of depletion of CD19+ cells (e.g. 
≤8 cells/µL) should be maintained throughout the treatment course in order to ensure desired 
efficacy.
PK/PD modeling on the Phase 2 data of Study OMS112831 suggested that a single dose of 
ofatumumab 20 mg sc is insufficient to reduce B-cell levels to ≤8 cells/µL. A loading 


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regimen of 3 separate 20 mg (at Day 1, 7 and 14) was required to attain target depletion 
(≤8 cells/µL) in > 95% of patients based on modeling, and is extrapolated to be more 
effective than a single 60 mg load. In Study OMS112831, patients dosed with 60 mg q4 
weeks showed no signs of B-cell repletion during the inter-dosing interval. Based on PK/PD 
modeling, ofatumumab 20 mg sc appears to be sufficient to either maintain or to further 
deplete B-cells in > 95% of patients who have previously depleted, even in patients with high 
repletion rates.
High number of PK values below the lower limit of quantification (LLQ) did not allow for use 
of a full PK/PD modeling. For this reason, a second modeling approach (PK-PD) was used to 
relate the individual time-course of B-cells to the dosing history and patient specific 
covariates, taking the inter-patient variability into account. This approach also confirmed that 
the desired levels of B-cell depletion in nearly all patients can be attained through the 
described loading/maintenance dose regimen.
With regards to safety and tolerability, the dose regimens of 60 mg q12 and q4 weeks were 
associated with more AEs than the lower dose regimens of 3 mg or 30 mg q12 weeks. In 
particular, post injection systemic reactions reported as SAEs on Day 1 were seen only with 
the 60 mg dose regimens. In the presence of B-cells at first dosing, and when B-cells have 
started repleting, systemic reactions are an expected AE and their severity is likely to be dose 
and B-cell count related.
With regards to repletion of B-cells after discontinuation of ofatumumab, simulations based 
on a model developed using the data from the Phase 2 study (OMS112831) predict that the 
vast majority of patients will replete their B-cells within 9 months of follow-up. Based on 
these simulations it is estimated that around 5 months are needed to achieve 80% of repletion 
after treatment discontinuation.
Since relapsing MS is a chronic disease with anticipated long-term treatment, dose selection 
should therefore aim to balance efficacy and safety aspects. The ofatumumab subcutaneous 
loading dose regimen of 20 mg at Day 1, 7 and 14, followed by a monthly maintenance dose 
regimen of 20 mg administered every 4 weeks (starting at Week 4) is selected to deplete and 
subsequently maintain B-cells at the levels below 8 cells/µL in nearly all patients. It is 
expected to have maximal clinical benefit and better tolerability than higher doses. Taken 
together, the strong relationship between MRI lesions and relapses (Sormani et al 2009; 
Sormani and Bruzzi 2013) and the observed inhibition of lesions at the cumulative doses 
tested, combined with maintaining B-cells below threshold support selection of the proposed 
dose regimen.
The results of the Study OMB112758 in East Asian (Japanese and Korean) patients with 
refractory chronic lymphocytic leukemia (CLL) and the Study OMB111773 in mainly 
Caucasian patients with refractory CLL demonstrated no evident PK difference between 
Japanese and non-Japanese subjects. Therefore, the same dosing regimen will be used in the 
patients from Japan and the other countries in this study (COMB157G1301).
Duration of treatment
The 24-week duration of the double-blind treatment period is sufficient to observe a relevant 
effect on reducing MRI disease activity and has been an accepted standard duration for 


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Phase 2 trials in relapsing MS. The available MRI data of ofatumumab in Phase 2 study 
(Study OMS112831) demonstrated that meaningful differences versus placebo could be 
detected in this time frame.
The 24-week double-blind treatment period is followed by the Extension part of at least 
24 weeks and no longer than 48 weeks, using open-label ofatumumab. The Extension part will 
continue until the last patient completes 24 weeks in this part and is transferred into the 
umbrella extension study (planned under a separate protocol).
3.4
Rationale for choice of comparator
The primary goal of this study is to demonstrate the efficacy of ofatumumab 2 0 mg sc every 
4 weeks on the inflammatory MRI lesions, by distinguishing ofatumumab from an appropriate 
control agent. The choice of placebo as a control agent is important to obtain information 
concerning the specific versus non-specific effects of the active treatment and provides the 
best way of evaluating the efficacy and of assessing the true safety and tolerability profile of 
ofatumumab.
The placebo-controlled study design allows the scientific and regulatory objectives of the 
study to be met with a smaller sample size than if an active comparator would be used, thus 
reducing the necessary number of patients especially from Japan and maintaining feasibility.
Currently, despite the availability of treatment for relapsing MS, the selection of placebo as a 
control agent in this study can be accepted by the following:

Patients who randomized to placebo in a 24-week Double-blind treatment period (Core 
part) and complete its period will have the opportunity to receive ofatumumab 20 mg sc 
every 4 weeks in the Extension part.

Patients should be informed by the investigators about locally available approved MS 
therapies for treating their MS and about the probability to receive the placebo based on 
randomization in a 2:1 ratio to either ofatumumab or placebo in this study. Patients need 
to consent in writing.

A standard short course of corticosteroids may be used to treat MS relapses based on 
investigator’s judgment. Patients who have MS relapses during this study will be 
informed again about the current available treatments for patients with relapsing MS. If 
the patients agree to stay in this study, they will be asked to sign the informed consent 
form to document their decision.

Patients can select to discontinue study treatment and consider to start treatment with an 
approved MS therapy. The duration of the washout period after last dose of study drug 
will depend on the type of therapy to be initiated and the patient’s clinical condition (see 
Section 5.6.2).
3.5
Purpose and timing of interim analyses/design adaptations
No interim analysis is planned for this study.
Regular analyses for safety and for benefit/risk assessment will be performed for the global 
program Data Monitoring Committee (DMC) of OMB157G by an independent team of 
statisticians and programmers who are not otherwise involved in the conduct of the studies of 
OMB157G. The data review including other OMB157G studies will be done by the DMC.


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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.
The risk for patients exposed to placebo to worsen will be minimized by limiting the placebo 
exposure to a maximum of 24 weeks, allowing patients to receive standard of care treatment 
in the case that they present with clinical relapses (i.e., high dose methyl -prednisolone), and 
requesting for patients presenting with clinical relapses that the investigator considers 
benefit/risk of continuing study drug or to switch to an approved disease-modifying therapy.
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 CLL are 100 times higher than the dose 
to be used in this study in MS.
The experience with ofatumumab in MS patients is limited. 267 of RRMS patients have been 
exposed to ofatumumab iv (N=38) and sc (N=229) in 2 Phase 2 studies (Study OMS115102 
and OMS112831). However, in parallel to this study (COMB157G1301), two global Phase 3 
studies (COMB157G2301 and G2302) are being conducted with a planned total sample size 
of 1800 randomized patients. A DMC will monitor the safety and risk/benefit for the entire 
OMB157G program including COMB157G2301, G2302 and G1301. 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 intravenous 
doses of ofatumumab up to 700 mg, adverse events reported more frequently on ofatumumab 
vs placebo included: rash, throat irritation, erythema, fatigue, viral infection and flushing. In 
the placebo-controlled, dose-ranging study of ofatumumab 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. There may be yet unknown risks to MS patients 
taking ofatumumab, which may be serious and unforeseen.
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 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.
Overall, the balance of benefit and risk supports the rationale of COMB157G1301 study to 
evaluate the efficacy and safety of ofatumumab sc to address the unmet medical need of 
patients with relapsing MS.


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4
Population
The study population will consist of adult patients with relapsing MS fulfilling all the 
eligibility criteria listed below.
A total of 60 patients, including 30 patients from Japan (neither Caucasian nor African) and 
30 patients from the other countries (mainly Caucasian, not East Asian), are planned to be
randomized.
The study is planned to be conducted in approximately 15 centers in Japan and approximately 
5 to 10 centers in Europe and/or North America. Patients, who have been randomized and 
prematurely discontinue study, will not be replaced.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
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
5. At least 1 appearance of a new neurological abnormality or worsening of pre-existing 
neurological abnormality during the previous 2 years prior to Screening AND an MRI 
activity (Gd-enhanced T1 lesions or new or enlarging T2 lesions) in brain during the 
previous 1 year prior to randomization. Note: Screening MRI scan may be used. 
6. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive)
7. Neurologically stable within 1 month prior to randomization
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible patients.
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. 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 human 
chorionic gonadotropin (hCG) laboratory test.
5. 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 (e.g., calendar, 


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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.
Note: Women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or 
tubal ligation at least six weeks 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.
6. Patients with an active chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjögren’s 
syndrome, Crohn’s disease, ulcerative colitis, etc.) or with immunodeficiency syndrome 
(hereditary immune deficiency, drug-induced immune deficiency)
7. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS 
or to test positive for HIV antibody at Screening
8. Patients with neurological findings consistent with PML or confirmed PML
9. Patients at risk of developing or having reactivation of syphilis or tuberculosis (e.g. 
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 syphilis testing, it should be done per local clinical 
practice (e.g. by positive rapid plasma reagin (RPR)). For tuberculosis testing, 
QuantiFERON®-TB Gold test will be done by the central laboratory to assess patient’s 
eligibility at Screening.
NOTE: 

For syphilis and tuberculosis skin test: patients can be enrolled if results are negative. 
If the test results are unclear or there is suspicion of false positive test results of a 
tuberculin skin test, the Investigator may consult with an infectious disease expert. If 
the infectious disease expert considers the test results false positive and not clinically 
relevant, the Investigator must document (in source data) that the test results are 
considered false positive and may then randomize the patient.


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
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.
10. 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 as below:

anti-HA Immunoglobulin (Ig) M (IgM)

HBs antigen positive or HBc IgM/IgG antibody positive, regardless of HBV DNA 
testing result

HBs antibody positive and other HBV parameters negative (HBs antigen negative and 
HBc IgM/IgG antibody negative) without known history of anti-HBV immunization

anti-HC IgG (if positive IgG, Hepatitis C Virus (HCV)-ribonucleic acid (RNA)
polymerase chain reaction (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) that the serology results are considered false 
positive and may then randomize the patient.
11. Have received any live or live-attenuated vaccines (including for varicella-zoster virus or 
measles) within 2 months prior to randomization
12. Have been treated with any of the medications listed below:
Medication
Exclusionary if used/used within 
required wash-out period
Systemic corticosteroids, adrenocorticotropic 
hormone
30 days prior to Screening MRI scan
Dimethyl fumarate
1 month prior to randomization
Intravenous immunoglobulin, plasmapheresis, 
fingolimod
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
Mildly to moderately 
immunosuppressive/chemotherapeutic medications 
(e.g. azathioprine, methotrexate)
6 months prior to randomization


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Medication
Exclusionary if used/used within 
required wash-out period
Highly immunosuppressive/chemotherapeutic 
medications (mitoxantrone, cyclophosphamide, 
cladribine)
B-cell targeted therapies such as rituximab, 
ocrelizumab
Laquinimod
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
Other strongly immunosuppressive treatments (with 
effects potentially lasting over 6 months)
Ofatumumab
Any time
13. 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
14. 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 e.g. completely excised with clear margins), within the past 5 years, 
regardless of whether or not there is evidence of local recurrence or metastases
15. Any of the following conditions or treatments that may impact the safety of the patient:

Cardiac or cardiac repolarization abnormality, including any of the following:

History of myocardial infarction (MI), angina pectoris, or coronary artery bypass 
graft (CABG) within 6 months prior to starting study treatment

Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., 
bifascicular block, Mobitz type II and third degree AV block) 

Resting the Fridericia QT correction formula (QTcF) ≥450 msec (male) or 
≥460 msec (female) at pretreatment (screening or baseline) or inability to determine 
the QTcF interval

Risk factors for Torsades de Point including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia or any of the following:

Long QT syndrome, family history of idiopathic sudden death or congenital long 
QT syndrome

Concomitant medication(s) with a “Known Risk of Torsades de Point” that 
cannot be discontinued or replaced by safe alternative medication.

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


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
Patients with severe renal impairment (Glomerular Filtration Rate 
< 30 ml/min/1.73 m2)

Any medically unstable condition as determined by the Investigator
16. Any of the following abnormal laboratory values prior to randomization:

Total or conjugated bilirubin (BIL) > 1.5 times upper limit of normal (ULN) range, 
unless in the context of Gilbert’s syndrome

Alkaline phosphatase (AP) > 1.5 times the ULN range

Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 1.5 times 
ULN or gamma-glutamyl-transferase (GGT) > 2 times ULN range

White blood cell (WBC) count < 3,500/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 (e.g. significant anemia, neutropenia, thrombocytopenia, signs of 
impaired bone marrow function)
17. 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 (CSSRS), 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 (i.e. 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 (e.g. stroke, traumatic brain or spinal 
injury, history or presence of myelopathy) or neurological disorders which may 
mimic MS
18. Patients unable or unwilling to undergo MRI scans (e.g. contraindications for MRI include 
like weight ≥140 kg, pacemaker, cochlear implants, presence of foreign substances in the 
eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary 
stent implanted within 8 weeks prior to the time of the intended MRI, claustrophobia or 
inability to receive gadolinium contrast agent (e.g. hypersensitivity, renal dysfunction))
19. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes
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 requirements, the local requirements must be followed.


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5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Investigational drug will be provided in pre-filled syringes for subcutaneous administration 
containing 20 mg ofatumumab (50 mg/ml, 0.4 ml content). Ofatumumab is clear to opalescent, 
colorless to pale yellow, essentially particle-free liquid in a pre-filled syringe. The matching 
placebo to ofatumumab pre-filled syringe will have the same appearance as the investigational 
drug.
Study drug will be supplied by Novartis.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and matching placebo are provided as 
part of study drug supplies for this study.
5.2
Treatment arms
The study includes 2 treatment arms:

Ofatumumab arm
<Core part>
Double-blind treatment period: Ofatumumab 20 mg sc injections on Day 1, 7, 14, 
Week 4 and every 4 weeks thereafter.
<Extension part>
Double-blind loading dose period: Ofatumumab 20 mg sc injections at Week 24 
and ofatumumab-matching placebo sc injections at Week 25 and 26.
Open-label treatment period: Ofatumumab 20 mg sc injections at Week 28 and 
every 4 weeks thereafter.

Placebo arm
<Core part>
Double-blind treatment period: Ofatumumab- matching placebo injections on 
Day 1, 7, 14, Week 4 and every 4 weeks thereafter.
<Extension part>
Double-blind loading dose period: Ofatumumab 20 mg sc injections at Week 24, 
25 and 26.
Open-label treatment period: Ofatumumab 20 mg sc injections at Week 28 and 
every 4 weeks thereafter.
5.3
Treatment assignment and randomization
Eligible patients will be randomized in a 2:1 ratio to either the active ofatumumab 20 mg 
group or to the placebo group. Randomization will be stratified by region (Japan or other 
countries) and baseline number of Gd-enhanced T1 weighted lesions (0 or ≥1).
On Day 1 (randomization visit), all eligible patients will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The Investigator or his/her delegate 


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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 number will not be 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and Investigator staff. A patient 
randomization list will be produced by the IRT 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 drug(s).
5.4
Treatment blinding
This study will be conducted using a double-blind design. Patients will be assigned to receive 
either active ofatumumab or ofatumumab-matching placebo as described in Section 5.2.
Patients, Investigator staff, persons performing the assessments, and data analysts will remain 
blinded to the identity of the treatment assignment from the time of randomization until 
database lock, using the following methods: (1) Randomization data are kept strictly 
confidential until the time of unblinding, and will not be accessible by anyone involved in the 
study with the following exceptions: DMC members, Independent Statisticians and 
Independent Programmers. (2) The identity of the treatments will be concealed by the use of 
study drugs that are all identical in packaging, labeling, schedule of administration and 
appearance.
The randomization codes associated with PK samples will be disclosed to the Bioanalysts 
who will keep PK and Anti-human antibodies (ADA) results confidential until database lock.
The following measures will be taken to protect the blinding of the Independent EDSS Rater 
(Rater):

Prohibited access to patients’ study data

Separate binders of worksheets and CRF materials for Investigator and the Rater

Prohibited cross-over of Investigator and Rater

Use of appropriate clothing by patients to cover potential injection sites during 
neurological examinations

Limited interactions between Rater and patient: permitting only a minimum required to 
perform the EDSS rating.
Additionally, potentially unblinding laboratory parameters (e.g. B-cell counts) will not be 
communicated to the Investigator or other study staff as described in Section 3.1 and 
Section 6.5.4.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the core part.


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5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise the Investigator 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 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 
CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
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 2 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). Immediately before dispensing 
the package to the patient, 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.
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 Sponsor local 
Quality Assurance contact.
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. Patients/subjects will 


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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 Sponsor monitor or to the Sponsor address provided 
in the Investigator folder at each site.
5.5.4
Instructions for prescribing and taking study treatment
The study medication (ofatumumab injections or ofatumumab-matching placebo 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).
In order to assess tolerability of the initial dose of study medication (injectable), 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 and Week 24, the first dose of Double-blind treatment period in 
the Core part and Double-blind loading dose period of the Extension part.
From Day 1 until Week 20, patients will receive the sc injection at site. The site staff (e.g. 
Investigator, Study Nurse/Study Coordinator) will administer the first sc injection on Day 1. 
From the second sc injection (on Day 7), patients or a caregiver may inject the study 
medication under supervision of the study staff. Site personnel will provide training to the 
patients on the correct procedure for self-administration of the sc injections.
Following all assessments required for the visit of Week 24, the injection of study medication 
begins the Double-blind loading dose period (see Section 5.2). Patients must remain at the site 
under observation for a minimum of 5 hours following dosing on Week 24.
From Week 25 onwards, patients may inject the study medication at home by themselves or 
have a caregiver who have been trained by the study staff on the proper technique and safety 
precautions, inject the study medication. Ability to self-administer injections must be 
demonstrated and documented before home-administration is permitted. If a patient is 
unable/unwilling to self-administer injections, home-administration may be performed by 
another individual (e.g. partner, relative or a healthcare professional) who has accompanied 
the patient to the site and has been trained on and demonstrated ability to correctly administer 
the sc injections. The patient may also continue to have injections administered at the site if 
this is the patient’s preference. Patients with severe neurological deficits should not 
self-administer injections.
From Week 28, patients will receive the open-label ofatumumab sc injection every 4 weeks.
Patients, who miss sc injections or temporarily interrupt study drug without discontinuing 
from the study or withdrawing consent, will be permitted to resume study drug if determine to 
be safe and appropriate in the opinion of the Investigator. When resuming study drug, the 
timing of the next sc injection will be determined based on the original study schedule as 
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
If one monthly injection is missed by 1 week or less, the patient should take the 
injection as soon as possible. The next injection should then be administered 
according to the original schedule.

If one monthly injection is missed by more than 1 week, the patient should skip the 
dose and take the next dose at the time when the next injection would be due 
according to the original schedule.

If 2 or more consecutive monthly injections are missed, the Investigator should 
inform the Sponsor before re-starting dosing. Missed injection syringes should not be 
used and returned to the site at the next visit.
All kits of study medication assigned by the IRT will be databased in the IRT system.
All dosages prescribed and dispensed to the patient and all dose interruptions during the study 
must be recorded on the appropriate Electronic Case Report Forms (eCRF).
The Investigator must promote compliance by instructing the patient to take the study 
medication exactly as prescribed and by stating that compliance is necessary for the patient ’s 
safety and the validity of the study. The patient must also be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed.
A patient injection instructions leaflet will be provided which includes detailed information, 
precautions and instructions for administering sc injections. This information should be 
reviewed with the patient (and his/her partner/relative as applicable) to ensure that they 
understand the correct procedure for self/home administration.
The patients will record information concerning their home study drug administrations in a 
diary provided for the Extension part in the study. The information to be recorded includes 
date and time of each sc injection and any symptoms related to the administration as well as 
any missed doses of study drug. The patient should be instructed to record any missed doses 
in the patient diary and to inform the study staff of any missed sc injection(s). This can be 
done at the visits and/or during the monthly structured telephone interviews (according to the 
script provided to the sites for the study) during which the study site staff will inquire about 
the patient’s status and compliance with study drug administration or issues related to the 
home administration. The Investigator will review the diary with the patient at each visit and 
record the information on the relevant eCRFs.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted during the study. Interruptions are 
permitted if clinically indicated.
Conditions/events that may lead to the study drug interruptions based on Investigator 
judgment and overall clinical assessment include:

reported serious adverse event;

emergency medical condition, unplanned hospitalization, involving use of excluded 
concomitant medications;

abnormal laboratory value(s) or abnormal test or examination result(s) 
Should the patient interrupt the study drug for whatever reason, re-start decision should be 
made on a case-by-case basis (refer also to Section 5.5.4). Should the Investigator decide, 


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after informing the Sponsor, to re-initiate treatment with study drug, depending on the 
duration of the interruption, the first sc at re-start may need to take place at the study site to 
ensure observation in a similar manner as on Day 1 and Week 24.
The reason for the interruption of treatment and date of interruption should be appropriately 
documented in the source documents as well as in the appropriate eCRF.
5.5.6
Recommendations for the treatment of MS relapses
MS relapses may be treated with a standard
short course of corticosteroids (e.g. 
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 eCRF.
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 (including dose 
changes), 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 Sponsor 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 inject ion of 
Double-blind treatment period (Day 1) and Double-blind loading dose period (Week 24), the 
addition of premedication with steroids (methylprednisolone 100 mg iv or 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.
Additional information in regards to premedication for home-administration use:
From Week 25 onwards, patients may inject study medication at home (refer to Section 5.5.4). 
Use of premedication is at the discretion of the Investigator. Based on the experience with the 
injections administered at the site and with the use of any premedication, the Investigator will 
evaluate whether or not premedication (such as acetaminophen and/or antihistamines) should 
be used before injections administered at home. If premedication is prescribed, the study staff 


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must ensure that the patient will receive a sufficient supply of premedication for home-use (i.e. 
to last at least until the next visit) and clear instructions (oral and written) about type and dose 
of premedication, and when to take it (i.e. 30-60 min before the injection). The Investigator 
will evaluate the need for premedication, or a change in the prescription, at each visit (planned
and unplanned) including at the monthly telephone interview appointments (interview script 
includes specific questions about any injection-related symptoms and the use of 
premedication). If, based on the telephone interview, a change in premedication may be 
needed, the patient should be asked to return to the site for an unplanned visit.
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. The patients will additionally receive an injection instructions leaflet 
(Instructions for Home administration and Use) which also includes information about such 
reactions, their management as well as Investigator/site contact numbers. 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 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
Additional action to be taken
Immunosuppressive/chemotherapeutic 
medications (including herbal) or procedures, 
including but not limited to cyclosporine, 
azathioprine, methotrexate, cyclophosphamide, 
mitoxantrone, lymphoid irradiation and 
hematopoietic 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 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, interferon beta, glatiramer 
acetate, dimethyl fumarate, 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.


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Medication
Additional action to be taken
Leflunomide, teriflumonide
Discontinue study treatment
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
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The Investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Sponsor monitor for the site and the Study Team that the code 
has been broken.
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The Investigator will provide:

protocol number

study drug name

patient number
In addition, oral and written information to the patient must be provided on how to contact the 
Investigator’s backup in cases of emergency, or when the Investigator is unavailable, to 
ensure that un-blinding can be performed at any time.
After an emergency treatment code break, the patient should discontinue study drug and will 
have their EOS visit as soon as possible (Table 6-1). Patients will be followed up for safety in 
the Safety FU period (Table 6-2).
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.


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The Safety FU will complete when all patients who entered have been followed for the 
stipulated period of time (for at least 36 weeks after study drug discontinuation) (see 
Section 3.1.3) 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 6.5.6 and Section 7.6)

Use of prohibited treatment (Table 5-1)

Diagnosis of PML

Patient with active serious infections or reactivation (e.g. tuberculosis, hepatitis B or C)

Skin and/or mucosal reactions which raise the suspicion of severe generalized major skin 
reactions (Stevens-Johnson syndrome, or toxic epidermal necrolysis-Lyell’s syndrome)

Hypersensitivity to the study medication

Any situation in which 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)

Laboratory abnormalities (e.g. 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.


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The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
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 patients should be encouraged to stay in the study and continue to follow 
the procedures and assessment schedule as specified in the protocol.
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. In some cases, as described below, information on the patient's 
circulating B-cell status may be requested if in the Investigator's opinion this is needed to 
ensure safe switch to another MS therapy.
The duration of the washout period after last dose of study drug will depend on the type of 
therapy to be initiated and the patient’s clinical status:

A washout period of at least 5 months is recommended before initiation of lymphocyte 
depleting/suppressing/trafficking blocking agents (e.g. alemtuzumab, fingolimod, 
natalizumab, teriflunomide, etc.). This is in line with the expected circulating B-cell 
repletion course after ofatumumab discontinuation (estimated around 5 months needed for 
80% repletion; see Section 3.3)

If, in the opinion of the Investigator, the safe initiation of another therapy cannot be 
considered without the patient's B-cell status, the Investigator must submit a request to 
Novartis in writing. The request of B-cell status must be justified based on clinical 
grounds. The Investigator must ensure data entry is complete for any such patients. The 
Investigator will be notified of whether or not the patient has B-cell counts at or above 
lower limit of normal or baseline values, whichever is lower. The detailed procedure for 
requesting and receiving the information on a patient's B-cell status will be provided 
separately.
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material


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In this situation, the Investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’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 patient 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 (EOS) at the time of the patient’s study withdrawal should be made as detailed in 
the schedule of assessments (Table 6-1).
5.6.4
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. 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 EOS visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by the Sponsor 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 and training/supervision of ability to 
self/home-administer. 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


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
Referral of patients with neurological symptoms consistent with MS relapse to the 
Independent EDSS Rater.

Management of adverse events and MS relapses.

Review of patient diaries

Ensuring that all site personnel are informed of concomitant medications excluded per 
protocol (e.g. 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 (other than the Independent EDSS Rater, e.g., a back-up 
physician or Study Nurse/Study Coordinator) at the study site to perform some of the tests and 
evaluations listed above. The Investigator is also responsible for ensuring access to 
appropriate expertise for consultation (e.g. infectious disease, ECG interpretation, mental 
health care) during the study as needed.
Independent EDSS Rater
The Independent 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
The Independent 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.
The Independent EDSS Rater must not be involved in any other aspect of the patient ’s care 
and/or management of his/her MS treatment and have no access to patient study data.
To ensure consistency in the EDSS scoring across Raters, the Independent 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 Independent EDSS Rater 
should remain the same throughout the study, whenever possible.
The communication of new neurological findings on the neurological examination, including 
the EDSS score, from the Independent EDSS Rater to the Investigator is not permitted after 
Randomization. The roles of the Investigator and the Independent EDSS Rater, including their 
back-ups, are not interchangeable. The Independent EDSS Rater must remain blinded to 
adverse events, concomitant medications, laboratory data and any other data that have the 
potential of revealing the treatment assignment.
The patient and his/her caregiver should be instructed to take care not to discuss aspects of the 
patient’s treatment or potential AEs, including injection site reactions, with the Independent 
EDSS Rater. During the examination, the patient should wear appropriate clothing that covers
injection sites.


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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 (returned syringe counts)

Administration and supervision of injections and training/supervision of ability to 
self/home-administer as delegated by the Investigator
 

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

Ensuring patient understanding of injection handling and home administration instructions, 
questionnaires, diaries and the completion of these

Providing patient with a Patient Information Card identifying patients as study participant 
in a clinical trial with pertinent information and site contact information (see also
Section 15.2)

Review of patient diaries, as delegated by the Investigator

Conducting monthly phone calls with the study patients, as delegated by the Investigator
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

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.
Patients should be seen for all visits on the designated day per the schedule of assessments, or 
as close to it as possible within the visit windows. Missed or rescheduled visits should not 
lead to automatic discontinuation.


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In case a visit is performed outside the schedule, subsequent visits shall be performed in 
keeping with the original visit schedule (one month is defined as 28 calendar days). In 
addition to the planned 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.
At Week 24, all assessments required for the Core part MUST be completed prior to the first 
study drug administration for the Extension part.
In the Extension part, patients will be asked to complete a diary to record information 
pertinent to study drug administration (including date and time of sc injections) and home 
pregnancy testing (date and results) for females of childbearing potential. The patient is 
requested to bring the completed diaries with them to each visit and the Investigator/Study 
Nurse/Study Coordinator must review these for completeness and for potential AEs, injection 
related reactions, study drug interruptions etc. and record information obtained from the 
diaries on the relevant CRFs.
A structured telephone interview script provided for the study will be conducted by site 
personnel only for patients who administer the monthly sc injection at home (Table 6-1). The 
interview should take place around time of the monthly sc self/home-injection to query about 
any new or worsening symptoms warranting an unplanned visit, injection reactions, and, as 
applicable, results of home pregnancy testing and compliance with contraception 
requirements. Conduct and results of home pregnancy testing is to be recorded in the source 
documentation.
Patients who stop taking study medication should be scheduled for the EOS visit as soon as 
possible and then enter the Safety FU according to schedule in Table 6-2. Patients who 
complete this study on study drug but do not enter the umbrella extension study (planned) will 
also have their EOS visit and then enter the Safety FU according to schedule in Table 6-2.


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Table 6-1
Assessment schedule
Part
Core part
Extension part
Period
Screening
Double-blind treatment
Double-blind 
loading dose
Open-label treatment
Visit
SCR
(D-45 to
D-8)
BL
(D-7 to D1 
(pre-
treatment)
D11
D2
D5
D7
D14
W4
(D28) W8
W12 W16 W20 W24 W2519 W2619 W28
W36 W48 W6020 W7220 EOS2
Visit No.
1
20
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
280
1999
Visit Window (days)
n.a.
n.a.
n.a.
0
−1
±1
±1
±3
±7
±7
±7
±7
±7
±1
±1
±3
±7
±7
±14
±14
n.a.
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
X
X
X
X
X
X
X
X
X
Dispense study 
drug17
X
X
X
X
X
X
X
X
X4
X
X
X
X5
X5
X5
X5
Pretreatment6
S/A/A
A/A
A/A
A/A
A/A
A/A
A/A
A/A S/A/A
A/A
A/A
A/A
A/A
A/A
A/A
A/A
Vital signs
X
X
X7
X7
X7
X7
X
X
X
X
X7
X
X
X
X
X
X
Weight
X
X
X
X
Physical Exam8
X9a
X9a
X
X
X
X
ECG
X9a
X9a
X
X
X
Lab samples 
including urine
X
X18
X
X
X
X
X
X
X
X
X
Sample for CD19+ B-
cells and CD3+CD20+
T-cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test10
X
X18
X
X
X
X
X
X
X
X
X
X
X
X


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Part
Core part
Extension part
Period
Screening
Double-blind treatment
Double-blind 
loading dose
Open-label treatment
Visit
SCR
(D-45 to
D-8)
BL
(D-7 to D1 
(pre-
treatment)
D11
D2
D5
D7
D14
W4
(D28) W8
W12 W16 W20 W24 W2519 W2619 W28
W36 W48 W6020 W7220 EOS2
Visit No.
1
20
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
280
1999
Visit Window (days)
n.a.
n.a.
n.a.
0
−1
±1
±1
±3
±7
±7
±7
±7
±7
±1
±1
±3
±7
±7
±14
±14
n.a.
Contraception 
status11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA sampling12
X
X
X
X
X
X
X
X
X
X
Total IgM, IgG levels
X9a
X9a
X
X
X
X
X
X
X
X
X
Serological markers 
for hepatitis A, B, C, 
and E
X
X
HIV test
X
MRI13
X
X
X
X
X
X
X
X14
EDSS
X
X9b
X9b
X
X
X
X
X
X
X
eCSSRS
X9a
X9a
X
X
X
X
X
X
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
X
X
X
X
X
X
MS Relapse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/Con Meds15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone interview16
X
X
monthly between planned visits
Patient diary review
X
X
X
X
X
X
X
Disposition
X
X
A/A=Acetaminophen/Antihistamine; ADA=Anti-drug-antibody; AEs=Averse events; BL=baseline; Con meds=Concomitant medications; D=day; Excl.=exclusion; 
Incl.=inclusion; n.a.=not applicable; S= Steroid; SCR=screening; W=week.


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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).
3.
Syphilis and Tuberculosis testing must be done as part of eligibility check (Exclusion criterion #9) unless completed in the last 6 months prior to screening with 
documented negative results. For syphilis testing, it should be done per local clinical practice (e.g. by positive RPR). For tuberculosis testing, QuantiFERON®-TB 
Gold test will be done by the central laboratory to assess patient's eligibility at Screening.
4.
All assessments required for the Core part MUST be completed before the patient receives the first dose for the Extension part at Week 24. Patients must remain 
at the site under observation for a minimum of 5 hours following dosing at Week 24.
5.
After Week 36 visit, patients may visit every 12 weeks. In this case, patients will need to continue study treatment every 4 weeks at home. For PK and ADA visits 
the patient should not take injection before coming to the site (see footnote 12).
6.
S/A/A means Steroid/Acetaminophen/Antihistamine. Premedication with acetaminophen and/or antihistamines (or equivalent) is recommended and may be 
administered at the discretion of the Investigator. For the first injection of Double-blind treatment period (Day 1) and Double-blind loading dose period (Week 24) 
only, the addition of premedication with steroids (methylprednisolone 100 mg iv or equivalent) is recommended. Premedication should be administered 30 to 60 
min prior to study drug injection.
7.
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 in the Core part and on the first injection in the Extension part (at 
Week 24).
8.
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.
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).
10.
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 planned visits as indicated in Table 6-1. After Week 28, 4-weekly urine pregnancy tests will be conducted at home between site visits. The 
patient must contact the Investigator immediately in the case of a positive test for confirmatory testing at the Investigator’s discretion.
11.
Patient’s contraception status must be reviewed and documented to ensure method of contraception continues to be appropriate per protocol requirement for 
highly effective contraception.
12.
PK and ADA visits: The PK (Plasma) and ADA (Serum) samples should be drawn before the patient takes their injection.
13.
In case of relapse, if an MRI for efficacy has been scheduled within 14 days of the initiation of steroid treatment, the MRI should be performed before steroid 
treatment is initiated. No MRI for efficacy should be performed while a patient is on steroid therapy for relapse and within 14 days upon termination of steroid 
therapy.
14.
MRI scan at the EOS is needed if there was no MRI scan in the last 3 months.
15.
Including corticosteroids used to treat MS relapse; any newly started MS treatment as applicable (for patients who have discontinued study medications).


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16.
Applicable for patients who take study treatment by home-administration. Telephone interview by site staff should take place around time of the sc self/home 
injection to query about any new or worsening symptoms warranting an unplanned visit, injection reactions, results of home pregnancy testing, compliance with 
contraception requirements as applicable.
17.
Patients will receive sc injections of Double-blind treatment period on Day 1, Day 7 (± 1 day), Day 14 (± 1 day), Week 4 (± 3 days), Week 8 (± 3 days), Week 12 
(± 3 days), Week 16 (± 3 days) and Week 20 (± 3 days), the sc injection of the Double-blind loading dose period at Week 24 (± 3 days), Week 25 (± 1 day) and 
Week 26 (± 1 day), and the Open-label ofatumumab sc injection from Week 28 (± 3 days), followed by every 4 weeks (± 3 days).
18.
Labs must be drawn to allow adequate time for results to be obtained before randomization to ensure patient's eligibility
19.
Patients do not have to visit the site at Week 25 and 26 if they are permitted to administer the sc injection at home at investigator’s discretion.
20.
If the trial is extended beyond Week 72, every 12 weeks visit (Week 84, 96 and so forth) will be performed with same measurements as at Week 60, 72 and so 
forth.


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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
Laboratory sample 
including sample for 
B-cells and T-cells
X
X
X
X
X
Sample for Total IgG, IgM
X
X
X
X
X
MS Relapse
X
X
X
X
X
EDSS
X
X
X
X
X
W=week.
1.
Time measured from the EOS visit.
2.
As needed for patients requiring prolonged B-cell plasma level monitoring (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 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
6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
their disposition recorded on the appropriate CRF. Demographics, inclusion/exclusion, and 
serious adverse event (SAE) data will be collected for these patients. Adverse events that are 
not SAEs will be followed by the Investigator and recorded only in the source data.
6.2
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), 
previous MS treatment and employment status will also be collected on the corresponding 
CRFs.


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6.3
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 
administered and intervals between visits. These data should be transcribed on the appropriate 
CRFs.
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
syringe counts and information provided by the patient (patient diary is provided for recording 
of missed doses). This information should be captured in the source document at each visit. A 
monitor will perform and document drug accountability during site visits and at the end of the 
study. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log.
6.4
Efficacy
This study includes the following efficacy assessments conducted at visits as shown in Table 
6-1:

MS relapse

EDSS

Magnetic resonance imaging (MRI)
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.
6.4.1
MS Relapse
Patients must be instructed to immediately report new neurological symptoms, re-occurring or 
worsening of previous symptoms to the Investigator. If a patient reports symptoms that may 
be consistent with relapse, an unplanned visit to the Investigator and the Independent EDSS 
Rater must be scheduled as soon as possible (whenever possible within 7 days of onset of the 
symptoms).
The assessment, management and reporting of MS relapse is made by the Investigator. 
Confirmation of MS relapse and severity grading, based on the EDSS score (provided by the 
Independent EDSS Rater), will be done centrally.
MS relapse definition: appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 
30 days from onset of a preceding clinical demyelinating event (McDonald et al 2001). The 
abnormality must have been present for at least 24 hours and occurred in the absence of fever 
(< 37.5°C) or known infection.
Diagnosing MS relapses during the study: a patient may report symptoms indicative of a 
relapse at a planned visit or at any other time. Patients will be instructed to immediately 
contact the Investigator if he/she develops new or re-occurring or worsening neurological 
symptoms. At each Telephone interview (Table 6-1), the patient will also be asked whether 
any such symptoms have occurred. If a patient reports new neurological symptoms or 
worsening of previous symptoms, an unplanned visit is to be scheduled as soon as possible, 


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preferably within 7 days. During this visit, the Investigator will first assess whether the 
new/worsening neurological abnormality is consistent with the definition of MS relapse above. 
If so, the standard neurological examination (for the EDSS score) will be performed by the 
Independent EDSS Rater. If there is any doubt in the opinion of the Investigator, the default 
must always be to refer the case to the Independent EDSS Rater to perform an EDSS rating. 
The independent EDSS rater should perform the EDSS rating the same day as the patient’s 
visit to the Investigator whenever possible. Later EDSS assessments can still be utilized for 
confirmation of MS relapses, but should be avoided to reduce the risk of changes in patient 
status in between the initial assessment by the Investigator and the EDSS rating by the 
Independent EDSS rater.
Confirmation of MS relapse: the definition of a confirmed MS relapse is one accompanied by 
a clinically relevant change in the EDSS performed by the Independent EDSS Rater, i.e. an 
increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional 
scores (FSs) or 2 points on one FS, excluding changes involving bowel/bladder or cerebral FS 
compared to the previous available rating (the last EDSS rating that did not occur during a 
relapse). Confirmation of MS relapse based on these definitions will be done centrally.
All MS relapses, regardless if they meet definition for confirmation based on EDSS or not, are 
reported on the appropriate CRF. Severity of MS relapse will be calculated centrally per 
criteria in Table 6-3 below. MS relapse should not be reported as an AE/SAE unless, in the 
judgment of the Investigator it is unusually severe or medically unexpected and warrants 
specific notification as an SAE (as described in Section 7.2.2.1).
Table 6-3
Severity of MS relapse
Mild relapse
Moderate relapse
Severe relapse
EDSS increase of 0.5 point
EDSS increase of 1 or 2 points
Exceeding Moderate criteria
or
or
or
1 point FS change in one to 
three systems
2-point FS change in one or two 
systems
Exceeding Moderate criteria
or
or
1-point change in four or more 
systems
Exceeding Moderate criteria
(Panitch et al 2002)
6.4.2
Expanded Disability Status Scale (EDSS)
EDSS will be determined, based on neurological examination, by the Independent EDSS 
Rater at planned visits according to Table 6-1 and in case of a suspected MS relapse.
The EDSS is an ordinal scale used for assessing neurologic impairment in MS based on a 
neurological examination. It consists of scores in each of seven functional systems (FSs) and 
an ambulation score that are then combined to determine the EDSS steps (ranging from 0 
(normal) to 10 (death due to MS)). The FSs are Visual, Brain Stem, Pyramidal, Cerebellar, 
Sensory, Bowel & Bladder, and Cerebral functions (Fatigue contributes). The FSs and EDSS 
steps will be assessed in a standardized manner. EDSS is a widely used and accepted 
instrument to evaluate disability status at a given time and, longitudinally, to assess 
accumulation of disability in clinical studies in MS.


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Definitions for disability worsening and disability improvement based on the EDSS 
 
 
Disability worsening should not be reported as an AE/SAE unless, in the judgment of the 
Investigator it is unusually severe or medically unexpected and warrants specific notification 
as an SAE (as described in Section 7.2.2.2).
6.4.3
Magnetic Resonance Imaging (MRI)
All patients will undergo MRI scanning of the brain according to the schedules in Table 6-1.
MRI scans will be read by the central MRI reading center. The central reading center will be 
blinded with no access to information on treatment assignments. Prior to the start of the study, 
MRI technician from each center will receive an MRI Manual, outlining technical 
implementation, image quality requirements and MRI administrative procedures. Each site 
will be asked to program the MRI scanner that is designated for evaluation of the study 
patients and perform and submit a dummy scan (so called “dummy or dry run”) to the MRI 
reading center to assess the image quality and to evaluate the compatibility of the electronic 
data carrier. Once the dummy run has been accepted, all the parameter settings for the study 
specific MRI sequences must remain unchanged for the duration of the study.
Each MRI scan performed for the study needs to be previewed by a local 
radiologist/neurologist. The Investigator will review the MRI performed during the Screening 
period to assess patient's eligibility. After Randomization, the Investigator will be contacted in 
case of unexpected or safety-related findings detected on the MRI scan. The investigator may 
review the MRI scans from Week 36 onwards, regardless of safety concerns.
During the study, the quality of each scan performed will be assessed by the central blinded 
MRI reading center. The MRI scan should be sent to the central MRI reading center upon 
completion. As soon as the scan is received by the central MRI reading center, it will be 
evaluated for quality, completeness and adherence to the protocol. Confirmation of MRI 
quality or a description of the quality problems, if detected, will be communicated to the site. 
If scan is incomplete or incorrectly performed, the study center will be asked to repeat it as 
soon as possible. After completion of the quality check, all scans will be analyzed according 
to the MRI protocol.
Restrictions for MRI schedule
To avoid interferences caused by steroids (in regards to Gd-enhancing lesions) for the 
treatment of MS relapse, the following restrictions apply for this study:

In case of relapse, if an MRI has been scheduled within 14 days of the initiation of 
steroid treatment, MRI (with Gd-enhancement) should be performed before steroid 
treatment is initiated.

No MRI (with Gd-enhancement) should be performed while a patient is on steroid 
therapy for relapse and within the following 14 days upon termination of steroid 
therapy.


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As a result of these restrictions, MRI scheduling can be adjusted accordingly. In case a visit is 
performed outside the visit window, any subsequent visits should be performed according to 
the original visit schedule.
Scanning
All sequences/scans will be performed according to the institute MRI manual.
Sequences include T1 hypointense images (with and without contrast medium, 
gadolinium-DTPA), T2-weighted images and brain volume will be performed.
The contrast medium may occasionally cause nausea and vomiting. Allergic reactions may 
also occur very rarely and, in extremely rare instances, can be potentially serious and require 
immediate anti-anaphylactic treatment.
6.4.5
Appropriateness of efficacy assessments
The relapse, disability (EDSS) and MRI assessments to be performed in this study are 
standard and widely accepted efficacy assessments used in clinical MS studies to monitor 
disease activity and to evaluate treatment effects. They also serve to characterize the patient 
population in terms of their MS disease status.
 
6.5
Safety
Safety assessments will include:

Adverse events

Physical examination (including skin)

Vital signs

Laboratory evaluations

Pregnancy testing (females of childbearing potential)


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
ECG

Columbia Suicide Severity Rating Scale (CSSRS) (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).
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.
Periodic safety reviews (generally twice a year) will be performed by the global program 
DMC.
6.5.1
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 section of the CRFs capturing 
medical history/current medical conditions. Significant findings seen after signing the 
informed consent and being randomized meet the definition of an AE and must be recorded 
on the appropriate CRF capturing AEs.
6.5.2
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 and Table 6-2.
For the injections on Days 1, 7, 14 and Week 4 in the Core part and on the first injection in 
the Extension part (at Week 24), vital signs should be obtained 30-60 min before sc injection 
and again approximately 60 min post-injection. 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.


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6.5.3
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.
6.5.4
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.
Parameters that may lead to unblinding to treatment assignment such as B-cell and T-cell 
counts will be blinded to the Investigator and Sponsor study team (e.g. will not be included on 
the routine safety lab reports sent to the Investigators by the central laboratory). This 
information will remain blinded during the Core part of this study until the treatment code for 
the study has been broken.
6.5.4.1
Hematology
Blood samples will be collected at the planned visits indicated in Table 6-1 and Table 6-2. 
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.
For study blinding purposes, the B-cell and T-cell counts will not be provided to the 
Investigators and Sponsor study team. B-cell and T-cell counts will be assessed by personnel 
not otherwise involved in the study for the purpose of determining if continued follow-up is 
required (Section 3.1).
6.5.4.2
Clinical chemistry
Blood samples will be collected at the planned visits indicated in Table 6-1 and Table 6-2. 
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 (TBIL), 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. See Appendix 1 and Appendix 2 for definition and follow-up requirements of 
liver and renal events.
6.5.4.3
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 


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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.
6.5.4.4
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 9,
Section 4.2). For syphilis testing, it should be done per local clinical practice (e.g. by positive 
RPR). For tuberculosis testing, QuantiFERON®-TB Gold test will be done by the central 
laboratory 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-hepatitis A virus IgM

HBs antigen positive or HBc IgM/IgG antibody positive, regardless of HBV DNA testing 
result

HBs antibody positive and other HBV parameters negative (HBs antigen negative and 
HBc IgM/IgG antibody negative) without known history of anti-HBV immunization

anti-hepatitis C virus IgG (if positive IgG, HCV-RNA PCR will be performed: if negative, 
patient can be included)

anti-hepatitis E virus IgM (positive IgG and/or IgM: do Hepatitis E virus (HEV)-RNA 
PCR: if negative, patient can be included).
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, 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 may 
document (in source data) that the serology results are considered false positive and 
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.
For study blinding purpose, the results of immunoglobulin levels will not be included as part 
of the laboratory reports provided to the Investigators or Sponsor study team during the study. 
IgM and IgG levels will be assessed by personnel, not otherwise involved in the study, for the 
purpose of safety and guidance provided in Appendix 3 should be followed.
Additional samples for PK, ADA,
will be 
taken (Section 6.6.1, Section 6.6.2,
6.5.5
Electrocardiogram (ECG)
An ECG will be performed at Screening, Week 24, Week 48, EOS visits. Additional 
unplanned ECGs may be performed at Investigator’s discretion if clinically indicated.


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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. 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.
6.5.6
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 and 
Table 6-2. In addition, the women will be provided with urinary pregnancy test kits for 
monthly home pregnancy testing required between the planned clinic visits after Week 28. 
The patients will document the date and result of each home pregnancy test in a diary 
provided for the study. A monthly structured telephone interview (Table 6-1) will also be 
conducted with the patients which includes questions to confirm that the home urine 
pregnancy testing was done and the result. In the case of a positive test result the patient must 
contact the Investigator immediately for confirmatory testing at the Investigator’s discretion.
In addition, the Investigator will review the contraception status with the patient at each visit 
per Table 6-1 and Table 6-2 to ascertain that the patient continues to comply with protocol 
requirements for highly effective contraception as applicable.
6.5.7
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).
The use of an instrument such as the CSSRS to detect suicidal ideation or behavior is 
currently mandated in studies of CNS active drugs.
6.6
Other assessments
Samples for PK, immunogenicity potential (ADA) 
 will also be assessed and 
evaluated as applicable in relation to efficacy, safety data and population under study.
6.6.1
Pharmacokinetics
Following a single sc injection of ofatumumab 20 mg, PK during the absorption and 
distribution phase will be assessed. PK trough values at steady state for ofatumumab will be 


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used to conduct a population pharmacokinetics analysis. Sampling time points are provided in 
Table 6-1. Samples for PK assessment should be taken prior to dosing at the visit. For PK 
visits after Week 36, if the visit coincides with the day the monthly injection is scheduled, the 
patient should not take the injection in the morning before coming to the site so that the PK 
sample can be drawn before the injection. The PK sample collection date and time must be 
recorded as instructed in the lab manual entered on the appropriate CRF.
Further details on sample collection, numbering, processing and shipment will be provided in 
the Laboratory Manual provided to the sites.
6.6.2
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. For ADA visits after Week 36, if the visit coincides with the day the 
monthly injection is scheduled, the patient should not take the injection in the morning before 
coming to the site so that the ADA sample can be drawn before the injection. 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 (e.g., 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 participation. 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


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
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:

the Common Terminology Criteria AE (CTCAE) grade (1-4)
If CTCAE grading does not exist for an adverse event, use:
1=mild
2=moderate
3=severe
4=life-threatening (see Section 7.2 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 for 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:

study treatment dose not changed (e.g. further observation only) 

study treatment dose increased/reduced

study treatment interrupted/withdrawn

concomitant medication or another therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; 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 if 
any required to treat it, and the outcome. The action taken to treat the adverse event should be 
recorded on the CRF capturing AEs. 


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Information about common side effects already known about the investigational drug 
(ofatumumab) can be found in the 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 ofatumumab that is identified between 
Investigators Brochure updates will be communicated as appropriate, for example, via an 
Investigator Notification (IN) 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 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 (e.g. hospitalization for MS relapse treatment)

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, e.g. 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.
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 


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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.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until the patient last visit (defined as EOS visit or End of 
Safety FU visit) must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this period should only be reported to Novartis 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, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment a Patient Safety 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 European Union 
(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.


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7.2.2.1
Reporting of MS Relapse as SAE
MS relapses are one of the efficacy endpoints in this study; hence they are exempt from SAE 
reporting although they may meet the SAE definition on the basis that they are considered 
medically significant and are frequently associated with hospitalization. These events will 
therefore be reported on the appropriate CRF capturing MS relapse instead of the SAE form. 
However, if, in the judgment of the Investigator, a MS relapse is unusually severe or 
medically unexpected and warrants specific notification, then an SAE form must be 
completed and submitted according to SAE reporting procedures outlined above.
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 (AE/SAE) and any contributing factors (concomitant medications, other 
co-morbid conditions/procedures), 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 in 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.
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
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 (e.g., 
disease, co-medications)

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 appropriate CRFs, including the liver event 
overview.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values should be considered during 
the course of the study:

Serum event:

confirmed (after ≥24 hours) increase in serum creatinine (sCR) 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. The renal AE/SAE and any contributing factors (concomitant medications, other 
co-morbid conditions/procedures) should be recorded in the appropriate CRFs. 
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 (European Medicines Agency (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 


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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 study 
treatment eCRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes 
Yes, even if not associated 
with a SAE
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 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 uses a detailed branched 
logic algorithm to perform the CSSRS 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 CSSRS 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 
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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. 
All SAEs relating to suicidal behavior must be reviewed by the DMC.
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 Sponsor
representative will review the protocol and CRFs with the Investigators and their staff. During
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(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 entries on the (e)CRFs, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight.
The Investigator must maintain source documents for each 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 CRF entries. 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 
patients/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 (eCRFs) using fully validated secure web-enabled software that conforms 
to United States (US) Code of Federal Regulations (CFR) 21 Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 


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data to the Contract Research Organisation (CRO) working on behalf of Novartis. 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.
The Principal Investigator is responsible for assuring that the data entered by the site 
personnel into CRF is complete, accurate, and that entry and updates are performed in a 
timely manner
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 World Health 
Organization (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 
Sponsor (or a designated CRO).
MRI scans will be analyzed centrally and derived results will be sent electronically to Sponsor 
(or a designated CRO).
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 Sponsor (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.
The code break functionality will remain available until study shut down or upon request of 
Sponsor.
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 the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Sponsor 
Development management.
8.4
Data Monitoring Committee
A global program DMC of OMB157G will be in place to oversee the studies of OMB157G. 
Details are provided in the DMC charter.
The DMC will be responsible for on-going review of enrollment, safety and, if requested by 
the DMC, efficacy data and will provide regular assessments on the safety and overall risk to 
benefit ratio of the study conduct, advice the Sponsor of a need for protocol 


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modification/amendment in order to minimize potential risk for patients, request additional 
information or make recommendation including stopping of enrollment and/or treatment, if 
needed.
A Sponsor designee will be responsible for the timely coordination and delivery of the data to 
the DMC on a regular basis. The chair of the DMC will be responsible for providing 
summaries/executive reports of each DMC meeting to Sponsor, arranging on-going 
communication between members of the DMC, arranging meetings and maintaining files with 
all correspondence pertaining to the study.
9
Data analysis
The data analysis will occur in three steps:
1. The first analysis will be conducted for the Core part. Data up to the Week 24 cut-off
will be used. The analysis will be performed when the last patient has completed the 
double-blind loading dose period until Week 28. This analysis will be used in support 
of the registration of ofatumumab in Japan.
2. A second data analysis will be conducted at the Week 48 cut-off (cut-off 2). The 
analysis will include assessments of maintenance of efficacy and extended safety and 
partial data from the Safety FU period.
3. The final analysis will be conducted at EOS (i.e. including all data from the Safety FU
period).
Any data analysis carried out independently by the Investigator should be submitted to 
Sponsor before publication or presentation.
9.1
Analysis sets
Full analysis set (FAS): The FAS comprises all randomized subjects with assigned 
treatments. Subjects will be analyzed according to the randomized treatment assignment 
following the intention-to-treat (ITT) principle, even if they actually received a different
treatment.
The FAS will be used for the summary of demography and baseline characteristics as well as 
for all efficacy analyses.
Per-protocol set (PPS): The PPS is a subset of FAS, consists of all randomized subjects who 
take at least one dose of study medication and have no major protocol deviations that could 
confound the interpretation of analyses conducted on the FAS. Major protocol deviations will 
be determined according to the pre-defined protocol deviation criteria before treatment 
unblinding (e.g. non-compliance for a large proportion of the time in study). For analyses 
performed on the PPS, only on-treatment assessments will be used.
The PPS will primarily be used for the supportive analyses of the primary efficacy variable.
Safety set (SAF): The SAF set includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to the actual treatment received. The Safety 
Set will be used for all safety analyses.


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9.2
Patient demographics and other baseline characteristics
Demographics, MS disease history, MRI baseline characteristics, MS medication history and 
employment status, will be summarized by treatment group for the FAS.
9.3
Treatments
Exposure to investigational study medication is defined as the number of days spent on study 
drug divided by 365.25 days. In this double-blind design all patient will receive injections 
(active or placebo) to maintain the blind. For the calculation of exposure to study medication 
the intended dosing frequency will be taken into account and intermediate treatment 
interruptions will be subtracted when deriving drug exposure.
Exposure to investigational study medication will be summarized by treatment with number 
and percentage of patients by time category, and with summary statistics of the number of 
patient years of exposure. Number of patient years will be summarized by age and gender, by 
gender and weight.
Time-at-risk is defined as the number of days spent in the study, from first dose to the last 
dose of study medication, plus the safety data cut-off of 100 days. Intermediate treatment 
interruptions will be included in time-at-risk calculations. Time-at-risk corresponds to the 
time window used for adverse event reporting and can serve as a denominator to safety (e.g. 
in exposure-adjusted incidence rates). Time-at-risk will be summarized in a similar way to 
exposure to investigational study medication.
9.4
Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
The primary variable is the number of Gd enhanced T1 weighted MRI lesions per scan.
9.4.2
Statistical model, hypothesis, and method of analysis
The null hypothesis is that there is no difference in the number of Gd-enhanced T1 weighted 
MRI lesions per scan between ofatumumab and placebo during the Core part. The alternative 
hypothesis is that there is a difference between the 2 treatment groups.

Superiority of ofatumumab over placebo will be concluded if the mean number of 
Gd-enhanced T1 weighted MRI lesions per scan in patients treated with ofatumumab 
is lower compared with placebo and the observed p-value for the between-treatment 
comparison is less than the two-sided significance level of 0.05.
The null hypothesis will be tested on the FAS using a negative binomial regression model 
with log-link. Each patient’s total number of Gd-enhanced T1 weighted MRI lesions during 
the Core part will be used as the response variable, and natural log of the number of MRI 
scans will serve as the offset variable to adjust for the different number of MRI scans between 
patients. The model will include treatment, region (Japan or other countries), and baseline 
number of Gd-enhanced T1 weighted lesions (0 or ≥1) as factors.


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9.4.3
Handling of missing values/censoring/discontinuations
The primary negative binomial model with an offset for the number of MRI scans adjusts for 
missing information (drop-out) under the assumption of non-informative drop-out, 
information is missing at random, and constant number of Gd-enhancing T1 weighted MRI 
lesions per scan within patient. Missing values will not be imputed. However, deviations from 
assumptions will be tested in sensitivity analyses.
9.4.4
Sensitivity analyses
The primary analysis will be repeated using the per-protocol set to provide an analysis of 
on-treatment data from subjects who have no major protocol violations.
The time-to-first relapse analysis (Section 9.5.1.3) does not assume a constant number of 
Gd-enhancing T1 weighted MRI lesions per scan and can be regarded as a sensitivity analysis 
to the primary analysis.
Additional sensitivity analyses may be defined in the analysis plan prior to database lock.
9.4.5
Consistency across regions
Consistency in efficacy across regions on the primary variable will be evaluated using a 
statistical model similar to the primary model, but with a treatment-by-region (Japan or other 
countries) interaction term added. The mean number of Gd-enhancing T1 weighted MRI 
lesions 
per 
scan 
will 
be 
provided 
by 
treatment 
and 
region. 
The 
rate-ratio 
(ofatumumab/placebo) will be presented for individual regions separately, together with 95% 
confidence intervals. The p-value of the treatment-by-region interaction will be displayed.
The estimates for individual regions will be displayed via a forest plot to visualize consistency.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables (Core part)
All efficacy analyses will be done based on the FAS, unless explicitly stated otherwise.
9.5.1.1
Number of new or newly T2 lesions on MRI scans
Analysis of the number of new or enlarging T2 lesions will be done based on the FAS using a 
negative binomial regression model with log-link. The number of new or enlarging T2 lesions 
on the last available MRI scan relative to baseline will be used as the response variable, and 
the natural log of the time (in years) of the MRI-assessment from the baseline/Screening scan 
will serve as the offset variable to adjust for the various lengths of follow-up times between 
patients in this study. The model will include treatment, region (Japan or other countries), 
baseline number of Gd-enhancing T1 weighted lesions (0 or ≥1) as factors, and baseline 
volume of T2 lesions as continuous covariates. 
The number of new or enlarging T2 lesions per year will be estimated by treatment with 95% 
confidence interval. The between treatment effect will be calculated as rate-ratio with 95% 
confidence interval and p-value. In addition the relative reduction in the number new or 
enlarging T2 lesions per year will be computed as the rate-ratio minus one (1) and expressed 
as a percentage.


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9.5.1.2
Annualized relapse rate (ARR)
Analysis of ARR will be done based on the FAS, using a negative binomial regression model 
with log-link, treatment, region (Japan or other countries), baseline number of Gd-enhancing 
T1 weighted lesions (0 or ≥1) as factors, and number of relapses in previous year and 
baseline EDSS as covariates. In the analysis, the response variable is the number of confirmed 
relapses observed from each patient and the patient’s time in study (natural log of time in 
years) is used as an offset variable to adjust for the varying lengths of patient’s time in the 
study. The adjusted ARR (i.e., model-based estimate adjusted for covariates) for each 
treatment and the corresponding 95% confidence interval, and ARR ratio (also expressed as 
percentage reduction relative to control group) along with the 95% confidence interval for the 
ARR ratio and the corresponding p-value will be obtained.
9.5.1.3
Time to first relapse
Analysis of time to first relapse will be done based on the FAS, using a Cox proportional 
hazard model with treatment, region (Japan or other countries), and baseline number of 
Gd-enhancing T1 weighted lesions (0 or ≥1) as factors, and number of relapses in previous 
year and baseline EDSS as covariates. The hazard ratio (also expressed as percentage 
reduction relative to control group) along with the 95% confidence interval for the hazard 
ratio and the corresponding p-value will be obtained.
In addition, Kaplan-Meier curves by treatment will be used to present the time-dependent 
cumulative frequency and percentage of subjects reaching the first relapse; by-treatment 
Kaplan-Meier estimates (with 95% confidence interval) at end of study will be obtained.
9.5.2
Safety variables (Core part)
Safety analyses will be conducted using the safety (SAF) dataset. Patients will be grouped by 
the actual treatment received. Safety data for the core part will be reported for the first time 
when the double-blind loading dose period has been completed by the last patient (data 
cut-off 1).
Unless explicitly otherwise stated, safety data will be reported up to and including the safety 
cut off of 30 days after permanent study drug discontinuation in patients who discontinued 30 
days or more prior to cut-off 1, and up to cut-off 1 in all other patients.
The assessment of safety will be primarily based on the frequency of adverse events 
(including death and non-fatal serious adverse events). Additional safety assessments include 
laboratory tests, physical examination (including examination of skin), vital sign measures, 
ECG evaluations and assessment of suicidality. Clinically significant findings in these 
additional safety assessments will be reported as adverse events and analyzed as such. In 
addition all safety assessments will be summarized or listed as appropriate. The analyses of 
additional safety assessments will be defined on the level of the statistical analysis plan.
9.5.2.1
Adverse events
Treatment emergent adverse events (TEAE) will be reported up to and including safety cut off 
of 30 days after permanent study drug discontinuation in patients who discontinued 30 days or 


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more prior to cut-off 1, for all other patients TEAE will be reported up to cut-off 1. All serious 
TEAEs and death will be included, regardless of safety cut-off.
TEAEs will be summarized (number of cases as a percentage of number at risk) by treatment 
group. Number and percentage of patients with TEAE will be summarized by primary system 
organ class and preferred term. Serious TEAEs, drug related TEAEs and TEAEs leading to 
premature discontinuation from study drug will be presented in a similar format as adverse 
events. In addition, TEAEs will be reported by CTCAE grade.
9.5.2.2
Laboratory data
The summary of laboratory evaluations will be presented for 3 groups of laboratory tests: 
Hematology, Chemistry and Urinalysis.
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values, and by presenting shift tables using clinically notable ranges (baseline to 
most extreme post-baseline value). Laboratory data, and specifically liver enzymes, will also 
be summarized by maximum change from baseline.
For liver enzymes, the number of subjects with newly occurring liver enzymes abnormalities 
will be summarized by treatment group. Newly occurring liver enzymes abnormalities are 
defined relative to the upper limit of normal (ULN). Example of a newly occurring liver 
enzyme event are ALT or AST > 3 x ULN & TBL > 2 x ULN & ALP ≤2 x ULN or a 
reported Hy’s Law case (refer also to Appendix 1). 
Standardised MedDRA Queries (SMQ) and preferred terms searches for drug-related hepatic 
disorders will be conducted. Results of these searches will be analyzed and presented in a 
similar format as other adverse events. In case of liver events detailed listings will be provided.
In case of renal events, the overall frequency of events and percentage of patients with renal 
events during the treatment period will be summarized and detailed listings provided. 
Additional analyses of renal events can be defined in the statistical analysis plan.
9.5.2.3
Vital signs
Vital sign measurements and their change from baseline will be summarized with descriptive 
(mean, median, standard deviation, min, max) by visit. The number and percentage of subjects 
with clinically notable vital signs will be presented.
9.5.2.4
Suicidality evaluations
The Columbia Suicide Severity Rating Scale (CSSRS) data will be mapped to Columbia 
Classification Algorithm for Suicide assessment (C-CASA) as per Food & Drug 
Administration (FDA) guidance on suicidality.
The proportion of subjects who have completed suicide, suicide attempt, preparatory actions 
toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without 
suicidal intent as per the C-CASA scale during the study will be summarized by treatment 
group.


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9.5.2.5
Other safety evaluations 
All clinically significant safety findings based on additional safety evaluations (e.g. ECG or 
physical examination including assessments of skin, lymph nodes, lung, etc.) must be reported 
as adverse events on the CRFs capturing AEs. The statistical analysis of these findings will be 
done in the analysis of adverse events.
Other safety data will be summarized or listed as appropriate.
9.5.2.6
Safety evaluation during the Safety Follow-up period
Safety data collected during the Safety Follow-up period includes adverse events, laboratory 
assessments to measure B-cell repletion. All safety assessments after study drug 
discontinuation will be analyzed, summarized or listed.
Safety data collected during the Safety Follow-up period will be reported separately. These 
analyses will include laboratory assessments including B-cell repletion, adverse events, vital 
signs, MS relapses and change in EDSS. For all patients change is defined relative to the End 
of Study visit (EOS). Since post-treatment safety follow-up in the Safety Follow-up period
may continue for up to 36 weeks (or longer if criteria for loner follow-up are met) after 
completion of the Treatment period study, the study report for the Core part (Screening and 
Double-blind treatment period) will be completed based on the completed core part i.e. based 
on all patients who have completed the Double-blind treatment period, and the partial data 
from the Safety Follow-up period available at that time. A complete analysis of the 
post-treatment safety follow-up will be provided in an addendum to the study report when all 
patients who entered the Safety Follow-up period have completed this period.
9.5.3
DNA
Not Applicable.
9.5.4
PK/PD
PK concentration and B-cell count data will be summarized by visit for the overall population, 
and separately by region (Japan or other countries) and provided together with by-patient 
listings in the study report.
 
 
 
 
9.5.5
Immunogenicity assessment
Samples will be analyzed for of the presence of human anti-drug antibodies (ADA). The 
proportion of patients with ADA will be summarized by visit and overall (i.e. proportion of 
patients with ADA) as an assessment of the immunogenicity potential of ofatumumab. A 
listing by patient will also be provided.


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9.7
Analysis of the Extension part
Analyses will include the combined data of the Core and Extension parts.
The extension FAS will include all available assessments of the Core and Extension parts. 
The main between-group comparisons of the efficacy variables will be based on the original 
randomization at the start of the Core part. The comparison will be between patients who were 
randomized to ofatumumab, and those who were initially randomized to placebo and received 
ofatumumab delayed, i.e. at the start of the Extension. Efficacy analyses will use similar 
models as described for the Core part of the study.
 
 
 
Extended safety and tolerability will be described by safety parameter summaries covering the 
whole period of continuous treatment with ofatumumab, i.e. by combining double-blind and 
open-label ofatumumab treatment. Placebo data will be excluded in this analysis. Details will 
be provided in the statistical analysis plan.
Details of analysis for the Extension part will be defined in a SAP document.
9.8
Interim analyses
No interim analysis will be conducted.
9.9
Sample size calculation
A total sample size of 60 patients, randomized 2:1 to ofatumumab and placebo, will provide 
more than 90% power for a statistical test of superiority of ofatumumab compared with 
placebo at a one-sided alpha level 0.025. The power was calculated based on a negative 
binomial model under the assumption of 1.0 Gd-enhancing lesions per scan for placebo and a 
92% relative reduction with ofatumumab (i.e. 0.08 Gd-enhancing T1 lesions per scan for 
ofatumumab), and a dispersion parameter κ = 4.5 (as observed in the combined Phase 3 
placebo-controlled studies of fingolimod, namely FREEDOMS and FREEDOMS II studies 
for the same parameter, data on file). The sample size allows for a dropout rate of 10%.
Sample size calculation was done in EAST 6, version 6.3, Cytel Inc.


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9.9.1
Evaluation of consistency in the treatment effect on the primary 
variable across regions
As a secondary objective the effect of ofatumuab on Gd-enhancing T1 lesion compared with 
placebo will be estimated for individual regions (Japan and other countries). It is planned to 
include 30 patients from Japan out of 60 in total.
The randomization will be stratified by region (Japan or other countries), and by Gd-lesion 
status on the screening scan (0 Gd-enhancing lesions or ≥1 Gd-enhancing lesions). Under the 
protocol assumptions for placebo, it is expected that approximately 2/3 of the patients will be 
free of Gd-enhancing lesions at baseline.
A simulation was performed to evaluate the consistency in efficacy on the primary variable 
across regions. Consistency is defined as a rate ratio < 1 in both Japan and other countries. For 
the simulation the following assumptions apply:

The assumptions for the primary variable are the same for Japan and other countries and 
identical to those for the primary endpoint (i.e. 1 Gd-enhancing lesion per scan, a 
rate-ratio of 0.08 between ofatumumab and placebo, dispersion 4.5)

In addition, it was assumed that the study would include 30 patients from Japan and 30
from other countries, and that patients would be randomized 2:1 to ofatumumab or 
placebo group in each region.
The probability to observe a consistent treatment effect between Japan and other countries
was estimated to be higher than 99% under these settings.
Furthermore, we estimated the probability to observe a difference in treatment effect 
(percentage lesion reduction between ofatumumb and placebo) between Japan and other 
countries under the same assumptions. The probability to observe a difference of 20% or more 
(one-sided) in treatment effect between Japan and other countries was estimated to be < 3%
(Table 9-1).
Table 9-1
Probability to observe a difference in Gd-lesion reduction across 
regions of more than delta
Delta*
Probability of a difference in percentage lesion reduction > Delta
5%
13.7%
10%
6.1%
20%
2.3%
30%
1.3%
*Delta=Percentage lesion reduction for other countries - percentage lesion reduction for Japan
9.9.2
Numerical comparison of annualized relapse rate (ARR)
As a secondary objective the ARR will be compared between patients treated with 
ofatumumab or placebo. We evaluated the probability to observe a treatment effect in favor of 
ofatumumab, as defined by an ARR-ratio (ofatumumab/placebo) less than 1 in the overall 
population. The following assumptions were made for this evaluation:

60 subjects in total are randomized 2:1 to ofatumumab or placebo.

The true ARRs are 0.4 in the placebo arm, and 0.16 in the ofatumumab arm.


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
The dispersion parameter, k, is 0.1.

The follow-up period is 6 months.
Under these settings, the probability to observe a lower ARR in patients treated with 
ofatumumab compared with placebo is > 80%.
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 International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients/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 (e.g. 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 (e.g., 
advertisements) and any other written information to be provided to patients/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 


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is 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 (CQA), 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 Standard Operating Procedures (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 patients/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 patients/subjects may be implemented immediately provided the health authorities 


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are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any 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; 
104:20882-7.
EMA/CHMP/771815/2011, Rev. 2. (2015) Guideline on clinical investigation of medicinal 
products for the treatment of Multiple Sclerosis.
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.
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.
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.


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Soerensen PS, Lisby S, Grove R, et al (2014) Safety and efficacy of ofatumumab in relapsing-
remitting multiple sclerosis. Neurology; 82:573-81.
Sormani MP, Bonzano L, Roccatagliata L, et al (2009) Magnetic resonance imaging as a 
potential surrogate for relapses in multiple sclerosis: a metaanalytic approach. Ann Neurol;
65(3):268-75.
Sormani MP and Bruzzi P (2013) MRI lesions as a surrogate for relapses in multiple sclerosis: 
a meta-analysis of randomised trials. Lancet Neurol; 12:669-76.
Wingerchuk DM, Lennon VA, Pittock SJ, et al (2006) Revised diagnostic criteria for 
neuromyelitis optica. Neurology; 66:1485-9.


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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 (e.g., 
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 (e.g. cognitive deficit, behavioral changes, cortical visual disturbances 
or any other neurological cortical symptoms/signs any symptom/sign suggestive of an 
increase of intracranial pressure) or accelerated neurological deterioration, the Investigator 
should schedule a complete physical and neurological examination and an MRI as soon as 
possible before beginning any steroid treatment. Conventional MRI as defined in the protocol 
as well as additional scanning such as Fluid-Attenuated Inversion Recovery (FLAIR) and 
Diffusion-weighted imaging (DWI) sequences 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 an MS relapse, assessment and treatment of 
the relapse will be performed as described in the protocol (Section 6.4.1 and Section 5.5.6, 
respectively). 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 (e.g. 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 eCRF 
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.


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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.
When evaluating a patient with a suspected infection, the most sensitive tests available should 
be used (i.e. 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 10). 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, 12, 24, 
28, 36, 48, subsequent visit for every 12 weeks, and EOS by the central laboratory and will be 
blinded to the Sponsor and the Investigator. They will only be communicated to the site after 


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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 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.

SAP_001.pdf: 
Clinical Development
OMB157/Ofatumumab
COMB157G1301 / NCT03249714
A 24-week, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study to evaluate the efficacy, 
safety and pharmacokinetics of ofatumumab in patients 
with relapsing multiple sclerosis followed by an extended 
treatment of at least 24 weeks with open-label ofatumumab
Statistical Analysis Plan (SAP)
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final v1.0 for final analysis
Release date:
4-September-2020
Number of pages:
61
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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COMB157G1301
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
09-Mar-
2018
Prior 
to 
FPFV
Creation of 
final version
N/A - First version
NA
13-
Dec-
2019
Prior 
to 
DBL
Amendment 
1
The variable “Gd-enhanced T1 lesion” was 
renamed “Gd-enhanced lesion”.
Overall except “1 
Introduction” and 
“3 Sample size 
calculation”
Overall rules on Cut-off 1 and Cut-off 
2/EOS analyses are additionally 
mentioned.
2.1 Data analysis 
general 
information
Documentation was updated to define “1 
month”.
2.1.1 General 
definition
It was clarified that visit windows are 
based on study days relative to Core part 
Day 1.
2.1.2 Visit
windows for data 
analysis
Extension FAS was defined for efficacy 
analysis including Extension part.
2.2 Analysis sets
Analysis plan on medical history was 
documented independently.
2.3.4 Medical 
history
Analysis plan on smoking/alcohol history 
was documented independently.
2.3.5 Smoking
Definition of time-at-risk was updated for 
AE analysis.
2.4.1 Study 
treatment / 
compliance
Analyses plans were added for impact 
assessment on potential unblinding issue.
2.7.3 Impact 
assessment of
potential 
unblinding
2.8.1 Adverse 
events (AE)
It was clarified which safety analysis to 
repeat for Cut-off 2/EOS analysis
2.8.1 Adverse 
events (AE)
2.8.3 Laboratory 
data
2.8.4.2 Vital 
signs.


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COMB157G1301
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
2.8.4.3 Suicidality 
evaluations
Analyses of AE leading to study drug 
interruption, AE by onset period, subgroup 
analyses of AE, and analysis of drug-
related CDS risks were added.
2.8.1 Adverse 
events (AE)
Documentation on liver and renal events 
was updated
2.8.3 Laboratory 
data
Analysis plan for suicidality evaluation was 
updated.
2.8.4.3 Suicidality 
evaluations
 
 
 
 
Section “Analysis for Japan CTD” was 
removed, and relevant analysis plans were 
moved to the section for adverse events
Also, box plots of lab parameters were 
cancelled.
N/A
The imputation rule was updated for 
relapse.
5.1 Imputation 
rules.
CTCAE grade is displayed in the 
document
5.3.4 CTCAE 
grades for 
laboratory 
parameters 
PD “INCL01A” was added.
5.6 Rule of 
exclusion criteria 
of analysis sets
“Randomization despite screen failure” 
was added to non-PD criteria. 
5.6 Rule of 
exclusion criteria 
of analysis sets
20-Jul-
2020
Prior 
to 
W48 
DBL
Amendment 
2 for Cut-off 
2 analysis
The visit windows for Cut-off 2 analysis 
were updated.
2.1.2 Visit 
windows for data 
analysis
Definitions of Extension FAS was updated. 
2.2 Analysis sets
Extension safety set was additionally 
defined
2.2 Analysis sets
Description on summary of PD was added.
2.3.1 Patient 
disposition


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SAP
COMB157G1301
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Data handling on the baseline data was
updated.
2.3 Patient 
disposition, 
demographics 
and other 
baseline 
characteristics
Summary on pre-post ofatumumab 
treatment was added.
2.4.2 Prior, 
concomitant and 
post therapies
Summary on MS relapse characteristics 
was added.
2.7 Analysis of 
secondary 
efficacy 
objective(s)
The analysis plan for AE by onset period 
was refined.
2.8.1 Adverse 
events
Efficacy analysis for Cut-off 2 were 
additionally documented.
2.15 Analysis on 
the Extension part 
not mentioned in 
the previous 
sections
Abnormality criteria was added on AST.
5.3.2 Newly 
occurring liver 
enzyme 
abnormalities.
4-Sep-
2020
Prior 
to 
final 
DBL
For final 
analysis
Analysis sets for patient disposition and 
baseline data were updated to FAS
2.3 Patient 
disposition, 
demographics 
and other 
baseline 
characteristics
“Gd-enhanced/enhancing lesions” was 
updated to “Gd-enhanced/enhancing T1
lesions” to align with study protocol and for 
consistency within this document.
Overall, wherever 
applicable


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COMB157G1301
Table of contents
Table of contents .................................................................................................................5
List of abbreviations............................................................................................................8
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Study objectives and endpoints .............................................................................13
2
Statistical methods.............................................................................................................14
2.1
Data analysis general information .........................................................................14
2.1.1
General definitions................................................................................14
2.1.2
Visit windows for data analysis ............................................................15
2.1.3
Nominal visits for ECG analysis...........................................................19
2.1.4
Treatment group for Cut-off 2 and final analysis..................................20
2.2
Analysis sets ..........................................................................................................20
2.2.1
Subgroups of interest.............................................................................21
2.3
Patient disposition, demographics and other baseline characteristics ...................22
2.3.1
Patient disposition.................................................................................22
2.3.2
Background and demographic characteristics.......................................22
2.3.3
MS baseline disease characteristics ......................................................22
2.3.4
Medical history......................................................................................23
2.3.5
Smoking history and alcohol history.....................................................23
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
2.4.1
Study treatment / compliance................................................................23
2.4.2
Prior, concomitant and post therapies...................................................25
2.5
Analysis of the primary objective..........................................................................27
2.5.1
Primary endpoint...................................................................................27
2.5.2
Statistical hypothesis, model, and method of analysis..........................27
2.5.3
Handling of missing values/censoring/discontinuations.......................27
2.5.4
Supportive analyses...............................................................................28
2.6
Analysis of the key secondary objective ...............................................................28
2.7
Analysis of secondary efficacy objective(s)..........................................................28
2.7.1
Secondary endpoints .............................................................................28
2.7.2
Statistical hypothesis, model, and method of analysis..........................29
2.7.3
Impact assessment of potential unblinding ...........................................31
2.7.4
Handling of missing values/censoring/discontinuations.......................31
2.8
Safety analyses.......................................................................................................31
2.8.1
Adverse events (AEs)............................................................................32


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2.8.2
Deaths....................................................................................................36
2.8.3
Laboratory data .....................................................................................36
2.8.4
Other safety data ...................................................................................37
2.9
Pharmacokinetic endpoints....................................................................................42
2.10
PD and PK/PD analyses.........................................................................................42
2.11
Immunogenicity assessment ..................................................................................43
2.12
Patient-reported outcomes .....................................................................................43
43
43
43
43
2.15
Analysis on the Extension part not mentioned in the previous sections................45
2.16
Interim analysis......................................................................................................46
3
Sample size calculation .....................................................................................................46
3.1
Evaluation of consistency in the treatment effect on the primary variable 
across regions.........................................................................................................46
3.2
Numerical comparison of annualized relapse rate (ARR).....................................47
4
Changes to protocol specified analyses.............................................................................47
5
Appendix ...........................................................................................................................48
5.1
Imputation rules.....................................................................................................48
5.1.1
Study drug.............................................................................................48
5.1.2
AE date imputation ...............................................................................48
5.1.3
Concomitant medication date imputation .............................................48
5.1.4
Relapse date imputation........................................................................48
5.1.5
Other imputations..................................................................................49
5.2
AEs coding/grading ...............................................................................................50
5.3
Laboratory parameters derivations ........................................................................50
5.3.1
Laboratory test groups and subgroups ..................................................51
5.3.2
Newly occurring liver enzymes abnormalities......................................52
5.3.3
Newly occurring renal events................................................................53
5.3.4
CTCAE grades for laboratory parameters.............................................53
5.4
Clinical notable vital signs.....................................................................................55
5.5
Statistical models...................................................................................................55
5.5.1
Primary analysis....................................................................................55
5.5.2
Key secondary analysis.........................................................................55
5.6
Rule of exclusion criteria of analysis sets..............................................................56


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5.7
Statistical method details for TEAEs.....................................................................59
5.7.1
Odds ratios and 95% confidence interval..............................................59
5.7.2
Exposure adjusted incidence rate and 95% confidence interval ...........60
6
Reference...........................................................................................................................61


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List of abbreviations
AE
Adverse event
ADA
Anti-drug-antibody
ALP
Alkaline Phosphate
ALT
Alanine Aminotransferase
ARR
Annualized Relapse Rate
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
BIL
Bilirubin
BMI
Body Mass Index
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
(e)CSSRS
(electronic) Columbia Suicide Severity Rating Scale
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
(e)EDSS
(electronic) Expanded Disability Status Scale
EOS
End of Study
FAS
Full Analysis Set
FDA
Food Drug Association
FU
Follow up
Gd
Gadolinium
GGT
Gamma-Glutamyltransferase
INR
International Normalized Ratio
ITT
Intention to treat
IRR
Injection related reaction
KM
Kaplan-Meier
LLN
Lower limit of Normal
M
Month
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic Resonance Image
MS
Multiple Sclerosis
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PD
Pharmacodynamics
PDS
Programming Datasets Specification


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PFS
Progression-Free Survival
PH
Proportional Hazard
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PT
Preferred term
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SOC
System Organ Class
TBIL
Total Bilirubin
TEAE
Treatment Emergent AE
TFLs
Tables, Figures, Listings
ULN
Upper Limit of Normal
WHO
World Health Organization


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1
Introduction
The purpose of Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol of study COMB157G1301. Protocol version 01 has 
been referenced at the time of finalization of the SAP. 
1.1
Study design
The study is designed, in conjunction with the global Phase 3 studies (COMB157G2301 and 
COMB157G2302), to provide the necessary data to support registration of ofatumumab for the 
treatment of relapsing MS in Japan.
The study will provide efficacy, safety, tolerability and pharmacokinetics data for ofatumumab 
20 mg subcutaneous injections every 4 weeks compared with placebo for 24 weeks in patients 
from Japan (neither Caucasian nor African) and the other countries (mainly Caucasian, not East 
Asian) and also provide the extended efficacy, safety, tolerability and pharmacokinetics data.
This study has 2 parts: A randomized, double-blind, placebo controlled Core part, and an 
Extension part in which all patients receive open-label ofatumumab.

Core part: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the efficacy, safety and tolerability and PK of 
ofatumumab in patients with relapsing MS.

Extension part: The Core part is followed by an Extension part in which all patients 
receive open-label ofatumumab. In the Extension part, patients are treated for at least 
24 weeks and no longer than 48 weeks. Patients who complete the Extension part will 
be given the option to transfer into a planned open label ofatumumab umbrella 
extension study (under separate protocol).
All patients who prematurely discontinue study treatment or who do not enter the separate 
umbrella extension study, will be followed for a total of at least 36 weeks after study drug 
discontinuation in the Safety Follow-up (FU) period.
It is planned that a total of 60 patients will be randomized in a 2:1 ratio to ofatumumab or 
placebo in the Core part; approximately half of the study patients will be from Japan (neither 
Caucasian nor African) and the other half from the other countries (mainly Caucasian, not East 
Asian). Randomization will be stratified by region (Japan or other countries) and baseline 
number of Gd-enhanced T1 weighted lesions (0 or ≥1).
The Core part consists of 2 periods; Screening period and Double-blind treatment period
(Figure 1-1).
The Screening period can last up to 45 days and consists of 2 sections; Screening section and 
Baseline section. The Baseline section can last up to the point of first study drug administration 
(Day −7 to Day 1). Patient eligibility will be determined based on the Screening and Baseline 
assessments.
The Double-blind treatment period will start on Day 1 with randomization of the patient. 
Patients will be randomly assigned in a 2:1 ratio to receive either ofatumumab 20 mg sc or 
matching placebo sc in a double-blind fashion. Injectable study treatments (ofatumumab or 


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placebo) will be administered on Day 1, Day 7, Day 14, Week 4 and every 4 weeks thereafter. 
The Double-blind treatment period will continue until the completion of all assessments 
required for the Core part at Week 24.
Patients who prematurely discontinue double-blind study medication will have their end of 
Study (EOS) visit as soon as possible and will be followed up for safety in the Safety FU period 
for a minimum of 36 weeks. 
The Extension part consists of 2 periods; Double-blind loading dose period and Open-label 
treatment period.
The Double-blind loading dose period will be applicable for patients who complete the 
Double-blind treatment period. All patients will receive ofatumumab 20 mg sc at Week 24; the 
Extension part starts with the injection of the Week 24. Patients randomized to ofatumumab in 
the Double-blind treatment period will receive the matching placebo sc at Week 25 and 26. 
Patients randomized to placebo in the Double-blind treatment period will receive ofatumumab 
20 mg sc at Week 25 and 26. All patients will receive the study drug in a double-blind manner 
at Week 25 and 26.
The Open-label treatment period will begin at Week 28 and all patients will receive 
open-label ofatumumab 20 mg sc every 4 weeks in this period. This period will continue until 
the last patient is transferred to a planned umbrella extension study (under separate protocol 
requiring another informed consent).
Patients who prematurely discontinue study treatment will have their EOS visits as soon as 
possible and will be followed up for safety in the Safety FU period for a minimum of 36 weeks.
After study drug discontinuation, during Core or Extension parts, patients may initiate 
alternative MS therapy according to local standard of care if clinically indicated.
The Safety FU period will be applicable for the following patients:

Patients who complete this study and do not enter the planned umbrella long-term 
extension study

Patients who prematurely discontinue study treatment in Core or Extension part
All Safety FU visits must be scheduled relative to the date of EOS visit.
These patients will be followed for a total of at least 36 weeks after study drug discontinuation 
(by 36 weeks the majority of patients are expected to have repleted their circulating B-cells, see 
Protocol Section 3.3).
A longer than 36 weeks of post-treatment Safety FU period will be required for patients who 
have not repleted their B-cells (i.e. B-cells not back to baseline value or to lower limit of normal 
(LLN) whichever comes first as determined by central lab) at 36 weeks.
These patients will continue to be followed with assessments every 12 weeks until their B-cell 
counts have repleted. To protect the study blind, the assessment of B-cell counts will be 
performed centrally and the Investigators and Sponsor study team will only be informed of 
whether or not continued follow-up is necessary.
Patients who have initiated therapy with another disease modifying/immunosuppressive therapy 
before the end of the 36-week follow-up will not be monitored beyond 36 weeks.


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Figure 1-1
Study design
* Patients randomized to placebo in the Double-blind treatment period will receive ofatumumab 20 mg sc at 
Week 24, 25 and 26 as loading dose regimen. Patients randomized to ofatumumab in the Double-blind treatment 
period will receive ofatumumab 20 mg sc at Week 24 and the matching placebo sc at Week 25 and 26. In all 
patients, the extension part starts with the Week 24 injection.
** Patients who prematurely discontinue study drug or patients who do not enter the umbrella extension study will 
enter the Safety FU period following their EOS visits.
*** Umbrella extension study (planned) will be conducted under separate protocol.
Data cut-off 1 is defined as the date the last patient completes all the assessments for Week 24.
Data cut-off 2 is defined as the date the last patient completes all the assessments for Week 48.
Three types of analyses to be conducted are described in the SAP. They will be referred to in 
this document as Cut-off 1 analysis, Cut-off 2 analysis, and EOS analysis: 
1. The Cut-off 1 analysis will be conducted for the Core part. Data up to the Week 24 
(cut-off 1) will be used. Data from the safety FU period for patients who prematurely 
discontinued from study treatment before Week 24 will also be included. The analysis 
will be performed when the last patient has completed the double-blind loading dose 
period at Week 28. This analysis will be used in support of the registration of 
ofatumumab in Japan.
2. The Cut-off 2 analysis will be conducted when the last patient completes all 
assessments up to the Week 48 visit. The analysis will also include assessments of 
maintenance of efficacy and extended safety during the extension part and data from 
the Safety FU period for patients who prematurely discontinued from study treatment 
before the cut-off 2. Any between treatment comparison will be based on treatment 
assignment in the core part. The analysis will also be used in support of the 
registration of ofatumumab in Japan.
3. The final analysis will be conducted when the last patient completes the EOS visit or 
Safety FU period.
Randomization
Ofatumumab 20 mg sc
Scree
ning
Placebo injections sc
Base
line
Week  
1 7 14 4
8
12
16
20
Ofatumumab 20 mg sc
32
36
40
44
48
52
Safety FU 
period** 
or 
Umbrella 
extension 
study***
EOS
Data cut-off 2
Double-blind 
Treatment period
Open-label 
Treatment period
Screening 
period
25 26
Double-
blind 
loading 
dose 
period*
24
28
Randomized in a 2:1 ratio
Data cut-off 1
Day  
MRI  
Core part
Extension part


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1.2
Study objectives and endpoints
Primary objective
The primary objective of the study is to demonstrate that ofatumumab is superior to placebo in 
reducing the cumulative number of Gd-enhanced T1 lesions across 4 MRI scans at Week 12, 
16, 20 and 24 in patients with relapsing MS. The primary objective will be assessed during the 
core part. (Section 2.5)
Secondary objectives
The secondary objectives are described separately for the core part and the extension part: 
Core part
Assess the consistency of the efficacy of ofatumumab versus placebo across regions (Japan vs 
other countries) in the cumulative number of Gd-enhanced T1 lesions on MRI scans at Week 12, 
16, 20 and 24. (Section 2.5.4)
Assess the efficacy of ofatumumab versus placebo in the number of new or enlarging T2 lesions 
on MRI scans. (Section 2.7)
Assess the efficacy of ofatumumab versus placebo in annualized relapse rate (ARR) and time 
to first relapse. (Section 2.7)
Assess the safety and tolerability of ofatumumab versus placebo. (Section 2.8)
Assess the similarity of the pharmacokinetics (PK) and B-cell count following the treatment 
with ofatumumab across regions (Japan vs other countries). (Section 2.9, Section 2.10, Section 
2.8)
Extension part (additional to objectives for Core part)
Assess extended safety and tolerability of ofatumumab. (Section 2.8)
Assess extended efficacy of ofatumumab in:

Number of Gd-enhanced T1 lesions (Section 2.5)

Number of new or enlarging T2 lesions (Section 2.7)

Annualized relapse rate (Section 2.7)

Time to first relapse (Section 2.7)
Assess the PK and B-cell count following the extended treatment with ofatumumab. (Section 
2.9, Section 2.10, Section 2.8)


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis statistical and programming team according to the data 
analysis Section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR. 
Important information is given in the following sections and details are provided, as applicable, 
in Appendix 16.1.9 of the CSR. 
SAS (version 9.4 or higher) will be used for generating study outputs used for clinical reports. 
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
population under consideration. Data will be summarized with respect to demographic and 
baseline disease characteristics, efficacy, and safety assessments. 
The three analysis conducted at:

Cut-off 1 (Core part data up to Week 24 visit), 

Cut-off 2 (all data obtained until the last patient completes all assessments up to Week 48 
visit ), 

Final, when the last patient completes the EOS visit or Safety FU period.
Each analysis will be conducted on all subject data available at the corresponding cut-off. Cut-
off 2 and final safety analysis will include only each patient’s assessments under ofatumumab 
treatment or during Safety FU.
In these analyses, data from Safety FU period will be analyzed separately if necessary.
The stratification factors, which are the number of Gd-enhanced T1 weighted lesions at baseline
(0 or >=1) and region (Japan or non-Japan), will be included in subgroup analysis where 
appropriate. 
2.1.1
General definitions
Study drug/treatment refers to the investigational drug Ofatumumab and placebo. 
“Date of Cut-off 2” is expected as the date the last patient completes all assessments at Week 
48 visit. If the last patient discontinues from the study prior to Week 48 visit, “date of Cut-off 
2” is the last patient’s last visit.
Date of first administration of study drug/treatment, or first date of study drug/treatment, is 
defined depending on the analysis purposes.


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
For Cut-off 1 analysis and Cut-off 2 and final efficacy analysis, it refers to the date 
when the first dose of randomized treatment is administered.

For Cut-off 2 and final safety analysis, it refers to the date when the first dose of 
ofatumumab is administered.
Date of last administration of study drug/treatment, or last date of study drug/treatment is 
defined by analysis time point.

For Cut-off 1 analysis, it refers to the date when the last dose of randomized
treatment is administered up to Week 24 visit.

For Cut-off 2 analysis, it refers to the date when the last dose of treatment is 
administered up to the date of Cut-off 2.

For final analysis, it refers to the date when the last dose of treatment is administered 
up to EOS visit.
Study day is defined as: if after first date of study drug, then (Study Day) = (Date) – (first date 
of study drug) +1; if before first date of study drug, then (Study Day) = (Date) – (first date of 
study drug); Study Day 1 is defined as the date of the first administration of study drug; there 
is no Study Day 0. 
Duration of an event is calculated as (event end date) – (event start date) +1. 
1 month is counted as 30 days unless otherwise specified.
Baseline is defined for each cut-off analysis.

For Cut-off 1 analysis, and Cut-off 2 and final efficacy analysis, baseline is defined as 
the last non-missing result before or on the first date of study drug.

For Cut-off 2 and final safety analysis, definition of baseline depends on each 
patient’s treatment course in the study

For a patient continuously having ofatumumab across Core and Extension parts, 
baseline is defined as the last non-missing result before or on the first date of 
study drug.

For a patient switching the treatment from placebo to ofatumumab when entering
the Extension part, baseline is defined as the dose date of ofatumumab at Week 
24. For analysis on vital signs, the baseline is defined as the pre-dose 
measurement at Week 24.
On-treatment period is defined as the one between the first date of study drug and 30 days after 
the last date of study drug. The on-treatment definition applies to efficacy analyses only.
“Safety cut-off” is defined as 100 days after the last dosing date of the study drug. 
2.1.2
Visit windows for data analysis
Visit windows for data analysis will be used in both efficacy and safety data summaries by visit. 
Visit windows define a time period around the targeted visit date as defined in the evaluation 
schedule of the clinical study protocol. Visit windows are non-overlapping, and defined without 


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gaps between consecutive visit windows. The width of visit windows may vary over the course 
of the study period. 
Baseline assessments are defined in Section 2.1.1 and do not require a visit window. 
The purpose of visit window is to analyze data based on the actual study days (rather than the 
nominal visits). E.g., if a patient’s Week 4 visit is delayed, then it is possible that the Week 4
data be re-aligned to visit window of Week 8 and be summarized under Week 8. 
For efficacy analyses, all nominal visits excluding unscheduled visits will be mapped into one 
of the defined visit windows. 
 
 
For safety analyses, all visits (scheduled and unscheduled) will be mapped to visit windows. 
Safety data from unscheduled visits may be reported separately if applicable. 
It is possible that more than one assessment of a patient fall into a particular visit window. 
Section 2.1.2.3 deals with the statistical approaches to handle multiple visits in a given visit 
window. 
Tables displaying summary statistics “by visit” will use the term “Visit-window” as column 
header; this is to remind the reviewer that multiple assessments of a patient might be 
summarized for one visit. Below tables provide visit windows definitions for applicable 
parameters. Visit windows will be defined relative to the date of first administration of study 
treatment assigned in the Core part, or date of first administration of ofatumumab, depending
on analysis variables and cut-off time points.
2.1.2.1
Visit windows during core and extension treatment periods
Table 2-1
Visit windows for MRI
Visit-window
Start day
Target day
End day
Week 12
1
84
98
Week 16
99
112
126
Week 20
127
140
154
Week 24 (Cut-off 1)
155
168
182
Week 36
183
252
294
Week 48
295
336
378
Day counts are relative to the first date of study drug in the Core part.
Table 2-2
Visit windows for 
 EDSS
Visit-window
Start day
Target day
End day
Week 12
1
84
126
Week 24 (Cut-off 1)
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462


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Visit-window
Start day
Target day
End day
Week 72
463
504
546
Week x*
x*7-42+1
x*7
x*7+42
*if study goes beyond Week 72, every 12 weeks the same assessments on Week 60 and Week 72 
will be performed. X will be a multiple of 12 weeks from Week 84 and beyond. 
Day counts are relative to the first date of study drug in the Core part.
Table 2-3
Visit windows for routine lab (including urine), ADA, and Total IgM, 
IgG levels
Visit-window
Start day
Target day
End day
Week 4
1
28
56
Week 12
57
84
126
Week 24 (Cut-off 1)
127
168
182
Week 28
183
196
224
Week 36
225
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week x*
x*7-42+1
x*7
x*7+42
*if study goes beyond Week 72, every 12 weeks the same assessments on Week 60 and Week 72 
will be performed. X will be a multiple of 12 weeks from Week 84 and beyond. 
Day counts are relative to the first date of study drug in the Core part for Cut-off 1 analysis, or the 
first date of ofatumumab for Cut-off 2 and final analysis.
Table 2-5
Visit windows for B-cell counts and T-cell counts: Cut-off 1 analysis
Visit-window
Start day
Target day
End day
Day 2
--
2
--
Day 5
3
5
--
Day 7
6
7
10
Day 14
11
14
21


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Visit-window
Start day
Target day
End day
Week 4
22
28
56
Week 12
57
84
126
Week 24 (Cut-off 1)
127
168
182
Day counts are relative to the first date of study drug in the Core part.
Table 2-6
Visit windows for B-cell and T-cell counts: Cut-off 2 and final analysis
Visit-window
Start day
Target day
End day
Week 4
1
28
56
Week 12
57
84
126
Week 24
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week x*
x * 7 - 42 + 1
x * 7
x * 7 + 42
*if study goes beyond Week 72, every 12 weeks the same assessments on Week 60 and Week 72 
will be performed. X will be a multiple of 12 weeks from Week 84 and beyond. 
Day counts are relative to the first date of ofatumumab.
Table 2-7
Visit windows for vital signs: Cut-off 1 analysis
Visit-window
Start day
Target day
End day
Week 8
1
56
70
Week 12
71
84
98
Week 16
99
112
126
Week 20
127
140
168
*if study goes beyond Week 72, every 12 weeks the same assessments on Week 60 and Week 72 
will be performed. X will be a multiple of 12 weeks from Week 84 and beyond. 
Data collected from Day 1, Day 7, Day 14, Week 4, and Week 24 are collected differently and not 
re-mapped. 
Day counts are relative to the first date of study drug in the Core part.
Table 2-8
Visit windows for vital signs: Cut-off 2 and final analysis
Visit-window
Start day
Target day
End day
Week 12
1
84
126
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week x*
x * 7 - 42 + 1 
x * 7
x * 7 + 42


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Visit-window
Start day
Target day
End day
*if study goes beyond Week 72, every 12 weeks the same assessments on Week 60 and Week 72 
will be performed. X will be a multiple of 12 weeks from Week 84 and beyond. 
Data collected from Week 24 are not re-mapped, because they are collected at pre- and post-dose 
and will not be included in by-visit summary.
Day counts are relative to the first date of ofatumumab.
2.1.2.2
Visit windows for Safety Follow-up
For patients who prematurely discontinues treatment or do not enter the umbrella study after 
EOS, Safety Follow-up period should be entered. Visit windows are also defined. 
The visit windows are defined in Table 2-9, where the start day, target day, and end day are 
relative to EOS visit. 
Table 2-9
Visit windows for Safety Follow-up period
Visit-window
Start day
Target day
End day
Week 12 post EOS
2
84
126
Week 24 post EOS
127
168
210
Week 36 post EOS
211
252
294
Week x post EOS*
x * 7-42+1
x * 7
x * 7+42
*if study goes beyond Week 36, every 12 weeks the same assessments on Week 36 will be 
performed. X will be a multiple of 12 weeks from Week 48 and beyond. 
All days are relative to EOS visit. These visit windows will be applied only to assessments after the 
last date of study drug.
2.1.2.3
Multiple assessments within visit windows
It is possible that multiple assessments of a patient fall into the same visit-window (e.g. due to 
unscheduled visits). All results (scheduled and unscheduled) will be displayed in listings, but 
only one value (observed or derived) will be selected for summary statistics by visit-window. 
For quantitative variables, the assessment closest to the target day will be selected. If more than 
one assessment is at the same distance to the target day, the later one will be selected. For tables 
displaying the worst case scenario, such as shift tables or notable abnormalities, all assessments 
within a visit window will be used to identify the worst (e.g. the maximum or the minimum 
depending on parameter). 
For qualitative variables, the worst record is selected; it is noted that in the relevant data 
subsection, worst case is always well defined. 
2.1.3
Nominal visits for ECG analysis
By-visit summary of ECG measurement uses nominal visits.  


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For Cut-off 2 and final analysis, analysis visits will be based on the treatment course of patients 
in the study.

For a patient having ofatumumab treatment across Core and Extension parts, 
assessments at study visits Week 24 and 48 will be included in the summary of 
corresponding visits.

For a patient switching the treatment from placebo to ofatumumab at Week 24, 
assessments from Week 48 visit will be included in the summary of Week 24 visit
2.1.4
Treatment group for Cut-off 2 and final analysis
For analysis based on Extension FAS, the following treatment groups will be displayed:

OMB 20mg: This will include patients randomized to ofatumumab treatment group 
and having at least one dose of ofatumumab in Extension part.

Placebo – OMB 20mg: This will include patients randomized to placebo treatment 
group, and having at least one dose of ofatumumab in Extension part.
For safety analysis based on Extension SAF, the following treatment groups will be displayed:

OMB 20mg: This will include patients treated with ofatumumab during Core part and 
having at least one dose of ofatumumab in Extension part. 

Placebo – OMB 20mg: This will include patients treated with placebo during Core 
part, and having at least one dose of ofatumumab in Extension part. For these patients, 
analysis will include only assessments on or after treatment at Week 24, and Safety 
FU period if necessary.
2.2
Analysis sets
Full analysis set (FAS): The FAS comprises all randomized subjects with assigned treatments. 
Subjects will be analyzed according to the randomized treatment assignment following the 
intention-to-treat (ITT) principle, even if they actually received no or a different treatment.
The FAS will be used for the summary of demography and baseline characteristics and all 
efficacy analyses.
Extension FAS (EFAS): The EFAS will include all FAS subjects who received at least one 
dose of ofatumumab during Extension part. Analyses on EFAS will include all available 
efficacy assessments of the Core and Extension parts.
Per-protocol set (PPS): The PPS is a subset of FAS, consists of all randomized subjects who 
take at least one dose of study medication and have no major protocol deviations that could 
confound the interpretation of analyses conducted on the FAS. Major protocol deviations will 
be determined according to the pre-defined protocol deviation criteria before treatment 
unblinding (e.g. non-compliance for a large proportion of the time in study). For analyses 
performed on the PPS, only on-treatment assessments will be used.
The PPS will primarily be used for the supportive analyses of the primary efficacy variable.


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Safety set (SAF): The SAF set includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to the actual treatment received. The Safety 
Set will be used for all safety analyses for Cut-off 1 analysis.
Extension Safety set (ESAF): The ESAF set includes all subjects who received at least one 
dose of ofatumumab during Extension part. Subjects will be analyzed according to the actual 
treatment received. The Extension Safety Set will be used for all Cut-off 2 and final safety 
analyses. Analyses on ESAF will include safety assessments only under ofatumumab treatment 
during the Core and Extension parts.
2.2.1
Subgroups of interest
Subgroup analyses by stratification factors (Japan vs non-Japan, Gd-enhanced T1 weighted 
lesions 0 or >=1). (Section 2.1). 
Subgroup analysis by age group, weight, and gender will be included for Safety analyses as 
stated in the applicable sections. The subgroup categories are: 
Age group (< 40, >= 40); 
Weight (< Median, >= Median); 
Gender (Male, female). 
In addition, for Cut-off 2 analysis, subgroup of home injection will be defined on basis of 
whether each patient had at least one home injection during the Extension part.


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2.3
Patient disposition, demographics and other baseline 
characteristics
Patient disposition, background and demographic characteristics, and MS baseline disease 
characteristics will be summarized by treatment group for Cut-off 1 and final analysis based on 
FAS, and for Cut-off 2 analysis based on EFAS. 
For final analysis, analyses will focus on patient disposition and demographics.
2.3.1
Patient disposition
The number and percentage of patients who are screened but do not enter treatment period will 
be presented. The summary will be on all screened patients. This summary will be included in 
Cut-off 1 analysis.
For Cut-off 1 analysis, the number and percentage of patients who complete the core part or 
prematurely discontinue study drug will be presented, along with the primary reason for 
discontinuation. Data collected on the end of double blind treatment period CRF page will be 
used to summarize this information. Similarly, the number and percentage of patients who 
complete the open label treatment period of the extension part or prematurely discontinue the 
study drug will be summarized and will be included in Cut-off 2 and final analysis. 
Then number and percentage of patients who enter and complete the Safety FU period as well 
as the number of patients who prematurely discontinue the Safety FU period (along with the 
primary reason for discontinuation) will be presented. Data collected on the end of Safety FU 
period CRF page will be used to summarize this information. For patients who join the separate 
umbrella extension study an additional line will be added in the summary. The summary will 
be based on the patients who enter Safety FU period or the umbrella extension study and will 
be included in Cut-off 2 and final analysis, if needed. 
The numbers of patients in each analysis set will be presented by treatment group. Protocol 
deviations will be summarized by deviation categories and treatment. In addition, protocol 
deviations that led to exclusion from the analysis set will be summarized by deviation category, 
deviation terms and treatment groups. Summary on protocol deviations will be based on FAS 
for Cut-off 1 analysis, and EFAS for Cut-off 2 or final analysis
2.3.2
Background and demographic characteristics
Demographic and background characteristics (age, gender, race, and ethnicity as collected on 
the Demography CRF), and prior/concomitant medications at screening visit, height, body 
weight, derived BMI, and employment status at baseline will be summarized by treatment group 
using frequency distributions (for categorical variables) and descriptive statistics of mean, 
standard deviation, minimum, median, and maximum (for continuous variables). 
2.3.3
MS baseline disease characteristics
MS disease history, MRI baseline characteristics, and MS medication history will be 
summarized by treatment group. 


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MS disease history includes duration of MS since diagnosis (years), duration of MS since first 
symptom (years), number of relapses in the last 12 months prior to screening, number of 
relapses in the 12 to 24 months prior to screening, time since onset of most recent relapse 
(months) prior to screening, type of MS at study entry, and time since onset of SPMS (years). 
MS baseline characteristics include EDSS, 
and key MRI parameters (e.g., number of 
Gd-enhancing T1 lesions, T2 lesion volume, and normalized brain volume). 
Duration of MS since diagnosis (years) will be derived as [(first dose date of the assigned 
treatment – MS diagnosis start date +1)/365.25]; duration of MS since first symptom (years) 
will be derived as [(first dose date of the assigned treatment – first MS symptom date 
+1)/365.25]; and time since onset of most recent relapse (months) will be derived as [(first dose 
date – most recent relapse onset date +1)/(365.25/12)]. In these calculations, partial dates if any 
will be imputed according to the rules specified in Section 5.1. 
MS medication history of previous disease-modifying drugs (coded by WHO drug dictionary) 
will be summarized by preferred term (PT) and treatment group. The number and proportion of 
treatment-naive patients (i.e., patients who have not been treated with any disease-modifying 
drug before study enrolment) will also be presented. 
2.3.4
Medical history
Medical history will be summarized by treatment group. Any condition entered on the Medical 
History (MH) CRF will be coded using the MedDRA dictionary. The medical history will be 
summarized by primary system organ class (SOC), preferred term (PT) and treatment group.
2.3.5
Smoking history and alcohol history
Data collected on smoking history and alcohol history CRF pages will be listed as appropriate.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Analyses detailed in this section will be performed for Cut-off 1 analysis, Cut-off 2 and final 
analysis. 
For the core part and the extension part, duration of exposure to study drug is defined as (last 
dose date) – (first dose date) + 31 – sum[(j+1)-th injection date – j-th injection date - 31], where 
j and j+1 refer to consecutive injections with injection dates more than 31 days apart (as patients 
are scheduled to take the subcutaneous injections every 28+/- 3 days). 
Duration of exposure to study drug of core part and extension part will be summarized by 
treatment with number and percentage of patients and by duration category (i.e., >= 1 
week, >= 2 weeks, >= 3 weeks, >= 4 weeks, >= 8 weeks, >= 12 weeks, >= 24 weeks, >= 36 
weeks, >= 48 weeks, >= 60 weeks, >= 72 weeks, until end of the study). The number of 
patient years of exposure is calculated as (the sum of the number of days of exposure for all 


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patients in the group)/365.25 and will be summarized for each treatment arm, and by 
stratification factor Japan vs non-Japan. 
Time at risk is the censoring time used for estimating exposure adjusted incidence rate of SAEs 
or AEs in patients who did not experience the event of interest. For patients who have 
experienced the event of interest, the actual date of the SAE, or AE onset will be used. Time at
risk corresponds to the time window used for adverse event reporting and can serve as a 
denominator to certain safety analyses (e.g. in exposure-adjusted incidence rates). 
Table 2-10 includes definition of time at risk for AE and SAE for Cut-off 1 analysis. It will 
determine the “end date of the Core part” when all randomized patients completed their 
assessment during the Core part.
Table 2-10
Time at risk for AE and SAE: Cut-off 1 analysis
Category
For those who completed Week 24 
visit
For those discontinued the study 
prior to Week 24 visit
Time at risk for AE
Number of days in the study from first 
date of study drug to Week 24 visit 
date
Number of days in the study from 
first date of study drug to the earlier 
date of the following:
- Safety cut-off
- “End date of the Core part”*
Time at risk for SAE
Number of days in the study from 
first date of study drug to “end date 
of the Core part”
*: “End date of the Core part” will denote the date when all randomized patients complete Week 24 
visit or discontinue study drug prior to Week 24 visit. This date is going to be declared by the study 
team, but not derived from any data.
Table 2-11 includes definition of time at risk for AE and SAE for Cut-off 2 and final analysis. 
It will determine the “date of Cut-off 2” when all patients entering the Extension part completed 
their assessment up to Week 48, or EOS visit following premature study drug discontinuation.


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Table 2-11
Time at risk for AE and SAE: Cut-off 2 and final analysis
Category
Definition for Cut-off 2 analysis
Definition for final analysis
Time at risk for AE
Number of days in the study from 
first date of ofatumumab treatment
to the earlier date of the following:
- Safety cut-off
- “Date of Cut-off 2”*
Number of days in the study from first 
date of ofatumumab treatment to safety 
cut-off.
Time at risk for 
SAE
Number of days in the study from
first date of ofatumumab treatment 
to “date of Cut-off 2”*
Number of days in the study from first 
date of ofatumumab treatment to the last 
visit date, including Safety FU period.
*: “Date of Cut-off 2” is defined in section 2.1.1
Time-at-risk for AE and time at risk for SAE will be summarized in a similar way to exposure 
to investigational study medication.
Compliance to the study drug administration schedule will be calculated as duration of exposure 
to study drug in (days)/duration of on-treatment period in (days) * 100%. This rule means that 
compliance will be measured during the time interval the patient took study medication: 
premature discontinuation from study drug will not be considered non-compliance. Compliance 
to study drug administration will be summarized descriptively on SAF by treatment group. In 
addition, compliance will be summarized with cumulative number and percentage of patients 
in each compliance category (i.e., >= 20%, >= 30%, >= 40%, >= 50%, >= 60%, >= 70%, >= 
80%, >= 90%, >= 95%, >= 98%, = 100%)
2.4.2
Prior, concomitant and post therapies
Analyses described in this section will be performed on the SAF for Cut-off 1 analysis, and on 
ESAF for Cut-off 2 analysis. 
2.4.2.1
Concomitant medication
Records on the Prior and Concomitant Medication CRF page will be coded using the WHO 
drug dictionary. All medications will be classified as prior, concomitant, or post-study drug 
discontinuation medication as follows

Prior medications are defined as drugs taken and stopped prior to first dose of study 
medication

Concomitant medications are defined as drugs taken at least once between first dose and 
last dose of study medication (including those started prior to first dose and continued 
into the treatment period). 

Post-study drug discontinuation medications will be drugs started after the 
discontinuation of randomized study medication. 


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For Cut-off 2 analysis, medications will be also classified by whether they are taken prior to or 
on or after start of ofatumumab treatment. 
Medications will be categorized into one (and only one) of above classes based on recorded or 
imputed start and end dates. When incomplete or missing, dates will be imputed according to 
Novartis standards (details in PDS). 
Medications in each of these 3 categories will be summarized separately by treatment group, 
ATC code and preferred term. ATC level 1 and level 3 will be used. 
Data collected from the Previous MS disease modifying treatment pages will not be included 
in this summary (See Section 2.3.3).
2.4.2.2
Surgical and medical procedures
Records on the surgical and medical procedures CRF page will be coded using the MedDRA 
dictionary. All procedures will be classified as prior, concomitant or post-study drug 
discontinuation procedure, in the same way as done for concomitant medications. Surgical and 
medical procedures in each of these 3 categories will be summarized separately by system organ 
class, preferred term and treatment group. 
Imputation rules for start and end dates will follow the same rule as for the concomitant 
medications. 
2.4.2.3
Injection related premedication
Injection related premedication will be identified by subcategory “Injection related 
premedication” in concomitant dataset. Injection related premedication will also be summarized 
separately for each injection as well as cumulatively for all injections by each cut-off. 
For Day 1 injection summary, the injection related premedication with start date on the same 
day as the first injection date will be included and summarized for each of the three protocol 
specified types (type 1: steroids, type 2: antihistamines and type 3: acetaminophen) and for the 
combination of the specified types (type 1 + type 2 + type 3 and type 2 + type 3). The steroids 
(type 1) will be identified by category “Steroid”. The antihistamine (type 2) will be identified 
by ATC level 3 “antihistamines for systemic use”. The antipyretics/analgesics (type 3) will be 
identified by ATC level 3 “other analgesics and antipyretics” and “anti-inflammatory and anti-
rheumatic products, non-steroids”. In summaries for each combination of types, the number and 
proportion of patients who took any combination of types of injection related premedication at 
specified injection will be provided. 
Rest injection specified summaries or cumulative summaries will be reported similarly. 


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2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary endpoint is the number of Gd enhanced T1 lesions per scan across 4 MRI scans at 
Week 12, 16, 20, and 24 during the core part.
2.5.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference in the number of Gd-enhanced T1 lesions per 
scan between ofatumumab and placebo during the Core part (Cut-off 1 analysis). The alternative 
hypothesis is that there is a difference between the 2 treatment groups.

Superiority of ofatumumab over placebo will be concluded if the mean number of 
Gd-enhanced T1 lesions per scan in patients treated with ofatumumab is lower 
compared with placebo and the observed p-value for the between-treatment 
comparison is less than the two-sided significance level of 0.05.
The null hypothesis will be tested on the FAS using a negative binomial regression model with 
log-link. Each patient’s total number of Gd-enhanced T1 lesions during the Core part will be 
used as the response variable, and natural log of the number of MRI scans will serve as the 
offset variable to adjust for the different number of MRI scans between patients. The model 
will include treatment, region (Japan or other countries), and baseline number of Gd-enhanced 
T1 lesions (0 or ≥1) as factors.
The number of Gd-enhanced T1 lesions per scan will be estimated by treatment with 95% 
confidence interval. The between treatment effect will be calculated as rate-ratio 
(ofatumumab/placebo) with 95% confidence interval and p-value will be provided. In addition, 
the relative reduction in the number of Gd-enhanced T1 lesions per scan will be computed as 
one (1) minus the rate-ratio and expressed as a percentage. 
The number of Gd-enhanced T1 lesions will be summarized descriptively by visit-window and 
treatment group. 
Analyses on Gd-enhanced lesions will exclude MRI evaluation performed within 14 days after 
termination of systemic corticosteroids and/or adrenocorticotropic hormone.
The above summary analyses will be repeated with additional data from the extension part at 
the Cut-off 2 analysis (Section 2.14). 
2.5.3
Handling of missing values/censoring/discontinuations
The primary negative binomial model with an offset for the number of MRI scans adjusts for 
missing information (dropout) under the assumption of non-informative dropout, information 
missing at random, and constant number of Gd-enhancing T1 lesions per scan within patient. 
Missing values will not be imputed. However, deviations from assumptions will be tested in 
sensitivity analyses.


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2.5.4
Supportive analyses
Sensitivity analysis
The primary analysis will be repeated using the per-protocol set to provide an analysis of 
on-treatment data from subjects who have no major protocol violations. The analysis will be 
performed for Cut-off 1 analysis. 
Additional sensitivity analyses may be defined in the analysis plan prior to database lock.
Consistency across regions
Consistency in efficacy across regions on the primary variable will be evaluated using a 
statistical model similar to the primary model, but with a treatment-by-region (Japan or other 
countries) interaction term added. The mean number of Gd-enhancing T1 weighted MRI lesions 
per scan will be provided by treatment and region. The rate-ratio will be presented for individual 
regions separately, together with 95% confidence intervals. The p-value of the treatment-by-
region interaction will be displayed.
The estimates for individual regions will be displayed via a forest plot to visualize consistency.
The consistency across regions will be examined at Cut-off 1 analysis. 
2.6
Analysis of the key secondary objective
There are no key secondary objectives. 
2.7
Analysis of secondary efficacy objective(s)
All efficacy analyses will be done based on the FAS, unless explicitly stated otherwise.
2.7.1
Secondary endpoints
The secondary efficacy endpoints are: 
Core part: 

Number of new or enlarging T2 lesions on MRI scans; 

Annualized relapse rate (ARR); 

Time to first relapse

MS relapse characteristics
Extension part, including Core part: assess extended efficacy of ofatumumab in

Number of Gd-enhanced T1 lesions

Number of new or enlarging T2 lesions

Annualized relapse rate (ARR)

Time to first relapse

MS relapse characteristics


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2.7.2
Statistical hypothesis, model, and method of analysis
Number of new or enlarging T2 lesions on MRI scans
Analysis of the number of new or enlarging T2 lesions will be done based on the FAS using a 
negative binomial regression model with log-link. The number of new or enlarging T2 lesions 
on the last available MRI scan relative to baseline will be used as the response variable, and the 
natural log of the time (in years) of the MRI-assessment from the baseline/Screening scan will 
serve as the offset variable to adjust for the various lengths of follow-up times between patients 
in this study. The model will include treatment, region (Japan or other countries), baseline 
number of Gd-enhancing T1 lesions (0 or ≥1) as factors, and baseline volume of T2 lesions as 
continuous covariates. 
The number of new or enlarging T2 lesions per year will be estimated by treatment with 95% 
confidence interval. The between treatment effect will be calculated as rate-ratio
(ofatumumab/placebo) with 95% confidence interval and p-value. In addition, the relative 
reduction in the number of new or enlarging T2 lesions per year will be computed as one (1) 
minus the rate-ratio and expressed as a percentage.
The number of new or enlarging T2 lesions on MRI scans will be summarized descriptively by 
visit-window and treatment group. 
The above summary analyses will be performed for both Cut-off 1 analysis and Cut-off 2 
analysis (Section 2.14). 
Annualized relapse rate (ARR)
Annualized relapse rate (ARR) is defined as the number of confirmed MS relapses in a year. 
Analysis of ARR will be done based on the FAS, using a negative binomial regression model 
with log-link. The model will include the number of confirmed relapses observed from each 
patient as the response variable, each patient’s natural log of time in study (years) as the offset 
variable, and treatment, region (Japan or other countries), baseline number of Gd-enhancing T1 
lesions (0 or ≥1) as factors, and number of relapses in previous year and baseline EDSS as 
covariates. 
In the case where the above model does not converge or has other statistical limitations, a 
simpler model with only the offset variables, treatment and region (Japan or other countries) as 
factors will be fit to the data.  
The adjusted ARR (i.e., model-based estimate adjusted for covariates) for each treatment and 
the corresponding 95% confidence interval, and ARR ratio (also expressed as percentage 
reduction relative to control group) along with the 95% confidence interval for the ARR ratio 
and the corresponding p-value will be obtained.
The definition of a confirmed MS relapse is one accompanied by a clinically relevant change 
in the EDSS assessment, i.e. an increase of at least 0.5 points on the EDSS (total) score, or an 
increase of at least 1 point on at least two Functional scores (FSs), or an increase of at least 2 
point on at least one FS, excluding changes involving bowel/bladder or cerebral FS, compared 
to the last EDSS assessment taken in the absence of (confirmed or unconfirmed) relapse and 
prior to the current relapse. EDSS obtained on the date as indicated on the Summary of MS 


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Relapse eCRF page will be used. If such EDSS assessment is missing or not meeting the criteria 
to confirm the relapse, all other EDSS assessment taken within 30 days from the relapse start 
date (i.e., EDSS assessment date – relapse start date <=30) and before the relapse end date 
(EDSS assessment date <=relapse end date) will be checked. If at least one of such available 
EDSS assessments meets the criteria, the relapse is a confirmed one. Otherwise, the relapse is 
considered an unconfirmed one. 
The patient’s time in study for ARR at each cutoff will be calculated as (Cutoff point – first 
dose date +1)/365.25. 
The analysis will be performed at Cut-off 1 analysis. The adjusted ARR for each treatment and 
the corresponding 95% confidence interval will be provided also for Cut-off 2 analysis (Section 
2.14). 
Time to first confirmed relapse
Time to first confirmed relapse will be calculated as (start date of first confirmed relapse – date 
of first administration of study drug + 1). For patients without confirmed relapses at a cutoff 
point, they are censored with censoring time as time in study at the corresponding cutoff point. 
Analysis of time to first relapse will be done based on the FAS, using a Cox proportional hazard 
model with treatment, region (Japan or other countries), and baseline number of Gd-enhancing 
T1 lesions (0 or ≥1) as factors, and number of relapses in previous year and baseline EDSS as 
covariates. The hazard ratio (also expressed as percentage reduction relative to control group) 
along with the 95% confidence interval for the hazard ratio and the corresponding p-value will 
be obtained. In the case where the above model does not converge or has other statistical 
limitations, a simpler model with only treatment and region (Japan or other countries) as factors 
will be fit to the data.  The Cox model analysis will be done only for Cut-off 1 analysis.
In addition, Kaplan-Meier curves by treatment will be used to present the time-dependent 
cumulative frequency and percentage of subjects reaching the first relapse; by-treatment 
Kaplan-Meier estimates (with 95% confidence interval) at both cut-off 1 and Cut-off 2 analyses
will be obtained (Section 2.14).
MS relapse characteristics
For MS relapse characteristics, summary statistics will be presented. The proportion of patients 
hospitalized for relapse and the proportion of patients with severe relapses will be compared 
between treatment groups using a Chi-square test. For Cut-off 2 analysis, summary statistics 
will be presented by study period (up to Week 24 or thereafter).
MS relapse characteristics include severity, recovery, hospitalization, and steroid treatment. 
The severity of MS relapses will be derived according to the criteria presented in Table 2-12. 
Severity will be derived for both types of relapses, confirmed and unconfirmed ones. It depends
on the type of relapses which EDSS is used to derive severity:

For confirmed relapses, the EDSS score used to confirm the relapse (as specified in Section 
2.7.2) will be used to determine the severity.

For unconfirmed relapses, all EDSS assessments taken within 30 days from the relapse start 
date and before the relapse end date will be checked among which the most severe case will 


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be selected to determine the severity. If no such EDSS assessment is available, the severity 
will be set to “missing EDSS”. If none of such EDSS assessments meets the mild, moderate 
or severe conditions, the severity will be set to “no worsening in EDSS”.
Table 2-12
Severity of MS relapse 
Mild relapse
Moderate relapse
Severe relapse
EDSS increase of 0.5 point
EDSS increase of 1 or 2 points
Exceeding Moderate criteria 
or
or
or
1 point FS change in one to 
three systems
2-point FS change in one or 
two systems
Exceeding Moderate criteria
or
or
1-point change in four or more 
systems
Exceeding Moderate criteria
Definition is based on the EDSS obtained to confirm the relapse as compared to the last EDSS 
(scheduled or unscheduled) taken in the absence of (confirmed or unconfirmed) relapse and prior 
to the current relapse.
EDSS refers to total score; FS refers to functional score; all of the 7 functional scores are 
considered in this derivation.
2.7.3
Impact assessment of potential unblinding
To assess impact of potential unblinding on evaluation of efficacy of ofatumumab on relapses, 
summary statistics of ARR (patient-based and time-based) will be displayed by subgroup 
defined by impact of potential unblinding and treatment group.
This analysis will be performed at Cut-off 1.
2.7.4
Handling of missing values/censoring/discontinuations
Missing data will not be imputed. 
2.8
Safety analyses
Safety analyses during the study will be detailed below. All safety analyses will be based on the 
SAF for Cut-off 1 analysis and ESAF for Cut-off 2 and final analysis, unless explicitly stated 
otherwise. 
Patients will be grouped by the actual treatment received. Safety data for the core part will be 
reported for the first time when the double-blind loading dose period has been completed by the 
last patient (Cut-off 1 analysis). Safety data for the extension part including Safety FU period 


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data will be reported for the first time when the last patient has finished 48 weeks of treatment 
(Cut-off 2 analysis). Safety data beyond the cut-off 2 will be reported separately. 
Unless explicitly otherwise stated, for patients who entered Safety FU period, safety data will 
be reported up to and including the safety cut-off.

For Cut-off 1 analysis, safety data reported up to safety cut-off, the latest visit date 
including Safety FU, or Week 24 visit date, whichever comes first.

For Cut-off 2 and final analysis, safety data reported up to safety cut-off or the latest visit 
date including Safety FU, whichever comes first.
The assessment of safety will be primarily based on the frequency of adverse events (including 
death and non-fatal serious adverse events). Additional safety assessments include laboratory 
tests, physical examination (including examination of skin), vital sign measures, ECG 
evaluations and assessment of suicidality. Clinically significant findings in these additional 
safety assessments will be reported as adverse events and analyzed as such. In addition, all 
safety assessments will be summarized or listed as appropriate. 
2.8.1
Adverse events (AEs)
Treatment emergent adverse events (TEAE) is defined as any adverse event which start on or 
after the day of the first dose of study drug.
TEAEs will be reported if their onset days are no greater than “time at risk for AE”. Similarly, 
serious TEAEs will be reported if their onset days are no greater than “time at risk for SAE”. 
TEAE will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the 
study will be described in a footnote. 
Incidence of TEAEs will be summarized (number and percentage of patients reporting any 
TEAE by primary SOC, preferred term, and treatment group. Serious TEAEs, drug related 
TEAEs, TEAEs leading to premature discontinuation from study drug, TEAE leading to study 
drug interruption, and most common TEAEs (>=5% in any of the treatment groups) will be 
presented in a similar format as adverse events. In addition, incidence of TEAEs will be 
summarized by SOC, preferred term, and maximum CTCAE grade. Missing CTCAE grade will 
not be imputed. The CTCAE version 5.0 will be used. 
For Cut-off 1 analysis, odds ratios (investigational drug vs. control) with 95% confidence 
intervals will be presented along with the summary of any TEAEs and the summary of serious 
TEAEs. Details in calculations of odds ratios and their 95% confidence intervals are provided 
in Section 5.7.1. Incidence of any TEAEs will be plotted by SOC, along with the odds ratio 
(and corresponding 95% confidence interval) for TEAEs in each SOC. Odds ratios provide 
appropriate inferences for events that are likely to occur at certain times (e.g., injection related 
reactions) while no constant risk over time is expected.
If a patient reports more than one adverse event within the same primary SOC, the patient will 
be counted only once with the maximum CTCAE grade at the SOC level, where applicable. 
All AEs will be presented in listings. 
The following summaries will be repeated for Cut-off 2 and final analysis:


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
Overall TEAE

TEAE by CTCAE grade

Serious TEAE

Drug-related TEAE

TEAE causing study drug discontinuation

TEAE leading to study drug interruption

Serious TEAE causing study drug discontinuation

Most common TEAE

Infections and infestations TEAE
2.8.1.1
Adverse events of special interest / grouping of AEs
Incidence of adverse events of special interest as defined in the latest version of case retrieval 
sheet (eCRS) at the time of each cut-off will be summarized by risk name, level, and treatment 
group. For Cut-off 1 analysis, odds ratios and 95% confidence intervals presented. The 
exposure-adjusted incidence rate of TEAEs that fulfill the risk search terms as defined in eCRS 
will also be summarized by risk name, preferred term and treatment group. For Cut-off 1 
analysis, incidence rate ratios and 95% confidence intervals presented. Similarly, separate 
summaries will be provided for serious TEAEs that fulfill the risk search terms as defined in 
eCRS. Additionally, incidence or any TEAEs that fulfill the search terms as defined in eCRS 
will also be summarized by risk name, level, and maximum CTCAE grade. 
2.8.1.1.1 Injection reaction related AEs
Incidence of injection site reaction AEs and injection systemic AEs as collected in the relevant 
CRF pages will be reported as part of the AE summary tables as two preferred terms 
respectively. 
Additionally, incidence of injection site reaction AEs and injection systemic reaction AEs will 
be reported separately for each injection and cumulatively for all injections at each cutoff. 
Symptoms listed in the injection site reaction or injection systemic reaction CRF pages will be 
summarized by providing the number and percentage of patients with each of the symptoms 
and pre-specified grouping of symptoms as well as overall. These summaries will be provided 
or each injection and cumulatively for all injections. 
For the injection site reaction, no grouping of symptoms will be specified. For the injection 
systemic reaction, symptoms will be grouped under 6 categories as defined below and the 
number and percentage of patients with at least one symptom reported under the category will 
be provided for each category as available. 

Skin/mucosal tissue symptoms: Rash, Urticaria, Pruritus general, Flushing

Respiratory compromise: Dyspnea, Bronchospasm, Chest discomfort, Cough

Related to change in vital signs: Hypotension, Hypertension, Dizziness, Tachycardia

Gastrointestinal symptoms: Nausea, Vomiting, Abdominal pain, Diarrhea


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
Musculoskeletal/connective tissue symptoms: Arthralgia, Myalgia, Back pain

Other manifestations: Fever, Headache, Chills, Asthenia, Fatigue, and other
For above summaries, reaction/symptom start date and time will be compared with the injection 
date and time. Only reactions/symptoms within 24 hours after injections will be included (i.e., 
time to onset of reaction <= 24 hours). The time to onset of reaction will be derived as (reaction 
start date/time – injection date/time). 
For the injection systemic reaction, time to onset of the first symptoms after each injection will 
be summarized by cumulative hour intervals (i.e., 0 to 1, 0 to 2, 0 to 3, etc. until 0 to 24 hours). 
These summaries will be provided for each injection and cumulatively for all injections.
The proportion of patients with injection site reactions and the proportion of patients with 
injection systemic reactions will be plotted by treatment group against the injection sequence 
labeled by the visit weeks of the corresponding injection.
Patients with injection site reactions and the corresponding category of the combination of the 
3 types (type 1: steroid, type 2: antihistamine, type 3: antipyretics/analgesics) will be listed by 
treatment. Specifically, 9 categories are defined as 1) no injection related premedication, 2) type
1, 3) type 2, 4) type 3, 5) type 1+ type 2, 6) type 1+ type 3, 7) type 2+ type 3, 8) type 1+ type 
2+ type 3, 9) Any injection related premedication. The types 1 to 3 refer to protocol specified 
three types of injection related premedication as stated in Section 2.4.2.3.
A separate listing for injection site reaction AEs and injection systemic reaction AEs will be 
provided where all reported injection related reactions (IRR) (regardless of timing) will be listed 
along with the corresponding visit with injection and time to onset from the most recent 
injection as well as from Day 1. The listing will be sorted by injection of first occurrence of 
symptoms. Specifically, under the first injection, patients whose first IRR was associated with 
the first injection will be listed; within a patient all IRRs to all injections will be listed 
chronologically. Under the second injection, patients whose first IRR was associated with the 
second injection will be listed; similarly, within a patient all IRRs to all injections will be listed 
chronologically. The listing will continue with subsequent injections until all patients with IRRs 
are included in the listing.
The following analyses will be repeated for Cut-off 2 analysis:

Line plots for proportions of injection-related symptoms

Proportion of patients with injection systemic reactions

Proportion of patients with injection site reactions
2.8.1.1.2 Liver safety related AEs
Standardized MedDRA Queries (SMQs) are groupings of terms from one or more MedDRA 
SOCs that relate to a defined medical condition or area of interest. They are intended to aid in 
case identification.
Standardised MedDRA Queries (SMQ) and preferred terms searches for drug-related hepatic 
disorders will be conducted. Results of these searches will be analyzed and presented in a 
similar format as other adverse events. In case of liver events, detailed listings will be provided.


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SMQ Table: The number and percentage of patients experiencing adverse events categorized 
under the SMQ module drug-related hepatic disorders – comprehensive search (SMQ code 
20000006, broad search) and its SMQ sub-modules will be reported.
SMQ-PT Table: The more detailed SMQ-PT table including the respective preferred term 
frequencies falling under the SMQ drug-related hepatic disorders – comprehensive search 
(SMQ code 20000006, broad search) and its SMQ sub-modules will be provided.
2.8.1.1.3 Drug-related adverse events for Japan package insert
For display in the Japan package insert, incidence rate of drug-related adverse events will be 
displayed. 
2.8.1.2
Adverse events by onset period
Incidence of TEAE will be displayed by first onset period. The following periods will be 
displayed:

Day 1 – Month 3 (Day 1 – Day 90)

Month 3 – Month 6 (Day 91 – Day 180)

Month 6 – Month 9 (Day 181 – Day 270)

Month 9 – Month 12 (Day 271 – Day 360)

Month 12 or later (Day 361 or later).
For each period, incidence of an AE will be the proportion of patients with the AE among 
patients “at risk”. As seen section 2.4.1, “time at risk” will be defined in two ways for overall 
AE and SAE. Then two types of summary will be provided:

Incidence of overall AE by first onset period: This will be based on time at risk for 
AE. Then no SAE will be counted if it is reported after safety cut-off in this analysis.

Incidence of SAE by first onset period: This will be based on time at risk for SAE. 
This analysis will be performed only for Cut-off 2 analysis.
2.8.1.3
Adverse events by subgroup
Incidences of TEAE will be displayed by the following subgroup.

Age (< 40 or >= 40)

Gender

Region (Japan or non-Japan)
This analysis will be performed for Cut-off 1 and Cut-off 2 analyses.
In addition, for Cut-off 2 analysis only, the following subgroup analyses will be provided:

Incidence of TEAE by region and CTCAE grade

Incidence of TEAE will be displayed by subgroup defined on basis of whether each 
patient had home-injection during the treatment period. 


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2.8.1.4
Impact assessment of potential unblinding
Incidence of the TEAEs will be summarized by subgroup defined by impact of potential 
unblinding.
This analysis will be performed only for Cut-off 1 analysis.
2.8.2
Deaths
Death, if any, will be listed by treatment group. All deaths as recorded in the database will be 
included at each analysis cut-off. 
2.8.3
Laboratory data
Data summaries will be provided in SI units. The summary of laboratory evaluations will be 
presented for 3 groups of laboratory tests: Hematology, Chemistry and Urinalysis. Subgroup
analyses as specified in Section 2.2.1 will be performed as needed. 
Laboratory data will be summarized by presenting summary statistics (mean, median, standard 
deviation, Min and Max) of raw data and change from baseline values to each study visit-
window by treatment group, and by presenting shift tables using clinically notable ranges 
(baseline to most extreme post-baseline value) by treatment group. Change from baseline (i.e. 
post baseline value – baseline value) will only be summarized for patients with both baseline 
and post baseline values. Laboratory data, and specifically liver enzymes, will also be 
summarized by maximum change from baseline.
The number and percentage of patients with new or worsening laboratory abnormalities based 
on CTCAE grade (Section 5.3.4) in each visit-window and at any time post baseline will be 
presented. Patients with specific laboratory abnormalities (defined by CTCAE grade 3 and 4) 
will be listed. 
For liver enzymes, the number of subjects with newly occurring liver enzymes abnormalities 
will be summarized by treatment group. Newly occurring liver enzymes abnormalities are 
defined relative to the upper limit of normal (Section 5.3.2. 
Liver function test will also be presented graphically as matrix plots of each of the parameters 
(ALT, AST, TBIL, ALP) maximum post-baseline/ULN normalized. 
For the shift tables, abnormalities based on CTCAE grades tables and liver frequency 
distribution tables, all applicable post-baseline values will be checked against the respective 
criteria and the rules for handling multiple laboratory assessments within visit windows will not 
be applied. 
For continuous variables databased as <lower limit, these will be imputed as being half of the 
lower limit. 
Regarding renal function, the overall frequency of events and percentage of patients with renal 
events during the treatment period will be summarized and detailed listings provided. Renal
events will be defined in section 5.3.3.
The following analyses will be repeated for Cut-off 2 analysis:

New or worsening abnormalities based on CTCAE grade


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
New or worsening liver enzyme abnormalities at any time post-baseline

Shift table

Renal events

Summary statistics
2.8.3.1
Serology at screening
Laboratory serology to determine patient’s eligibility includes parameters with respect to 
hepatitis and HIV viruses, syphilis (RPR), and tuberculosis. Parameters with respect to hepatitis
include 1) anti-hepatitis A virus IgM; 2) hepatitis B surface antigen and anti-hepatitis B core 
IgM/IgG antibody; 3) anti-hepatitis C virus IgG; 4) anti-hepatitis E virus IgM.
The result of each serology parameter is a categorical value. The number and percentage of 
patients with values in each of the categories will be provided by treatment group for all above-
mentioned parameters. Serology test should be performed once at screening. For patients with 
multiple assessments, the latest result will be used in the summary. Additional serology data 
with numerical values may be collected but will not be reported.
2.8.3.2
Other special lab results
Other non-routine laboratory data include pregnancy test results, CD19+B-cell counts, CD3+, 
CD20+T-cell counts, total IgG, total IgM, 
 
 All data will be listed appropriately.
The B-cell counts, T-cell counts, total IgG, total IgM, 
 will 
be summarized using descriptive statistics by treatment group and visit-window.
In addition, number and percentage of patients with B-cells < the lower limit of normal (LLN)
will be presented by treatment group and visit-window. Graphic presentation of B-cell counts
distribution via box-plots will also be provided by treatment group and visit-window.
Number and percentage of patients meeting the notable low level criteria in IgG or IgM at least 
once will be provided by treatment group. 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.
The following analyses will be repeated for Cut-off 2 analysis:

Number and percentage of patients with B-cells < LLN by visit window

Number and percentage of patients meeting the notable low level criteria in IgG and 
IgM

Summary statistics
2.8.4
Other safety data
2.8.4.1
ECG 
ECG data will be collected at baseline visit, Week 24 visit, Week 48 visit, and EOS visit. 
Clinically significant findings from ECG evaluations will be reported as AEs and included in 


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the analysis of AEs. ECG parameters include max heart rate, mean PR duration, mean QT 
duration, mean QRS duration, and QT corrected using Fridericia’s correction formula (all as 
collected on the ECG CRF). Descriptive statistics of each ECG parameter will be provided by 
treatment group for baseline and for the 3 nominal visits (i.e., Week 24, Week 48, and EOS 
visits).
The number and percentage of patients meeting the criteria defined in Table 2-13 will be 
provided for each criterion by treatment group for baseline and for the 2 nominal visits.
Table 2-13
Criteria for relevant ECG absolute or change from baseline values
Absolute values criteria: 
Changes from baseline criteria: 
Heart rate: HR<40 or HR>120 beats/min
QRS complex: increase>25% compared to 
baseline
Pulse rate: PR<110 or PR>200 msec
QTcF > 500 msec and QTcF increase > 60 
msec
QRS complex =: <70 msec or >120 msec
QTcF <350 or >450 msec (males)
QTcF <360 or >460 msec (females)
2.8.4.2
Vital signs
Vital sign measurements and their change from baseline will be summarized with descriptive 
(mean, median, standard deviation, min, max) by visit window. The number and percentage of 
subjects with clinically notable vital signs will be presented.
Vital sign measurements include sitting systolic and diastolic blood pressure, sitting pulse, body 
temperature, height and body weight. 
Three sitting measurements of blood pressure (SBP and DBP) and pulse will be taken at each 
vital sign assessment. 
For post baseline assessments, the blood pressure and pulse values will be the average of the 
non-missing values of the 3 measurements. If more than one blood pressure/pulse assessment 
(scheduled or unscheduled) exists in a particular visit-window (Section 2.1.2) the blood 
pressure/pulse value will be the average of all assessments. Derivation of baselines for blood 
pressure and pulse are provided in Section 2.1.1. 
Height will be collected at screening visit only and will be summarized in the baseline 
characteristic summary only. 
Analyses of vital sign measurements (excluding data collected on Day 1, Day 7, Day 14, Week 
4 and Week 24) using descriptive summary statistics (mean, median, standard deviation, min, 
max) for the change from baseline for each post-baseline visit-window will be performed. These 
descriptive summaries will be presented by vital sign parameter and treatment group. Change 
from baseline will only be summarized for patients with both baseline and post-baseline values. 


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The number and percentage of patients with clinically notable vital signs will be presented. For 
clinical notable vital signs values, refer to Section 5.4. This analysis will be repeated for Cut-
off 2 analysis.
For vital signs data collected on Day 1, Day 7, Day 14, Week 4, and Week 24 protocol scheduled 
visit, pre and post-injection vital signs data including temperature, pulse rate and blood pressure 
are collected. Change from pre-injection to post-injection in these 3 parameters will be 
summarized by nominal visit. This analysis will be performed for Cut-off 1 analysis only.
2.8.4.3
Suicidality evaluations
In this study, the C-SSRS questionnaire will be administered electronically (eC-SSRS), via an 
interactive voice response (IVR) system. However, as per internal Novartis guidelines, a CRF 
page ‘Supplemental Data for Suicidal Ideation and Behavior Categories’ is also used as an 
unplanned/unscheduled visit for those cases when the subject did not conduct the interview 
because, e.g. the subject was hospitalized and unable to conduct the interview or the subject 
refused to conduct the interview/withdrew from the study and external information on suicidal 
ideation and behavior is required. In such cases, SIB information will still be collected from 
external parties (spouse, caregiver, nurse, investigator, etc.) through means of this CRF page. 
Further, for deaths due to suicide, the site should fill out the Supplemental Data CRF 
(“completed suicide” tickbox) to ensure accurate reporting of such cases. When reporting the 
SIB data, data from both sources (eC-SSRS and Supplemental CRF) will be used in a pooled 
manner and no distinction will be made between the two. 
Definition of all prior history and recent history
SIB assessments obtained before the first dose of study drug will be defined by two components: 
all prior history and recent history.
All prior history will be defined as the SIB results obtained from the lifetime assessment, and
recent history will be defined as the SIB results obtained from the assessment in past 6 months 
or past 24 months of the screening or baseline visit.
In case multiple assessments collected before first dose of study drug, results should be derived 
as the worst case value per the reporting timeframe. Worst case is defined by an answer ‘yes’
to the SIB category.
Data summary
SIB data will be summarized for the Safety Set. The number and percentage of subjects with 
suicidal ideation, suicidal behavior and self-injurious behavior without suicidal intent will be 
presented by analysis-period (recent history, all prior history and any time post-baseline) and 
treatment group. The following 4 types of events will be included in the summary table:

Each of the 11 categories listed in Table 2-14 separately 

Any suicidal ideation or behavior (a ‘yes’ answer  to at least one of the 10 suicidal 
ideation and behavior questions in analysis-period of interest)

Any suicidal ideation (answered ‘yes’ to at least one of the 5 suicidal ideation 
questions in analysis-period of interest)


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
Any suicidal behavior (answered ‘yes’ to at least one of the 5 suicidal behavior 
questions in analysis-period of interest).
In addition, the number and percentage of subjects with the following post-baseline events will 
be presented (Nilsson et al, 2013):


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Table 2-14
Standard SIB events 
Categ
ory 
numbe
r
C-SSRS category
Suicidal Ideation
1
   Wish to be dead
2
   Non-specific active suicidal thoughts
3
   Active suicidal ideation with any methods (not plan) without intent to act
4
   Active suicidal ideation with some intent to act, without specific plan
5
   Active suicidal ideation with specific plan and intent
Suicidal behavior
6
   Preparatory acts or behavior
7
   Aborted attempt
8
   Interrupted attempt
9
   Actual attempt
10
   Completed suicide
Self-injurious behavior, without suicidal intent
11
   Non-suicidal self-injurious behavior
Note: in these definitions, a category of 0 is assigned to a subject without suicidal ideation (i.e. 
a ‘no’ answer to all suicidal ideation categories)

Worsening suicidal ideation compared to recent history: An increase in the maximum 
suicidal ideation category at any time post-baseline from the maximum suicidal 
ideation category during pre-treatment recent history. 

Worsening serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation category to 4 or 5 at any time post-baseline from not 
having serious suicidal ideation (categories of 0-3) during pre-treatment recent 
history. 

Emergence of serious suicidal ideation compared to recent history: A maximum 
suicidal ideation category of 4 or 5 at any time post-baseline from no suicidal ideation 
(category 0) during pre-treatment recent history.

Improvement in suicidal ideation at last on-treatment measurement compared to 
recent history: A decrease in suicidal ideation score at last on-treatment measurement 
from pre-treatment recent history.   

Emergence of suicidal behavior compared to all prior history: The occurrence of 
suicidal behavior (Categories 6-10) at any time post-baseline from not having suicidal 
behavior (Categories 6-10) prior to treatment (includes “lifetime” and any other 
assessments prior to treatment taken prior to treatment). 
For those analyses, each subject can only be counted once for each event. However, a subject 
can be counted in several different events.


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Suicidal ideation and behavior data will be listed. Detailed answers to C-SSRS items will be 
listed separately for subjects with any suicidal ideation at any time post-baseline (i.e. a ‘yes’ 
answer to at least one of the five suicidal ideation questions at any time post-baseline) and for 
a subject with any suicidal behavior at any time post-baseline (i.e. a ‘yes’ answer to at least one 
of the five suicidal behavior questions at any time post-baseline). 
This analysis will be repeated for Cut-off 2 analysis with focusing on post-baseline.
2.8.4.4
Safety evaluation during the Safety follow-up
Safety data collected during the Safety Follow-up period includes adverse events, laboratory 
assessments (hematology, chemistry, urinalysis, B-cells, T-cells and Immunoglobulins) and 
eCSSRs. All safety assessments after study drug discontinuation will be analyzed, summarized 
or listed.
Safety data collected during the Safety Follow-up period will be reported separately. These 
analyses will include laboratory assessments including B-cell repletion, adverse events, vital 
signs, and eCSSRS. MS relapses and change in EDSS will also be collected. For all patients 
change is defined relative to the End of Study visit (EOS). Since post-treatment safety follow-
up in the Safety Follow-up period may continue for up to 36 weeks (or longer if criteria for 
longer follow-up are met) after completion of the Treatment period study, the study report for 
the Core part (Screening and Double-blind treatment period) will be completed based on the 
completed core part i.e. based on all patients who have completed the Double-blind treatment 
period, and the partial data from the Safety Follow-up period available at that time. A complete 
analysis of the post-treatment safety follow-up will be provided in an addendum to the study 
report when all patients who entered the Safety Follow-up period have completed this period.
2.9
Pharmacokinetic endpoints
All completed subjects will be included in the pharmacokinetic (PK) data analysis.  
Concentrations will be given in mass per volume units.  Missing values or those below the limit 
of quantification (LOQ) will be indicated in the data listings and treated as zero in data 
presentations and calculations.  Pharmacokinetic parameters, expressed as mean, SD, and CV, 
with geometric means will be summarized.  
2.10
PD and PK/PD analyses
PK concentration and B-cell count data will be summarized by visit for the overall population, 
and separately by region (Japan or non-Japan) and provided together with by-patient listings in 
the study report. All patients in FAS with non-missing values will be included in these analyses. 
 
 
 
 


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2.11
Immunogenicity assessment
Samples will be analyzed for the presence of human anti-drug antibodies (ADA). The 
proportion of patients with ADA will be summarized by visit window and overall (i.e. 
proportion of patients with ADA) as an assessment of the immunogenicity potential of 
ofatumumab. A listing by patient will also be provided. All patients in FAS with non-missing 
values will be included. 
2.12
Patient-reported outcomes
Not applicable. 


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2.15
Analysis on the Extension part not mentioned in the previous 
sections
Switch effect from placebo to ofatumumab on the number of Gd-enhancing T1
lesions 
Mean numbers of Gd-enhancing T1 lesions per scan, defined as
(total number of Gd-enhancing T1 lesions) / (total number of scans),
will be calculated by treatment and study period (up to Week 24, or thereafter).
Also, mean numbers of Gd-enhancing T1 lesions per scan will be summarized by region and 
study period.
In addition, mean numbers of Gd-enhancing T1 lesions per scan will be summarized by 
subgroup of home injection and study period.
Switch effect from placebo to ofatumumab on the number of new or enlarging 
T2 lesions
Annualized rate of new or enlarging T2 lesions, defined as 
(total number of new or enlarging T2 lesions) / (total time of MRI assessment),
will be calculated by treatment and study period (up to Week 24, or thereafter).
For this calculation, each patient’s number of new or enlarging T2 lesions will be relative to 
Week 24. In addition, definition of time of MRI assessment will depend on the study part:

For the period up to Week 24, the time of MRI assessment will be defined as (Week 
24 visit date) – (first dose date in the Core part) + 1 divided by 365.25.

For the period after Week 24, the time of MRI assessment will be defined as (Week 
48 visit date) – (Week 24 visit date) divided by 365.25. If Week 48 visit is not 
available, the time of MRI assessment will be defined as (last visit date up to Week 
48) – (Week 24 visit date) divided by 365.25.


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Switch effect from placebo to ofatumumab on the annualized relapse rate 
(ARR)
ARR (time-based and patient-based) will be summarized by study period (up to Week 24 or 
thereafter).
Here definition of time in study will depend on the study part:

For the period up to Week 24, the time in study will be defined as (Week 24 visit date) –
(first dose date in the Core part) + 1 divided by 365.25.

For the period after Week 24, the time in study will be defined as (last visit date up to date 
of Cut-off 2) – (Week 24 visit date) divided by 365.25.
2.16
Interim analysis
No interim analysis will be conducted. 
3
Sample size calculation
A total sample size of 60 patients, randomized 2:1 to ofatumumab and placebo, will provide 
more than 90% power for a statistical test of superiority of ofatumumab compared with placebo 
at a one-sided alpha level 0.025. The power was calculated based on a negative binomial model 
under the assumption of 1.0 Gd-enhancing T1 lesions per scan for placebo and a 92% relative 
reduction with ofatumumab (i.e. 0.08 Gd-enhancing T1 lesions per scan for ofatumumab), and 
a dispersion parameter κ = 4.5 (as observed in the combined Phase 3 placebo-controlled studies 
of fingolimod, namely FREEDOMS and FREEDOMS II studies for the same parameter, data 
on file). The sample size allows for a dropout rate of 10%.
Sample size calculation was done in EAST 6, version 6.3, Cytel Inc.
3.1
Evaluation of consistency in the treatment effect on the primary 
variable across regions
As a secondary objective the effect of ofatumumab on Gd-enhancing T1 lesion compared with 
placebo will be estimated for individual regions (Japan and other countries). It is planned to 
include 30 patients from Japan out of 60 in total.
The randomization will be stratified by region (Japan or other countries), and by Gd-lesion 
status on the screening scan (0 Gd-enhancing T1 lesions or ≥1 Gd-enhancing T1 lesions). 
Under the protocol assumptions for placebo, it is expected that approximately 2/3 of the patients 
will be free of Gd-enhancing T1 lesions at baseline.
A simulation was performed to evaluate the consistency in efficacy on the primary variable 
across regions. Consistency is defined as a rate ratio < 1 in both Japan and other countries. For 
the simulation the following assumptions apply:

The assumptions for the primary variable are the same for Japan and other countries and 
identical to those for the primary endpoint (i.e. 1 Gd-enhancing T1 lesion per scan, a 
rate-ratio of 0.08 between ofatumumab and placebo, dispersion 4.5)


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
In addition, it was assumed that the study would include 30 patients from Japan and 30 
from other countries, and that patients would be randomized 2:1 to ofatumumab or 
placebo group in each region.
The probability to observe a consistent treatment effect between Japan and other countries was 
estimated to be higher than 99% under these settings.
Furthermore, we estimated the probability to observe a difference in treatment effect 
(percentage lesion reduction between ofatumumab and placebo) between Japan and other 
countries under the same assumptions. The probability to observe a difference of 20% or more 
(one-sided) in treatment effect between Japan and other countries was estimated to be < 3% 
(Table 3-1).
Table 3-1
Probability to observe a difference in Gd-lesion reduction across 
regions of more than delta
Delta*
Probability of a difference in percentage lesion reduction > Delta
5%
13.7%
10%
6.1%
20%
2.3%
30%
1.3%
*Delta=Percentage lesion reduction for other countries - percentage lesion reduction for Japan
3.2
Numerical comparison of annualized relapse rate (ARR)
As a secondary objective the ARR will be compared between patients treated with ofatumumab 
or placebo. We evaluated the probability to observe a treatment effect in favor of ofatumumab, 
as defined by an ARR-ratio (ofatumumab/placebo) less than 1 in the overall population. The 
following assumptions were made for this evaluation:

60 subjects in total are randomized 2:1 to ofatumumab or placebo.

The true ARRs are 0.4 in the placebo arm, and 0.16 in the ofatumumab arm.

The dispersion parameter, k, is 0.1.

The follow-up period is 6 months.
Under these settings, the probability to observe a lower ARR in patients treated with 
ofatumumab compared with placebo is > 80%.
4
Changes to protocol specified analyses
Below changes to protocol specified analyses are included in this document: 
1. Cut-off 2 analysis will be conducted when the last patient completes all assessments up 
to the Week 48 visit, which includes all data from the Safety FU period obtained up to 
the date of Cut-off 2 as defined above. 
2. Final analysis will be conducted when all patients completed the EOS visit or Safety FU 
period. 


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3. Used 100 days for Safety cut-off instead of 30 days based on the half life of the 
compound. 
4. Removed Time to first confirmed relapse from the sensitivity analyses section. 
5. Defined a simpler negative binomial model with only treatment and region (Japan or 
other countries) as factors as a fallback option on the ARR analysis and time to first 
confirmed relapse analysis, in case the model specified in the protocol do not converge 
or has other statistical limitations. 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing or partial dates are not allowed in completing the study drug administration CRF pages. 
The end date of study drug will be the last end date or last injection date for patients randomized 
to ofatumumab or placebo, respectively. 
5.1.2
AE date imputation
For the start and end dates of the adverse event records, when incomplete or missing, dates will 
be imputed according to Novartis standards (details will be given in PDS document). 
5.1.3
Concomitant medication date imputation
For the start and end dates of the concomitant medication records, when incomplete or missing, 
dates will be imputed according to Novartis standards (details will be given in PDS document). 
5.1.3.1
Prior therapies date imputation
Same as above. 
5.1.3.2
Post therapies date imputation
Same as above. 
5.1.4
Relapse date imputation
Missing or partial dates are not allowed for completing the start date of relapses on the MS 
relapses CRF pages. Sites are required to provide best estimate if patients don’t have the exact 
date. In the rare cases when partial date (unknown day with month and year available) exist in 
the final database, the following rule will apply:

A partial start date will be imputed by the first day of the month or the first dose date 
if it occurs in the same month as the first dose date.

A partial end date will be imputed by the last day of the month or truncated to have a 
duration of maximally 90 days.


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5.1.5
Other imputations
For the calculation of duration or time since relevant history events as specified in section 2.3.3 
(MS disease baseline characteristics), partial dates will be imputed for the MS diagnosis start 
date, the first MS symptom date, the most recent relapse onset date via below imputation rules. 

If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be imputed as
missing. 

If the year is not missing and possible, but the month is impossible or missing (e.g. 17-
XXX-2010), then the year will be kept and date will be imputed as July 1st (e.g., 1-July-
2010). 

If the year and the month are not missing and possible, but the day is impossible or 
missing (e.g., 31-FEB-2009), then the year and month will be kept, and date will be 
imputed as 15th (e.g., 15-FEB-2009). 

The imputed dates should be prior to the screening visit date. That is, if imputed dates 
are on or after the screening visit date, the dates will be imputed to be one day before 
the screening visit date. 
5.1.5.1
Data manipulation for relapses within 30 days of onset of previous 
relapses or relapses with duration beyond 90 days
According to protocol definition of MS relapses, the start date of a new relapse has to be at least 
30 days after the start date of a previous relapse (i.e., start date of a new relapse – start date of 
a previous relapse >=30). If a relapse is recorded with a start date less than 30 days after the 
start date of a previous relapse, below data manipulation will be done to combine them into a 
single relapse by creating a new relapse record with the following information.

Start date: take the earliest start date.

End date: take the latest end date. If one of the end dates is missing, set it to missing.

Date of EDSS intended to confirm the relapse: 
o
Take the date of EDSS by which the relapse can be confirmed.
o
If more than one EDSS assessments meet the above criteria, take the date of 
EDSS by which the worst severity value is derived.
o
If no EDSS assessment meets the above criteria, take the earliest date of EDSS 
as captured on the relapse CRF page.

Severity: take the value representing the worst case (severe>moderate>mild>missing)

“Did the relapse affect daily activities?”, “Hospitalization?”, “Steroid used?”, 
“Recovery status”: for each of these characteristics, take the value representing the worst
case (yes>no for first 3 questions; no>partial>complete recovery for last question). 


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According to CRF completion guidelines, maximum duration of a relapse is 90 days. If a relapse 
is recorded with a duration longer than 90 days, the end date will be truncated to have a duration 
of exactly 90 days. This applies also to the artificial record created by above procedure.
5.2
AEs coding/grading
AEs are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
The latest MedDRA version will be used and will be described in the footnote of relevant 
outputs. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). The CTCAE grade of 5 (death) 
is not used; rather, “fatal” is collected as AE outcome and death information is also collected 
on a separate CRF page. 
5.3
Laboratory parameters derivations
For each patient, the estimated creatinine clearance values (without collecting urine) will be 
calculated using the Cockcroft-Gault formula (as specified in Table 5-1). In these calculations, 
the body weight is the last measurement collected on or before the day when the patient takes 
the laboratory test and age should also be calculated based on the time when the patient takes 
the laboratory test. 
If the creatinine value is collected in the unit μmol/L (SI unit), it will be converted to mg/dL 
in order to use the formulas. The conversion is via the equation below: 

mg/dL = 88.4 μmol/L (e.g., creatinine = 2.0 mg/dL = 176.8 μmol/L).
Table 5-1
Creatinine clearance calculation
Variable
Formula
Creatinine clearance [mL/min]
Using Cockcroft-Gault formula
= (140 - A) * W / (72 * C) * G
Where
A is age [years]
W is body weight [kg]
C is the serum concentration of creatinine 
[mg/dL]
G is a constant: G=1 for males and G=0.85 for 
females.
The estimated creatinine clearance will be included as one of the laboratory parameters. 


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5.3.1
Laboratory test groups and subgroups
On presenting lab results, grouping parameters by family will ease the review. Table below 
shows a possible set of lab parameters and their corresponding classification. 
Table 5-2
Laboratory tests
Order
Laboratory Group
  Subgroups
Tests [SI unit]
1
Hematology
  Red Blood Cells
  White Blood Cell Differential
  B-cells
  T-cells
  
  Immunoglobulin
Hematocrit [%]
Hemoglobin [mmol/L]
Platelets [10E9/L]
Red cell count [10E12/L]
Absolute Basophils [10E9/L]
Absolute Eosinophils [10E9/L]
Absolute Lymphocytes [10E9/L]
Absolute Monocytes [10E9/L]
Basophils [%]
Eosinophils [%]
Lymphocytes [%]
Monocytes [%]
Neutrophils [%]
White Cell Count [10E9/L]
CD19+ B-cell counts [cells/μl]
CD3+ CD20+ T-cell counts [cells/μl]
Total IgG [g/L]
Total IgM [g/L]
2
Chemistry
  Renal Function
  Liver Function Test
Creatinine [umol/L]
Blood urea nitrogen [mmol/L]
ALT [U/L]
Albumin [g/L]
Alkaline Phosphatase [U/L]
AST [U/L]
Bilirubin (direct/conjugated) [umol/L]
GGT [U/L]
Total Bilirubin [umol/L]
Total protein [g/L]


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Order
Laboratory Group
  Subgroups
Tests [SI unit]
  Other Enzymes
  Lipids
  Other
  Electrolytes / Metabolism Tests
Amylase [U/L]
Cholesterol HDL [mmol/L]
Cholesterol LDL [mmol/L]
Triglycerides [mmol/L]
Total Cholesterol [mmol/L]
Random glucose [mmol/L]
C-Reactive protein CRP [mg/L]
Bicarbonate [mmol/L]
Calcium [mmol/L]
Chloride [mmol/L]
Magnesium [mmol/L]
Phosphate [mmol/L]
Potassium [mmol/L]
Sodium [mmol/L]
3
Urinalysis
Blood
Glucose
Specific gravity
Albumin
Protein
5.3.2
Newly occurring liver enzymes abnormalities
Below lists the criteria for “events” of newly occurring liver enzymes abnormalities: 

ALT > 3, 5, 10, 20x ULN

ALT or AST > 3, 5, 8, 10, 20x ULN

AST > 3, 5, 8, 10, 20x ULN

ALT or AST > 3x ULN & TBIL > 1.5x ULN

ALT or AST > 3x ULN & TBIL > 2x ULN

ALP > 1.5, 2, 5x ULN

TBIL > 1, 1.5, 2x ULN

ALP > 3, 5x ULN & TBIL > 2x ULN


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
ALT or AST > 3x ULN & TBIL > 2x ULN & ALP ≤ 2x ULN
When a criterion contains multiple laboratory parameters (e.g., ALT > 3xULN & TBL > 
2xULN), unless otherwise requested by the project clinical team/Brand Safety Leader (BSL), 
the criterion should be only considered to be met when the elevation in both parameters occurs 
on the same sample day (as evidenced by the same date that the lab samples were taken). 
The “events” are defined in the Novartis safety guideline on hepatotoxicity, section: Safety 
parameters for special liver event analyses. 
5.3.3
Newly occurring renal events
Below lists the criteria for newly occurring renal events: 

SCr increase >= 25% and <50% from baseline

SCr increase >=50% from baseline

New onset dipstick proteinuria (confirmed) (≥1+)

New onset dipstick glycosuria (≥1+)

New onset dipstick hematuria (≥1+)
5.3.4
CTCAE grades for laboratory parameters
Table 5-3
CTCAE grades for laboratory parameters (CTCAE Version 5)
Grade
Abnormality
Lab parameter
1
2
3
4
Hematology
Anemia
Hemoglobin
(g/L)
<LLN - 100 g/L
<100 - 80 g/L
<80 g/L
transfusion 
indicated
Platelet count 
decreased
Platelets 
(thrombocytes) 
(109/L)
<LLN-75.0 x 109/L
<75.0 - 50.0 x 
109/L
<50.0 - 25.0 x 
109/L
<25.0 x 109/L
White blood cell 
decreased
Leukocytes 
(WBCs)
(109/L)
<LLN - 3.0 x 109/L
<3.0 - 2.0 x109/L
<2.0 - 1.0 x 109/L
<1.0 x 109/L
Neutrophil count 
decreased
Absolute 
neutrophil count 
(109/L)
<LLN - 1.5 x109/L
<1.5 - 1.0 x109/L
<1.0 - 0.5 x109/L
<0.5 x109/L
Lymphocyte
count decreased
Absolute 
lymphocyte count
(109/L)
<LLN x 0.8 - 109/L 
<0.8 - 0.5 x 109/L
<0.5 - 0.2 x 109/L 
<0.2 x 109/L
Lymphocyte 
count increased
Absolute 
lymphocyte count
(109/L)
>4 – 20 x 109/L
> 20 x 109/L
Chemistry


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Grade
Liver function
Alanine 
aminotransferase 
increased
ALT (SGPT)
(U/L)
>ULN – 3.0 x ULN 
if baseline was 
normal; >1.5 – 3.0 
x baseline if 
baseline was 
abnormal
>3.0 – 5.0 x ULN 
if baseline was 
normal; >3.0 – 5.0 
x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Aspartate 
aminotransferase 
increased
AST (SGOT)
(U/L)
>ULN – 3.0 x ULN 
if baseline was 
normal; 1.5 – 3.0 
x baseline if 
baseline was 
abnormal
>3.0 – 5.0 x ULN 
if baseline was 
normal; >3.0 – 5.0 
x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Blood bilirubin 
increased
Bilirubin
(µmol/L)
>ULN – 1.5 x ULN 
if baseline was 
normal; >1.0 – 1.5 
x baseline if 
baseline was 
abnormal
>1.5 – 3.0 x ULN 
if baseline was 
normal; >1.5 – 3.0 
x baseline if 
baseline was 
abnormal
>3.0 – 10.0 x ULN 
if baseline was 
normal; >3.0 –
10.0 x baseline if 
baseline was 
abnormal
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal
GGT increased
Gamma-glutamyl 
transferase 
(GGT) (U/L)
>ULN – 2.5 x ULN 
if baseline was 
normal; 2.0 – 2.5 
x baseline if 
baseline was 
abnormal
>2.5 – 5.0 x ULN 
if baseline was 
normal; >2.5 – 5.0 
x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Alkaline 
phosphatase 
increased
Alkaline 
Phosphatase 
(U/L)
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 – 2.5 
x baseline if 
baseline was 
abnormal
>2.5 - 5.0 x ULN if 
baseline was 
normal; >2.5 – 5.0 
x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Renal function Note: A semi-colon (;) indicates ‘or’ within the description of the grade.
Creatinine 
increased*
Creatinine 
(µmol/L)
>ULN - 1.5 x ULN
>1.5 - 3.0 x 
baseline;
>1.5 - 3.0x ULN
>3.0 baseline;
>3.0 - 6.0 x ULN
>6.0 x ULN
Other enzymes
Serum amylase 
increased
Amylase 
(U/L)
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN;
>2.0 - 5.0 x ULN 
and 
asymptomatic
>2.0 - 5.0 x ULN 
with signs or 
symptoms; >5.0 x 
ULN and 
asymptomatic
>5.0 x ULNand 
with signs or 
symptoms
Serum amylase** 
increased
Amylase 
(U/L)
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN;
>2.0 - 5.0 x ULN 
>5.0 x ULN
Lipids
Cholesterol high
Cholesterol Total 
(mmol/L)
>ULN- 7.75 
mmol/L
>7.75-10.34 
mmol/L
>10.34-12.92 
mmol/L
>12.92 mmol/L
Hypertriglyceride
mia
Triglycerides
(mmol/L)
1.71 - 3.42 
mmol/L
>3.42 - 5.7 
mmol/L
>5.7 - 11.4 
mmol/L
>11.4 mmol/L


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Grade
*Highest grade will be assigned if more than one grade criteria are met for an observed value of a patient.
**CTCAE 4.03 definition. For reporting in CSR, the grade definition per CTCAE 4.03 will be used for this parameter only.
5.4
Clinical notable vital signs
Clinically notable vital sign values to be used for this study are listed below. 
Vital sign
Notable criteria
Pulse (beats/min, bpm)
>120 bpm
Or <50 bpm
Systolic Blood Pressure (mmHg)
>=160 mmHg
Or <=90 mmHg
Diastolic Blood Pressure
>=100 mmHg
Or <=50 mmHg
Temperature (°C)
>38.3oC (>101 oF)
Body weight (kg)
>=7% from baseline weight
5.5
Statistical models
5.5.1
Primary analysis
The null hypothesis is that there is no difference in the number of Gd-enhanced T1 lesions per 
scan between ofatumumab and placebo during the core part. The alternative hypothesis is that 
there is a difference between the 2 treatment groups. 
The null hypothesis will be tested using a negative binomial regression model with log-link, 
each patient’s total number of Gd-enhanced lesions during the Core part as the response variable, 
and natural log of the number of MRI scans as the offset variable to adjust for the different 
number of MRI scans between patients. The model will include treatment, region (Japan or 
other countries), and baseline number of Gd-enhanced lesions (0 or ≥1) as factors.
The SAS procedure GENMOD will be used to conduct the analysis. In GENMOD, the log of 
the dispersion parameter will be used (lognb) as an option in model statement. The natural log 
of number of MRI scans is used as an offset by specifying offset option in the model statement.
5.5.2
Key secondary analysis
For the secondary endpoints Number of new or enlarging T2 lesions on MRI scans and 
Annualized Relapse Rate (ARR), statistical model is similar with that of the primary endpoints 
(Section 5.5.1), in that a negative binominal model is used. 
For the secondary endpoint Time to relapse, a Cox proportional hazard model with treatment, 
region (Japan or other countries), and baseline number of Gd enhancing lesions (0 or ≥ 1) as 
factors, and number of relapses in previous year and baseline EDSS as covariates will be used 
to test H0: λo/λt = 1 vs. Ha: λo/λt < 1. Where λo and λt are hazard of relapse in ofatumumab 
and placebo groups respectively. 


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The SAS procedure PHREG will be used to conduct the Cox PH analysis. The SAS procedure 
LIFETEST will be used to conduct the KM analysis.
5.6
Rule of exclusion criteria of analysis sets 
Patient classification in the analysis sets is entirely based on protocol deviation and non-
protocol deviation criteria. Details are provided in Table 5-4 and Table 5-5. 


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Table 5-4
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in 
Analyses
EXCL01
Patients with primary progressive MS or SPMS without disease 
activity
Excluded from 
PPS
EXCL02
Patients meeting criteria for neuromyelitis optica
Excluded from 
PPS
EXCL06
Patients with an active chronic disease (or stable but treated) of the 
immune system other than MS or with a known immunodeficiency 
syndrome
Excluded from 
PPS
EXCL11
Systemic steroid or adrenocorticotropic hormone treatment within 
30 days prior to Screening MRI
Excluded from 
PPS
EXCL12
Dimethyl fumarate within 1 month prior to randomization
Excluded from 
PPS
EXCL13
Fingolimod taken within 2 months prior to randomization
Excluded from 
PPS
EXCL15
Daclizumab within 4 months prior to randomization
Excluded from 
PPS
EXCL16
Natalizumab treatment within 6 months prior to randomization
Excluded from 
PPS
EXCL17
Teriflunomide within 3.5 months prior to randomization or 1 month 
prior to randomization following accelerated elimination procedure 
and documented teriflunomide plasma level below 0.02 mg/L
Excluded from 
PPS
EXCL18
Mild to moderately Immunosuppressive / chemotherapeutic 
medications (e.g. azathioprine, methotrexate) within 6 months prior 
to randomization
Excluded from 
PPS
EXCL19
Highly immunosuppressive/chemotherapeutic 
medications(Mitoxantrone, cyclophosphamide, cladribine)or any B-
cell targeted therapy(rituximab, ocrelizumab)or laquinimod within 2 
years before randomization
Excluded from 
PPS
EXCL20
Mitoxantrone with evidence of cardiotoxicity following treatment or a 
cumulative life-time dose of more than 60 mg/m2, at any time prior 
to randomization
Excluded from 
PPS
EXCL21
Lymphoid irradiation; bone marrow transplantation; other strongly 
immunosuppressive treatments (with effects potentially lasting over 
6 months), at any time prior to randomization
Excluded from 
PPS
EXCL22
Ofatumumab or alemtuzumab use at any time
Excluded from 
PPS
EXCL23
Use of other investigational drugs at screening or within the prior 30 
days, or five elimination half-lives, or until the expected 
pharmacodynamics effect has returned to baseline, whichever is 
longer
Excluded from 
PPS
EXCL24
History of malignancy of any organ system within the past 5 years, 
regardless of evidence of local recurrence or metastases.
Excluded from 
PPS
EXCL46
History of clinically significant CNS disease (e.g. stroke, traumatic 
brain or spinal injury, history or presence of myelopathy) or 
neurological disorders which may mimic MS
Excluded from 
PPS


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Deviation 
ID
Description of Deviation
Exclusion in 
Analyses
EXCL47
Patients with neurological findings consistent with Progressive 
Multifocal Leukoencephalopathy (PML) or confirmed PML at 
Screening
Excluded from 
PPS
EXCL48
Patients unable or unwilling to undergo MRI scans
Excluded from 
PPS
EXCL49
History of hypersensitivity to any of the study drugs or to drugs of 
similar chemical classes
Excluded from 
PPS
INCL01
Study Informed consent Date = missing
Excluded from All 
analysis sets
INCL01A
Incorrect ICF procedure
Excluded from All 
analysis sets
INCL03
No diagnosis of MS as defined by 2010 revised McDonald criteria
Excluded from 
PPS
INCL05
No appearance of new neurological abnormality or worsening of 
pre-existing neurological abnormality during the previous 2 years 
prior to Screening
Excluded from 
PPS
INCL06
No appearane of MRI activity, namely no appearance of Gd-
enhanced T1 lesions or new/enlarging T2 lesions in brain during the 
previous 1 year prior to randomization
Excluded from 
PPS
INCL07
Neurologically Unstable (i.e. Clinical relapse) within 1 month prior to 
randomization
Excluded from 
PPS
WITH09
Patient withdraws consent but study treatment was not discontinued
Excluded from 
PPS
WITH11
Patient diagnosed with PML and study treatment was not 
discontinued
Excluded from 
PPS
TRT01
Patient recieved incorrect study drug
Excluded from 
PPS
TRT02
Patient recieved damaged or expired study drug
Excluded from 
PPS
COMD01
Immunosuppressive medicines such as cyclosporine, azathioprine, 
methotrexate, cyclophosphamide, mitoxantrone or lymphoid 
irradiation, hematopoietic stem cell  transplantation on study 
treatment
Excluded from 
PPS
COMD02
Monoclonal antibodies targeting the immune system such as 
natalizumab, alemtuzumab, daclizumab and B-cell depleting agents 
such as rituximab, ocrelizumab and obinutuzumab on  study 
treatment
Excluded from 
PPS
COMD03
Any other immunomodulatory treatment such as fingolimod, 
interferon beta, glatiramer acetate, dimethyl fumarate, IVIG, 
plasmapheresis or chronic corticosteroids on  study treatment
Excluded from 
PPS
COMD04
Leflunomide or teriflunomide while taking study treatment
Excluded from 
PPS
OTH01
EDSS rater acted as a treating physician or treating physician acted 
as EDSS rater
Excluded from 
PPS
OTH02
Not following per protocol blinding procedures such that the integrity 
of the study is compromised  
Excluded from 
PPS


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Table 5-5
Patient Classification
Analysis Set
PD ID that cause patients to be 
excluded
Non-PD criteria that cause 
patients to be excluded
FAS
INCL01
INCL01A
Not assigned a valid randomization number;
Randomization despite screen failure
PPS
As listed in Table 5-4
Not in FAS;  
Compliance to study drug administration < 80%
EDSS baseline value >=7.0
SAF
INCL01,
INCL01A
No double-blind study drug taken
5.7
Statistical method details for TEAEs
5.7.1 Odds ratios and 95% confidence interval
For an investigational drug group with n1 patients at risk, independent from the control group 
with n0 patients at risk, of whom x1 and x0 experience a certain event with probability π1 and π0
respectively, the odds ratio (OR) is estimated as
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p


  with p1= x1/n1 and p0=x0/n0, simplifying to 
)
(
)
(
1
1
0
0
0
1
x
n
x
x
n
x




.  
The OR and a conditional exact 95% confidence interval will be obtained by using the SAS 
procedure PROC FREQ with statement EXACT OR. The data set will include a patient level 
response variable indicating whether a patient has at least one AE of a specific type (1=yes, 
0=no).
By default SAS sets the OR to missing if the odds for one of the treatments cannot be calculated 
(no infinity in SAS). This is problematic as infrequent but very serious adverse events that 
happen exclusively on active treatment can easily be missed if the OR for such highly 
imbalanced advents is set to missing and sorted last. To ensure that potentially important 
imbalances appear at the top of a table if it is sorted by OR, the following additional rules are 
applied (considering the numerator and the denominator of the OR that would lead to divisions 
by zero):

NO CASE CLAUSE [0/0]: If (x1=0 and x0=0) or (x1=n1 and x0=n0), i.e. there are either 
no events in both treatment groups, or all patients in both treatment groups had the event, 
then the OR cannot be estimated. The OR can be left missing for the sorting, but should 
be displayed on the output as “N.E.” indicating not estimable (if it has to be shown on 
the table, in this case it needs to be explained in the footnote).

SAFETY CLAUSE[~/0]: If (x0=0 and x1≠0) or (x0≠n0and x1=n1), i.e. there are no events 
on control, but some on investigational drug, or everyone on investigational drug 
experienced the event, but not everyone on control, then OR will be imputed as 100000 


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for the sorting (so that it comes up top if sorted by the OR). On the output present the 
OR as “>100”.

EFFICACY CLAUSE[0/~]: If (x1=0 and x0 ≠0) or (x1≠n1 and x0 =n0), i.e. there are no 
events on investigational drug, but some on control, or, everyone on control experienced 
the event, but not everyone on investigational drug, then OR will be imputed as 
1/100000 for the sorting (so that it comes prior to the missing ones). On the output 
present the OR as “<1/100”.
5.7.2 Exposure adjusted incidence rate and 95% confidence interval 
It will be assumed that for each of n patients in a clinical trial the time tj (j=1,...,n) to the first 
incidence of a certain event is observed, or if the event was not experienced, the time is censored 
at the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process θ with constant intensity λ. The rate 
parameter λ will be estimated by 
T
D

ˆ
, where 



n
j
jt
T
1
and D is the number of patients with 
at least one event. Conditionally on T, an exact 95% confidence interval for a Poisson variable 
with parameter θT and observed value D can be obtained based on (Garwood, 1936), from 
which an exact 95% confidence interval for 
T
D

ˆ
will be derived as follows (Sahai, 1993; Ulm, 
1990):
Lower confidence limit   
T
c
L
D
2
,
2
/
5.0


for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D
2
2
,
2
/
1
5.0




where
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
The SAS procedure GENMOD will be used to fit a Poisson regression model with only 
treatment as factor, the log-link and natural logarithm of time as the offset variable. The 
incidence rate (and 95% confidence intervals) are obtained as the exponentiated estimates by 
treatment (e.g. obtained by statement LSMEANS with option EXP). The data set will include a 
patient level response variable indicating whether the patient experienced at least one event of 
a specific type (1=yes, 0=no) and a patient level time variable which is derived as follows: 

For patients who had at least one event of that type: time is calculated as (start day of the 
first event - date of first administration of study drug+1). 

For patients who did not have an event of that type: time at risk as defined inSection 
2.4.1will be used.
The time will be divided by 365.25 before taking the logarithm transformation as offset variable 
so that the estimated incidence rate corresponds to an annualized rate.


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6
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Garwood F. (1936) Fiducial Limits for the Poisson Distribution. Biometrika 28, 437-442.
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Keene ON, Jones MRK, Lane PW, Anderson J. (2007) Analysis of exacerbation rates in 
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Sahai H, Khurshid A (1993). Conﬁdence intervals for the ratio of two Poisson means. The 
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