A Randomized, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Ofatumumab Versus Teriflunomide in Patients With Relapsing Multiple Sclerosis.
Phase: PHASE3
Conditions: Relapsing Multiple Scelrosis
Sponsor: Novartis Pharmaceuticals

Global Clinical Development - General Medicine 
OMB157/Ofatumumab 
Clinical Trial Protocol COMB157G2302 / NCT02792231 
A randomized, double-blind, double-dummy, parallel-group 
study comparing the efficacy and safety of ofatumumab 
versus teriflunomide in patients with relapsing multiple 
sclerosis 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2015-005419-33 
Version number: 
v02 Clean 
Clinical trial phase: 
III 
Release date: 
06-Aug-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 

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Table of contents 
Table of contents ............................................................................................................. 2 
List of tables.................................................................................................................... 6 
List of figures .................................................................................................................. 6 
List of abbreviations ........................................................................................................ 7 
Glossary of terms .......................................................................................................... 10 
Amendment 2 ................................................................................................................ 11 
Amendment 1 effective 19-JAN-2017 .......................................................................... 13 
Protocol summary ......................................................................................................... 16 
1 
Introduction................................................................................................................... 20 
1.1 
Background ....................................................................................................... 20 
1.2 
Purpose .............................................................................................................. 22 
2 
Study objectives and endpoints ...................................................................................... 22 
2.1 
Primary objective(s) ........................................................................................... 22 
2.2 
Secondary objective(s) ....................................................................................... 22 
 
 23 
3 
Investigational plan ....................................................................................................... 24 
3.1 
Study design ...................................................................................................... 24 
3.2 
Rationale for study design .................................................................................. 27 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment ... 28 
3.4 
Rationale for choice of comparator .................................................................... 30 
3.5 
Purpose and timing of interim analyses/design adaptations................................. 30 
3.5.1 
Interim analysis for Data Monitoring Committee (DMC) ................... 30 
3.5.2 
Reviews of blinded study data ............................................................ 30 
3.6 
Risks and benefits .............................................................................................. 31 
4 
Population ..................................................................................................................... 32 
4.1 
Inclusion criteria ................................................................................................ 32 
4.2 
Exclusion criteria ............................................................................................... 32 
5 
Treatment ...................................................................................................................... 37 
5.1 
Study treatment .................................................................................................. 37 
5.1.1 
Investigational and control drugs........................................................ 37 
5.1.2 
Additional treatment .......................................................................... 38 
5.2 
Treatment arms .................................................................................................. 38 
5.3 
Treatment assignment and randomization .......................................................... 38 
5.4 
Treatment blinding ............................................................................................. 38 
5.5 
Treating the patient ............................................................................................ 39 

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5.5.1 
Patient numbering .............................................................................. 39 
5.5.2 
Dispensing the study drug .................................................................. 40 
5.5.3 
Handling of study and additional treatment ........................................ 40 
5.5.4 
Instructions for prescribing and taking study treatment ....................... 40 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 42 
5.5.6 
Recommendations for the treatment of MS relapses ........................... 43 
5.5.7 
Concomitant medication .................................................................... 43 
5.5.8 
Prohibited medication ........................................................................ 44 
5.5.9 
Emergency breaking of assigned treatment code ................................ 45 
5.6 
Study Completion and Discontinuation .............................................................. 45 
5.6.1 
Study completion and post-study treatment ........................................ 45 
5.6.2 
Discontinuation of Study Treatment ................................................... 46 
5.6.3 
Withdrawal of informed consent ........................................................ 48 
5.6.4 
Loss to follow-up ............................................................................... 49 
5.6.5 
Early study termination by the Sponsor .............................................. 49 
5.6.6 
Role of Key site personnel ................................................................. 49 
6 
Visit schedule and assessments ...................................................................................... 52 
6.1 
Information to be collected on screening failures................................................ 58 
6.2 
Patient demographics/other baseline characteristics............................................ 59 
6.3 
Treatment exposure and compliance .................................................................. 59 
6.4 
Efficacy ............................................................................................................. 59 
6.4.1 
MS Relapse........................................................................................ 60 
6.4.2 
Expanded Disability Status Scale (EDSS) .......................................... 61 
6.4.3 
Magnetic Resonance Imaging (MRI) .................................................. 61 
6.4.4 
Neurofilament light chain (NfL) ......................................................... 62 
6.4.5 
Timed 25-Foot Walk (T25FW) .......................................................... 63 
6.4.6 
Nine Hole Peg Test (9HPT) ............................................................... 63 
6.4.7 
Symbol Digit Modalities Test (SDMT) .............................................. 63 
6.4.8 
Multiple Sclerosis Impact Scale (MSIS-29) ........................................ 63 
6.4.9 
Appropriateness of efficacy assessments ............................................ 64 
6.5 
Safety ................................................................................................................ 64 
6.5.1 
Physical examination ......................................................................... 64 
6.5.2 
Vital signs .......................................................................................... 65 
6.5.3 
Height and weight .............................................................................. 65 
6.5.4 
Laboratory evaluations ....................................................................... 65 
6.5.5 
Electrocardiogram (ECG) .................................................................. 67 

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6.5.6 
Pregnancy and assessments of fertility ............................................... 68 
6.5.7 
Appropriateness of safety measurements ............................................ 68 
6.6 
Other assessments .............................................................................................. 68 
 
 68 
6.6.2 
Pharmacokinetics ............................................................................... 70 
6.6.3 
Immunogenicity ................................................................................. 70 
 
 70 
 
 71 
7 
Safety monitoring .......................................................................................................... 71 
7.1 
Adverse events ................................................................................................... 71 
7.2 
Serious adverse events ....................................................................................... 73 
7.2.1 
Definition of SAE .............................................................................. 73 
7.2.2 
SAE reporting .................................................................................... 74 
7.3 
Liver safety monitoring ...................................................................................... 75 
7.4 
Renal safety monitoring ..................................................................................... 76 
7.5 
Reporting of study treatment errors including misuse/abuse ............................... 76 
7.6 
Pregnancy reporting ........................................................................................... 77 
7.7 
Prospective suicidality assessment ..................................................................... 77 
7.8 
Accelerated elimination procedure related to active comparator teriflunomide ... 78 
8 
Data review and database management .......................................................................... 79 
8.1 
Site monitoring .................................................................................................. 79 
8.2 
Data collection ................................................................................................... 79 
8.3 
Database management and quality control.......................................................... 79 
8.4 
Data Monitoring Committee .............................................................................. 80 
9 
Data analysis ................................................................................................................. 81 
9.1 
Analysis sets ...................................................................................................... 81 
9.2 
Patient demographics and other baseline characteristics ..................................... 81 
9.3 
Treatments ......................................................................................................... 81 
9.4 
Analysis of the primary variable ........................................................................ 82 
9.4.1 
Statistical model, hypothesis, and method of analysis ......................... 82 
9.4.2 
Handling of missing values/censoring/discontinuations ...................... 84 
9.4.3 
Sensitivity analyses ............................................................................ 85 
9.5 
Analysis of secondary variables ......................................................................... 85 
9.5.1 
Efficacy variables .............................................................................. 85 
9.5.2 
Safety variables .................................................................................. 94 
 
 96 

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 96 
9.5.5 
PK/PD modelling ............................................................................... 97 
9.5.6 
Immunogenicity assessment ............................................................... 97 
 
 97 
 
 
 97 
 
 97 
 
 98 
9.7 
Interim analyses ................................................................................................. 98 
9.7.1 
Unblinding interim analysis ............................................................... 98 
9.7.2 
Blinded data reviews .......................................................................... 99 
9.8 
Summary of sample size calculation ................................................................. 101 
9.8.1 
Sample size for the primary endpoint (ARR) .................................... 102 
9.8.2 
Sample  size  for  3-month   confirmed   disability  worsening 
(3mCDW) ........................................................................................ 103 
9.8.3 
Sample  size  for  6-month   confirmed   disability  worsening 
(6mCDW) ........................................................................................ 104 
9.8.4 
Sample size for 6-month confirmed disability improvement 
(6mCDI) .......................................................................................... 104 
9.8.5 
Sample size for number of Gd-enhancing lesions per scan ................ 104 
9.8.6 
Sample size for annualized rate of new/newly enlarging T2 lesions .. 105 
9.8.7 
Sample size for NfL ......................................................................... 105 
9.8.8 
Sample size for annualized rate of brain volume loss (BVL) ............. 105 
10 Ethical considerations .................................................................................................. 105 
10.1 
Regulatory and ethical compliance ................................................................... 105 
10.2 
Informed consent procedures ........................................................................... 106 
10.3 
Responsibilities of the Investigator and IRB/IEC.............................................. 106 
10.4 
Publication of study protocol and results .......................................................... 107 
10.5 
Quality Control and Quality Assurance ............................................................ 107 
11 Protocol adherence ...................................................................................................... 107 
11.1 
Protocol Amendments ...................................................................................... 107 
12 References .................................................................................................................. 108 
13 Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up  
Requirements .............................................................................................................. 110 
14 Appendix 2: Specific Renal Alert Criteria and Actions ................................................ 112 
15 Appendix 3: Safety monitoring Guidance .................................................................... 112 
15.1 
Guidance on monitoring of patients with symptoms of neurological 

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deterioration suggestive of PML ...................................................................... 112 
15.2 
Guidance on monitoring of patients with infections .......................................... 113 
15.3 
Guidance on immunization .............................................................................. 114 
15.4 
Guidance on monitoring of patients with low immunoglobulin levels............... 114 
16 Appendix 4: List of drugs/drug classes with teriflunomide interaction potential ........... 114 
17 Appendix 5: Statistical appendix (information from a controlled clinical trial with 
count data) .................................................................................................................. 116 
 
 
List of tables 
Table 5-1 
Prohibited medication ........................................................................ 44 
Table 6-1 
Assessment schedule .......................................................................... 54 
Table 6-2 
Assessment schedule for Safety Follow-up epoch............................... 58 
Table 6-3 
Severity of MS relapse ....................................................................... 60 
Table 9-1 
Criterion for disability worsening based on change in EDSS score ..... 86 
Table 9-2 
Criterion for disability improvement based on change in EDSS 
score .................................................................................................. 87 
Table 9-3 
Anticipated cumulative event probabilities on teriflunomide .............. 99 
Table 13-1 
Liver Event and Laboratory Trigger Definitions ............................... 110 
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers .110 
Table 14-1 
Specific Renal Alert Criteria and Actions ......................................... 112 
 
 
List of figures 
Figure 3-1 
Study design ...................................................................................... 27 
Figure 9-1 
Testing procedure and type-I-error control ......................................... 83 

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List of abbreviations 
 
Ab 
Antibody 
ACR 
Albumin/Creatinine Ratio 
ADA 
Anti-drug-antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse Event 
AEP 
Accelerated Elimination Procedure 
AIDS 
Acquired Immune Deficiency Syndrome 
Alb 
Albumin 
ALT 
Alanine Aminotransferase 
AP/ALP 
Alkaline Phosphatase 
ARBA 
Annualized Rate of Brain Atrophy 
ARR 
Annualized Relapse Rate 
AST 
Aspartate Aminotransferase 
BCRP 
Breast Cancer Resistant Protein 
BIL 
Bilirubin 
BUN 
Blood Urea Nitrogen 
BVL 
Brain Volume Loss 
C-CASA 
Columbia Classification Algorithm for Suicide Assessment 
CDC 
6mCCD 
Complement-dependent cytotoxicity 
6-month Confirmed Cognitive Decline 
CDI 
Confirmed Disability Improvement 
6mCDI 
6-month Confirmed Disability Improvement 
CDW 
Confirmed Disability Worsening 
3mCDW 
3-month Confirmed Disability Worsening 
6mCDW 
6-month Confirmed Disability Worsening 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessments 
CQA 
Compliance Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
(e)CSSRS 
(electronic) Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRD 
Clinical Trial Results Database 
DAR 
Dose Administration Record 
DMC 
Data Monitoring Committee 
DMT 
Disease-Modifying Therapy 
DNA 
Deoxyribonucleic Acid 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 

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EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
 
 
EU 
European Union 
FAS 
Full Analysis Set 
FS 
Functional System 
FU 
Follow-up 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
GGT 
Gamma-Glutamyl-Transferase 
HA, HB, HC, HE 
Hepatitis A, B, C, E 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
9HPT 
9-Hole Peg Test 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ITT 
Intention-To-Treat 
Ig 
Immunoglobulin 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
iv 
Intravenous(ly) 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KM 
Kaplan-Meier 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LLQ 
Lower Limit of Quantification 
M 
Month 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Image 
MS 
Multiple Sclerosis 
MSIS 
Multiple Sclerosis Impact Scale 
n.a. 
Not applicable 
NB 
Negative Binomial 
NEDA 
No Evidence of Disease Activity 
NYHA 
New York Heart Association 
NfL 
Neurofilament light chain 
OC/RDC 
Oracle Clinical/Remote Data Capture 
PBVC 
Percentage Brain Volume Change 

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PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PG 
Pharmacogenetics 
PK 
Pharmacokinetic 
PML 
Progressive Multifocal Leukoencephalopathy 
po 
oral(ly) 
PRO 
Patient Reported Outcome 
PT 
Prothrombin Time 
q4, q12 
Every 4, every 12 
qd 
Once a Day 
QM 
Quality Management 
RBC 
Red Blood Cell 
RMS 
Relapsing MS 
RNA 
RoW 
Ribonucleic Acid 
Rest of the world 
RRMS 
Relapsing-Remitting MS 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
sc 
Subcutaneous(ly) 
sCR 
Serum Creatinine 
SDMT 
Symbol Digit Modalities Test 
SPMS 
Secondary progressive MS 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T25FW 
Timed 25-Foot Walk 
TBIL/TBL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
US 
United States 
VAS 
Visual Analog Scale 
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) 
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) 
Epoch 
A portion of the study which serves a specific purpose. Typical epochs 
are: Screening/recruitment, wash-out, treatment, and follow-up 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
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 
Personal Data 
Subject information collected by the Investigator that is 
transferred to Novartis for the purpose of the clinical trial. This 
data includes subject identifier information, study information 
and biological samples. 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
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 
defined study treatment completion date 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
Withdrawal of consent from the study occurs only when a 
subject does not want to participate in the study any longer, and 
does not allow any further collection of personal data 

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Amendment 2 
 
 
Amendment rationale 
 
Amendment 2 was created to update the secondary objectives of the study and to provide 
clarification of the rescreening of patients. 
Modifications to the secondary objectives include: 
• Addition of endpoints related to neurofilament light chain (NfL) as secondary objectives 
• Additional endpoint related to cognitive decline as measured on the Symbol Digit 
Modalities Test (SDMT) 
• Addition of composite endpoint related to physical disability and cognition, as measured 
by disability worsening on Expanded Disability Status Scale (EDSS) and cognitive decline 
on SDMT 
The Withdrawal of consent and study discontinuation language have been modified to fully 
implement the European Economic Area General Data Protection Regulation. 
Other non-substantial changes and updates have been made to correct/clarify minor errors or 
omissions throughout the protocol. 
 
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Protocol summary and Section 2.2: additions to the secondary objectives: 
• Neurofilament light chain (NfL) concentration in serum as key secondary objective 
• Time to a 6-month confirmed cognitive decline (6mCCD), defined as a 4-point worsening 
on Symbol Digit Modalities Test (SDMT), and a composite endpoint of time to 6-month 
confirmed disability worsening (6mCDW) or 6-month confirmed cognitive 
decline(6mCCD) as other secondary objectives 
• Analyses related to NfL in the subgroup of newly diagnosed, treatment-naïve patients 
Section 3.1: addition of the allowance of rescreening in patients. 
Section 5.5.1: clarification of numbering when patients are rescreened. 
Section 5.5.6: clarification on multiple sclerosis (MS) relapse treatment. 
Section 5.5.8: clarification on the prohibited medications. 
Section 5.6.3: clarification on the withdrawal of consent 
Section 5.6.6: text was updated to provide further clarity that T25FW, 9HPT, SDMT may be 
administered by the Investigator or another qualified healthcare professional, including the 
EDSS rater 
Table 6-1: addition of footnote for liver function test (LFT) testing at Day 14. 
Section 6.4: addition of NfL as efficacy assessment. 

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Section 6.4.3: modification of the contrast that is used as standard. 
Section 6.4.4: addition of section regarding NfL. 
Section 6.4.7: addition of reference on SDMT. 
Section 6.5.2: clarification on number of pulse measurements taken. 
Figure 9-1: update to reflect changes in analysis. 
Section 9.4.1.1: added NfL as part of secondary analysis. 
Section 9.5.1.1.1: clarification on analysis with cognition. 
Section 9.5.1.1.2: additional confirmation of analysis for disability-related endpoints. 
Section 9.5.1.1.5: additional section added on NfL. 
Section 9.5.1.2: clarification on the other secondary endpoints 
 
 
Section 9.8: addition of NfL to sample size calculation 
Section 9.8.7: additional section added on NfL sample size calculations 
Section 12: additional references added 

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Amendment 1 effective 19-JAN-2017 
 
 
Amendment rationale 
Amendment 1 was created at the request of several Health Authorities to provide additional 
guidance to the Investigators in regards to: 
• switching to alternative disease modifying therapy for patients that have discontinued study 
drug 
• re-evaluation of benefit/risk of continuing study treatment in patients, who experience 
relevant progression of their disease (have met criterion for 6-month confirmed disease 
worsening) while on study medication. 
Further clarification and instructions to Investigators in regards to the use of pre-medication in 
the home-administration setting have been added. This was part of the Local Amendment 1 for 
Germany (COMB157G2302 v00.01 DE, clean version electronic document identifier 
090095a889dac40e) which was created and released on 18 October 2016 at the request of the 
Paul-Ehrlich Institut (PEI, German Federal Institute for Vaccines and Biomedicines). Since the 
study in Germany has not yet started, the decision was taken to incorporate these clarification 
and instructions in the amendment 1. The amendment 1 will replace the local amendment in 
Germany. 
In addition, procedures and assessments, including administration of T25FW, 9HPT and SDMT 
no longer required to be administered by Independent personnel, have been clarified based on 
feedback from Investigators. 
Other non-substantial changes and updates have been made to correct/clarify minor errors or 
omissions throughout the protocol. 
 
 
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Section 3.1: a new sentence has been added to clarify that after study drug discontinuation, 
patients who continue to stay in the study may initiate an alternative MS therapy if clinically 
appropriate and corresponding reference to section 5.6.2, where details are provided, has been 
inserted. 
Section 3.5.1: the purpose of the interim analyses for DMC has been clarified. 
Section 4.2: the exclusion criteria # 11, 12, 14, 19 and 23 have been updated: 
• #11 with a footnote stating that Quantiferon®-TB Gold test may be requested to be done 
by the Central laboratory to assess patient's eligibility 
• #12 with the hepatitis C testing steps 
• #14 with daclizumab, which is now an approved MS therapy 
• #19 to clarify that this exclusion criterion refers to either one or both serum immunoglobulin 
(IgG, IgM) level(s) below LLN 

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• # 23 clarifies that in regards to lactose intolerance only severe conditions are exclusionary 
Section 5.5.4: the time window for Day7 and Day14 subcutaneous injection has been added and 
guidance on missing injections and subsequent injections has been clarified. 
Section 5.5.7: this section has been modified to add and clarify specific instructions for the 
Investigators in regards to the use of premedication in the home-administration setting and to 
ensure that appropriate information and material on potential injection related reactions and 
their treatment are provided to the patients. 
Table 5-1: daclizumab has been added to prohibited medications while patients are on study 
medication. 
Section 5.6.2: a paragraph has been added to clarify that study drug discontinuation should be 
considered if patients meet the criterion for 6-month confirmed disability worsening on EDSS 
and if the Investigator assesses the benefit/risk as negative for study treatment continuation. 
Section 5.6.2: a paragraph has been added to clarify that after study drug discontinuation, 
patients may initiate alternative MS therapy if clinically appropriate and guidance on switching 
to another MS therapy is provided. 
Sections 5.6.6 and 6.4.3: the starting point (randomization) of blinding of efficacy data (EDSS 
and MRI) has been clarified. 
Section 5.6.6: T25FW, 9HPT and SDMT may be administered by the Investigator or another 
qualified health care professional experienced with the administration of these assessments. 
Therefore no specific blinding procedures apply to these assessments. 
Table 6-1: clarifications have been provided: 
• the line for Samples for Total IgG and IgM has been shaded in grey to clarify that this 
sample should be taken as per schedule after study drug discontinuation 
• the following footnotes have been updated: 
• #8 to clarify that it refers to both End of Study (EOS) and End of Treatment (EOT) 
• #18 to clarify the need to test syphilis and tuberculosis as part of the eligibility check 
(unless completed in the last 6 months prior to screening with documented negative 
results) and that the Quantiferon®-TB Gold test may be requested to be done by the 
Central laboratory to assess patient's eligibility 
• #20 has been updated with timing of the pre and post-injection vital signs collection 
• #23 has been added to clarify that routine laboratory must be drawn to allow adequate 
time for results to be obtained before randomization to ensure patient's eligibility 
• the starting points for additional LFT testing (Day 14) and phone interviews (Month 2) have 
been clarified. 
Table 6-2: time points for Routine laboratory and for Total IgG and Ig M assessments have 
been added. 
Sections 6.4.5 and 6.4.6 and 6.4.7: T25FW, 9HPT and SDMT may be administered by the 
Investigator or another qualified health care professional experienced with the administration 
of these assessments. 

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Section 6.5.2: the timing of the pre and post-injection vital signs collection has been added for 
clarity. 
Section 6.5.4.4: the hepatitis C testing steps have been clarified, In addition clarity has been 
provided on the need to test syphilis and tuberculosis as part of the eligibility check (unless 
completed in the last 6 months prior to screening with documented negative results) and on the 
possibility to request the Central laboratory to do the Quantiferon®-TB Gold test to assess 
patient's eligibility. 
Section 7.2.2: the first paragraph has been updated to clarify the SAE reporting time frame. 
Section 12: new reference has been added. 
Section 15.1: clarification has been added with regards to the MRI sequences recommended for 
differential diagnosis. 
In addition, several updates have been made in the Data analysis section (Section 9) to correct 
some errors and align with the Statistical Analysis Plan. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Protocol summary 
Protocol number 
COMB157G2302 
Title 
A randomized, double-blind, double-dummy, parallel-group study 
comparing the efficacy and safety of ofatumumab versus teriflunomide in 
patients with relapsing multiple sclerosis 
Brief title 
Study of efficacy and safety of ofatumumab compared to teriflunomide in 
patients with relapsing multiple sclerosis 
Sponsor and Clinical 
Phase 
Novartis 
Phase 3 (confirmatory) 
Investigation type 
Biological (human IgG1k lytic monoclonal antibody (mAb) to human CD20 
antigen) 
Study type 
Interventional 
Purpose and rationale 
Study, 
in 
conjunction 
with 
second 
study 
of 
identical 
design 
(COMB157G2301) conducted in parallel, to provide data in support of 
regulatory approval worldwide as a treatment for patients with relapsing 
multiple sclerosis 
Primary Objective 
To demonstrate that ofatumumab is superior to teriflunomide in reducing 
the frequency of confirmed relapses as evaluated by the annualized 
relapse rate (ARR) in patients with relapsing MS 
Secondary Objectives 
Key secondary objectives 
To evaluate if ofatumumab is superior to teriflunomide on: 
• 
Time to disability worsening as measured by 3-month confirmed 
worsening (3mCDW) on Expanded Disability Status Scale (EDSS) 
• 
Time to disability worsening as measured by 6-month confirmed 
worsening (6mCDW) on EDSS 
• 
Time to disability improvement as measured by 6-month confirmed 
improvement (6mCDI) on EDSS 
• 
Number of T1 gadolinium (Gd)-enhancing lesions per Magnetic 
Resonance Image (MRI) scan 
• 
Number of new or enlarging T2 lesions on MRI per year (annualized 
T2 lesion rate) 
• 
Neurofilament light chain (NfL) concentration in serum 
• 
Rate of brain volume loss (BVL) based on assessments of percentage 
brain volume change from baseline 
Other secondary objectives 
To evaluate if ofatumumab is superior to teriflunomide on: 
• 
Time to first relapse 
• 
Annualized relapse rates > 8 weeks after the onset of treatment 
• 
Risk of a 3mCDW > 8 weeks after the onset of treatment 

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• 
Risk of a 6mCDW > 8 weeks after the onset of treatment 
• 
Time to a 6-month confirmed cognitive decline (6mCCD), defined as a 
4-point worsening on Symbol Digit Modalities Test (SDMT) 
• 
Time to 6mCDW or 6mCCD, whichever is reached first 
• 
Change in cognitive performance relative to baseline as measured by 
the SDMT 
• 
Time to 6-month confirmed worsening of at least 20% in the timed 
25-foot walk test (T25FW) 
• 
Time to 6-month confirmed worsening of at least 20% in the 9-hole peg 
test (9HPT) 
• 
Time to 6mCDI sustained until end of study as measured by EDSS 
• 
Number of new or enlarging T2 lesions between Month 12 and End of 
Study (EOS) 
• 
Change in T2 lesion volume relative to baseline 
• 
Proportion of patients with no evidence of disease activity (NEDA-4) at 
year 1 and 2 
• 
Physical and psychological impact of MS disease as measured by the 
Multiple Sclerosis Impact Scale (MSIS-29) 
In the subgroup of newly diagnosed, treatment-naïve patients, evaluate if: 
• 
High NfL (above median) concentration at baseline is predictive of 
higher disease activity post baseline 
• 
Patients with a high NfL (above median) concentration at baseline 
benefit from a stronger relative treatment effect of ofatumumab vs 
teriflunomide 
• 
The safety profile of ofatumumab vs terifluomide is comparable in 
patients with high NfL (above median) concentration at baseline 
To evaluate the safety and tolerability of ofatumumab compared to 
teriflunomide 
To evaluate the pharmacokinetic (PK) of ofatumumab 
Study design 
Randomized, 
double-blind, 
double-dummy, 
parallel-group, 
active- 
comparator controlled, adaptive design, maximal treatment duration of 30 
months for an individual patient 
Population 
Adult patients with relapsing multiple sclerosis (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: relapsing-remitting course (RRMS), or secondary 
progressive (SPMS) course with disease activity 
• Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive) 
• Documentation of at least: 1 relapse during the previous 1 year OR 2 
relapses during the previous 2 years prior to Screening OR a positive 
Gd-enhancing MRI scan during the year prior to randomization (Note: 

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Screening MRI scan may be used if no positive Gd-enhancing scan 
exist from prior year). 
• Neurologically stable within 1 month prior to randomization 
Key Exclusion criteria 
• 
Patients with primary progressive MS or SPMS without disease activity 
• 
Patients meeting criteria for neuromyelitis optica 
• 
Disease duration of more than 10 years in patients with an EDSS score 
of 2 or less 
• 
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 
• 
Sexually active males unless they agree to use condom during 
intercourse while on study drug 
• 
Patients with an active chronic disease of the immune system other 
than MS 
• 
Patients with neurological findings consistent with 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) indicating acute or chronic infection 
• 
Patients with active systemic infections or known to have AIDS or to 
test positive for 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, ofatumumab, rituximab, ocrelizumab, 
alemtuzumab, 
natalizumab, 
cyclophosphamide, 
teriflunomide, 
leflunomide, 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 
Ofatumumab (OMB157G) 20 mg sc injections once every 4 (q4) weeks 
(following initial loading regimen of three 20 mg sc doses/week in first 14 
days) + teriflunomide-matching placebo capsules orally once daily 
Teriflunomide 14 mg capsules orally once daily + ofatumumab-matching 
sc placebo injections 
Efficacy assessments 
MS relapse, Expanded Disability Status Scale (EDSS), Magnetic 
Resonance Imaging (MRI), Timed 25-Foot Walk (T25FW), Nine Hole Peg 
Test (9HPT), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis 
Impact Scale (MSIS-29), Neurofilament light chain (NfL) 
Key safety 
assessments 
Adverse events, Physical examinations (including skin), Vital signs, 

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Laboratory 
evaluations 
(blood 
and 
urine), 
Pregnancy 
testing, 
electrocardiogram (ECG), Columbia Suicide Severity Rating Scale 
(CSSRS) 
Other assessments 
Pharmacokinetics, 
 
 
Data analysis 
All efficacy data will be analyzed according to the intent-to-treat principle. 
The primary analysis (ARR) will use a negative binomial regression model 
with log-link and time-in-study as offset. Key-secondary analyses include 
disability endpoints (i.e., time-to-3mCDW, 6mCDW and 6mCDI all 
analyzed in Cox proportional hazards models), MRI-endpoints (i.e., 
number of T1 Gd-enhancing lesions, number of new/ enlarging T2 lesions 
both analyzed in negative binomial regression models and percentage 
brain volume change analyzed in a random coefficients model) and 
log(NfL) analyzed in a repeated measures model . 
The primary hypothesis (ARR) and all MRI- and NfL-related hypotheses 
will be addressed within the present study (COMB157G2302). All disability 
endpoints will be addressed in the combined data from 2 studies of 
identical design (COMB157G2302 and COMB157G2301). To adjust for 
multiplicity, a testing procedure is implemented in order to control the 
Type-I error rate. 
Key words 
Interventional, clinical trial, efficacy and safety, double-blind/double- 
dummy, ofatumumab, teriflunomide, relapsing multiple sclerosis 

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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 is the most frequent clinical presentation of the disease. Approximately 
85% of patients present with relapsing-remitting MS (RRMS), characterized by recurrent acute 
exacerbations (relapses) of neurological dysfunction followed by recovery. After 15-20 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. SPMS can be segregated based on whether patients continue to 
experience relapses (relapsing SPMS) or not (purely progressive SPMS). 
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 (Klaus 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 
RMS (Hauser et al. 2015). These studies showed that ocrelizumab significantly reduced relapse 
rates, reduced MRI disease activity and, delayed the time to disability worsening vs interferon 
beta 1a over 2 years. 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 (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 monoclonal antibody (mAb) rituximab. CD20-binding of 
ofatumumab induces B-cell lysis primarily through complement-dependent cytotoxicity (CDC) 

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and antibody-dependent cell-mediated cytotoxicity (ADCC). As a fully human antibody (Ab), 
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 2 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 3mg, 30mg, or 60mg 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). 
MRI and relapse outcomes, safety and tolerability and B-cell counts were also assessed. 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 ≥ 30mg 
(p < 0.001). Dose-dependent decreases were maintained up to week 48, with the greatest 
reduction in the ofatumumab 60 mg q4 weeks treatment group versus other dose groups. 
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 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 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 

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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’s Brochure. 
 
1.2 
Purpose 
The study is designed, in conjunction with a second study of identical design conducted in 
parallel, to provide efficacy, safety and tolerability data for ofatumumab sc compared to oral 
(po) teriflunomide (Aubagio®) in patients with relapsing MS. The data will support regulatory 
approval to make ofatumumab sc available for clinical use worldwide as a treatment for this 
patient population. 
 
2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
Demonstrate that ofatumumab 20 mg sc once every 4 (q4) weeks is superior to teriflunomide 
14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the 
annualized relapse rate (ARR) in patients with relapsing MS. 
 
2.2 
Secondary objective(s) 
Key secondary objectives 
All disability-related key-secondary objectives will be addressed in the combined data (meta- 
analysis) from this study and the second study of identical design. All other objectives will be 
addressed based on the data from this study alone. 
The key secondary objectives are to evaluate if ofatumumab 20 mg sc q4 weeks is superior to 
teriflunomide 14 mg po once daily on the following efficacy measures: 
• Time to disability worsening as measured by 3-month confirmed worsening (3mCDW) on 
The Expanded Disability Status Scale (EDSS) 
• Time to disability worsening as measured by 6-month confirmed worsening (6mCDW) on 
EDSS 
• Time to disability improvement as measured by 6-month confirmed improvement (6mCDI) 
on EDSS 
• Number of T1 Gd-enhancing lesions per MRI scan 
• Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate) 
• Neurofilament light chain (NfL) concentration in serum 
• Rate of brain volume loss (BVL) based on assessments of percentage brain volume change 
from baseline 
 
Other secondary objectives 
Evaluate if ofatumumab 20 mg sc q4 weeks is superior to teriflunomide 14 mg po once daily 
on the following efficacy measures: 

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• Time to first relapse 
• Annualized relapse rates > 8 weeks after the onset of treatment 
• Risk of a 3mCDW > 8 weeks after the onset of treatment 
• Risk of a 6mCDW > 8 weeks after the onset of treatment 
• Time to a 6-month confirmed cognitive decline (6mCCD), defined as a 4-point worsening 
on Symbol Digit Modalities Test (SDMT) 
• Time to 6mCDW or 6mCCD, whichever is reached first 
• Change in cognitive performance relative to baseline as measured by the SDMT 
• Time to 6-month confirmed worsening of at least 20% in the timed 25-foot walk test 
(T25FW) 
• Time to 6-month confirmed worsening of at least 20% in the 9-hole peg test (9HPT) 
• Time to 6mCDI sustained until End of Study (EOS) as measured by EDSS 
• Number of new or enlarging T2 lesions between Month 12 and EOS 
• Change in T2 lesion volume relative to baseline 
• Proportion of patients with no evidence of disease  activity  (NEDA-4;  defined  in  
Section 9.5.1.2) at year 1 and 2 
• Physical and psychological impact of MS disease as measured by the Multiple Sclerosis 
Impact Scale (MSIS-29) 
In the subgroup of newly diagnosed, treatment-naïve patients, evaluate if: 
• High NfL (above median) concentration at baseline is predictive of higher disease activity 
post baseline 
• Patients with a high NfL (above median) concentration at baseline benefit from a stronger 
relative treatment effect of ofatumumab vs teriflunomide 
• The safety profile of ofatumumab vs terifluomide is comparable in patients with high NfL 
(above median) concentration at baseline 
Evaluate the safety and tolerability of ofatumumab 20 mg sc q4 weeks compared to 
teriflunomide 14 mg po once daily. 
Evaluate the pharmacokinetics (PK) of ofatumumab. 
 

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3 
Investigational plan 
3.1 
Study design 
This is a randomized, double-blind, double-dummy, active comparator-controlled, parallel- 
group, multi-center study with variable treatment duration in approximately 900 patients with 
relapsing MS. The treatment duration for individual patients will be variable based on when the 
End of Study (EOS) criteria are met. The maximal duration for an individual patient will be 30 
months (2.5 years). 
Eligible patients will be randomized to receive either ofatumumab 20 mg sc injections q4 weeks 
(after initial loading regimen of three weekly 20 mg doses in the first 14 days) or teriflunomide 
14 mg orally once daily. In order to blind for the different formulations, a double-dummy design 
will be used: patients in the active ofatumumab treatment arm will additionally take placebo 
capsules orally once daily; patients in the active teriflunomide treatment arm will additionally 
take q4 weeks placebo-containing sc injections (after initial regimen of three weekly injections 
in the first 14 days) (Section 5.5). Other measures to protect study blind include: 
• Use of an independent EDSS rater for clinical efficacy assessments (Section 5.6.6), who is 
not the same person as the Investigator (Section 5.6.6) 
• MRI scans are read by a blinded central MRI reading center (Section 6.4.3) 
• And laboratory assessments that may lead to potential unblinding (Section 6.5.4) will not 
be revealed to the site staff or Sponsor study team. 
A second study of identical design (COMB157G2301) will be conducted simultaneously. Both 
studies have the same primary (reduction in ARR) and key-secondary objectives. Both studies 
will be conducted globally, but individual sites can only participate in one study to ensure 
independence between the 2 studies. Key-secondary hypotheses with high sample size 
requirements, i.e. those related to disability worsening or disability improvement, will be tested 
on the basis of the combined data from the 2 studies (meta-analysis). Multiplicity adjustments 
are defined in Section 9.4.1.1. Poolability of the 2 studies will be assumed on the basis of the 
identical design, the simultaneous and global conduct of the 2 studies. For information only, the 
heterogeneity of the treatment effect between the 2 studies will be tested for disability-related 
outcomes in the meta-analysis. 

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Prior to the completion of enrolment, a blinded data review (i.e. the treatment code will not be 
broken) will be performed for the 2 studies to re-assess sample size assumptions for ARR (for 
each study separately) and for 3mCDW (for pooled studies). Based on this blinded review, the 
number of patients to be enrolled may be increased to a maximum number of 1250 randomized 
patients in each study (Section 9.7.2.1). 
End of Study (EOS) will be reached for both studies when all of the following conditions are 
met simultaneously: 
1. Each study has collected sufficient data to provide 90% power for the primary ARR 
endpoint. 
2. Across the 2 studies, sufficient 3mCDW events have been observed to provide 90% power 
for the key-secondary 3mCDW endpoint. 
3. Across the 2 studies sufficient 6mCDW events have been observed to provide 80% power 
for the key-secondary 6mCDW endpoint. 
An analysis of blinded data will be conducted to determine the time point at which EOS is 
reached. Blinded data reviews are described in Section 9.7.2 and a formal definition of the EOS 
criteria can be found in the statistical Section 9.7.2.2. 
The EOS analysis will be based on the completed core study i.e. based on all patients who have 
completed the Treatment epoch including partial data from the Safety Follow-up epoch 
available at the time of EOS cut-off (Section 9.5.2.6). 
The core study consists of 3 epochs; Screening epoch (including Baseline), Treatment epoch 
(double-blind) and Safety Follow-up (FU) epoch (Figure 3-1). Patients who complete the 
double-blind Treatment epoch may be eligible to enter an open-label ofatumumab Extension 
study that is planned (under separate protocol). Patients who complete the Treatment epoch (on 
study drug), but do not enter the Extension study will be followed up for safety in the Safety 
Follow-up (Safety FU) for a minimum of 9 months. 
The Screening epoch can last up to 45 days and consists of 2 periods, Screening and Baseline: 
The Baseline period 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/or Baseline assessments. 
If a patient is declared a screen failure, he/she may be rescreened and all assessments must be 
repeated. 
 
The double-blind Treatment epoch will start on Day 1 with randomization of the patient. 
Patients will be randomly assigned to receive either sc ofatumumab or oral teriflunomide in a 
double-blind, double-dummy fashion. In the first 4 weeks, injectable study treatment 
(ofatumumab or placebo) will be administered on Day 1, Day 7 and Day 14 and Day 28 (Week 
4, study Month 1). Thereafter, injections will be administered every 4 weeks. All patients will 
also take one capsule orally once daily (teriflunomide or placebo) starting on Day 1. The 
Treatment epoch for an individual patient will continue until the End of Study (EOS) has been 
declared, or for a maximal duration of 30 months, if the EOS has not been declared earlier. 
All patients will receive their first sc injection at the site administered by the study staff 
(Investigator or Study Nurse/Study Coordinator), and will return to the site on Day 7, Day 14 
and Day 28 (Month 1) for sc injections under supervision of the study staff (refer to Section 

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5.5.4 for further details). Patients will thereafter return to the site for assessments at Month 3 
and every 3 months thereafter for the duration of the Treatment epoch. All patients will have an 
EOS Visit at the end of the Treatment epoch (either when EOS is declared for all patients, or 
when the patient has reached the maximum of 30 months, or if the patient discontinues from 
study drug and is not willing to follow the Treatment epoch visits and assessments further). 
Patients who prematurely discontinue double-blind study medication and agree to continue to 
follow the assessment schedule of the Treatment epoch (recommended) will have their end of 
treatment (EOT) visit and assessments at the time of study medication discontinuation. These 
patients will then be asked to continue to follow the schedule of assessments (Table 6-1) and 
have their EOS Visit at the end of the Treatment epoch. After study drug discontinuation, 
patients may initiate alternative MS therapy according to local standard of care if clinically 
indicated (see Section 5.6.2). 
The Safety FU epoch (Table 6-2) will be applicable for the following patients: 
• Patients who complete the Treatment epoch on study drug and do not enter the planned 
Extension study 
• Patients who prematurely discontinue study treatment and do not agree to continue to be 
followed in the Treatment epoch 
• Patients who have prematurely discontinued study treatment, are being followed in the 
Treatment epoch but have had less than 9 months of off-treatment follow up at the time of 
EOS/Month 30 (whichever is earlier) 
All Safety FU visits must be scheduled relative to the EOS Visit. 
All patients will be followed for a total of at least 9 months after study drug discontinuation in 
the Treatment epoch and/or the Safety FU epoch (by 9 months the vast majority of patients are 
expected to have repleted their circulating B-cells, see Section 3.3). The duration of the Safety 
FU epoch for an individual patient will depend on how long the patient has been off study drug 
at the time he/she enters the Safety FU epoch. For example, a patient who completes the 
Treatment epoch on study drug and has EOS (and does not enter the extension study), will be 
followed for at least 9 months in the Safety FU epoch. However, a patient who discontinues 
study drug at an earlier time point and had 4 months of follow up after study drug 
discontinuation in the Treatment epoch, may only need to be followed for an additional 5 
months in the Safety FU epoch (for a total of 9 months). 
A longer than 9 months of post-treatment follow up in the Safety FU epoch will be required for 
the following patients: 
• 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 9 months 
• Patients in whom teriflunomide plasma levels are above 0.02 mg/L (analyzed centrally) at 
9 months 
These patients will continue to be followed with 3-monthly assessments until their B-cell counts 
have repleted or teriflunomide plasma levels are below 0.02 mg/L. To protect the study blind, 
the assessment of B-cell counts and teriflunomide plasma levels will be performed centrally 
and the Investigators and Sponsor study team will only be informed of whether or not continued 
follow up is necessary. 

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Screening epoch 
Treatment epoch 
(double-blind, double-dummy) 
Safety FU epoch* or 
Extension study** 
Baseline 
Teriflunomide 14 mg po qd + placebo injections sc 
M1 
M2 
M3 
M4 
M5 
EOS 
Randomization 
Ofatumumab 20 mg sc + placebo capsules po qd 
 
Patients who have initiated therapy with another disease modifying/immunosuppressive therapy 
before the end of the 9-month follow up will not be monitored beyond 9 months. 
Due to the long elimination of teriflunomide (8 months up to 2 years), all patients who have 
discontinued study drug and have completed at least 9 months of follow up (in the Treatment 
epoch or the Safety FU epoch) and who plan to become pregnant/father a child or do not agree 
to continue to use highly effective contraception, should undergo the teriflunomide-accelerated 
elimination procedure (AEP) described in Section 7.8. To protect study blind, the decision to 
do the accelerated elimination procedure must be made without knowledge of the core study 
treatment assignment. Patients may not re-start study drug after accelerated elimination. 
Patients who complete the Treatment epoch (while on study drug) may be eligible to participate 
in the long-term, open-label ofatumumab Extension study. The details of the design and 
assessments of the Extension study will be described in a separate protocol. This extension will 
last for up to 5 years for individual patients or until the development of ofatumumab in relapsing 
MS has been decided to be discontinued, if earlier. 
 
Figure 3-1 
Study design 
 
*Patients who complete the Treatment Epoch and do not enter the planned Extension study or who prematurely 
discontinue study drug and do not agree to complete the study Treatment epoch or have less than 9 months of 
follow up after study drug discontinuation, will enter the Safety FU epoch. **Extension study will be conducted 
under separate protocol. M=month, EOS=End of Study, FU=Follow-Up, po qd= orally once a day 
 
3.2 
Rationale for study design 
Double-blind, parallel group, active comparator design is an established scientific method to 
assess safety and efficacy of a new therapy in conditions where approved medications are 
available. Double-dummy blinding is necessary to blind treatment group assignment when the 
investigational and comparator drugs utilize different formulations/routes of administration. 
Screening 

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The study has a flexible duration where the end of the study is determined by an analysis of 
blinded data. The End of Study is declared when sufficient data has been collected to provide 
the required power for the statistical tests (explained in Section 9.7.2.2). 
The sample size of the study can be adjusted if the disease activity of the recruited patient 
population is lower than initially assumed as indicated by an analysis of the blinded data 
(explained in Section 9.7.2.1). Adaptive design features aim to maximize the efficiency of the 
trial by limiting the exposure of patients to double-dummy treatment to the minimum that is 
required to address the scientific objectives of the study. All design adaptations in this study are 
based on an analysis of blinded data and do not jeopardize the scientific integrity of the study. 
Two studies (COMB157G2302 and COMB157G2301) of identical design will be conducted in 
parallel as part of the ofatumumab Phase 3 program in order to allow an assessment of the 
reproducibility of the primary results. Both studies will be independently powered to address 
the primary objective (ARR) and key secondary MRI objectives, and results from the 2 studies 
will be independent as centers/sites/Investigators can only participate in one or the other trial 
(but not in both). The design makes efficient use of the patients’ data. If the ARR is significantly 
lower in ofatumumab treated patients compared with those treated with teriflunomide in both 
studies, all disability-related key-secondary endpoints will be analyzed in a meta-analysis of the 
combined data from the 2 studies. Poolability of the studies is justified based on the identical 
design and the simultaneous global conduct. A testing procedure and multiplicity adjustments 
are specified to control the false positive rate (one-sided) to ≤ 2.5% within study (Section 
9.4.1.1). 
Patients with relapsing MS (RRMS or SPMS with disease activity as defined by Lublin et al. 
2014) with EDSS scores 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 one or 2 years before 
enrollment or one or more Gd-enhancing lesions on MRI in the year prior to randomization. 
The defined trial population is typical for relapsing MS. 
Given the long-lasting effect of ofatumumab on B-cells and the long half-life of teriflunomide, 
all patients who discontinue study drug (prematurely or at study completion) and do not enter 
the planned long-term Extension study, will continue to be followed up for safety for at least 9 
months until B-cell repletion or teriflunomide plasma levels are below 0.02 mg/L (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 monthly maintenance dose regimen of 20 mg administered 
every 4 weeks starting at week 4. 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 

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• A continued maintenance dose that would keep B-cell depletion levels below desired 
threshold. 
The Phase 2 study of ofatumumab sc 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. 
Pharmacokinetic/pharmacodynamic (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 regimen of 3 separate 20 mg (at weeks 0, 1 and 2) 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, 20 mg ofatumumab 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 (K-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 adverse events (AEs) than the lower dose regimens of 3 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, Day 7 and Day 14, followed by a monthly maintenance 
dose regimen of 20 mg administered every 4 weeks (starting at week 4) is selected because it 
will deplete and subsequently maintain B-cells at the levels below 8 cells/µL for nearly all 
patients and it is expected to have maximal clinical benefit and better tolerability than higher 

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doses. Taken together, the strong relationship between MRI lesions and relapses (Sormani et al. 
2009; Sormani et al. 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. 
 
Duration of treatment 
The treatment duration is variable for individual patients. Double-blind treatment will end for 
all patients when End of Study is declared based on reaching a sufficient amount of data for the 
primary endpoint (ARR) and disability worsening-related key secondary endpoint analyses 
(see Section 3.1). For an individual patient the maximum treatment duration will be 30 months, 
if the End of Study has not been reached earlier. 
 
3.4 
Rationale for choice of comparator 
The comparator used in this study is teriflunomide (Aubagio®). Teriflunomide is an oral, once 
daily tablet approved as a first line disease modifying treatment for patients with relapsing MS. 
It is approved at once daily doses of 14 mg in countries and regions worldwide including the 
United States (US) and the European Union (EU). In the US, teriflunomide is additionally 
approved at a lower 7 mg dose. Since this study will be conducted globally, the dose of 14 mg 
will be used in this study. The efficacy and safety of teriflunomide 14 mg once daily in reducing 
clinical and MRI disease activity and brain volume loss in patients with relapsing MS has been 
demonstrated in Phase 3 clinical studies (O’Connor et al. 2011; Confavreux et al. 2014; 
Freedman 2013; Radue et al. 2015). 
Oral administration increases compliance compared to treatments requiring frequent injections 
such as interferon-beta and glatiramer acetate. As an oral, once daily treatment, teriflunomide 
is becoming increasingly used as an alternative to these current injectable first line therapies. 
Furthermore, an once daily oral agent is preferred in a double-blind/double-dummy design as 
frequently injected comparators (e.g. interferon-beta) increases the difficulty of successful 
blinding, a critical element for the design of a successful trial. 
For these reasons, teriflunomide was selected as an appropriate agent to be used as active 
comparator in this study of ofatumumab in patients with relapsing MS. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
No unblinding interim analysis for efficacy is planned for this study. 
 
3.5.1 
Interim analysis for Data Monitoring Committee (DMC) 
Regular interim analyses for safety and for benefit/risk assessment will be performed for the 
DMC by an independent team of statisticians and programmers who are not otherwise involved 
in the conduct of the study. The review will be done by the DMC. 
 
3.5.2 
Reviews of blinded study data 
The purpose of blinded data reviews by the Sponsor team is to adapt design features (e.g. sample 
size, follow-up time) in order to maximize the efficiency of the study by limiting patient 
exposure to study drug to what is needed for addressing the scientific objectives of the study. 

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Reviews of aggregate data (i.e. analysis that consider all patients as one group without revealing 
treatment allocation) do not pose a scientific risk in terms of bias or type-I-error control and can 
be used to modify the sample size or follow up time if this is indicated by the results. 
Blinded data in this study will be reviewed for: 
1. Sample size re-assessment: The initial sample size for this trial is planned as 900 
randomized patients. The sample size can be increased to a maximum of 1250 randomized 
patients following an analysis-based review of blinded relapse and disability data if the 
activity of the recruited patient is lower than initially anticipated. The blinded sample size 
re-assessment will be done prior to completion of enrollment  and  is  described  in  
Section 9.7.2.1. 
2. Declaration of End of Study: Patients are followed up for a flexible period of time (but for 
a maximum of 30 months) in this study. The  amount  of  information  (defined  in  
Section 9.7.2.3) for the primary ARR analysis, and the number of confirmed disability 
worsening will be monitored in the accumulating blinded data. End of study (as defined in 
Section 9.7.2.2) will be declared when sufficient information has been captured to provide 
sufficient power for the primary and the key-secondary objectives of this study. End of study 
will be declared only once as described in Section 9.7.2. 
 
3.6 
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with eligibility criteria, close 
clinical monitoring, avoidance of prohibited treatments and adherence to protocol contraception 
requirements and Investigator guidance regarding specific safety areas. 
Ofatumumab is approved for patients with chronic lymphocytic leukemia 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 infection and reactivation, and bowel obstruction (please refer to Arzerra® Prescribing 
Information). 
The experience with ofatumumab in MS patients to date is limited (approximately 267 RRMS 
patients in total exposed to ofatumumab iv (N=38) and sc (N=229) in 2 Phase 2 studies). No 
unexpected safety findings were observed to date. 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 RRMS patients in the Phase 2 studies. Confirmation of 
clinical efficacy will be evaluated in the present study. 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. 2015). Taken together, available information 
provides support for the potential of ofatumumab to demonstrate efficacy on relevant clinical 
and MRI outcomes in patients with relapsing MS. 

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The comparator, teriflunomide is approved for the treatment of relapsing MS. The risks of 
teriflunomide in patients with relapsing MS include: elevated liver enzymes (especially alanine 
aminotransferase (ALT)), infections, elevated blood pressure, respiratory reactions, 
hematological reactions, skin reactions, peripheral neuropathy and teratogenicity (please refer 
to the local product information for details). The efficacy of teriflunomide in reducing clinical 
(ARR and disability progression) and MRI disease activity as well as brain volume loss, has 
been demonstrated in Phase 3 clinical trials (Confavreux et al. 2014; O’Connor et al. 2011; 
Freedman 2013; Radue et al. 2015). 
The inclusion of an active comparator arm ensures all patients in the study will receive active 
therapy (i.e. no placebo arm). 
Overall, the balance of benefit and risk supports the proposed clinical study to evaluate the 
potential of ofatumumab sc as an effective and safe therapy to address the medical need in the 
target population of patients with relapsing MS. 
 
4 
Population 
The study population will consist of adult patients with relapsing MS fulfilling all the eligibility 
criteria listed below*. 
The study is planned to be conducted in approximately 300 centers worldwide. It is aimed to 
randomize a total of 900 patients. To reach this number it is anticipated that the total number of 
patients to be screened is approximately 1250. 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: relapsing-remitting course (RRMS), or secondary progressive (SPMS) 
course with disease activity, as defined by Lublin et al 2014 
5. Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive) 
6. Documentation of at least: 1 relapse during the previous 1 year OR 2 relapses during the 
previous 2 years prior to Screening OR a positive Gd-enhancing MRI scan during the year 
prior to randomization. Note: Screening MRI scan may be used if no positive Gd-enhancing 
scan exist from prior year. 
7. Neurologically stable within 1 month prior to randomization 
 
4.2 
Exclusion criteria 
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. 

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1. Patients suspected of not being able or willing to cooperate or comply with study protocol 
requirements in the opinion of the Investigator 
2. Patients with primary progressive MS (Polman et al. 2011) or SPMS without disease activity 
(Lublin et al. 2014) 
3. Patients meeting criteria for neuromyelitis optica (Wingerchuk et al. 2006) 
4. Disease duration of more than 10 years in patients with EDSS score of 2 or less 
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
6. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for at least 12 months after stopping study medication. Given the long 
elimination time of teriflunomide of up to 2 years, women planning to become pregnant 
may undergo the accelerated elimination process (as per teriflunomide label) after the 12- 
month period. 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, 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. 
7. Sexually active males, unless they agree to use a condom during active treatment. Male 
patients should not father a child in this period. Given the long elimination time of 
teriflunomide of up to 2 years, the male patient wishing to father a child during the study 
should discontinue study drug and undergo the accelerated elimination process (refer to 

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Section 7.8). A condom is required to be used also by vasectomized males in order to 
prevent accidental exposure of their female partner to study drug via seminal fluid 
8. 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) 
9. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS 
or to test positive for HIV antibody at Screening 
10. Patients with neurological findings consistent with PML or confirmed PML 
11. Patients at risk of developing or having reactivation of syphilis or tuberculosis (e.g. patients 
with known exposure to or history of syphilis or tuberculosis). 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. Testing should be done per 
local clinical practice (for syphilis e.g. by positive rapid plasma reagin (RPR); for 
tuberculosis** e.g. skin test or blood test as per local practice). 
NOTE: The Investigator may consult with an infectious disease expert if e.g. test results are 
unclear or there is suspicion of false positive test results. If the infectious disease expert 
considers the test results false positive and not clinically relevant, the Investigator must 
document (in source data and as a comment in the electronic case report form (eCRF)) that 
the test results are considered false positive and may then randomize the patient. 
12. Patients at risk of developing or having reactivation of hepatitis: Positive results at 
Screening for serological markers for hepatitis (H) A, B, C, and E indicating acute or chronic 
infection: 
• anti-HA Immunoglobulin (Ig) M (IgM) 
• HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA) 
• anti-HBs negative and Anti-HBc positive 
• anti-HC IgG (if positive IgG, HCV-RNA PCR will be performed and if negative, patient 
can be randomized) 
• anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative, patient 
can be randomized) 
NOTE: If the Investigator suspects false positive hepatitis serology results, such as an 
antibody pattern indicating acute hepatitis infection but no corresponding elevated liver 
enzymes and no signs or symptoms of liver disease, an infectious disease expert may be 
consulted. If the infectious disease expert finds no evidence of acute or chronic hepatitis 
infection and considers the serology results false positive and not clinically relevant, the 
Investigator must document (in source data and as a comment in the eCRF) that the 
serology results are considered false positive and may then randomize the patient. 
13. Have received any live or live-attenuated vaccines (including for varicella-zoster virus or 
measles) within 2 months prior to randomization 

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14. Have been treated with any of the medications listed below (Note: no wash-out period is 
required in the case of prior treatment with interferon-β or glatiramer acetate): 
Medication 
Exclusionary if used/used within required 
wash-out period 
Systemic corticosteroids, adrenocorticotropic 
hormone 
30 days prior to Screening MRI scan 
Dimethyl fumarate 
1 month prior to randomization 
Intravenous immunoglobulin, fingolimod, 
natalizumab (patients who have discontinued 
natalizumab in the 6 months prior to 
randomization should be evaluated to rule out 
PML) 
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 AEP and has documented 
teriflunomide plasma level below 0.02 mg/L 
before randomization (if discontinued for 
reason related to safety or lack of efficacy, 
patient is not eligible, see below) 
Mildly to moderately 
immunosuppressive/chemotherapeutic 
medications (e.g. azathioprine, methotrexate) 
6 months prior to randomization 
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 
Teriflunomide (if discontinued for reasons 
related to safety or lack of efficacy) 
Any time 
15. Patients currently treated with or needing treatment with cholestyramine (unless for 
accelerated teriflunomide elimination, Section 7.8) or leflunomide during the study 
16. 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 
17. 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 

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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 
18. Any of the following conditions or treatments that may impact the safety of the patient: 
• History of, or current, significant cardiac disease including cardiac failure (NYHA 
functional class II-IV), myocardial infarction (within 6 months), unstable angina (within 
6 months), transient ischemic attack (within 6 months), stroke, cardiac arrhythmias 
requiring treatment or uncontrolled arterial hypertension 
• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker on Screening electrocardiogram (ECG) 
• History of familial long QT syndrome or known family history of Torsades de Pointe 
• History of or active severe respiratory disease, including Chronic Obstructive 
Pulmonary Disease, interstitial lung disease or pulmonary fibrosis 
• Patients with asthma requiring regular treatment with oral steroids 
• Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary disease 
• Patients with severe renal impairment (Glomerular Filtration Rate < 30 ml/min/1.73 m2) 
• Any medically unstable condition as determined by the Investigator 
19. Any of the following abnormal laboratory values prior to randomization: 
• Total or conjugated bilirubin (BIL) greater than 1.5 times upper limit of normal (ULN) 
range, unless in the context of Gilbert’s syndrome 
• Alkaline phosphatase (ALP) greater than 1.5 times the ULN range 
• AST or ALT greater than 1.5 times ULN or gamma-glutamyl-transferase (GGT) greater 
than 2 times ULN range 
• White blood cell (WBC) count < 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) 
20. Patients with severe hypoproteinaemia e.g. in nephrotic syndrome 
21. 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 (C-SSRS), if this ideation occurred in the past 6 months, or “yes” 
on any item of the Suicidal Behavior section, except for the “Non-Suicidal Self- 

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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 
22. Patients unable or unwilling to undergo MRI scans 
23. History of hypersensitivity to any of the study drugs or excipients (including rare hereditary 
problems of galactose intolerance, Lapp lactase deficiency and glucose-galactose 
malabsorption) 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 
(e.g. in regards to a higher legal age for study participation) or regulatory (e.g. in regards to 
compliance with local prescribing informations) requirements, the local requirements must be 
followed. 
** For sites that don’t have the possibility to test tuberculosis locally, Quantiferon®-TB Gold 
test may be requested to be done by the Central laboratory to assess patient's eligibility. 
 
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 (OMB157) 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. 
Control treatment, teriflunomide (Aubagio®) 14 mg, will be provided as over-encapsulated 
tablets (either a hard gelatin capsule or a hydroxy propyl methyl cellulose (vegetarian-based) 
capsule will be used, referred to as capsule hereafter) for oral administration. Teriflunomide- 
matching placebo capsule (capsule containing placebo-tablet) will have the same appearance as 
the active comparator. Teriflunomide and teriflunomide-matching placebo capsules will be 
provided in blisters. It is possible that a switch from blisters to bottles will be performed during 
the course of the study. 
Study drug will be supplied by Novartis. 

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5.1.2 
Additional treatment 
No additional treatment beyond investigational drug and comparator drug are provided as part 
of study drug supplies for this study. 
 
5.2 
Treatment arms 
The study includes 2 treatment arms: 
• Ofatumumab arm: ofatumumab 20 mg sc injections on Day 1, 7, 14, Week 4 (Study 
Month 1) and every 4 weeks thereafter + teriflunomide-matching placebo capsule orally 
once daily. 
• Teriflunomide arm: teriflunomide 14 mg capsule orally once daily + ofatumumab- 
matching placebo injections on Day 1, 7, 14, Week 4 (Study Month 1) and every 4 weeks 
thereafter. 
 
5.3 
Treatment assignment and randomization 
Eligible patients will be randomized in a 1:1 ratio to either the active ofatumumab 20 mg group 
or to the active teriflunomide 14 mg group. The randomization will be stratified by geographical 
region and by MS subtype (RRMS, SPMS). Study sites can only participate in one of the 2 
studies to ensure independence of each study. 
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 
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 
investigational treatment 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, double-dummy design. Patients will be 
assigned to receive either active ofatumumab (plus teriflunomide-matching placebo) or active 
teriflunomide (plus ofatumumab-matching placebo) as described in Section 5.2. 
A double-dummy design is used because the identity of the study drug cannot be disguised, as 
the drug products utilize different formulations. 

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Patients, Investigator staff, persons performing the assessments, and data analysts will remain 
blinded to the identity of the treatment 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: Data Monitoring Committee (DMC) members, Independent Statisticians and 
Independent Programmers. (2) The identity of the treatments will be concealed by the use of 
investigational treatment that are all identical in packaging, labeling, schedule of administration, 
appearance, taste and odor. 
The randomization codes associated with PK samples will be disclosed to the Bioanalysts who 
will keep PK and ADA results confidential until data base 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, teriflunomide 
plasma level results) 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 study. 
 
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 Patient Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the Investigator (as described below). 
Once assigned to a patient, the Subject Number will not be reused. 
If an enrolled patient fails to be randomized or treated for any reason, the reason will be entered 
on the Screening Study Disposition CRF. If the patient is re-screened later on, a new Patient 
Number will be assigned; site will capture the re-screening information in the CRF book. Upon 
signing the informed consent form, the patient is assigned the next sequential number by the 
Investigator. 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. At each site, the first patient 
is assigned patient number 1, and subsequent patients/subjects are assigned consecutive 
numbers (e.g. the second patient is assigned patient number 2; the third patient is assigned 
patient number 3). The Investigator or his/her staff will contact the IRT and provide the 

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requested identifying information for the patient to register them into the IRT. Once assigned 
to a patient, the patient number will not be reused. The site must select the CRF book with a 
matching Subject Number from the electronic data capture (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 Screening epoch 
Study Disposition 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 
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 + teriflunomide-matching placebo containing 
capsules or teriflunomide containing capsules + ofatumumab-matching placebo injections) will 
be dispensed starting at the Randomization Visit (Day 1). Drug will then be dispensed at 
scheduled visits throughout the treatment period according to Table 6-1. 

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In the first 4 weeks after randomization, patients will receive 4 sc injections of ofatumumab or 
matching placebo (on Day 1, Day 7, Day 14 (loading dose regimen) and week 4 (study Month 
1)), followed by once monthly (every 4 weeks) sc injections (maintenance dose regimen). 
Injection volume is 0.4 ml. Patients will receive their first sc injection on site administered by 
the study staff (e.g. Investigator, Study Nurse/Study Coordinator) and will return to the site on 
Day 7, Day 14 and week 4 (study Month 1) for sc self-injections 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. Ability to self-administer must be demonstrated and 
documented before home-administration is permitted after Month 1. 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. 
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. 
Capsules (teriflunomide or matching placebo) must be taken orally once a day, preferably at the 
same time every day, with or without food and should be swallowed whole. The first capsule 
on Day 1 will be taken on site under the supervision of the study staff (e.g. Study Nurse/Study 
Coordinator). 
In order to assess tolerability of the initial dose of study medication (injectable + oral), 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. 
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). Injections may not be advanced by more than 3 days. The patient should be instructed 
to record any missed doses in the patient diary provided for the study 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. 
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 followed: 
• 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 
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• If one monthly injection in 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 local Sponsor Medical Advisor before re-starting dosing. Missed injection syringes 
should not be used and returned to the site at the next visit. 
If a patient misses any daily capsules, daily dosing should be resumed as soon as possible (i.e. 
patients should not compensate for a missed dose by increasing the frequency on subsequent 
doses). The patient should be instructed to record any missed doses in the patient diary provided 
for the study and to inform the study staff at the next visit or during the monthly telephone 
interview of any missed doses. The patient should be instructed to return any missed doses. If 
more than 3 consecutive months are missed, resumption of oral dosing should only be initiated 
if it is determined to be safe and appropriate in opinion of the Investigator. 
All kits of study medication assigned by the IRT will be databased in the IRT system. 
All dosages prescribed to the patient and all dose interruptions/changes during the study must 
be recorded on the Dosage Administration Record 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. 
The patients will record information concerning their home study drug administrations in a 
diary provided for 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 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, both sc and oral study 
medication must be interrupted. Re-start decision should be made on a case-by-case basis (refer 
also to Section 5.5.4). Should the Investigator decide, after informing the Sponsor, to re-initiate 
treatment with study drug, depending on the duration of the interruption, the first sc and oral 
dose at re-start may need to take place at the study site to ensure observation in a similar manner 
as on Day 1. 

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The reason for the interruption of treatment and date of interruption should be appropriately 
documented in the source documents as well as in the Dosage Administration Record eCRF. 
 
5.5.6 
Recommendations for the treatment of MS relapses 
The decision to treat MS relapses should be based on the Investigator’s judgement and or local 
clinical practices. If MS relapses require treatment, the standard treatment should consist of a 
short course of corticosteroids of 3-5 days and up to 1,000 mg methylprednisolone/day or 
equivalent on an impatient or outpatient basis. Standard of care will be followed during 
treatment. 
Taper with oral steroids is not permitted. Plasmaspheresis may be used if subject does not 
respond to standard treatment with corticosteroids. 
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration. 
Use of steroids for treatment of relapse must be recorded on the Prior or Concomitant 
medications 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 
concomitant medications / surgical and medical procedures CRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the Investigator should contact the Sponsor Medical Advisor before 
randomizing a patient or allowing a new medication to be started. 
If a patient is receiving dalfampridine (Ampyra®) concomitantly with study drug, the patient 
should remain as far as possible on stable dose throughout the Treatment epoch. 
Based on the double-blinded design, the Investigator will need to consider the drug interaction 
potential of teriflunomide when study drug is co-administered with certain classes of drugs 
(refer to list of drugs and potential interactions in Appendix 4). 
 
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. For the first injection only, the 
addition of premedication with steroids (methylprednisolone 100 mg iv or equivalent) is 
recommended. Premedication should be administered 30 to 60 minutes prior to study drug 
injection. 
Any administration of premedication must be recorded in the Prior and Concomitant 
medications CRF. 
Additional information in regards to premedication for home-administration use: 

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From Month 2 (5th injection) 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 initial 4 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 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 minutes before the injection). The Investigator will evaluate the need for premedication, 
or a change in the prescription, at each visit (scheduled and unscheduled) including at the 
monthly 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 unscheduled 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 
Medical Advisor. 

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Medication 
Additional action to be taken 
Any other immunomodulatory or disease- 
modifying MS treatment, including but not limited 
to fingolimod, interferon beta, glatiramer acetate, 
dimethyl fumarate 
Discontinue study treatment, increase vigilance 
regarding infections. 
Systemic corticosteroids (except for when given 
for MS relapse treatment as defined in Section 
5.5.6). 
Interrupt study treatment, increase vigilance 
regarding infections. 
Leflunomide 
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 
continue to be followed in the study Treatment epoch (Table 6-1) or in the Safety Follow-up 
(Table 6-2) (if the patient does not agree to be followed under Table 6-1). If the patient does 
not agree to stay in the study, the EOS Visit should be competed. 
 
5.6 
Study Completion and Discontinuation 
5.6.1 
Study completion and post-study treatment 
A patient has completed the core study when the patient has completed the End of Study (EOS) 
visit of the double-blind core study Treatment epoch. 

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The core study is completed for all patients when EOS is declared for the study as described in 
Section 3.1. 
Patients, who complete the core study (Table 6-1) on study drug, may be eligible for inclusion 
in the planned Extension study (under separate protocol). 
Patients who complete the core study on study drug and do not enter the Extension study will 
enter the Safety Follow-up period (Table 6-2) for continued follow up. 
Patients who prematurely discontinue study drug and either a) complete the core study 
Treatment epoch off study drug but have less than 9 months of follow up after study drug 
discontinuation, or b) do not agree to complete the Treatment epoch, will enter the Safety 
Follow-up period (Table 6-2) for continued follow up. 
The Safety Follow-up is complete when all patients who entered have been followed for the 
stipulated period of time 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. After stopping 
the treatment, the patient is encouraged to return for all regular visits as detailed in the schedule 
of assessments (Table 6-1). The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for an end of treatment visit (EOT). EOT visit assessments 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 

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• 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 
Study treatment discontinuation should be considered under the following circumstance: 
• For patients who meet the criterion for 6-month confirmed disability worsening on EDSS 
(see definition in Section 9.5.1.1.1) during the study, the benefits and risks of continuing 
study treatment must be reassessed by the Investigator. The Investigator will also discuss 
the further treatment with the patient, including any other MS treatment options that may 
be available to the patient. The outcome of the discussion with the patient must be 
documented in the patient's file. 
• In case the Investigator deems the benefit-risk of continuing study treatment to be 
unfavorable or if the patient does not wish to continue the study treatment, the patient will 
be discontinued from study treatment and continues to follow the schedule of assessments 
(Table 6-1 and/or Table 6-2 as applicable). The Investigator will be notified by the Sponsor 
when a patient meets the criterion for 6-month confirmed disability worsening. 
 
If the patient cannot attend any further study visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient, unless the 
patient has withdrawn informed consent (see Section 5.6.3). This telephone contact should 
preferably be done according to the study visit schedule. 
The Investigator must also contact the IRT to register the patient's discontinuation from study 
treatment. 
After discontinuation of study drug, the patient may undergo the teriflunomide accelerated 
elimination procedure (Section 7.8) if the Investigator deems this to be indicated. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9. 
Note: Patients who discontinue from study drug, but agree to follow in the assessment schedule 
should have an EOT evaluation at the time of discontinuation from study drug. Every patient 
will have an EOS assessment when discontinuing from the study. Follow-up in the Safety 
follow-up epoch (Table 6-2) may be required after EOS if patients have not had at least 9 months 
of follow up after last dose of study drug. 

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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, etc.). This is in line with the teriflunomide product information (at least 3.5 
months washout in absence of accelerated elimination) and the expected circulating B-cell 
repletion course after ofatumumab discontinuation (estimated around 5 months needed for 
80% repletion; see protocol 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. 
The patients should be encouraged to stay in the study and continue to follow the procedures 
and assessment schedule as specified in the protocol. 
 
5.6.3 
Withdrawal of informed consent 
 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation (EOS) at the time of the subject’s study withdrawal should be made as detailed in 
the schedule of assessments (Table 6-1). 

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Novartis/Sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
 
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form. 
 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
 
5.6.4 
Loss to follow-up 
For 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 scheduled End of Study 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 withdrawn 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 initial 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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• Administration of T25FW, 9HPT and SDMT (may be delegated to the Independent 
EDSS rater, a back-up physician, a Study Nurse/Study Coordinator or other 
accordingly experienced medical professionals) 
• 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 
scheduled or unscheduled visits 
• Obtaining an EDSS score based on detailed neurological examination at scheduled visits 
• Administration of T25FW, 9HPT and SDMT if delegated by the Investigator and if 
experienced with the administration of these assessments 
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 (highest 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 

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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. 
 
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 capsule and syringe 
counts) 
• Administration and supervision of initial injections and training/supervision of ability 
to self/home-administer as delegated by the Investigator 
• Administration of T25FW, 9HPT and SDMT as delegated by the Investigator and if 
experienced with the administration of these assessments 
• 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) 
• 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 
Neuroradiologist/Radiologist 
The local neuroradiologist/radiologist will be responsible for: 

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• Reviewing each MRI scan performed for the study patients and contacting the 
Investigator in case of unexpected 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. 
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 
scheduled visits, patients may have unscheduled visits due to a MS relapse, an acute illness of 
undetermined cause, for other reasons, or at the discretion of the Investigator. Data collected 
during unscheduled visits will be recorded in the unscheduled visit CRFs. 
 
Patients who stop taking study medication should be scheduled for the end of treatment (EOT) 
visit as soon as possible. The patients will be asked to remain in the study and continue 
completing the study visits and assessments (shaded in Table 6-1) until the end of the study 
(EOS). 
End of treatment (EOT) visit is not mandatory for all patients. It is only applicable to patients 
who prematurely discontinue double-blind study treatment and will continue to follow the 
assessment schedule of the Treatment epoch (Table 6-1). 
End of study (EOS) visit is mandatory for all patients. The EOS Visit is conducted at the end 
of the Treatment epoch (i.e. when the patient has completed up to 30 months, or when EOS is 
declared for all patients, or at time of premature withdrawal from study). At the time EOS is 
declared for all patients, all patients ongoing in the Treatment epoch should be contacted and 
their EOS Visit should be scheduled to occur as soon as possible. 
Patients who prematurely discontinued study drug but do not agree to continue to be followed 
in the study Treatment epoch per Table 6-1, but agree to continued safety follow up, will have 
their EOS Visit and then enter the Safety Follow-up (FU) according to schedule in Table 6-2 . 
Patients who complete the Treatment epoch on study drug but do not enter the Extension study, 
will have their EOS Visit and then enter the Safety Follow-up (FU) schedule in Table 6-2. 
During the study, patients will be asked to complete a diary from Month 1 onwards 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 every month starting at Month 2 (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 

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warranting an unscheduled visit, injection reactions, and, as applicable, results of home 
pregnancy testing, compliance with contraception requirements and with any scheduled local 
LFT lab testing. 
Some protocol procedures may be done via an outpatient setting (e.g. at patient's home) with 
the support of study staff or a healthcare professional registered with the study site for the study, 
if this is permissible per the local regulatory authority. 

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Table 6-1 
Assessment schedule 
 
Epoch 
Screening 
Treatment 
Visit 
SCR 
(D-45 
to 
D-8) 
BL 
(D -7 
to D1 
(pre- 
treat 
ment) 
D11 
D7 
D14 
M1 
M3 
M6 
M9 
M12/24 
M15/21/279 
M18 
EOT9 
EOS9 
Visit No. 
1 
2 
101 
102 
103 
104 
105 
106 
107 
108/112 
109/111/113 
110 
198 
199 
Visit Window (days) 
n.a. 
n.a. 
n.a. 
±1 
±1 
±3 
±14 
±14 
±14 
±14 
±14 
±14 
n.a. 
n.a. 
Informed consent 
X 
Demography, Height 
X 
Medical history 
X 
MS History/Treatments 
X 
Incl/Excl 
X18 
X 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone interview 
monthly between scheduled visits11 
Physical Exam21 
X2a 
X2a 
X 
X 
X 
X 
X 
Patient diary review 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception status16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, Weight 
X 
X 
X20 
X20 
X20 
X20 
X 
X 
X 
X 
X 
X 
X 
X 
Routine lab samples19, 
including urine 
X3 
X23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample for B-cells 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Teriflunomide plasma 
levels 
X15 
Additional LFT testing 
X10 
X10 
Sample for Total IgG, 
IgM 
X2a 
X2a 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Epoch 
Screening 
Treatment 
Visit 
SCR 
(D-45 
to 
D-8) 
BL 
(D -7 
to D1 
(pre- 
treat 
ment) 
D11 
D7 
D14 
M1 
M3 
M6 
M9 
M12/24 
M15/21/279 
M18 
EOT9 
EOS9 
Visit No. 
1 
2 
101 
102 
103 
104 
105 
106 
107 
108/112 
109/111/113 
110 
198 
199 
Pregnancy Test4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X2a 
X2a 
X 
X 
MRI 
X 
X 
X8 
X8 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Con Meds14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample for population 
PK13 
X 
X 
X 
X 
X 
X 
X 
Sample for ADA13 
X 
X 
X 
X 
X 
X 
Samples for 
biomarkers22 
X2a 
X2a 
X 
X 
X 
X 
eCSSRS 
X6 
X6 
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 
EDSS 
X 
X2b 
X2b 
X 
X 
X 
X 
X 
X 
X 
X 
T25FW 
X2a 
X2a 
X 
X 
X 
X 
X 
X 
X 
X 
9HPT 
X2a 
X2a 
X 
X 
X 
X 
X 
SDMT (oral) 
X2a 
X2a 
X 
X 
X 
X 
X 
MSIS-297 
X2a 
X2a 
X 
X 
X 
X 
X 
PRO completion form 
X2a 
X2a 
X 
X 
X 
X 
X 
AEP 
X12 
End of Treatment 
X 
X17 

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Epoch 
Screening 
Treatment 
Visit 
SCR 
(D-45 
to 
D-8) 
BL 
(D -7 
to D1 
(pre- 
treat 
ment) 
D11 
D7 
D14 
M1 
M3 
M6 
M9 
M12/24 
M15/21/279 
M18 
EOT9 
EOS9 
Visit No. 
1 
2 
101 
102 
103 
104 
105 
106 
107 
108/112 
109/111/113 
110 
198 
199 
Study Phase 
Completion 
X 
ADA= Anti-drug-antibody ; AEs= Averse events; AEP= Accelerated elimination procedure; BL=baseline; D= day; 
 eCSSRS=electronic 
Columbia-Suicide Severity Rating Scale; EDSS=Expanded Disability Status scale; 
; EOS=End of Study: EOT=End of 
Treatment; Excl.=exclusion; HPT=9-Hole Peg Test; Ig= immunoglobulin; Incl.=inclusion; IRT= Interactive response technology; LFT=liver function test; M=month; 
MRI=magnetic resonance imaging ;MS=multiple sclerosis; MSIS= Multiple Sclerosis Impact Scale; n.a=not applicable; PK=pharmacokinetic; PRO= Patient Reported 
Outcome; SDMT= Symbol Digit Modalities Test; T25FW=Timed 25-foot Walk; 
 
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 
2. 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). 
3. Serology testing to check patient eligibility conducted at Screening only 
4. Female patients only: Serum pregnancy tests will be conducted at Screening, EOT and EOS Visits. Urine pregnancy test on Day 1 should be conducted 
prior to dosing on Day 1. Urine pregnancy tests will be conducted at all other scheduled visits as indicated in Table 6-1. In addition monthly urine 
pregnancy tests 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 
 
6. The eCSSRS must be assessed once before randomization, either at the Screening (recommended) or the Baseline visit. 
 
8. MRI scan at the End of Treatment (EOT) and/or End of Study (EOS) is needed if there was no MRI scan in the last 3 months 
9. For patients who reach Month 27 visit, the next (and last) 3-monthy scheduled visit is the EOS Visit; EOS assessments will be done for all patients; 
End of treatment (EOT) assessments are done only for patients who prematurely discontinue study drug (at the time of study drug discontinuation) 
and who continue to stay in the Treatment epoch 

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10. Additional monthly LFT testing will be required at Month 2, 4 and 5 i.e. between scheduled lab visits in first 6 months in all patients. More frequent LFT 
testing may be required in patients in countries/regions where the local teriflunomide prescribing information stipulates more frequent LFT testing. E.g. 
in the EU LFT testing should be performed every 2 weeks in the first 6 months and every 8 weeks thereafter (i.e., once between 3-monthly scheduled 
visits). A local lab for the additional LFT testing may be used (Section 6.5.4.2) 
11. Telephone interview by site staff every month starting at Month 2. The interview should take place around time of the monthly sc self/home injection to 
query about any new or worsening symptoms warranting an unscheduled visit, injection reactions, results of home pregnancy testing, compliance with 
contraception requirements and compliance with local LFT lab testing as applicable 
12. AEP: applicable only for patients who have permanently discontinued study drug. Patients may undergo an accelerated elimination process at 
Investigator’s discretion (Section 7.8) 
13. PK and ADA visits: at the Month 1 visit, the PK and ADA samples should be drawn before the patient takes their Month 1 injection. For later PK and 
ADA visits, if the monthly injection is scheduled for the same day as the visit, the patient should take the injection after the PK/ADA sample has been 
drawn (patient should be instructed not to take the injection before coming to the site for the visit) 
14. Including corticosteroids used to treat MS relapse; any newly started MS treatment as applicable (for patients who have discontinued study medications) 
15. Only for patients who had EOT ≥ 9 months earlier 
16. Patients contraception status must be reviewed and documented to ensure method of contraception continues to be appropriate per protocol 
requirement for highly effective contraception 
17. Only for patients for whom the EOT page has not already been completed (i.e. have not had an EOT visit) 
18. Syphilis and Tuberculosis testing must be done as part of eligibility check (Exclusion criterion #11) unless completed in the last 6 months prior to 
screening with documented negative results. If sites don’t have the possibility to test tuberculosis locally, Quantiferon®-TB Gold test may be requested 
to be done by the Central laboratory to assess patient's eligibility. 
19. More frequent hematology testing (excluding B-cells and IgG and IgM for blinding purpose) may be performed by local laboratory if this is required by 
the local regulatory authority 
20.  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, Day 7, Day 14 and Month 1 
21.  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 
22. Samples for biomarkers will be collected as described in Section 6.6.5 
23. Labs must be drawn to allow adequate time for results to be obtained before randomization to ensure patient's eligibility 
Note: Patients who have prematurely discontinued study drug (EOT) and continue to be followed under the Table 6-1 schedule after study drug 
discontinuation, will only do the assessment shaded in grey 

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1. 
Time measured from the EOS Visit. M=month. 
2. 
If scheduled 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 epoch, the End of Safety-FU 
assessments should be done at time of withdrawal. 
3. 
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. 
4. 
AEP. Patients may undergo an accelerated elimination process at Investigator’s discretion as 
described in Section 7.8 
5. 
As needed for patients requiring prolonged B-cell/teriflunomide plasma level monitoring (Section 
3.1) 
6. 
As needed (teriflunomide level assessed only when patient has had a total of at least 9 months of 
follow up and then 3-monthly as needed after study drug discontinuation as described in Section 
3.1) 
*including steroids for MS relapse and newly started DMT as applicable 
 
 
Table 6-2 
Assessment schedule for Safety Follow-up epoch 
 
Visit Month1 
(relative to EOS) 
+M3 
+M6 
+M9 
Every 3 months5 
End of Safety-FU2 
Visit Number 
201 
202 
203 
204/20X 
299 
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 
test3 
X 
X 
X 
X 
X 
Contraception status 
X 
X 
X 
X 
X 
Routine lab samples 
X 
X 
X 
X 
X 
Sample for Total IgG, 
IgM 
X 
X 
X 
X 
X 
Sample for B-cells 
X 
X 
X 
X 
X 
Sample for 
teriflunomide plasma 
level6 
X 
X 
X 
X 
X 
MS Relapse 
X 
X 
X 
X 
X 
EDSS 
X 
X 
X 
X 
X 
AEP 
X4 
AEs= 
Averse 
events; 
AEP=Accelerated 
elimination 
procedure; 
DMT=disease 
modifying 
therapy; 
eCSSRS=electronic Columbia-Suicide Severity Rating Scale; EOS=End of Study: FU=Follow-up 
 
6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the Screening disposition CRF for the Screening epoch completed. 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. 

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6.2 
Patient demographics/other baseline characteristics 
Patient demographic data and baseline characteristics to be collected on the Demography CRF 
will include date of birth, 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 medical history CRF 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. 
 
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 Dosage 
Administration Record CRFs. 
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
syringe and capsule 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) 
• Neurofilament light chain (NfL) 
• Timed 25-foot walk (T25FW) 
• Nine Hole Peg Test (9HPT) 
• Symbol Digit Modalities Test (SDMT) 
• Multiple Sclerosis Impact Scale 29 items (MSIS-29) 
An overview of each of these assessments is provided in the sections below. Details of the 
administration of each of these assessments will be provided in the site manuals. 

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6.4.1 
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 unscheduled 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 scheduled 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 unscheduled visit is to be scheduled as soon as possible, 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 MS relapse 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 

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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 
EDSS=Expanded Disability Status Scale; FS=Functional Score 
(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 scheduled 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. 
Definitions for disability worsening and disability improvement based on the EDSS and 
confirmation of worsening (3 and 6-month confirmed worsening) and improvement (6-month 
confirmed improvement) are provided in Section 9.5.1.1. 
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 
neuroradiologist/radiologist. The Investigator will review the MRI performed during the 
screening epoch to assess patient's eligibility. After Randomization, the Investigator will be 

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contacted in case of unexpected findings (e.g. not consistent with MS) detected on the MRI 
scan. 
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 30 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 30 days upon termination of steroid therapy. 
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 MRI manual. 
Sequences include T1 hypointense images (with and without gadolinium-based contrast agent), 
T2-weighted images, and brain volume will be performed. 
The gadolinium based 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. 
 
6.4.4 
Neurofilament light chain (NfL) 
Blood samples for analysis of NfL levels will be drawn according to the schedule in Table 6-1 
(refer to Samples for Biomarkers). NfL is a component of the neuronal cytoskeleton and is 
released into the cerebrospinal fluid and into subsequently blood following neuro-axonal 
damage. It has been identified as biomarker to indicate treatment response and to predict 
disability worsening in patients with MS (Kuhle et al. 2016; Disanto et al. 2017; Piehl et al. 
2017; Barro et al. 2018; Siller et al. 2018). 
The details describing the collection, handling, storage, and shipment requirements of samples 
will be provided in the laboratory manuals. 

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6.4.5 
Timed 25-Foot Walk (T25FW) 
The Timed 25-Foot Walk (T25FW) will be assessed according to the schedule in Table 6-1. 
The T25FW is an objective quantitative test of neurological function. It is widely used in clinical 
MS trials. It is an ambulation measurement assessing speed of walking: a timed (in seconds) 
walk of 25 feet (7.62 meters). The T25FW will be administered (2 trials) according to 
standardized instructions by the Investigator or by another qualified health care professional 
experienced with the administration of the T25FW (refer to Section 5.6.6). 
 
6.4.6 
Nine Hole Peg Test (9HPT) 
The Nine Hole Peg Test (9HPT) will be assessed according to the schedule in Table 6-1. The 
9HPT is an objective quantitative test of neurological function. It is widely used in clinical MS 
trials to assess upper extremity function. It is measured to assess both right and left arm scores, 
the metric is the time, in seconds, required to insert and remove 9 pegs. The 9HPT will be 
administered (2 trials per hand) according to standardized instructions by the Investigator or by 
another qualified health care professional experienced with the administration of the 9-HPT 
(refer to Section 5.6.6). 
 
6.4.7 
Symbol Digit Modalities Test (SDMT) 
The SDMT will be assessed according to the schedule in Table 6-1. The SDMT is a sensitive 
and specific test to assess processing speed which is typically affected in cognitive impaired 
MS patients (Benedict et al. 2017). During the administration of the SDMT only the examiner 
and the patient should be in the testing room. The SDMT will be administered according to 
standardized instructions by the Investigator or another qualified health care professional 
experienced with the administration of the SDMT (refer to Section 5.6.6). Patients are presented 
with a test instrument at the top of which is a row of nine numbers paired with unique symbols. 
Below this part of the test instrument is an array of symbols paired with empty spaces, the 
patient's task is to verbally match the number for each symbol as rapidly as possible. The SDMT 
incorporates a number of practice items at the start of each test to familiarize the patient (these 
results are not included in the final score). The test takes approximately 5 minutes to administer. 
Alternate versions of the SDMT will be used in an alternating pattern to minimize learning 
effects. The test scoring is calculated based on the number of correct answers in 90 seconds. 
 
6.4.8 
Multiple Sclerosis Impact Scale (MSIS-29) 
The Multiple Sclerosis Impact Scale (MSIS-29) version 2 (Hobart and Cano, 2009) will be used 
to assess health-related quality of life and will be evaluated according to the schedule in Table 
6-1. MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical 
and psychological. Responses are captured on a 4-point scale ranging from “not at all” (1) to 
“extremely” (4), where higher scores reflect greater impact on day to day life. 
It is a clinically useful and scientifically sound measure of the impact of MS from the patient's 
perspective suitable for clinical trials and epidemiological studies (Hobart et al. 2001). It is 
considered a reliable, valid and responsive PRO measure that complements other indicators of 
disease severity used to improve our understanding of the impact of MS. 

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The questions in the scale ask the patient for their views about the impact of MS on their day- 
to-day life during the past 2 weeks. The MSIS-29 takes approximately 5 minutes to complete, 
and has been translated into many languages. 
 
6.4.9 
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. 
The T25FW, 9HPT, SDMT and MSIS-29 assess ambulation (walking speed), upper extremity 
function, cognitive function (processing speed) and physical and psychological impact of 
disease, respectively. They are widely used in MS clinical trials and assess relevant additional 
aspects of the MS pathology. 
 
6.5 
Safety 
Safety assessments will include: 
• Adverse events 
• Physical examination (including skin) 
• Vital signs 
• Laboratory evaluations 
• Pregnancy testing (females of childbearing potential) 
• ECG 
• Columbia Suicide Severity Rating Scale (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 a Data Monitoring 
Committee (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 medical history/current medical conditions 

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CRF. Significant findings seen after signing the informed consent and being randomized meet 
the definition of an AE and must be recorded on the adverse events CRF. 
 
6.5.2 
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 first 4 injections (Days 1, 7, 14 and Month 1), vital signs should be obtained 30-60 
minutes before sc injection and again approximately 60 minutes 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 minutes, 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 pulse will also be measured 3 times. The repeat sitting measurements of 
blood pressure and pulse will be made at 1-2 minute intervals. If an automated blood pressure 
device is used, it will need to have been calibrated according to the manufacturer’s guidelines. 
In case the cuff sizes available are not large enough for the patient's arm circumference, a 
manual sphygmomanometer with an appropriately sized cuff may be used. 
 
6.5.3 
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 (exception: additional 
frequent LFT panels as described in Section 6.5.4.2 below). 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 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 double-blind Treatment epoch and Safety FU epoch until the 
treatment code for the study has been broken. 
 
6.5.4.1 
Hematology 
Blood samples will be collected at the scheduled 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) and CD19+ B-cell counts. 

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For study blinding purposes, the B-cell counts will not be provided to the Investigators and 
Sponsor study team. B-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 scheduled 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). 
To assist for patients with travel restrictions, blood samples for liver panel assessments as 
described in Table 6-1 (LFT-only Visits) may be drawn by a local lab and the results report sent 
to the Investigator within 48 hours of obtaining the results. The LFT battery will include ALT, 
AST, AP, GGT, BIL (total and conjugated). If any significant findings are observed on these 
reports, a confirmatory blood sample should be drawn by the site and sent to the central 
laboratory. If no significant findings are observed then the results of any local laboratory values 
(including reference ranges) should be included in the local liver function test results CRF to 
document the values. Blood samples for these visits may also be obtained by other methods as 
appropriate in a particular country or region and processed through the central laboratory (e.g., 
flying nurse, local phlebotomist etc.). 
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 scheduled visits indicated in Table 6-1 and the dipstick parameters 
assessed will include: blood, glucose, specific gravity and protein. In case of an abnormal 
dipstick test, a urine sample will be sent to the central laboratory for testing including additional 
parameters such as microscopy and white blood cell and red blood cell sediments. 
 
6.5.4.4 
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 11, Section 
4.2). If sites don’t have the possibility to test tuberculosis locally, Quantiferon®-TB Gold test 
may be requested to be done by the Central laboratory to assess patient's eligibility. 
A positive result for any of the following serological markers for hepatitis A, B, C, and E 
indicating acute or chronic infection is an exclusion criterion: 
• anti-hepatitis A virus IgM 

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• hepatitis B surface antigen and anti-hepatitis B core antigen IgM/IgG, HBV-DNA 
PCR: if negative, patient can be included 
• 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 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 and in a CRF comment) 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 
• teriflunomide plasma levels 
For study blinding purpose, the results of these tests will not be included as part of the 
laboratory reports provided to the Investigators or Sponsor study team during the study. 
Teriflunomide levels 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). 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 (Sections 6.6.2 to 6.6.5) 
 
6.5.5 
Electrocardiogram (ECG) 
An ECG will be performed in this study as part of the eligibility assessment and at end of 
treatment/end of study. Additional unscheduled ECGs may be performed at Investigator’s 
discretion if clinically indicated. 
Single 12 lead ECGs are collected. The ECG should be recorded (after 10 minutes rest in the 
supine position to ensure a stable reading) according to the local site practice. Clinically 
significant ECG findings at Baseline must be discussed with the Sponsor before administration 
of study treatment. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions. 
The original ECGs on non-heat-sensitive paper / and a certified copy on non-heat sensitive 
paper), appropriately signed, must be collected and archived at the study site. Each ECG tracing 
must be labeled with study number, subject initials, subject number, date and time, and filed in 
the study site source documents. 

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Findings and clinically significant abnormalities must be recorded on the relevant section of the 
Medical history/Current medical conditions and AE CRF page as appropriate. 
 
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, EOT and EOS Visits. Urinary pregnancy tests will be conducted for all women 
who are of child bearing potential at all other scheduled 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 scheduled 3-monthly clinic visits. 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 (Investigator’s Brochure) and the teriflunomide (Aubagio®) prescribing information. 
The use of an instrument such as the C-SSRS to detect suicidal ideation or behavior is currently 
mandated in studies of CNS active drugs. 
 
6.6 
Other assessments 
MS is associated with a variable combination of symptoms, including sensory loss, imbalance, 
mobility loss, bladder and bowel dysfunction, cognitive dysfunction, spasticity, pain, and sexual 
dysfunction. Measurement of these wide-ranging effects of MS on the lives of patients is 
beyond the scope of the clinician assessed endpoints commonly used to evaluate therapeutic 
effectiveness in MS studies. Patient-reported outcome measures 
 are 
included in this study to provide an empirical assessment from the patient's perspective of the 
benefits of treatment that cannot be gained from MRI, EDSS, or relapse measurement. 
Samples 
for 
PK, 
immunogenicity 
potential 
(ADA), 
 
 
 will also be assessed and evaluated as applicable 
in relation to efficacy, safety data and population under study. 
 
 

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6.6.2 
Pharmacokinetics 
PK trough values at steady state for ofatumumab will be 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 Month 1 visit. For any later PK visits, 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 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. 
 
6.6.3 
Immunogenicity 
ADA will be assessed to evaluate the immunogenicity potential of ofatumumab. Sampling time 
points are provided in Table 6-1. Samples for ADA assessment should be taken prior to dosing 
at the Month 1 visit. For any later ADA visits, 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. 

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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 
• 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). 

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Adverse events must be recorded in the Adverse Events CRF 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) 
CTCAE Grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (Study Completion, Death/Survival). 
There may be cases where a CTCAE with a grade of 4 (life-threatening) may not necessarily 
be an SAE (e.g. certain laboratory abnormalities in the absence of meeting other seriousness 
criteria) 
• its relationship to the study treatment 
o Yes 
o No 
• 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: 
• no action taken (e.g. further observation only) 
• study treatment dosage increased/reduced 
• study treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• patient hospitalized/patient's hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions if any 
required to treat it, and the outcome. The action taken to treat the adverse event should be 
recorded on the Adverse Event CRF. 
Information about common side effects already known about the investigational drug 
(ofatumumab) can be found in the Investigator Brochure (IB). For information about risks and 

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common side effects related to the comparator (teriflunomide), please refer to the local product 
label. 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 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. 

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Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse. 
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 End of Study (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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
(DS&E) Department associate may urgently require further information from the Investigator 
for health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all Investigators involved in any study with the same study treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 

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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 MS relapse CRF 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, which will require close observation, follow-up monitoring and 
completion of the standard base liver CRF pages 
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 Liver CRF pages. 

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Repeat laboratory tests must be entered on the appropriate unscheduled local laboratory CRF 
page. 
• 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 CRF pages, including the liver event 
overview CRF pages. 
 
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 ≥ 24h) 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. Renal-related events should be recorded on the Renal event CRF pages. 
 
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. 

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Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) CRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE. 
 
 
 
Treatment error 
type 
Document in Dose 
Administration 
(DAR) CRF (Yes/No) 
Document in AE 
CRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes, 
Yes, even if not 
associated with a SAE 
 
 
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 Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
 
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 unscheduled visits. 
A validated version of the CSSRS will be used to capture self-reported C-SSRS data via an 
interactive voice response telephone system (eCSSRS). The eCSSRS uses a detailed branched 
logic algorithm to perform the C-SSRS 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 

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treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the Investigator in consultation with the mental health professional to whom the patient is 
referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a patient 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the Suicidal Behavior section) should be reported as AEs and 
assigned the appropriate severity grade. 
All SAEs relating to suicidal behavior must be reviewed by the DMC. 
 
7.8 
Accelerated elimination procedure related to active comparator 
teriflunomide 
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination 
procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, 
although, because of individual variations in drug clearance, it may take as long as 2 years. The 
teriflunomide label includes guidance on accelerated elimination of teriflunomide in patients in 
whom a rapid elimination is desirable. 
In order to protect the blind and integrity of the present study (double-blind/double-dummy 
study of ofatumumab vs teriflunomide), a decision to initiate the teriflunomide-specific 
accelerated elimination procedure must be taken without knowledge of the patient's treatment 
assignment. 
It is recommended that patients who permanently discontinue study drug undergo the 
accelerated elimination procedure (during study Treatment epoch or during Safety Follow-up) 
if this is in the patient's best interest as determined by the Investigator or in order to facilitate 
further treatment or management decisions. This procedure (described below) must be carried 
out under the supervision of the Investigator. 
For patients who develop an SAE (e.g. serious infection, liver event) leading to study drug 
discontinuation per protocol criteria or per the Investigators clinical judgment, an accelerated 
elimination may similarly be considered. 
As described in the EU and US labels for teriflunomide (Aubagio®), elimination of 
teriflunomide can be accelerated by either of the following procedures: 
• Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g 
3 times a day is not well tolerated, cholestyramine 4 g 3 times a day can be used. 
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days. 
• If either elimination procedure is poorly tolerated, treatment days do not need to be 
consecutive unless there is a need to lower teriflunomide plasma concentration rapidly. 
The procedure should be documented on the Accelerated Elimination Procedure CRF. Any AEs 
reported during the procedure must be recorded on the AE CRF. 

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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 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 Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated Investigator site staff will not be 
given access to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated Investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the Investigator will receive copies of the patient data for archiving at the 
investigational site. 
 
8.3 
Database management and quality control 
Sponsor staff (or Contract Research Organization (CRO) working on behalf of Sponsor) review 
the data entered into the CRFs by investigational staff for completeness and accuracy and 

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instruct the site personnel to make any required corrections or additions. Queries are sent to the 
investigational site using an electronic data query. Designated Investigator site staff is required 
to respond to the query and confirm or correct the data. If the electronic query system is not 
used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign 
the faxed copy and fax it back to Sponsor staff that will make the correction to the database. 
The signed copy of the Data Query Form is kept at the Investigator site. 
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 database 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 Data Monitoring Committee (DMC) will be in place to oversee the study. 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, advise the Sponsor of a need for protocol modification/amendment 

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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 analysis will be conducted on all subject data at the time of EOS (i.e. including partial data 
from the Safety Follow-up epoch). 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 and 
selected key secondary variables. 
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. 
 
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-dummy design all patient will receive capsules 
(active or placebo) and injections (active or placebo) to maintain the blind. For the calculation 
of exposure to study medication only the active drug will be considered. Intermediate treatment 
interruptions will be subtracted from drug exposure. 

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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, as well as by race. 
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 
The primary endpoint is the annualized relapse rate (ARR), which is defined as the number 
confirmed MS relapses in a year. In the primary analysis, the ARR is estimated based on the 
FAS which follows the intent-to-treat principle in a negative binomial model by using 
individual relapse count as the response variable with time in study as an offset variable. 
Two variables are required for the calculation of the ARR (excluding covariates): 
• The cumulative number of confirmed MS relapses by patient is the response variable in 
the negative binomial model. The confirmation based on EDSS will be derived as 
defined in section 6.4.1. 
• The time-in-study by patient will be used as an offset variable to adjust for the various 
length patients have been observed and at-risk of a confirmed MS relapse in the study. 
 
9.4.1 
Statistical model, hypothesis, and method of analysis 
The null hypothesis is that there is no difference in the ARR between ofatumumab 20 mg sc 
once monthly and teriflunomide 14 mg po once daily in reducing the frequency of confirmed 
MS relapses as measured by ARR. The alternative hypothesis is that there is a difference 
between the 2 treatment groups. 
• 
Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
the observed ARR on ofatumumab 20 mg sc is lower than on teriflunomide 14 mg po 
and if the null hypothesis can be rejected at the two-sided significance level of 0.05. 
The null hypothesis will be tested based on the FAS, using a negative binomial regression model 
with log-link, treatment and region as factors, number of relapses in previous year, baseline 
EDSS, baseline number of Gd-enhancing lesions and the patient's age at baseline 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. 

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The definition of Region is intended to correspond to that used for the stratification of the 
randomization. However, the definition of Region may be modified and defined in the statistical 
analysis plan if that is indicated based on statistical criteria (e.g. non-convergence of models). 
In addition, the statistical analysis plan may define a process how the primary model can be 
simplified (e.g. by excluding covariates) in case of non-convergence. 
 
9.4.1.1 
Multiplicity adjustment 
The planned submission consists of 2 studies of identical design (COMB157G2302 and 
COMB157G2301), each with multiple endpoints. In order to control the type-I error rate (“false 
positive rate”) at the level of the individual studies, and at the level of the submission as a whole, 
the testing strategy illustrated in Figure 9-1 below will be implemented. 
 
Figure 9-1 
Testing procedure and type-I-error control 
Testing procedure and type-I-error control in the planned ofatumumab submission which 
consists of studies COMB157G2302 and COMB157G2301 (both with identical design). 
Hypotheses can only be tested in sequential order as indicated by the arrows. The number 

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associated with each hypothesis (α, or α-α2) indicates the significance level at which that 
hypothesis can be tested. If the null-hypothesis for the primary objective (ARR) can be rejected 
within a study, MRI- and NfL-related hypotheses will be tested in sequential order within that 
study as long as all proceeding hypotheses can successfully be rejected. Disability-related 
hypotheses will only be tested in the combined data of the 2 studies, if the primary null- 
hypotheses can be rejected in both studies first. At the study-level, the type-I error rate (one- 
sided) is controlled at ≤ 0.025. In the submission, the type-I error rate is controlled at ≤ 0.000625 
(=0.0252) for the primary hypothesis and at ≤ 0.025 when considering all endpoints. 
The primary hypothesis (ARR) and all MRI- and NfL-related key-secondary hypotheses will 
be tested in hierarchical order within study (Figure 9-1). The testing procedure starts with the 
statistical test of the primary null-hypothesis (ARR) and continues to lower ranking hypotheses 
as long as the proceeding null hypotheses can all be rejected in favor of ofatumumab in a two- 
sided statistical test with a p-value ≤ 0.05. This testing procedure controls the type-I error rate 
to ≤ 0.05 within study. 
If both studies independently reject the primary null-hypothesis (ARR) in favor of ofatumumab 
in a two-sided statistical test with p-value ≤ 0.05, disability-endpoints will be addressed in the 
combined data of COMB157G2302 and COMB157G2301, at the submission level. Disability 
endpoints will be tested in hierarchical order as indicated by arrows in Figure 9-1. The testing 
procedure continues to the next lower ranking disability-hypothesis as long as the previous null- 
hypothesis can be rejected in favor of ofatumumab in a two-sided statistical test with a p-value 
≤ 0.04875 (=2*[0.025-0.0252]). 
Provided the primary hypothesis can be rejected in both studies, disability-related endpoints can 
be tested regardless of the outcome of MRI- and NfL-related endpoints, and vice-versa. 
Under the global null-hypothesis (i.e. no difference between ofatumumab and teriflunomide), 
the testing procedure controls the type-I error rate (one-sided) at the study-level to ≤ 0.025, and 
at the submission level to ≤ 0.000625 (=0.0252). Considering all possible configurations of true 
and false positive null hypotheses, the type-I error control at the level of the submission is ≤ 
0.000625 for the primary objective, and ≤ 0.025 for all hypotheses. 
The type-I error is controlled by the testing procedure. All confidence intervals and p-values in 
the study report will be presented without adjustments. 
 
9.4.2 
Handling of missing values/censoring/discontinuations 
The primary NB (negative binomial) model with an offset for the time in study adjusts for 
missing information (drop-out) under the assumption of non-informative drop-out, information 
is missing at random, and constant relapse rate over time. According to the protocol, subjects 
who discontinue study treatment should remain in the study and follow the assessment schedule. 
The primary analysis will use all available data collected in the double-blind treatment epoch, 
irrespective if collected after the permanent discontinuation of study treatment. In addition, a 
sensitivity analysis will be conducted to allow for the possibility that relapse rates may be non- 
constant over time (i.e. higher during the onset-of action of both drugs for a period of 8 weeks). 

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9.4.3 
Sensitivity analyses 
The primary analysis will be repeated based on all reported MS relapses (rather than on only 
the confirmed ones). 
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. Relapses which occurred 
after permanent discontinuation of study medication will be excluded and natural log (time on 
study drug in years) rather than natural log (time on study in years) will be used as the offset 
variable in the negative binomial model. 
To estimate relapse rates and the treatment effect between ofatumumab 20 mg sc once monthly 
and teriflunomide 14 mg po once daily during the initial “onset of action” period of 8 weeks (≤ 
56 days=8*7 days), and relapse rates and the treatment effect thereafter (> 56 days; long-term 
efficacy) a sensitivity analysis will be conducted. This analysis will be implemented as a 
piecewise negative binomial model assuming different event rates and ARR-ratios before and 
after week 8, but constant dispersion. Per patient, 2 cumulative count-records (confirmed 
relapses ≤ 56 days, and > 56), and 2 corresponding time records (time-in-study ≤ 56 days, and > 
56) will be calculated. The negative binomial model will be defined with the number of 
confirmed relapses as the response variable, with log-link and time-in-study as the offset 
variable. The model will use the same factors and covariates as the primary model. 
For each time period (≤ 56 days, and > 56 days), the adjusted ARR (i.e., model-based estimate 
adjusted for covariates) and the corresponding 95% confidence intervals will be provided by 
treatment, together an ARR ratio between ofatumumab 20 mg sc once monthly and 
teriflunomide 14 mg po once daily (also expressed as percentage reduction relative to control 
group) with corresponding 95% confidence intervals and p-values. 
Additionally, the time-to-first relapse will be analyzed in a Cox proportional hazards model. In 
comparison with the primary analysis in a negative binomial model, the Cox proportional 
hazards model does not assume constant relapse rates (but rather it assumes proportional 
hazards). The Cox proportional hazards model will be specified with treatment, region, number 
of relapses in previous year, baseline EDSS, baseline number of T1 Gd-enhancing lesions and 
the patient's age at baseline as covariates. 
Additional sensitivity analyses may be defined in the analysis plan prior to database lock. 
 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
All efficacy analysis will be done based on the FAS, unless explicitly stated otherwise 
 
9.5.1.1 
Key-secondary efficacy endpoints 
 
9.5.1.1.1 Disability worsening (3-month or 6-month confirmed) 
A 3-month confirmed disability worsening (3mCDW) is defined as an increase from baseline 
in EDSS sustained for at least 3 months (Table 9-1). Analogously, a 6-month confirmed 
disability worsening (6mCDW) is defined as an increase from baseline in EDSS sustained for 

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at least 6 months. This means that after a scheduled or unscheduled visit at which the patient 
fulfills the disability worsening criterion, all EDSS assessments (scheduled or unscheduled) 
need to also fulfill the worsening criteria until the worsening (“the event”) can be confirmed at 
the first scheduled visit that occurs 3-months (or 6 months) after the onset of the worsening, or 
later. 
Censoring occurs in all patients who did not experience a 3mCDW (or 6mCDW) event in the 
study (censoring also occurs in patients who had a “tentative” disability worsening that could 
not be confirmed due to an early discontinuation or any another reason). The censoring time is 
defined as the time from the first dose to the last available EDSS assessment. 
 
Table 9-1 
Criterion for disability worsening based on change in EDSS score 
 
Total EDSS at baseline* 
“Disability worsening” criterion 
0 
≥ +1.5 
1 to 5 
≥ +1 
≥5.5 
≥ +0.5 
EDSS=Expanded Disability Status Scale 
A 3-month confirmed disability worsening (3mCDW) can have an onset at any scheduled or unscheduled visit if 
the disability worsening criterion is met. A disability worsening can only be confirmed at a scheduled visit if, 
over a period of 3 months (≥ 90 days=3*30) time interval, all assessments meet the worsening criterion. 
A 6-month confirmed disability worsening (6-mCDW) can have an onset at any scheduled or unscheduled visit 
if the disability worsening criterion is met. A disability worsening event can only be confirmed at a scheduled 
visit if, over a period of 6 months (≥ 166 days=6*30-14) time interval, all assessments meet the worsening 
criterion. 
If a patients dies due to MS (EDSS=10 at any time), it will be considered a confirmed disability worsening 
regardless of the baseline EDSS or the change in EDSS. 
* Baseline EDSS is defined as the last EDSS assessment prior to the first dose of study medication (protocol 
inclusion criterion is EDSS 0-5.5) 
 
Hypothesis and Analysis of disability worsening (3mCDW, 6mCDW) 
The hypothesis and the analysis methods will be identical for 3mCDW and 6mCDW. For 
brevity the hypothesis and analysis methods are only specified in full for 3mCDW. 
The null hypothesis is that there is no difference in the time to 3mCDW between ofatumumab 
20 mg sc and teriflunomide 14 mg po 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
there is a reduction in risk (estimated hazard ratio from Cox-model< 1) in patients 
treated with ofatumumab compared with teriflunomide and the observed p-value for the 
between-treatment comparison is less than the two-sided significance level of 
≤ 0.04875 (=2*[0.025-0.0252]). The multiplicity adjustment explained in Section 
9.4.1.1 applies. 
Confirmatory analysis for disability-related endpoints: The confirmatory analysis of time- 
to-3mCDW will be done in a meta-analysis based on the combined FAS populations from 
COMB157G2302 and COMB157G2301. 

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The null hypothesis will be tested using a stratified Cox proportional hazards model with study 
as stratum, treatment, and region as factors and baseline EDSS as a continuous covariate. The 
model will contain a treatment-by-study interaction. For confirmatory purposes the hazard ratio 
between ofatumumab and teriflunomide will be estimated with 95% confidence interval and p- 
value from the combined data from both studies in this meta-analysis. In addition, between- 
study heterogeneity will be tested as the type-3 test of the treatment-by-study interaction; the 
corresponding p-value will be provided. For information only, the hazard ratio for each study 
will be estimated by study from the same model with corresponding 95% confidence intervals 
and p-values. 
Supportive analysis: Kaplan-Meier curves (and/or cumulative incidence plots) will be 
provided by treatment for the combined study populations as well as by-study to present the 
time-dependent cumulative probability of subjects reaching 3mCDW. 
By-treatment Kaplan-Meier (KM) estimates (and/or 1-KM estimates) will be calculated for the 
combined study data at Month 6, and in 6 monthly intervals from there until less than 100 
patients per arm are at-risk, with 95% confidence intervals. Similar estimates will be provided 
by study. 
To estimate the hazard ratio between ofatumumab 20 mg sc once monthly and teriflunomide 14 
mg po once daily during the initial “onset of action” period of 8 weeks (≤ 56 days=8*7 days), 
and thereafter (> 56 days; long-term efficacy) a sensitivity analysis will be conducted. The Cox- 
proportional hazards model will be specified as above, but in addition a time-dependent 
indicator variable (0 if record corresponds to the first 8 weeks, 1 otherwise) and an indicator- 
by-treatment interaction will be included in the model. From this model separate hazard ratios 
with 95% confidence intervals and p-values will be estimated for the first 8 weeks of treatment 
and the time period thereafter. 
A sensitivity analysis to the confirmatory Cox proportional hazard ratio will consider all 
patients who discontinue from the study due to “lack of efficacy” as patients with a confirmed 
event. The event time for these patients will be calculated based on the date of the 
discontinuation from study relative to the first dose date. Additional analyses or imputation 
schemes may be described in the statistical analysis plan prior to database lock. 
 
9.5.1.1.2 Disability improvement (6-month confirmed) 
A 6-month confirmed disability improvement (6mCDI) is defined as a decrease from baseline 
EDSS sustained for at least 6 months (Table 9-2). Censoring occurs in patients who did not 
experience a 6mCDI event in the study. The censoring time is defined as the time from the first 
dose to the last EDSS assessment. 
 
Table 9-2 
Criterion for disability improvement based on change in EDSS score 
 
Total EDSS at baseline* 
“Disability improvement” criterion 
0 to 1.5 
No improvement possible 
≥2 to 6 
≤ -1 
≥6.5 to 9.5 
≤ -0.5 
EDSS=Expanded Disability Status Scale; 6mCDI=6-month Confirmed Disability Improvement. 

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Hypothesis and Analysis of disability improvement 
The null hypothesis is that there is no difference in the time to 6mCDI between ofatumumab 20 
mg sc and teriflunomide 14 mg po 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
there is an improved chance of a 6mCDI (estimated hazard ratio from Cox-model > 1) 
in patients treated with ofatumumab compared with teriflunomide and the observed p- 
value for the between-treatment comparison is less than the two-sided significance level 
of ≤ 0.04875 (=2*[0.025-0.0252]). The multiplicity adjustment explained in Section 
9.4.1.1 applies. 
Confirmatory analysis for disability-related endpoints: The confirmatory analysis of time- 
to-6mCDI will be done in a meta-analysis based on the combined FAS populations from 
COMB157G2302 and COMB157G2301. 
The null hypothesis will be tested using a stratified Cox proportional hazards model with study 
as stratum, treatment, and region as factors and baseline EDSS as a continuous covariate. The 
model will contain a treatment-by-study interaction. For confirmatory purposes the hazard ratio 
between ofatumumab and teriflunomide will be estimated with 95% confidence interval and p- 
value from the combined data from both studies in this meta-analysis. In addition, between- 
study heterogeneity will be tested as the type-3 test of the treatment-by-study interaction; the 
corresponding p-value will be provided. For information only, the hazard ratio for each study 
will be estimated by study from the same model with corresponding 95% confidence intervals 
and p-values. 
Kaplan-Meier curves (and/or cumulative incidence plots) and by-treatment Kaplan-Meier (KM) 
estimates (and/or 1-KM estimates) will be calculated for the combined study data at Month 6, 
and in 6 monthly intervals from there until less than 100 patients per arm are at-risk, with 95% 
confidence intervals. Similar estimates will be provided by study. 
A similar analysis (Cox proportional hazards model, Kaplan-Meier curves) will be performed 
for 6mCDI sustained until the End of Study. 
 
9.5.1.1.3 Number of Gd-enhancing lesions per scan 
The null hypothesis is that there is no difference in the number of Gd-enhancing lesions per 
scan between ofatumumab 20 mg sc and teriflunomide 14 mg po 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
there are fewer Gd-enhancing lesions per scan (estimated rate ratio from a negative 
binomial model< 1) in patients treated with ofatumumab compared with teriflunomide 
and the observed p-value for the between-treatment comparison is less than the two- 
6mCDI: A disability improvement can have an onset at any scheduled or unscheduled visit if the disability 
improvement criterion is met. A disability improvement can only be “confirmed” at a scheduled visit if, over a 
period of 6 months (≥166 days=6*30-14) time interval, all assessments meet the improvement criterion. A 
6mCDI sustained until the End of Study is defined as a 6mCDI after which all EDSS assessments meet the 
disability improvement criterion through End of Study. 
*protocol inclusion criterion is EDSS 0-5.5 

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sided significance level of 0.05. The multiplicity adjustment explained in Section 9.4.1.1 
applies. 
Confirmatory analysis of the number of Gd-enhancing lesions per scan: The confirmatory 
analysis of the number of Gd-enhancing lesions per MRI-scan will be done based on the FAS 
using a negative binomial regression model with log-link. The total number of Gd-enhancing 
lesions (cumulative count of Gd-enhancing lesions across all the MRI-scans per patient) will be 
used as the response variable, and the 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 related to the 
flexible follow-up time in this study. The model will include treatment and region (factors), and 
age, and number of Gd-enhancing lesions at baseline as continuous covariates. 
The number of Gd-enhancing lesions per scan 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 of Gd- 
enhancing lesion per scan will be computed as the rate ratio minus one (1) and expressed as a 
percentage. 
 
9.5.1.1.4 Annualized rate of new or enlarging T2 lesions 
The null hypothesis is that there is no difference in the number of new or enlarging T2 lesions 
between ofatumumab 20 mg sc and teriflunomide 14 mg po 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
there are fewer new or enlarging T2 lesions (estimated rate ratio from a negative 
binomial model< 1) in patients treated with ofatumumab compared with teriflunomide 
and the observed p-value for the between-treatment comparison is less than the two- 
sided significance level of 0.05. The multiplicity adjustment explained in Section 9.4.1.1 
applies. 
Confirmatory analysis of the Annualized rate of new or enlarging T2 lesions: The 
confirmatory analysis of the annualized rate 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 and region 
(factors), and age, 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. 
The number of new or enlarging T2 lesions are a cumulative measure of disease activity. Since 
the number of new or enlarging T2 lesion is assessed relative to the MRI scan collected at 
Screening (i.e. well before the start of study medication intake), it is expected that this analysis 
underestimates the true treatment effect. Therefore, a supportive analysis will be performed 

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based on the new or enlarging T2 lesions between the Month 12 scan and the End of Study scan 
(this analysis is described in Section 9.5.1.2). 
 
9.5.1.1.5 Neurofilament light chain 
The null hypothesis is that there is no difference in NfL between ofatumumab and 20 mg sc 
teriflunomide 14 mg po by month 3. 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
NfL levels are already lower at month 3 in patients treated with ofatumumab compared 
with teriflunomide and the observed p-value for the between-treatment comparison is 
less than the two-sided significance level of 0.05. The multiplicity adjustment explained 
in Section 9.4.1.1 applies. 
 
Confirmatory analysis of NfL: The NfL concentration (geometric mean concentration) will 
be estimated by treatment and time point with 95% confidence intervals using a repeated 
measures model on the basis of all evaluable log-transformed NfL values. The treatment 
effect will be estimated in terms of a geometric mean ratio with 95% confidence interval per 
time point. The statistical hypothesis test will be based on the treatment contrast and p-value 
obtained at month 3. An unstructured covariance matrix will be used. The model will include 
treatment, region and the time point as factors, and age, number of Gd-enhancing lesions at 
baseline, baseline T2 lesion volume and the log-transformed NfL baseline concentration as 
continuous adjustments. The treatment effect of ofatumumab versus teriflunomide will be 
visualized in a line plot with confidence intervals. 
 
 
9.5.1.1.6 Brain volume loss 
The null hypothesis is that there is no difference in brain volume change between ofatumumab 
20 mg sc and teriflunomide 14 mg po 
• Superiority of ofatumumab 20 mg sc over teriflunomide 14 mg po will be concluded if 
there is less brain volume loss (positive difference in slope from the random coefficient 
model) in patients treated with ofatumumab compared with teriflunomide and the 
observed p-value for the between-treatment comparison is less than the two-sided 
significance level of 0.05. The multiplicity adjustment explained in Section 9.4.1.1 
applies. 
Confirmatory analysis of brain volume loss: The percentage change from baseline in brain 
volume will be estimated on the basis of all scans up to the last available MRI scan that 
evaluated percentage brain volume change relative to baseline. A random coefficients model 
will be used as main analysis for this endpoint in order to adjust for the various length of follow- 
up time in this study (brain volume change was approximately linear over time and 
approximately normally distributed in 3 independent studies of the fingolimod Phase 3 
program). The random coefficients model will include treatment, region as fixed effects 
(factors), and time, number of Gd-enhancing lesions at baseline, baseline T2 volume, and 
normalized brain volume at baseline as continuous covariates. Time is defined as the time from 

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first dose date to the date of MRI scan in year and will be calculated by ((MRI scan date – date 
of last scan prior to the first dose of study medication) +1)/365.25. Time as a continuous 
covariate allows for estimation of different slopes and intercepts among treatment groups. The 
model will also contain random terms to account for deviations about the population slope and 
intercept. The statistical test will address the question whether there is a difference in the slope 
of brain volume change by treatment group. The annual rate of percent change from baseline in 
brain volume is approximated as the population slope within the treatment group. Since the 
random coefficients model allows for the estimation of different slopes and intercepts among 
the treatment groups, differences between treatments at any time can be summarized using this 
model. Model estimates of percentage brain volume change at Month 12 and 24 will be provided 
by treatment with corresponding 95% confidence interval. Treatment differences will be 
estimated at the same time points with confidence interval and a p-value for the test of a 
difference in slope. 
Additionally, percentage brain volume change (PBVC) and the annualized rate of brain atrophy 
(ARBA) will be summarized by visit. ARBA describes the “averaged annual percentage change” 
in brain volume. It is designed to adjust for differences in the time spent between 2 scans that 
are compared by standardizing the percentage change in brain volume to 1 year. The logic of 
interest rates applies. ARBA = [(PBVC/100+1)(365.25/days)-1]*100, where “PBVC” represents the 
percentage brain volume change obtained between 2 scans and “days” stands for the number of 
days between the 2 scans that are being compared. Cross-sectional comparisons at each visit 
will be made using ANCOVA models with ARBA as the response variable, treatment and 
region as factors, number of Gd-enhancing lesions at baseline, baseline T2 volume, and 
normalized brain volume at baseline as continuous covariate. Line plots of percentage brain 
volume change over time by treatment will be provided. 
In addition, the percentage change from baseline in brain volume will be estimated on the basis 
of all available MRI scans that evaluated percentage brain volume change relative to baseline 
in a repeated measures model. A repeated measure model with the percent change in brain 
volume from baseline up to end of study as the dependent variables with unstructured 
covariance matrix will be used. The model will include treatment and scanning time point as 
factors, region, number of Gd-enhancing lesions at baseline, baseline T2 volume and 
normalized brain volume at baseline as covariates. For the purpose of this model, visit windows 
will be used to map all available MRI assessments to Month 12 or 24. The comparison of 
treatment differences in mean at Month 12, 24 will be made using this model. 
Percentage brain volume change is cumulative measure of disease activity. Since the percentage 
brain volume change is assessed relative to the MRI scan collected at Screening (i.e. well before 
the start of study medication intake), it is expected that these analyses tend to underestimate the 
true treatment difference between study drugs. 
 
9.5.1.2 
Other secondary efficacy variables 
• The analysis of “Time of first relapse” and “Annualized relapse rates > 8 weeks after the 
onset of treatment” is described in (Section 9.4.3) as sensitivity analysis to the primary 
analysis. 

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• The analysis of the “Risk of a 3mCDW > 8 weeks after the onset of treatment” and “Risk 
of a 6mCDW > 8 weeks after the onset of treatment” is described in (Section 9.5.1.1.1) as 
a supportive analysis to the key-secondary 3mCDW and the 6mCDW, respectively. 
• Time to 6mCCD will be analyzed in the combined FAS from studies COMB157G2301 and 
COMB157G2302, in a Cox proportional hazards model with study as stratum, treatment 
and region as factors, and baseline SDMT as continuous covariates. 
• Time to 6mCDW or a 6mCCD, whichever is reached first, will be analyzed in the combined 
FAS from studies COMB157G2301 and COMB157G2302, in a Cox proportional hazards 
model with study as stratum, treatment and region as factors, and baseline EDSS and 
baseline SDMT as continuous covariates. 
• SDMT scores and change from baseline will be summarized by visit and by treatment. The 
change from baseline will be analyzed and compared between treatments in a repeated 
measures mixed effects model. 
• Time to 6-month confirmed worsening of at least 20% in the timed 25-foot walk test 
(T25FW) will be analyzed in the combined FAS from studies COMB157G2302 and 
COMB157G2301, in a Cox proportional hazards model with study as stratum, treatment, 
and region as factors and the baseline T25FW-result as a continuous covariate. The baseline 
25TWT-result is defined as the last assessment prior to the first dose of study medication; 
the 20% worsening is defined relative to this reference value. 
• Time to 6-month confirmed worsening of at least 20% in the 9-hole peg test (9HPT) will be 
analyzed in the combined FAS from studies COMB157G2302 and COMB157G2301, in a 
Cox proportional hazards model with study as stratum, treatment, and region as factors and 
baseline 9HPT-result as a continuous covariate. The baseline 9HPT-result is defined as the 
last assessment prior to the first dose of study medication; the 20% worsening is defined 
relative to this reference value. 
• Change in T2 lesion volume on MRI will be summarized by visit. Cross-sectional analyzes 
will be done by using a rank ANCOVA with treatment and region (factors), and baseline 
T2 volume as a continuous covariate. 
• Number of new or enlarging T2 lesions on MRI between Month 12 and EOS will be 
analyzed in a negative binomial regression model, and presented similarly to that used for 
the annualized rate of new or enlarging T2 lesions. The number of new T2 lesions on the 
EOS scan relative to the Month 12 scan will be used as the response variable, the natural 
log of the time (in years) of the EOS MRI-assessment from the Month 12 scan will serve as 
the offset variable to adjust for the various lengths of follow-up times between patients in 
this study. 
• Proportion of patients free of clinical and MRI disease activity (No evidence of disease 
activity; NEDA-4) will be analyzed cross-sectionally at year 1 and year 2 in a logistic 
regression model with treatment and region as factor, and age, baseline EDSS, and number 
of Gd-lesions at baseline as covariates. NEDA-4 is defined as no 3mCDW, no confirmed 
MS relapse, no new or enlarging T2 lesions on any MRI scan compared to baseline, and 
brain volume change > -0.4%/year on all MRI scans (brain volume as measured by ARBA, 
see Section 9.5.1.1.5). The main analysis will consider only those patients who were 

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followed-up to the assessment time point in the analysis (e.g. only patients with ≥ 12 months 
of follow-up in the 12-month assessment of disease freedom, etc.). Intermediate missing 
values (e.g. due to missing MRI assessments) will be considered not free of disease activity. 
A sensitivity analysis will be conducted considering all patients who discontinued from the 
study prior to the assessment timepoint, or have missing MRI assessments prior to the 
assessment timepoint, as not free of disease activity. 
• MSIS-29 physical impact score (items 1-20), psychological impact score (items 21-29) and 
the corresponding changes from baseline will be summarized by visit. The change from 
baseline at specific post-baseline visits will be compared between treatment groups using a 
repeated measures mixed effects analysis. 
If ofatumumab significantly reduces NfL as compared with teriflunomide, the following 
additional analyses will be performed: In the subgroup of newly diagnosed (within 3 years prior 
to the screening visit), treatment-naïve (no prior MS DMT) patients, the hypotheses will be 
tested that patients with a high (>median) NfL concentration at baseline will experience more 
new or enlarging T2 lesions, a higher ARR and tend to have a worse disease course on EDSS 
during the study compared with patients with low (≤median) NfL concentration at baseline: 
• The T2 lesion rate will be estimated using a negative binomial model similar to the one 
specified in section 9.5.1.1.4. In addition, the model will include a treatment-by-NfL 
baseline category interaction. The T2 lesion rate will be estimated by treatment within 
baseline NfL category. The treatment effect will be expressed as a lesion rate ratio with 95% 
confidence interval, for low and high baseline NfL category, respectively. The statistical 
hypothesis test with regards to the prognostic value of NfL for new lesion formation will be 
based on the high vs low baseline NfL category contrast in the teriflunomide group. 
• The ARR will be estimated using a negative binomial model similar to the primary model 
specified in section 9.4. In addition, the model will include a treatment-by-NfL baseline 
category interaction. The ARR will be estimated by treatment within baseline NfL category. 
The treatment effect will be expressed as an ARR-ratio with 95% confidence interval, for 
low and high baseline NfL category, respectively. The statistical hypothesis test with 
regards to the prognostic value of NfL for on-study relapses will be based on the high vs 
low baseline NfL category contrast in the teriflunomide group. 
• The disease course based on EDSS will be analyzed as time to 3mCDW, 6mCDW or 6mCDI 
using Kaplan-Meier curves and a Cox proportional hazard model based on the combined 
data from COMB157G2301 and COMB157G2302. The model will include study as stratum, 
treatment, region and baseline NfL category as factors and baseline EDSS as a continuous 
covariate. The treatment effect will be expressed as hazard ratio with 95% confidence 
interval, for low and high baseline NfL category, respectively. The statistical hypothesis test 
of the prognostic value of NfL for disability changes will be based on the main effect of 
NfL category (due to the expected low number of events in this subgroup). It is 
acknowledged that the study will not be powered to show an effect on disability outcomes 
in subgroups. 
• The benefit/risk profile of ofatumumab in the subgroup of newly diagnosed, treatment-naïve 
patients with high NfL will be compared to the overall trial results based on the above 
described efficacy analyses. The safety profile in the subgroup of newly diagnosed, 

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treatment-naïve patients with high NfL will be compared to the overall trial population by 
summarizing adverse events by treatment side-by-side for the subgroup and the overall trial. 
 
9.5.2 
Safety variables 
Safety analyses will be conducted using the safety (SAF) dataset. Patients will be grouped by 
the actual treatment received. Unless explicitly otherwise stated, only data up to and including 
the safety cutoff of 100 days after permanent study drug discontinuation will be included in the 
analysis and data beyond this time point for a given patient will be excluded from the safety 
analysis. The safety cutoff of 100 days (5 x 20 days) takes the long half-life of the comparator- 
drug into account. 
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 100 days after permanent study drug discontinuation. 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. 
Given the flexible follow-up of the study, TEAEs will also be summarized by reporting 
exposure-adjusted incidence rates (assuming a Poisson-process for adverse events). This will 
be done for all TEAEs, and for only serious TEAEs, per primary system organ class and 
preferred term. The analysis will be performed in a time-at-risk as defined in Section 9.3. 
Similar tables can be produced for selected risks (e.g. SMQs) on an as-needed basis. 
 
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. 

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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 > 3xULN & TBL > 2xULN & ALP ≤ 2xULN or a reported Hy’s Law 
case (refer also to Appendix 1). 
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 (C-SSRS) data will be mapped to Columbia 
Classification Algorithm for Suicide assessment (C-CASA) as per 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. 
 
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 AE CRF. 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 epoch 
Safety data collected during the Safety Follow-up epoch 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 epoch 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 patients who discontinued from study drug but 
followed the assessment schedule of the Treatment epoch, change variables will be defined 
relative to the end of treatment visit (EOT), for all other patients change is defined relative to 
the End of Study visit (EOS). Since post-treatment safety follow-up in the Safety Follow-up 
epoch may continue for up to 9 months (or longer if criteria for loner follow up are met) after 

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completion of the Treatment epoch study, the study report for the core study (Screening and 
Treatment epoch) will be completed based on the completed core study i.e. based on all patients 
who have completed the Treatment epoch, and the partial data from the Safety Follow-up epoch 
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 epoch have completed this epoch. 
 
 

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9.5.5 
PK/PD modelling 
PK concentration data summarized by visit together with by-patient listings will be provided in 
the study report. 
 
 
 
 
 
9.5.6 
Immunogenicity assessment 
Samples will be analyzed for of the presence of human anti-drug antibodies (ADA). The data 
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 
Interim analyses 
9.7.1 
Unblinding interim analysis 
No unblinding interim efficacy analysis is planned for this study. 
Regular safety interim analyses will be performed for the independent DMC by an independent 
team of statisticians and programmers who are not otherwise involved in the conduct of the 

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study. The data review will be done by the DMC. The DMC will be independent of Novartis 
and the team involved in the study conduct. 
 
9.7.2 
Blinded data reviews 
The purpose of the blinded data reviews is to ensure an adequate sample size and follow-up 
time to address the scientific objectives of the study without un-necessarily exposing patients 
by adapting design features such as sample size and follow-up duration as indicated by the 
accumulating data. 
Blinded data reviews will be conducted in this study for: 
(1) Blinded sample size re-assessment: relapse- (and disability) -related assumptions will 
be re-assessed based on a review of blinded data to adjust sample size if indicated by 
the accumulating data. This review will occur prior to the completion of enrolment. 
(2) Declaration of End of Study: the ‘Information’ (Section 9.7.2.3) collected by the study 
on relapse rates and disability worsening events will be monitored. End of Study will 
be declared only once when sufficient information has been collected to address the 
study’s primary and key-secondary objectives. 
 
9.7.2.1 
Blinded sample size re-estimation 
A blinded data review will be done prior to the completion of recruitment based on the initially 
assumed sample size. 
The purpose of the blinded sample size re-estimation is to re-adjust the sample size depending 
on the activity of the population. If indicated by the data, the sample size of the study can be 
increased from initially 900 randomized patients to a maximum of 1250 randomized patients. 
• The ARR (λ) and the between-patients variability (κ, dispersion parameter) in the 
overall patient population (i.e., without revealing the treatment code) will be estimated 
from the blinded data by fitting a negative binomial regression model with log-link to 
the data, with intercept and age at baseline as the only continuous covariate. Given the 
1:1 randomization ratio and the assumed relapse rates by treatment (Section 9.8), the 
blinded ARR is expected at λblinded=0.224 and the dispersion parameter at 0.82. Sample 
size can be increased if the study acquires ‘Information’ for ARR at a lower rate than 
initially anticipated. 
• A secondary objective of the blinded review is to review the rate of accumulation of 
disability. The time to the first 3mCDW and the time to the first 6mCDW will be 
reviewed based on Kaplan-Meier curves for the overall patient population without 
revealing the treatment code. These curves will be compared to those expected under 
the assumption of an exponential distribution of event times and the hazard ratios 
provided in Section 9.8. Sample size can be increased if rates are substantially lower 
than anticipated (Table 9-3). 
 
Table 9-3 
Anticipated cumulative event probabilities on teriflunomide 
 
Time-at-risk 
3mCDW 
6mCDW 
6 months 
4.0% 
3.1% 

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1 year 
7.8% 
6.2% 
2 years 
15% 
12% 
3mCDW=3-month Confirmed Disability Worsening; 6mCDW=6-month Confirmed Disability Worsening 
The blinded hazard rates, due to the 1:1 randomization ratio, are assumed as the mean of those assumed for 
ofatumumab and teriflunomide (Section 9.8). 
 
9.7.2.2 
Review of blinded data to declare End of Study 
The accumulating blinded data will be analyzed and End of Study (EOS) will be declared for 
both studies simultaneously when all of the following conditions are met. 
• Each study (COMB157G2302 and COMB157G2301) have individually collected ≥ 40.3 
units of Information for the primary ARR endpoint ("Information" is defined and explained 
in Section 9.7.2.3). At this time-point both studies will provide 90% power for the detection 
of a 40% relative treatment effect on ARR in the primary statistical test at a one-sided alpha 
level of 0.025. 
• In the combined data of the 2 studies (COMB157G2302 and COMB157G2301) ≥ 178 
3mCDW events have been observed. At this time-point the combined studies have collected 
sufficient information to provide 90% power for the detection of 38.6% (hazard ratio=0.614) 
relative reduction in risk of a 3mCDW in a log-rank test at a one-sided alpha-level of 
0.025-0.0252. 
• In the combined data of COMB157G2302 and COMB157G2301 studies ≥ 133 6mCDW 
events have been observed. At this time-point the combined studies have collected sufficient 
information to provide 80% power for the detection of 38.6% (hazard ratio=0.614) relative 
reduction in risk of a 6mCDW in a log-rank test at a one-sided alpha-level of 0.025-0.0252. 
9.7.2.3 
Statistical ‘Information’ for annualized relapse rates 
The primary endpoint of the study is the annualized relapse rate (ARR). We assume that the 
number of MS relapses follows a negative binomial distribution, which is a common 
assumption in MS. The primary hypothesis will be tested in a negative binomial regression 
model based on the estimation of the ARR-ratio between treatments (the ‘estimate’). The power 
of the statistical test of the primary hypothesis (ARR) does not depend on the sample size or the 
treatment duration per se; instead, it depends on the Information collected. 
- Information is defined as the reciprocal of the estimate’s variance, as in a group 
sequential design. 
In the blinded review we will estimate the amount of information (I) generated by the study 
based on a blinded analysis-based review of the relapse activity (λ) of the recruited patient 
population and the observed dispersion parameter (κ) in the accumulated study data. A 
mathematical derivation of the ‘information’ for a negative binomial distribution is provided in 
Appendix 5. 
Equation 1: Information I = [1/n {1/(λ1T) + 1/ (λ2T) + 2 κ}]-1 
where n = number of patients per arm, T the common follow-up time (i.e., the study duration), 
λ1 = ARR for ofatumumab and λ2 = ARR for teriflunomide, and κ = the dispersion parameter 
(κ > 0) which describes the between-patient variability. 

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i
tota
 
For this study, ≥ 90% power is required for the primary endpoint. The sample size assumptions 
for this study are initially T=1.5 years, λ1=0.168, λ2=0.28, and κ=0.82 which would provide 
I=40.3 units of statistical information which corresponds to 90% power for the statistical test of 
the ARR-ratio between ofatumumab and teriflunomide at the one-sided 2.5% alpha level. 
Trial designs with another sample size, or follow-up time, but the same amount of statistical 
Information, also provide an equivalent power for the detection of 40% reduction in ARR at the 
one sided 2.5% alpha level. Therefore the first EOS-criterion is met when I ≥ 40.3 units of 
Information have been collected. 
 
Estimating ‘Information’ for ARR in a blinded review 
As in a blinded sample size review (Friede and Schmidli 2010), fitting a negative binomial 
model to the aggregate data (i.e., the relapse data of all patients combined) provides an estimate 
of the overall ARR λ and the dispersion parameter κ. For an assumed rate ratio (clinically 
meaningful difference) of θ = λ1/λ2, estimates can be obtained of the ARRs in the two groups, 
λ1 = 2* λ* θ/(1+ θ) for ofatumumab, and λ2=2* λ/(1+ θ) for teriflunomide. 
Since the treatment allocation of the patients (i = 1,…ni) is unknown in this blinded review but 
randomization was done in a 1:1 ratio, we make the assumption that the follow-up times in the 
two groups (j = 1,2 with 1 = ofatumumab and 2 = teriflunomide) are the same, i.e., that T.1 = T.2 
= Ttotal/2 , where Ttotal is the total of the follow-up times at the review time. It is further assumed 
that the sum of the squared follow-up times is the same in both groups, i.e., that Σi Ti12 = Σi Ti22 
=  Σj  Σi  T  2/2 = T2 
/2. The evaluation of the information in Appendix 5 based on blinded 
information is then: 
Equation 2: Information I = [2/ (λ1 Ttotal ) + 2/( λ2 Ttotal ) + 4 κ T2total/Ttotal2]-1 
where λ1, λ2, and κ are the re-estimated values at the blinded review. 
The information will then be estimated based on Equation 2. The first EoS-criterion is met when 
≥40.3 units of information have been collected. The study is then powered at ≥90% for the 
detection of a 40% reduction in ARR at the one-sided alpha level of 0.025. 
 
9.8 
Summary of sample size calculation 
Sample size requirements for this study are primarily driven by the disability-related key 
endpoints. A total of approximately 900 patients will be randomized to study drug in a 1:1 
ratio (450 per treatment arm). A second study of identical design with the same sample size 
will be conducted in parallel. Both studies are independently powered to address the primary 
endpoint (ARR) and all key-secondary MRI endpoints. 
Key-secondary outcomes related to disability will be analyzed in the combined populations of 
both trials, provided the primary null-hypothesis can be rejected in both studies. Other 
secondary efficacy endpoints, as well as safety will be analyzed by study. 
The total sample size of this study can be increased from 900 patients per study to a maximum 
of 1250 patients per study based on a blinded sample size re-estimation if either the blinded 
relapse rate or the event rate of 3mCDW is substantially lower than expected. 
All sample size calculations were done in EAST 6, version 6.3, Cytel Inc. 

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Primary endpoint: 
• ARR: The total sample size of 900 randomized patients for this trial is sufficient to 
achieve 90% power for the demonstration of superiority of ofatumumab over 
teriflunomide based on the primary endpoint (ARR). 
 
Key-secondary endpoints: 
The power mentioned for the key-secondary endpoints is conditional on the successful rejection 
of the null hypothesis for the primary endpoint (ARR), and the successful rejection of all key- 
secondary endpoints that are to be tested at a higher hierarchical level. Multiplicity adjustments 
and the testing procedure are defined in Section 9.4.1.1. 
• 3mCDW: A total sample size of 1800 patients across 2 studies of identical design is 
required and sufficient to provide ≥ 90% power and for the demonstration of superiority 
based on the 3mCDW. 
• 6mCDW and 6mCDI: A total sample size of 1800 patients across 2 studies of identical 
design is sufficient to provide ≥ 80% power for an analysis of 6mCDW and 6mCDI. 
• MRI endpoints: A total sample size of 900 randomized patients for this trial is 
sufficient to provide ≥ 80% power for all MRI endpoints which are part of the testing 
procedure (Number of Gd-T1 lesions per scan, annualized rate of new or newly 
enlarging T2 lesions, annualized rate of BVL). 
• NfL: A total sample size of 900 randomized patients for this trial is sufficient to provide 
a ≥ 90% power for an analysis of the NfL concentration in serum. 
 
9.8.1 
Sample size for the primary endpoint (ARR) 
A negative binomial distribution of relapses is assumed for the primary analysis; this is a 
common assumption in MS. The demonstration of a relative reduction of the ARR in patients 
treated with ofatumumab (λofa=0.168) compared with those treated with teriflunomide 
(λter=0.28) by 40% (λofa / λter =0.6) with a power of 90% at a one-sided alpha-level of 0.025 in 
a study with 1.5 years follow-up and under the assumption of a dispersion parameter κ=0.82 
requires a sample size of 322 completers per treatment arm (644 completers for the study). 
Allowing for 20% uninformative dropouts equally distributed across treatment arms, a total 
sample size of 805 randomized patients is required for the study to demonstrate superiority of 
ofatumumab based on ARR. A sample size of 900 patients per trial (driven by the 3mCDW 
endpoint), under otherwise the same assumptions as before, would provide approximately 95% 
power for the demonstration of superiority of ofatumumab over teriflunomide at a one-sided 
alpha level of 0.000625 (=0.0252) using the pooled data from 2 studies of identical design. The 
formula proposed by Keene et al. 2007 was used for the sample size calculation for the primary 
endpoint. 
 
9.8.1.1 
Justification of assumptions for primary endpoint 
In the pivotal studies, patients treated with teriflunomide 14 mg (the control treatment for this 
study) had an ARR=0.32 (Confavreux et al. 2014) and ARR=0.37 (O’Conner et al. 2011). In 
an additional Phase 3 study of teriflunomide versus Interferon beta-1a, patients treated with 

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teriflunomide 14 mg had an ARR=0.26 which was not significantly different from that observed 
in patients treated with Interferon beta-1a (ARR=0.22). For the purpose of this study an ARR= 
0.28 is assumed for patients treated with teriflunomide 14 mg. 
Ocrelizumab is an anti-CD20 monoclonal antibody with a similar mode of action as 
ofatumumab but is administered as infusion. In the ocrelizumab Phase 3 trials an ARR of 0.156 
(OPERA I) and 0.155 (OPERA II) (Hauser et al. 2015) were observed for patients treated with 
Ocrelizumab 600 mg, the corresponding interferon beta-1a controls had an ARR of 0.292 
(OPERA I) and 0.290 (OPERA II); the corresponding relative reductions in ARR were 46% 
(OPERA I) and 47% (OPERA II). In the ocrelizumab Phase 2 trial, patients treated with 
ocrelizumab 600 mg had an ARR=0.13, those treated with 1000 mg an ARR=0.17 (Kappos et 
al. 2011). Compared with the Interferon beta-1a control in the same trial (ARR=0.36), 
ocrelizumab 600 mg and 2000 mg reduced the ARR by 64% or 53%, respectively. Compared 
to placebo controls from the same trial (ARR=0.64), ocrelizumab 600 mg and 2000 mg reduced 
the ARR by 80% or 73%, respectively. 
Ofatumumab 60 mg every 12 weeks administered subcutaneously showed in the Phase 2 trial 
(unpublished data) approximately 34% relative reduction in relapse rate versus placebo over 
the first 24 weeks, but 60% in the second 12 weeks (Week 12 to 24). The relative reduction of 
Gd-enhancing lesions of approximately 90% observed in patients treated with ofatumumab 
relative to those treated with placebo was similar to that observed with ocrelizumab and placebo, 
suggesting similarly strong anti-inflammatory potency of ofatumumab and ocrelizumab. Based 
on the combined findings, a relative reduction in the ARR of 40% is assumed between patients 
treated with ofatumumab compared to those treated with teriflunomide, which corresponds to 
an absolute ARR=0.168 for patients treated with ofatumumab, similar to that observed with 
ocrelizumab in Phase 2 and 3. 
The dispersion parameter of k=0.82 is assumed based on the values observed for relapse data   
in the fingolimod Phase 3 program. In the pivotal teriflunomide Phase 3 program 290/1086=27% 
of the patients discontinued over 104 weeks (O’Connor et al. 2011) in one trial, and 
348/1196=30% over 130 weeks in another one (Confavreux et al. 2014). In OPERA I and 
OPERA II discontinuation rates were lower. For the purpose of the primary analysis we 
conservatively assume that 20% of the randomized patients will not contribute to the primary 
analysis at all. This is a conservative assumption because patients who discontinue prematurely 
from the study can contribute with partial data (relapse counts, exposure) to the primary analysis. 
In this information-based design patients will be followed until the end of the trial (see EoS 
criteria), rather than to be observed for a fixed time period. Based on the 3mCDW endpoint it   
is anticipated that the majority of patients will be exposed for 1 to 2 years. For ease of 
calculation a fixed follow-up time of 1.5 years is assumed for the primary endpoint. Of note,   
the power for the primary endpoint will depend on the actual follow-up. 
 
9.8.2 
Sample size for 3-month confirmed disability worsening (3mCDW) 
For planning purposes only an exponential distribution of event times and proportional hazard 
is assumed. The cumulative event probability over 2 years is assumed as 15% vs 9.5% in 
patients treated with teriflunomide vs ofatumumab, respectively. The assumed cumulative event 
rates translate to a relative risk reduction of 38.6% (hazard ratio=0.614) in patients treated with 
ofatumumab compared with teriflunomide. The detection of a hazard ratio of 0.614 in a log- 

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rank test with 90% power at a one-sided alpha-level of 0.025-0.0252 requires 178 qualifying 
events. Allowing for 20% dropouts over 2 years in both arms, a total sample size of 1774 
randomized patients is required. Assuming an accrual with 500 patients in the first 6 months, 
and 1500 patients per year thereafter, it is expected that accrual can be completed within 
approximately 18 months, and that the study duration is projected to last between 2.5 to 3 years. 
For comparison to these assumptions, in the pivotal trials of teriflunomide, the cumulative 
probability of a 3-month confirmed disability worsening over 2 years in patients treated with 
teriflunomide 14 mg was 15.8% (Confavreux et al. 2014) and 20% (O’Connor et al. 2011), 
respectively. Furthermore, in combined ocrelizumab Phase 3 studies (Hauser et al. 2015) the 
Kaplan-Meier estimates were 15.2 and 9.8 at year 2 for interferon beta-1a and ocrelizumab 600 
mg, respectively; this corresponds to a hazard ratio 0.6 (40% relative risk reduction between 
ocrelizumab and interferon beta-1a). 
 
9.8.3 
Sample size for 6-month confirmed disability worsening (6mCDW) 
The cumulative event probability over 2 years is assumed as 12% vs 7.548% in patients treated 
with teriflunomide vs ofatumumab, respectively. The assumed cumulative event rates translate 
to a relative risk reduction of 38.6% (hazard ratio=0.614) in patients treated with ofatumumab 
compared with teriflunomide. The detection of a hazard ratio of 0.614 in a log-rank test with 
80% power at a one-sided alpha-level of 0.025-0.0252 requires 133 qualifying events. Allowing 
for 20% dropouts over 2 years in both arms, a total sample size of 1662 randomized patients 
is required (831 per arm). 
For comparison: In combined ocrelizumab Phase 3 studies (OPERA 1 and OPERA 2, Hauser et 
al. 2015) the Kaplan-Meier estimates were 12.0 and 7.4 at year 2 for interferon beta-1a and 
ocrelizumab 600 mg, respectively; this corresponds to a hazard ratio 0.6 (40% relative risk 
reduction between ocrelizumab and interferon beta-1a). 
 
9.8.4 
Sample size for 6-month confirmed disability improvement (6mCDI) 
The cumulative event probability over 2 years is assumed as 12% vs 18.8% in patients treated 
with teriflunomide vs ofatumumab, respectively. The assumed cumulative event rates translate 
to a relative increase in chance by 63% (hazard ratio=1/0.614=0.163) in patients treated with 
ofatumumab compared with teriflunomide. The detection of a hazard ratio of 1/0.614 in a log- 
rank test with 80% power at a one-sided alpha-level of 0.025- 0.0252 requires 133 qualifying 
events. Allowing for 20% dropouts over 2 years 1052 patients who contribute to the analysis 
are required; due to the definition of 6mCDI, patients with a baseline EDSS < 2 cannot 
contribute to this analysis. Based on the combined fingolimod Phase 3 trials (FREEDOMS, 
FREEDOMS II and TRANSFORMS, data on file) it is assumed that approximately 35% of all 
randomized patients will have baseline EDSS < 2. Hence, 1620 (1052/0.65) randomized 
patients are required to provide 80% power. 
 
9.8.5 
Sample size for number of Gd-enhancing lesions per scan 
We assume a negative binomial distribution of the number of Gd-enhancing lesions per scan. 
Assuming 0.26 Gd-enhancing lesions per scan for teriflunomide and a 90% relative reduction 
with ofatumumab (i.e. 0.026 Gd-enhancing lesions per scan for ofatumumab), and a dispersion 
parameter κGd=5.3 (as observed in the combined FREEDOMS and FREEDOMS II studies for 

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the same parameter, data on file), a total sample size of 210 patients with available MRI scans 
would be sufficient to provide 90% power for the statistical test at a one-sided alpha 0.025. 
Allowing for 20% dropouts, a total sample size of 264 randomized patients (132 per arm) is 
required for this endpoint. 
 
9.8.6 
Sample size for annualized rate of new/newly enlarging T2 lesions 
We assume a negative binomial distribution of the number of T2 lesions. Assuming 2.1 new or 
newly enlarging T2 lesions over 1.5 years for teriflunomide (1.4 new or enlarging T2 lesions 
per year with a mean follow-up of 1.5 years) and an 80% relative reduction with ofatumumab 
(i.e. 0.42 T2 lesions over 1.5 years; 0.28 lesions per year for ofatumumab) and a dispersion 
parameter κGd=3.1 (as observed in the combined fingolimod Phase 3 placebo-controlled trials, 
data on file) for the same parameter), a total sample size of 74 patients with available MRI scans 
would be sufficient to provide 90% power for the statistical test at a one-sided alpha 0.025. 
Allowing for 20% dropouts, a total sample size of 94 randomized patients (47 per arm) is 
required for this endpoint. 
 
9.8.7 
Sample size for NfL 
We assume a log-normal distribution for NfL concentrations. At month 3, geometric mean NfL 
concentrations of μ1=25 pg/ml in teriflunomide and μ2=17pg/ml in ofatumumab treated patients 
are assumed, leading to an assumed treatment difference on the log-scale of 0.386 pg/ml. We 
further assume a common standard deviation of 0.700 pg/ml. A total sample size of 139 
randomized patients with available NfL assessments would be sufficient to provide 90% power 
for the statistical test at a one-sided alpha 0.025. Allowing for 20% dropouts, a total sample size 
of 174 patients (87 per arm) is required for this endpoint. 
 
9.8.8 
Sample size for annualized rate of brain volume loss (BVL) 
We assume a normal distribution for the percentage brain volume change. Assuming a mean 
annualized rate of BVL of 0.45% on teriflunomide and 0.338% on ofatumumab (25% relative 
reduction) and a common standard deviation of 0.5%, a sample size of 621 patients with 
available MRI assessments would provide 80% power at a one-sided alpha level of 0.025. 
Allowing from 20% dropouts, a total sample size of 778 randomized patients are required for 
this endpoint (ca. 390 per arm). 
 
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 Conference 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. 

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10.2 
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient's representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 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 and period after discontinuation of study drug. 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, 
written 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 
is requested by a regulatory authority, the Investigator must inform Novartis immediately that 
this request has been made. 

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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 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 is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
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 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. 

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12 
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Sormani MP, Bruzzi P (2013) MRI lesions as a surrogate for relapses in multiple sclerosis: a 
meta-analysis of randomised trials. Lancet Neurol 2013; 12: 669-676 
 
Wingerchuk DM, Lennon VA, Pittock SJ, et al. (2006) Revised diagnostic criteria for 
neuromyelitis optica. Neurology; 66:1485-89 

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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 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x 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 
 
 
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
• 
Discontinue the study treatment 
ALT, AST, TBL, Alb, PT/INR, AP and 
casea 
immediately 
GGT until resolutionc (frequency at 
• 
Hospitalize, if clinically appropriate 
Investigator discretion) 
• 
Establish causality 
• 
Complete liver CRF 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study treatment 
immediately 
ALT, AST, TBL, Alb, PT/INR, AP and 
GGT until resolutionc (frequency at 
• 
Hospitalize if clinically appropriate 
Investigator discretion) 
• 
Establish causality 
• 
Complete liver CRF 
> 3 × ULN and 
• 
Discontinue the study treatment 
ALT, AST, TBL, Alb, PT/INR, AP and 
INR > 1.5 
immediately 
GGT until resolutionc (frequency at 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
> 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 
• 
Complete liver CRF 
Investigator discretion) 
 
 
 
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 
accompanied by 
symptomsb 
 
 
 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic) 
ALP (isolated) 
> 2 × ULN (in the 
absence of known 
bone pathology) 
 
TBL (isolated) 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
 
 
 
 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient 
 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish causality 
• 
Complete liver CRF 
 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, discontinue the 
study drug immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient 
ALT, AST, TBL, Alb, PT/INR, AP and 
GGT until resolutionc (frequency at 
Investigator discretion) 
 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
 
 
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) 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
Jaundice 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Complete liver CRF 
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 
• 
Complete liver CRF 
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. 
 

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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 24-48h 
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase ≥ 
50% compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Consider 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 24-48h 
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: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
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. 
 
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 neuroradiologist. The Investigator will contact the Medical 
Advisor at Novartis to discuss findings and diagnostic possibilities as soon as possible. A copy 
of the unscheduled MRI should be sent to the MRI Evaluation Center designated by 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, 

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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 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 respective AE eCRF 
pages. Treatment and additional evaluations will be performed at discretion of the Investigator. 
The Investigator should remind the patient of the risk of infections and instruct them to promptly 
report any symptoms of infections to the Investigator. The patients must also be reminded to 
always carry their Patient Information Card (with site contact information and which identifies 
them as participants in a clinical study with investigational and control agents with potential 
immunosuppressive effects) and to show this to any local healthcare provider they may consult 
and ask that the Investigator be contacted. 
In the case of suspected or confirmed serious (CTCAE, Grade 3-4) or atypical infection, study 
drug interruption should be considered. The Investigator should inform the Sponsor Medical 
Advisor of any such cases. 
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 hepatitis B virus (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). The MS patients 
enrolled in the study who are at potential risk of HBV reactivation (e.g. patients with evidence 
of prior HBV infection (anti-HBc positive and HBsAg negative) and whose HBV DNA test is 
negative at Screening, should be closely monitored for signs of active HBV infection or 
reactivation during the study. In patients with suspicion of HBV infection (active/reactivation), 
laboratory testing for HBV should be done. For patients who show evidence of hepatitis B 
infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc 
positive), the Investigator is advised to consult with physicians with expertise in managing 
hepatitis B regarding monitoring and consideration for HBV antiviral therapy. 

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In patients who develop reactivation of HBV while receiving study drug, 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 when B-cells are depleted. 
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 each visit from 
Month 1 to EOS by the central laboratory and will be blinded to the Sponsor and the Investigator. 
They will only be communicated to the site after baseline in case of notably low levels. A 
notably low IgG level is defined as a level that is 20% below the LLN and a notably low IgM 
level is defined as a level 10% below the LLN. Following notification, the immunoglobulin 
level should be repeated within 2 weeks by the central lab to confirm the reading. If the repeat 
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. 
 
16 
Appendix 4: List of drugs/drug classes with teriflunomide 
interaction potential 
Based on the double-blinded design, the Investigator will need to consider the drug interaction 
potential of teriflunomide when the blinded study drug is co-administered with certain classes 
of drugs. The below information has been obtained from the US teriflunomide (Aubagio®) 
prescribing information (Revised 10/2014): 
 
Effect of teriflunomide on CYP2C8 substrates 
Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking teriflunomide, exposure of 
drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may 

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be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized 
by CYP2C8 as required. 
 
Effect of teriflunomide on warfarin 
Coadministration of teriflunomide with warfarin requires close monitoring of the international 
normalized ratio (INR) because teriflunomide may decrease peak INR by approximately 25%. 
 
Effect of teriflunomide on oral contraceptives 
Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. 
Consideration should be given to the type or dose of contraceptives used in combination with 
teriflunomide. 
 
Effect of teriflunomide on CYP1A2 substrates 
Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking teriflunomide, 
exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) 
may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) 
metabolized by CYP1A2 as required. 
 
Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates 
Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking teriflunomide, exposure 
of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, 
ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients 
and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required. 
 
Effect of teriflunomide on BCRP and organic anion transporting polypeptide B1 
and B3 (OATP1B1/1B3) substrates 
Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking 
teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates 
of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), 
especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, 
and simvastatin), consider reducing the dose of these drugs and monitor patients closely for 
signs and symptoms of increased exposures to the drugs while patients are taking teriflunomide. 
Additional drugs belonging to the classes above include but are not limited to: 
• rifampicin (a medicine used to treat tuberculosis and other infections) 
• carbamazepine, phenobarbital, phenytoin (for epilepsy) 
• St. John’s wort (a herbal medicine for depression) 
• indometacin, ketoprofen (for pain or inflammation) 
• rosuvastatin for hypercholesterolemia (for treatment of high cholesterol) 
• sulfasalazine (for inflammatory bowel disease or rheumatoid arthritis) 
• cholestyramine (for high cholesterol or relief from itching in liver disease); may 
accelerate elimination of teriflunomide (refer also to Section 7.8) 

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17 
Appendix 5: Statistical appendix (information from a 
controlled clinical trial with count data) 
Background 
The ARR is the primary clinical endpoint in this Study. The trial compares ofatumumab with 
teriflunomide. 
 
Objective 
To mathematically derive the information obtained from a clinical trial in MS on the ARR ratio 
of test versus control, on the log-scale based on a negative binomial distribution. The treatment 
effect is based on the estimation of the ARR-ratio (the ‘estimate’) between ofatumumab and 
teriflunomide. The information is defined as the reciprocal of the estimate’s variance, as in 
group sequential designs. 
 
Model 
We assume that the number of relapses follows a negative binomial distribution, which is a 
common assumption in MS trials. More specifically, the available data for patient i in treatment 
arm j is: 
Yij = number of relapses in follow-up time Tij, 
for i = 1,…nj and j = 1,2 (1 = test, 2 = control). 
The negative binomial model is then written as: 
Yij   ~ NegBin( λj Tij , κ) , 
with annual relapse rate λj (> 0) and over-dispersion parameter κ (> 0). 
With this parametrization, 
E(Yij) = μij and Var(Yij) = μij (1 + κ μij), where μij = λj Tij. 
An estimate of λj is given by rj = Y.j / T.j , where Y.j = Σi Yij and T.j = Σi Tij. 
Using the delta-method (see details in a next section), a normal approximation for the logarithm 
of the estimated relapse rate ratio is obtained: 
log(r1/r2) ~ N(log(λ1/λ2) , 1/(λ1 T.1) + 1/(λ2 T.2) 
+ κ{Σi Ti12 / T.12 + Σi Ti22 / T.22}) 
The information is the reciprocal of the variance, ie, information: 
I = [ 1/(λ1  T.1  ) + 1/(λ2  T.2  ) + κ{Σi Ti12/T.12   + Σi Ti22/T.22}]-1 
(1) 
For the case where Tij =T, nj = n, 
Information I = [1/n {1/(λ1T) + 1/ (λ2T) + 2κ}]-1 
(2) 
Of note: Study designs with different parameterizations, but an equivalent amount of 
information also have an equivalent power for the detection of the specified treatment effect at 
a fixed alpha-level. 

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Blinded evaluation of the information 
As in a blinded sample size review (Friede and Schmidli 2010), fitting a negative binomial 
model to the aggregate data (i.e. the relapse data of all patients combined) provides an estimate 
of the overall annual relapse rate λ and of the dispersion κ. For an assumed rate ratio of θ = λ1/λ2, 
we obtain estimates of the annual relapse rates in the 2 groups, λ1 and λ2. 
We also make the assumption that the follow-up times in the 2 groups are the same, i.e., that 
T.1 = T.2 = Ttotal/2 , where Ttotal is the total of the follow-up times at the review time. We further 
assume that the sum of the scuared follow-up times is the same in both groups, i.e., that Σi Ti12 
= Σi T 2 = Σj Σi Tij2 / 2 = T2total/2. 
i2 
The evaluation of the Information (1) based on blinded information is then 
Information I = [2/(λ1  Ttotal ) + 2/(λ2  Ttotal ) + 4 κ T2total/Ttotal2]-1 
(3) 
where λ1, λ2, and κ are the re-estimated values at the blinded review. 
Note: if Tij =T, nj = n, then Ttotal = 2 n T, and T2total = 2 n T2, and one obtains again (2). 
Additional details (delta-method) 
For a random variable X with expectation μ and variance σ2 , the transformed random variable 
g(X) has approximately expectation g(µ) and variance σ2 g’(µ)2 (delta-method). 
For the estimate of λj given by rj = Yj/Tj, we have: 
E(rj) = λj and Var(rj) = λj/Tj + κ λj2 Σi Tij2/T.j2 
Using the delta-method, the log-transformed annual relapse rate estimate has expectation and 
variance: 
E(log(rj)) = log(λj) 
Var(log(rj)) = 1/(λj T.j ) + κ Σi Tij2/T.j2 
Hence, approximately: 
log(rj) ~ N(log(λj)), 1/(λj T.j) + κ Σi Tij2/T.j2) 
Note that for the special case of Tij = T, we obtain: 
log(rj) ~ N(log(λj), 1/(λj n T) + κ/n) 
This approximation is used for sample size calculation and re-calculation with negative 
binomial count data (Keene et al. 2007, Friede and Schmidli 2010).