Conditions: Relapsing Multiple Sclerosis
Keywords: Relapsing multiple sclerosis Ofatumumab adult OMB157 multiple sclerosis T1 lesions T2 lesions relapse GD-enhancing MRI McDonald criteria RRMS SPMS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 930
Healthy volunteers: no

Brief summary:
To compare the efficacy and safety of ofatumumab administered subcutaneously (sc) every 4 weeks versus teriflunomide administered orally once daily in patients with relapsing multiple sclerosis

Detailed description:
This was a randomized, double-blind, double-dummy, active comparator-controlled, parallel-group, multi-center study with variable treatment duration in approximately 900 patients with relapsing multiple sclorosis (RMS). The maximal treatment duration in the study for an individual patient was 2.5 years.

Eligible patients were randomized to receive either experimental ofatumumab subcutaneous (s.c.) injections every 4 weeks or active comparator teriflunomide orally once daily. The dose regimen for ofatumumab for this study was a loading dose regimen of 20 mg at Day 1, Day 7 and Day 14, followed by a maintenance dose regimen of 20 mg administered every 4 weeks starting at Week 4. In order to blind for the different formulations, double-dummy masking was used i.e. all patients will take injections (containing either active ofatumumab or placebo) and oral capsules (containing either active teriflunomide or placebo).

Arms:
arm 1: Ofatumumab 20 mg pre-filled syringes for subcutaneous injectionon on days 1 ,7 ,14, week 4 and every 4 weeks thereafter and a teriflunomide- matching placebo, taken orally once daily arm 2: Teriflunomide 14 mg oral capsule taken once daily and matching placebo for subcutaneous injections to ofatumumab on days 1, 7, 14, week 4 and every 4 weeks thereafter

Interventions: intervention 1: Ofatumumab subcutaneous injection intervention 2: Teriflunomide-matching placebo capsules intervention 3: Teriflunomide capsule intervention 4: Matching placebo of ofatumumab subcutaneous injections
Intervention descriptions: intervention 1: Ofatumumab 20 mg pre-filled syringes for subcutaneous injection on days 1, 7, 14, week 4 and every 4 weeks thereafter intervention 2: Placebo capsule, matching in appearance to teriflunomide, taken orally once daily intervention 3: Teriflunomide 14 mg oral capsule taken once daily intervention 4: Matching placebo of ofatumumab subcutaneous injections on days 1, 7, 14, week 4 and every 4 weeks thereafter

Protocol document:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
OMB157/Ofatumumab 
Clinical Trial Protocol COMB157G2301 / NCT02792218
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: 
2015-005418-31 
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 
 
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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 (COMB157G2301 v00.01 DE, clean version electronic document identifier 
090095a889dadead) 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. 
Section 6.4.5, 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 
COMB157G2301 
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 
(COMB157G2302) 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 (COMB157G2301). All disability 
endpoints will be addressed in the combined data from 2 studies of 
identical design (COMB157G2301 and COMB157G2302). 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 (COMB157G2302) 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 (COMB157G2301 and COMB157G2302) 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 
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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. 
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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 
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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 


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patient and identifying adverse events. Clinically notable laboratory findings are defined 
according to the Common Terminology Criteria for Adverse Events (CTCAE). 
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. 


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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 
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 
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Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be 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 
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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. 
 
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 


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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. 
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. 


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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the 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. 


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If, at any time after Screening and/or Baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the CSSRS or “yes” on any item of the Suicidal Behavior section, 
the patient must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the Investigator in consultation with the mental health professional to whom the patient is 
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 (COMB157G2301 and 
COMB157G2302), 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 COMB157G2301 and COMB157G2302 (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 COMB157G2301 and COMB157G2302, 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 
COMB157G2301 and COMB157G2302. 


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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 
COMB157G2301 and COMB157G2302. 
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 COMB157G2301 and 
COMB157G2302, 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 COMB157G2301 and COMB157G2302, 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 (COMB157G2301 and COMB157G2302) 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 (COMB157G2301 and COMB157G2302) ≥ 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 COMB157G2301 and COMB157G2302 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 
References 
References are available upon request. 
Archelos JJ, Storch MK, Hartung HP. (2000) The role of B-cells and autoantibodies in multiple 
sclerosis. Ann Neurol; 47:694-706 
Arzerra® US prescribing information (1/2016). 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf 
Barro C, Benkert P, Disanto G, et al (2018) Serum neurofilament as a predictor of disease 
worsening and brain and spinal cord atrophy in multiple sclerosis. BRAIN, 141;2382-2391 
Bouaziz JD, Yanaba K, Venturi GM et al. (2007) Therapeutic B-cell depletion impairs adaptive 
and autoreactive CD4+ T-cell activation in mice. Pro. Natl. Acad. Sci. USA; 104: 20882-20887 
Benedict RHB. DeLuca J, Phillips G et al (2017) Validity of the symbol digit modalities test as 
a cognition performance outcome measure for multiple sclerosis. Mult Scler 23(5)721-733 
Confavreux C, O'Connor P, Comi G et al. (2014) Oral teriflunomide for patients with relapsing 
multiple sclerosis: a randomized, double-blind, placebo-controlled, Phase 3 trial. Lancet Neurol; 
Mar;13(3):247-56 
Disanto G, Barro C, Benkert P, et al.(2017) Serum Neurofilament Light: A Biomarker of 
Neuronal Damage in Multiple Sclerosis/ ANN NEUROL 81: 857-870 
 
Freedman MS. (2013) Teriflunomide in relapsing multiple  sclerosis:  therapeutic  utility.  
Ther Adv Chronic Dis; 4(5):192-205 
Friede T, Schmidli H. (2010) Blinded sample size reestimation with negative binomial counts 
in superiority and non-inferiority trials. Methods Inf Med; 49(6):618-24 
Frohman EM, Racke MK, Raine CS. (2006) Multiple sclerosis – the plaque and its pathogenesis. 
New Engl J Med; 354:942-955 
Hauser SL, Waubant E, Arnold DL et al. (2008) B-cell Depletion with Rituximab in Relapsing- 
Remitting Multiple Sclerosis. New Engl J Med; 358:676-688 
Hauser SL, Comi GC, Hartung HP et al. (2015) Efficacy and safety of ocrelizumab in relapsing 
multiple sclerosis - results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA 
I and II studies. ECTRIMS Online Library. Hauser S. Oct 9, 2015; 116634 
Hobart J, Lamping D, Fitzpatrick R, et al. (2001) The Multiple Sclerosis Impact Scale (MSIS- 
29) A new patient-based outcome measure. Brain; 124:962-973 
Hobart J, Cano S (2009) Improving the evaluation of therapeutic interventions in multiple 
sclerosis: the role of new psychometric methods. Health Technology Assessment; 13: No. 12 
Kappos L, Li D, Calabresi PA et al. (2011) Ocrelizumab in relapsing-remitting multiple 
sclerosis: a Phase 2, randomized, placebo-controlled, mutlicentre trial. Lancet; 378:1779-87 
Keene ON, Jones MRK, Lane PW, Anderson J. (2007) Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharmaceutical 
Statistics; 6:89-97 


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Klaus Lehmann-Horn, MD, Helena C.Kronsbein, MD, Martin S. Weber, MD (2013) 
Targeting B-cells in the Treatment of Multiple Sclerosis. Ther Adv Neurol Disorders;6(3):161- 
173 
Kuhle J, Barro C, Disanto G, et al.(2016) Serum Neurofilament light chain in early relapsing 
remitting MS is increased and correlated with CSF level and with MRI measures of disease 
severity Vol 22(12)1550-1559 
Lublin FD, Reingold SC, Cohen JA et al. (2014) Defining the clinical course of multiple 
sclerosis. Neurology; 83:278-286 
Lund FE (2008) Cytokine-producing B lymphocytes – key regulators of immunity. Curr Opin 
Immunol. 20(3):332–38 
McDonald WI, Compston A, Edan G, et al. (2001) Recommended diagnostic criteria for 
multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. 
Ann Neurol; 50:121-27 
McFarland HF (2008) The B-cell--old player, new position on the team. N Engl J Med; 
358:664-5 
O’Connor P, Wolinsky JS, Confavreux C et al (2011) Randomized Trial of Oral Teriflunomide 
for Relapsing Multiple Sclerosis. N Engl J Med; 365:1293-303 
Panitch H, Goodin DS, Francis G, et al (2002) Randomized, comparative study of interferon 
beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology; 59(10):1496-1506. 
Piehl F, Kockum I, Khademi M, et al.(2017): Plasma neurofilament light chain levels in 
patients with MS switching from injectable therapies to fingolimod. MSJ 1-9 
Polman CH, Reingold S, Banwell B, et al. (2011) Diagnostic criteria for multiple sclerosis: 
2010 revisions to the McDonald criteria. Ann Neurol; 68:292-302 
Radue E-W, Sprenger T, Gaetano L, et el (2015) Teriflunomide slows brain volume loss in 
relapsing MS: a SIENA analysis of the TEMSO MRI dataset. ECTRIMS Online Library. Radue 
E. Oct 10, 2015; 116702 
 
Siller N, Kuhle J, Muthuraman M, et al.(2018) Serum Neurofilament light chain is a 
biomarker of acute and chronic neuronal damage in early multiple sclerosis MSJ 1-9 
Soerensen PS, Lisby S, Grove R et al. (2014) Safety and efficacy of ofatumumab in relapsing- 
remitting multiple sclerosis. Neurology; 82:573-581 
Sormani MP, Bonzano L, Roccatagliata L, et al. (2009) Magnetic resonance imaging as a 
potential surrogate for relapses in multiple sclerosis: a metaanalytic approach. Ann Neurol. 
65(3):268-75 
Sormani MP, 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). 

SAP_000.pdf: 
Clinical Development
OMB157/Ofatumumab®
COMB157G2301/COMB157G2302
NCT02792218/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
Statistical Analysis Plan (SAP)
Authors:
Document type:
SAP Documentation
Document status:
Final (Addendum 1)
Release date:
17-Oct-2019
Number of pages:
86
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
OMB157G2301
Document History – Changes compared to previous final version of SAP
Date
Time
point
Reason for 
update
Outcome for 
update
Section and title impacted (Current)
15-
Jul-
2016
Prior 
to 
FPFV
Creation of 
final version
N/A -
First 
version
NA
10-
Jan-
2019
Prior 
to 
DBL
Protocol 
amendments 
(1 and 2)
Amendment 1
Sections impacted by protocol 
amendments 1 or 2:
- Section 1.2: Study objectives and 
endpoints
- Section 2.2.1: Subgroup of interest
- Section 2.5.3: Multiplicity adjustment
- Section 2.6: Analysis of key 
secondary objectives
- Section 2.7: Analysis of secondary 
objectives
- Section 2.11: Patient reported 
outcomes
 
- Section 5.3.3: CTCAE grades 
definition
- Section 3: Sample size calculation
Section 2.8.6: Suicidality evaluation (to 
be consistent with latest MAP on eCSSRS 
data)
Section 2.8.1: AEs (to add analyses to be 
used in legal requirements of 
ClinincalTrials.gov)
Section 5.6: Rule of exclusion criteria of 
analysis sets (to add relevant PD that is 
updated in study PD document)
Clarifications and minor corrections 
throughout the document


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SAP
OMB157G2301
Date
Time
point
Reason for 
update
Outcome for 
update
Section and title impacted (Current)
May 
2019
Prior 
to 
DBL
Align with 
submission 
planning 
and update 
for 
corrections 
and clarity
Amendment 2
Section 2.1: General definition (Updated 
the CSR name to be consistent with name 
planned for submission)
Section 2.4.1: Time at risk for AE/SAE 
(Applied the analysis data cutoff date)
Section 2.4.2.3: Injection premedication 
(Updated to include medications either 
start or end on the injection date for 
completeness)
Sections 2.6.2.1 and 2.6.2.2: Analysis for 
disability worsening and improvement 
(Updated model specifications for clarity 
and accuracy) 
Section 2.6.2.5: NfL (Added subgroup 
analysis on brian volume change to align 
with NfL pre-submission meeting briefing 
book submitted to FDA on Feb 8th 2019)
Section 2.8.1: AEs (Added summary of 
AEs causing study drug interruptions as 
required by CSR)
Section 2.8.5: Vital signs (minor correction 
to be consistent with Section 2.1.2.3)
Section 2.8.7: Safety data after study drug 
discontinuation (Clarification that data 
within 100 days safety cutoff will be 
included in both “on-treatment” summary 
as well as in this section)
 
 
 
 
 
 
 
 
 


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SAP
OMB157G2301
Date
Time
point
Reason for 
update
Outcome for 
update
Section and title impacted (Current)
July
2019
Prior 
to 
DBL
Update 
region 
definition 
used in 
statistical 
model based 
on blinded 
dry-run data 
and for 
corrections 
and clarity
and align 
with TFL 
shells
Amendment 3
Section 2.1: General Definition (Region to 
be adjusted in the statistical model was 
updated based on statistical criteria as 
expected)
Section 
2.4.2.3:
Injection 
related 
premedication (Updated the by-injection 
summary to replace injection 10+ with 
injection 10)
Section 2.6.2.1: Analysis of key secondary 
endpoints 3mCDW and 6mCDW (Updated 
to present only month 18 and month 24 
KM estimates)
Section 2.6.2.2: Analysis of key secondary 
endpoint 6mCDW (same update as above)
Section 2.6.2.5: Analysis of key secondary 
endpoint NfL (Updated the supportive 
analysis to include NfL baseline category 
as main effect which was missed in last 
version)
Section 2.8.1.1.1: Injection reaction related 
AEs (Updated the by-injection summary to 
replace injection 10+ with injection 10;
this will make trend in figure more 
interpretable)
Section 5.5.2: Appendix on key secondary 
analysis (Removed the test related to 
proportional hazard assumptions but kept 
the visual check through log-log plots)
Other minor corrections or clarifications 
made in the document;
Oct 
2019
After 
DBL
Update to 
correct B-
cell 
depletion 
analysis
Addendum 1
Section 2.8.3.4: Other special lab results 
[Updated to 1) correct the B-cell depletion 
definition from “<LLN or <baseline” to 
“<LLN”; 2) correct the data cutoff for B-
cell depletion summaries from general 
safety cutoff to on-treatment period cutoff. 
Both updates are made in order to provide 
more accurate information on B-cell 
depletion from a scientific point of view: 
1) 
the 
original 
depletion 
definition 


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Date
Time
point
Reason for 
update
Outcome for 
update
Section and title impacted (Current)
included “or <baseline” condition which 
can’t represent a real depletion by itself but 
by chance that 50% of patients could have 
post-baseline values < Basline values; this
specific definition of depletion therefore 
would artificially inflate the proportion of 
patients in comparator arm that have 
depletion and mask the differences in 
depletion 
between 
ofatumumab 
and 
comparator, leading to a potentially non-
conservative estimate of the difference; the 
corrected definition “<LLN” captures the 
real depletion; 2) The original 
safety 
cutoff (i.e., last dose date +100) would mix 
repletion and depletion to some degree
because fast B-cell repletion is expected 
after study drug discontinuation; the 
corrected cutoff using on-treatment period 
will concentrate on B-cell depletion as a 
result of study drug intake.]


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Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................9
1
Introduction .......................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Study objectives and endpoints .............................................................................14
1.2.1
Primary objective ..................................................................................14
1.2.2
Key secondary objectives......................................................................14
1.2.3
Other secondary objectives ...................................................................15
16
2
Statistical methods.............................................................................................................16
2.1
Data analysis general information .........................................................................16
2.1.1
General definitions................................................................................17
2.1.2
Visit windows........................................................................................20
2.2
Analysis sets ..........................................................................................................24
2.2.1
Subgroup of interest ..............................................................................25
2.3
Patient disposition, demographics and other baseline characteristics ...................26
2.3.1
Patient disposition.................................................................................26
2.3.2
Background and demographic characteristics.......................................27
2.3.3
MS baseline disease characteristics ......................................................27
2.3.4
Medical history......................................................................................28
2.3.5
Smoking history and alcohol history.....................................................28
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................28
2.4.1
Exposure to study treatment / compliance / time at risk.......................28
2.4.2
Prior, concomitant and post therapies...................................................29
2.5
Analysis of the primary objective..........................................................................31
2.5.1
Primary endpoint...................................................................................31
2.5.2
Statistical hypothesis, model, and method of analysis..........................31
2.5.3
Multiplicity adjustment .........................................................................32
2.5.4
Handling of missing values/censoring/discontinuations.......................34
2.5.5
Supportive analyses...............................................................................34
2.6
Analysis of the key secondary objectives..............................................................35
2.6.1
Key secondary endpoints ......................................................................35
2.6.2
Statistical hypothesis, model, and method of analysis..........................38
2.6.3
Handling of missing values/censoring/discontinuations.......................44
2.7
Analysis of secondary efficacy objective(s)..........................................................45


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2.7.1
Secondary endpoints .............................................................................45
2.7.2
Statistical model and method of analysis..............................................48
2.7.3
Handling of missing values/censoring/discontinuations.......................49
2.8
Safety analyses.......................................................................................................49
2.8.1
Adverse events (AEs)............................................................................50
2.8.2
Deaths....................................................................................................53
2.8.3
Laboratory data .....................................................................................53
2.8.4
ECG data...............................................................................................55
2.8.5
Vital signs..............................................................................................56
2.8.6
Suicidality evaluations ..........................................................................56
2.8.7
Safety evaluation during the Safety follow-up......................................58
2.9
Pharmacokinetic endpoints....................................................................................59
59
2.9.2
Immunogenicity assessment..................................................................59
2.10
PD and PK/PD analyses and modelling.................................................................59
2.11
Patient-reported outcomes .....................................................................................60
2.11.1
MSIS-29 ................................................................................................60
60
61
.62
63
63
2.14
Interim analysis......................................................................................................63
2.14.1
Unblinding interim analysis..................................................................63
2.14.2
Analysis for Data Monitoring Committee (DMC)................................63
2.14.3
Blinded data reviews.............................................................................63
3
Sample size calculation .....................................................................................................64
3.1.1
Sample size for the primary endpoint (ARR) .......................................65
3.1.2
Sample size the number of GdT1 lesions per scan ...............................66
3.1.3
Sample size for the annualized rate of new or enlarging T2 lesions.....66
3.1.4
Sample size for NfL ..............................................................................66
3.1.5
Sample size for the annualized rate of brain volume loss (BVL) .........67
3.1.6
Sample size for 3-month confirmed disability worsening 
(3mCDW)..............................................................................................67
3.1.7
Sample size for 6-month confirmed disability worsening 
(6mCDW)..............................................................................................67


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3.1.8
Sample size for 6-month confirmed disability improvement 
(6mCDI)................................................................................................68
4
Change to protocol specified analyses ..............................................................................68
5
Appendix ...........................................................................................................................68
5.1
Imputation rules.....................................................................................................68
5.1.1
Study drug.............................................................................................68
5.1.2
AE date imputation ...............................................................................69
5.1.3
Concomitant medication date imputation .............................................69
5.2
AEs coding/grading ...............................................................................................70
5.3
Laboratory parameters derivations ........................................................................71
5.3.1
Laboratory test groups and subgroups ..................................................71
5.3.2
Newly occurring liver enzymes abnormalities......................................73
5.3.3
CTCAE grades for laboratory parameters.............................................73
5.4
Clinical notable vital signs.....................................................................................75
5.5
Statistical models...................................................................................................76
5.5.1
Primary analysis....................................................................................76
5.5.2
Key secondary analysis.........................................................................76
5.5.3
Important supportive analysis of primary or key secondary 
endpoints ...............................................................................................77
5.6
Rule of exclusion criteria of analysis sets..............................................................79
5.7
Statistical method details for TEAEs.....................................................................82
5.7.1
Odds ratios and 95% confidence interval..............................................82
5.7.2
Exposure adjusted incidence rate and 95% confidence interval ...........83
5.8
Regions for randomization stratification ...............................................................83
6
References .........................................................................................................................86


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List of abbreviations
AE
Adverse Event
ADA
Anti-drug-antibody
ALP
Alkaline Phosphate
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ARBA
Annualized Rate of Brain Atrophy
ARR
Annualized Relapse Rate
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
BIL
Bilirubin
BMI
Body Mass Index
BVL
Brain Volume Loss
BSSR
Blinded Sample Size Re-estimation
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CDI
Confirmed Disability Improvement
CDW
Confirmed Disability Worsening
CNS
Central Nervous System
CRF
Case Report/Record Form (paper or electronic)
eCRF
Electronic Case Report Form
CRO
Contract Research Organization
CSPD
Clinical Summary Preparation Document
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
(e)CSSRS 
(electronic) Columbia Suicide Severity Rating Scale
DMC
Data Monitoring Committee 
DMT
Disease Modifying Treatment
EAST
Software for trial designs; name is derived from the benefit of “Early stopping” a 
trial due to futility interim analysis
ECG
Electrocardiogram
(e)EDSS
(electronic) Expanded Disability Status Scale
EOS
End of Study
EOT
End of Treatment
FAS
Full Analysis Set
FDA
Food Drug Association
FS
Functional System/Functional score
FU
Follow up
Gd
Gadolinium
GdE
Gadolinium Enhancing
GGT
Gamma-Glutamyltransferase


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9HPT
9-Hole Peg Test
Ig
Immunoglobulin
INR
International Normalized Ratio
ITT
Intention to treat
iv
Intravenous
IRR
Injection related reaction
IRT
Interactive Response Technology
KM
Kaplan-Meier
LDD
Last Dose Date
LFT
Liver Function Test 
LLN
Lower Limit of Normal
M
Month
MedDRA
Medical Dictionary for Regulatory Activities 
MH
Medical History
MRI
Magnetic Resonance Image
MS
Multiple Sclerosis
MSIS
Multiple Sclerosis Impact Scale
NB
Negative Binomial
NfL
Neurofilament light chain
NEDA
No Evidence of Disease Activity
od
once a day
PBVC
Percent Brain Volume Change
PD
Pharmacodynamics
PDS
Programming Datasets Specification
PG
Pharmacogenetics
PH
Proportional Hazard
PK 
Pharmacokinetic
PML
Progressive Multifocal Leukoencephalopathy
po
oral(ly)
PPS
Per-Protocol Set
PRO
Patient Reported Outcome
PT
Preferred Term
q4, q12
Every 4, every 12
RMS
Relapsing MS
RRMS
Relapsing-Remitting MS
SAE
Serious Adverse Event
SAF
Safety Set
SAS
Statistical Analysis Software
sc
Subcutaneous
SDMT
Symbol Digit Modality Test
SPMS
Secondary progressive MS
SAP
Statistical Analysis Plan
SMQ
Standardized MedDRA Query


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SOC
System Organ Class
TEAE
Treatment Emergent AE
TFLs
Tables, Figures, Listings
T25FW
Timed 25-foot Walk 
TBIL
Total Bilirubin
ULN
Upper Limit of Normal
VAS
Visual Analog Scale
WHO
World Health Organization 


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol for studies COMB157G2301 (G2301) and 
COMB157G2302 (G2302), which are of identical design conducted in parallel. 
There will be three reports resulting from this SAP: (1) The clinical study report (CSR) of the 
G2301 study, (2) the CSR of the G2302 study, and (3) a combined report containing side-by-
side presentation of demography and baseline characteristics between the two ASCLEPIOS 
studies, and key-secondary analyses on the pooled data from the two studies as defined in the 
clinical study protocols. Specifically the combined report will contain the analysis results 
concerning disability worsening and disability improvement from the combined data of the two 
studies. These three reports will be generated twice and referred to as 1) registration CSR and 
2) final CSR. The registration CSR will be completed at the time of submission for new drug 
application. The final CSR will be completed after the final database lock.
This document is consistent with the current study protocols (version 02).
The analyses that will be performed for the blinded interim data reviews are out of the scope in 
this SAP and will be documented in a separate analysis plan.
 
 
 These analyses will be documented in separate analysis plans or 
modeling reports and are out of scope for the present SAP.
1.1
Study design
Study G2301 is a randomized, double-blind, active comparator-controlled, parallel-group, 
multi-center study with variable treatment period in approximately 900 patients with relapsing 
multiple sclerosis (MS). The treatment duration for an individual patient 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 once every 4 weeks (after initial loading regimen of three doses/week in the 
first 14 days) or teriflunomide 14 mg orally once daily via Interactive Response Technology 
(IRT). The randomization will be stratified by geographical region and by MS subtype (RRMS, 
SPMS).
A second study of identical design (G2302) will be conducted in parallel. Both studies have the 
same primary objective (reduction of annualized relapse rate (ARR)) and key secondary 
objectives, 
. Both studies will be conducted globally, but 
centers/sites can only participate in one study to ensure independence between the two 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 
two studies (meta-analysis). Multiplicity adjustments are defined in Section 2.5.3. Poolability 
of the two studies will be assumed on the basis of the identical design, as well as the 
simultaneous and global conduct of the two studies. For information only, the heterogeneity of 
the treatment effect between the two studies will be tested for disability-related outcomes in the 
meta-analysis. 


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There is no unblinded efficacy interim analysis planned. Prior to the completion of enrolment, 
a blinded data review will be performed for the two studies to re-assess sample size assumptions 
for the ARR for each study separately and for 3-month confirmed disability worsening 
(3mCDW) for pooled studies. Based on this blinded review, the number of randomized patients 
to be enrolled may be increased to a maximum number of 1250 patients in each study. 
The EOS will be reached for both studies when all of the following conditions are met 
simultaneously (in blinded data review):
1) Each study has collected sufficient data to provide 90% power for the primary ARR 
endpoint.
2) Across the two studies, sufficient 3mCDW events have been observed to provide 90% 
power for the key secondary 3mCDW endpoint.
3) Across the two studies, sufficient 6-month confirmed disability worsening (6mCDW)
events have been observed to provide 80% power for the key secondary 6mCDW 
endpoint.
Details of the statistical analysis plan with respect to blinded data reviews are provided in the 
BSSR SAP.
The core study consists of three epochs: Screening epoch (including baseline), Treatment 
epoch (double-blind) and the post-treatment Safety Follow up epoch (Figure 1-1). Patients 
who complete the double-blind Treatment epoch (on study drug) may be eligible to enter an 
open-label ofatumumab Extension study that is planned (under a separate protocol). 
All patients will have an EOS visit at the end of the Treatment epoch. 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 assessments 
(EOT) at the time of study medication discontinuation. 
Patients who complete the Treatment epoch (on study drug), but do not enter the Extension 
study will be followed up for safety in the post-treatment Safety Follow-up (Safety FU) for a 
minimum of 9 months (or longer if indicated). 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 completed the Treatment epoch on 
study drug and had EOS (and will not enter the extension study), will be followed for at least 9 
months in the Safety FU epoch. However, a patient who discontinued study drug earlier 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). 
Continued follow up beyond 9 months will be required for patients who have not repleted their 
B cells (to LLN or baseline values) or in whom teriflunomide plasma levels are still above 0.02 
mg/L at 9 months, unless they have already started treatment with another MS disease 
modifying treatment (DMT).


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Figure 1-1
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
1.2
Study objectives and endpoints
1.2.1
Primary objective
Demonstrate that ofatumumab 20 mg sc once every 4 weeks (q4w) is superior to teriflunomide 
14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the ARR 
in patients with relapsing MS.
1.2.2
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 q4w is superior to 
teriflunomide 14 mg po once daily on the following efficacy measures:
1.
Time to disability worsening as measured by 3-month confirmed worsening (3mCDW) 
on The Expanded Disability Status Scale (EDSS) 
2.
Time to disability worsening as measured by 6-month confirmed disability worsening 
(6mCDW) on EDSS
3.
Time to disability improvement as measured by 6-month confirmed improvement 
(6mCDI) on EDSS
4.
Number of T1 Gd-enhancing lesions per MRI scan
5.
Number of new or enlarging T2 lesion on MRI per year (annualized T2 lesion rate)
Randomization
Screening
Teriflunomide 14 mg po qd + placebo injections sc
Ofatumumab 20 mg sc + placebo capsules po qd 
Baseline
Safety FU epoch* or
Extension study**
Screening epoch
Treatment epoch
(double-blind, double-dummy)
M1 
M2 
M3 
M4 
M5 
EOS 


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6.
Neurofilament light chain (NfL) concentration in serum
7. 
Rate of brain volume loss (BVL) based on assessments of percentage brain volume 
change from baseline
1.2.3
Other secondary objectives
Evaluate if ofatumumab 20 mg sc q4w is superior to teriflunomide 14 mg po once daily on the 
following efficacy measures: 
•
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 the 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 2.7.1) at year 1 and 2
•
Physical and psychological impact of MS disease as measured by the 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 q4w compared to teriflunomide 
14 mg po once daily
Evaluate the pharmacokinetics (PK) of ofatumumab


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2
Statistical methods
2.1
Data analysis general information
Novartis statistical and programming team will be performing the CSR analysis as planned in 
this document unless otherwise specified. The Statistical Analysis System (SAS) 9.4 and/or R 
15.2.1 or higher versions will be used.
Statistical safety analyses for the independent Data Monitoring Committee (DMC) will be 
conducted by a CRO. The process is described in the DMC charter. 
Unless otherwise stated, summary tables/figures/listings will be on all patients in the respective 
analysis sets. Categorical data will be presented as frequencies and percentages. For continuous 
data, mean, standard deviations, median, 25th and 75th percentiles (optional), minimum and 
maximum will be presented.
The registration CSR analysis cut-off date will depend on the EOS date. All data up to this date 
will be included in the registration CSR. A complete analysis of the post-treatment safety
follow-up will be provided in the final CSR when all patients have completed Safety FU epoch.
For efficacy analyses on the full-analysis set (FAS), all available data until the end of treatment
epoch date (i.e., excluding the data collected in the safety follow-up epoch) will be considered 
and no other cut-offs will be applied.
For efficacy analyses on the per-protocol set (PPS), only on-treatment (as defined in Section 
2.1.1) data will be considered, that is, for patients randomized to receive ofatumumab, data 
obtained 30 days after the last injection date will be excluded from the analyses; for patients 


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randomized to receive teriflunomide, data obtained after the last dose date of randomized study 
medication will be excluded from the analyses. 
For safety analyses on the safety set, only data up to and including the safety cutoff of 100 days 
(5 x 20 days takes the long half-life of the comparator-drug into account) after last 
administration of study drug will be considered. Therefore, observations obtained more than 
100 days after last administration of study drug will be excluded from the analyses. 
Nevertheless, all serious adverse events  (SAE) and all deaths, regardless of the safety cut-off 
will be summarized. 
Statistical models will include adjustments for regions by pooling centers to regions. The 
definition of region is intended to correspond to that used for the stratification of the 
randomization (as defined in Section 5.8). However, the definition of region may be modified 
if that is indicated based on statistical criteria (e.g., non-convergence). For statistical analysis 
where region is adjusted in the statistical models, regions “Asia Pacific” and “Latin America” 
will be combined with region “Other” due to small number of patients in these 2 regions. 
Presentation of p-values: p-values from statistical tests will be presented with 3 decimal places, 
or as <.001 where applicable. Statistically significant p-values will be flagged with an asterisk. 
In general, this is when p-values ≤0.05. For key-secondary disability-related hypotheses, two 
asterisks will be used if p-value ≤0.04875 (=2*[0.025-0.025*0.025]) as these hypotheses will 
be tested at alpha minus alpha-squared (this condition will be footnoted on the relevant outputs).
All data (collected or derived) will be listed appropriately.
2.1.1
General definitions 
Below summarize some general definitions to be used in the rest of the document.
Table 2-1
general definitions
Study treatment/Study drug
Both the investigational drug (ofatumumab) and the active 
comparator (teriflunomide) will be referred as study 
treatment or study drug.
Actual treatment
Actual treatment patients received. Ideally, actual treatment 
should be the same as randomized treatment. It could be 
different in case study drug is mis-dispensed. If patients 
received both investigational drug and active comparator 
accidentally during the study, their actual treatment will be
the treatment to which they were exposed longer in duration. 
For safety analysis, patients will be analyzed according to 
the actual treatment received. 
Date of first administration of 
study drug/first dose date
The first dose date of active study drug administration. For 
determining this date, matching placebo dummy treatment 
records will be excluded.
Date of last administration of 
study drug/last dose date
The last dose date of active study drug administration. For 
determining this date, matching placebo dummy treatment 
records will be excluded.


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Study Day 1 or Day 1
The date of first administration of study drug/first dose date.
Study Day
All other study days will be labeled relative to Day 1. For 
events with dates on or after Day 1, study day for the event 
is calculated as (event start date – first dose date + 1). For 
events with dates before Day 1, study day for the event is 
calculated as (event start date – first dose date).
Day 0 will not be used.
Duration of an event
Duration of an event is calculated as (event end date – event 
start date +1).
1 month
30 days; to be used in defining 3-month or 6-month 
confirmed disability worsening or improvement.
4 weeks
28 days; to be used in determining target days of scheduled 
visits. It is based on the scheduled injection frequency for 
ofatumumab (during the maintenance phase).
Day post-study drug 
discontinuation
Day post-study drug discontinuation for a particular event is 
calculated as (event start date – study drug discontinuation 
date). 
Baseline
Baseline is the last assessment obtained prior to the first 
administration of study drug. No visit windows will be 
needed for the identification of baseline assessment.
For pulse and blood pressure vital sign values, the baseline 
is the average of the non-missing values of the 3 
measurements taken on the last visit prior to the first 
administration of study drug. The pre-injection assessment 
values on Day 1 vital sign CRF page will not be used for 
baseline derivations.
On-treatment period
For patients randomized to receive ofatumumab, on-
treatment period includes days from the first injection date 
until 30 days after the last injection date; for patients 
randomized to receive teriflunomide, on-treatment period 
includes days from the first dose date until the last dose date. 
This definition considers patients on ofatumumab are 
scheduled to inject every 28 +/- 3 days. The on-treatment 
definition applies to efficacy analyses only.
For calculation of compliance to study drug administration, 
similar definition of on-treatment period except based on 
actual treatment assignment will be used.
Safety cutoff (off-treatment)
Safety cutoff: Unless explicitly otherwise stated (e.g. SAEs 
and deaths), data up to and including the safety cutoff of 100 
days after permanent study drug discontinuation will be 


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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 (5x20 days) takes the long half-life 
of both investigational and comparator-drug into account. 
The safety cutoff applies to safety analyses only.
Nominal visits
Nominal visits are defined as all scheduled visits as per the 
clinical study protocol including the EOS and EOT visits. 
The definition of nominal visit excludes unscheduled visits.
Only vital signs data collected on Day 1, Day 7, Day 14 and 
Month 1 protocol scheduled visit and ECG data collected on 
EOT and EOS visits will be summarized by nominal visit.
End of Study (EOS) 
EOS, used in the context of individual patients, refers to 
EOS visit. 
EOS, used in the context of the entire study, refers to 
completion of treatment epoch for all patients.
End of Treatment (EOT)
EOT refers to EOT visit. Only patients who prematurely 
discontinue study drug but agree to continue to follow the 
schedule of assessments in the treatment epoch will have 
EOT visit.
End of treatment epoch date
This date is the date of discontinuation/study phase 
completion as recorded in the Study Phase Completion CRF 
page.
Last assessment on drug
It is the last assessment with non-missing value taken before 
or on the date of last administration of study drug. No visit 
windows will be needed for the identification of the last 
assessment on drug evaluation.
Table 2-2
Definition of time in key analyses
Time in study (ARR)
Time in study for ARR will be calculated as (end of 
treatment epoch date – first dose date+1)/365.25. 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.
Time from screening scan 
(MRI: key secondary analysis 
related)
T2 lesions: The time from screening scan will be calculated 
as (date of last scheduled MRI scan with a non-missing value 
for the number of new or enlarging T2 lesions during the 
treatment epoch – date of screening scan +1)/365.25.
Brain volume change: Time of MRI assessment from 
screening scan will be calculated as (date of the scheduled 
MRI scan – date the screening scan +1)/365.25.


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Time at risk for AE
Time at risk for AE is defined as the number of days spent 
in the study, from first to last administration of study drug, 
plus the safety data cut-off of 100 days. Time at risk for AE 
will be used for tables reporting AEs (including both SAE 
and non-SAE). If the corresponding last day of time at risk 
for AE is after the analysis cut-off date, then it will be 
truncated by the analysis cut-off date as defined in Section 
2.1.
Time at risk for SAE
Time at risk for SAE is defined as the number of days spent 
in the study from the day of first administration of study drug 
to the end of study date (including safety follow up epoch). 
Time at risk for SAE will be used only for tables reporting 
SAEs. If a patient is still in safety follow up epoch at the time 
of reporting, time at risk for SAE is the number of days from 
the day of first administration of study drug to the analysis 
cut-off date as defined in Section 2.1.
2.1.2
Visit windows
2.1.2.1
Visit windows for treatment epoch
Visit-windows will be used for both efficacy and safety data summaries by visit. Visit windows 
define a time period “around” the targeted visit date as defined in the evaluation schedule of the 
clinical study protocol. Visit-windows are non-overlapping, and defined without gaps between 
consecutive visit windows. The width of visit windows may vary over the course of the study 
period.
Baseline assessments are defined in Section 2.1.1 and do not require a visit window. 
The purpose of visit windows is to analyze data based on the actual study days (rather than 
"nominal" visits). E.g., if a patient’s Month 1 visit is delayed; it is possible that the Month 1 
data be re-aligned to visit-window Month 2 and be summarized under Month 2.
- For efficacy analyses (including PK concentration by visit analysis) all nominal visits (i.e. 
excluding unscheduled visits) will be mapped into one of the defined visit-windows. Note: for 
the derivation of disability worsening or improvement all visits (scheduled and unscheduled) 
need to be considered before the worsening or improvement can be confirmed (see Section 
2.6.1.1). Similarly, for No Evidence of Disease Activity (NEDA-4), all visits (scheduled and 
unscheduled) need to be considered (Section 2.7.1).
-For safety analyses all visits (scheduled and unscheduled) will be mapped to visit windows. 
Safety data from unscheduled visits may be reported separately if applicable.
It is possible that more than one assessment of a patient fall into a particular visit-window. 
Section 2.1.2.3 deals with the statistical approaches to handle multiple visits in a given visit-
window.


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Tables displaying summary statistics “by visit” will also use the term visit-window as column 
header; this is to remind the reviewer that multiple assessments of a patient might be 
summarized. Below tables provide visit-windows definitions for applicable parameters.
Table 2-3
Visit-windows for EDSS*/T25FW
Visit-window
Start day
Target Day
End day
Week 12
1
84
126
Week 24
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week 84
547
588
630
Week 96
631
672
714
Week 108
715
756
798
Week 120
799
840
881
* For EDSS, assessment on Day 1 will be excluded as baseline EDSS can occur on Day 1 per 
protocol.
Table 2-4
Visit-windows for 9HPT/SDMT/MSIS-29/
Visit-window
Start day
Target Day
End day
Week 24
1
168
252
Week 48
253
336
420
Week 72
421
504
588
Week 96
589
672
756
Week 120
757
840
923
Table 2-5
Visit-windows for MRI/
Visit-window
Start day
Target Day
End day
Week 48
1
336
504
Week 96
505
672
839
Table 2-6
Visit-windows for routine laboratory values
Visit-window
Start day
Target Day
End day
Week 4
1
28
56
Week 12
57
84
126
Week 24
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546


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Week 84
547
588
630
Week 96
631
672
714
Week 108
715
756
798
Week 120
799
840
881
Table 2-7
Visit-windows for vital signs* 
Visit-window
Start day
Target Day
End day
Week 12
1
84
126
Week 24
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week 84
547
588
630
Week 96
631
672
714
Week 108
715
756
798
Week 120
799
840
881
*Data collected from Day 1, Day 7, Day 14 and Month 1 protocol scheduled visit will not be mapped to 
the visit windows due to different data collection on those visits.
Table 2-8
Visit-windows for B-cell counts
Visit-window
Start day
Target Day
End day
Week 1
1
7
10
Week 2
11
14
21
Week 4
22
28
56
Week 12
57
84
126
Week 24
127
168
210
Week 36
211
252
294
Week 48
295
336
378
Week 60
379
420
462
Week 72
463
504
546
Week 84
547
588
630
Week 96
631
672
714
Week 108
715
756
798
Week 120
799
840
881
Table 2-9
Visit-windows for ADA data
Visit-window
Start day
Target Day
End day
Week 4
1
28
98
Week 24
99
168
252


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Week 48
253
336
504
Week 96
505
672
839
Table 2-10
Visit-windows for biomarker data
Visit-window
Start day
Target Day
End day
Week 12
1
84
210
Week 48
211
336
504
Week 96
505
672
839
Table 2-11
Visit-windows for PK data
Visit-window
Start day
Target Day
End day
Week 4
1
28
56
Week 12
57
84
126
Week 24
127
168
252
Week 48
253
336
504
Week 96
505
672
839
2.1.2.2
Visit windows after study drug discontinuation
For summaries of data collected after study drug discontinuation, data from both treatment 
epoch and safety follow-up epoch will be considered. All reporting will be done based on visit 
windows defined relative to the last administration of study drug.
The visit window definitions are provided in Table 2-12 where the Start day and End day are 
relative to the date of last administration of study drug. For the “Last assessment on drug”, the 
last assessment with non-missing value taken before or on the date of last administration of 
study drug will be summarized (no visit window applies). For the “Week 12 after LDD” visit-
window, assessments taken at least 1 day after but no more than 126 days after the date of last 
administration of study drug will be considered. LDD stands for last dose date and will be 
footnoted in applicable outputs.
Table 2-12
Visit-windows after study drug discontinuation
Visit-window
Start day 
Target Day
End day
Last assessment on drug
NA
NA
NA (see above or section 
2.1.1)
Week 12 after LDD
2 
84
126
Week 24 after LDD
127
168
210
Week 36 after LDD
211
252
294
Week 48 after LDD
295
336
378
Week 60 after LDD
379
420
462


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Week 72 after LDD
463
504
546
Week 84 after LDD
547
588
630
Week 96 after LDD
631
672
714
Week 108 after LDD
715
756
798
Week 120 after LDD
799
840
881
2.1.2.3
Multiple assessments within visit windows
It is possible that multiple assessments of a patient fall into the same visit-window (e.g. due to 
unscheduled visits). All results (scheduled and unscheduled) will be displayed in listings, but 
only one value (observed or derived) will be selected for summary statistics by visit-window.
For quantitative variables, the assessment closest to the target day will be selected. If more 
than one assessment is at the same distance to the target day, the later one will be selected. For 
tables displaying the worst case scenario, such as shift tables or notable abnormalities, all 
assessments within a visit window will be used to identify the worst (e.g. the maximum or the 
minimum depending on parameter). Where applicable it will be defined for each parameter 
what the worst case is.
For qualitative variables, the worst record is selected; it is noted that in the relevant data 
subsection, worst case is always well defined. 
2.2
Analysis sets
All screened patients (SCR): The SCR set comprises all patients who were screened.
Full analysis set (FAS): The FAS comprises all randomized patients with assigned treatments. 
Patients will be analyzed according to the randomized treatment assignment following the 
intention-to-treat (ITT) principle, even if they actually received no or a different treatment. 
The FAS will be used for the summary of demography and baseline characteristics as well as 
for all efficacy analyses.
Per-protocol set (PPS): The PPS is a subset of FAS, consists of all randomized patients 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 efficacy data assessed during the on treatment period (as defined 
in Section 2.1.1) will be included. 
The PPS will be used for the supportive analyses of the primary efficacy variable and selected 
key secondary variables. 
Safety set (SAF): The SAF set includes all patients who received at least one dose of study 
medication. Patients will be analyzed according to the actual treatment received. If patients
received both investigational drug and active comparator accidentally during the study, they 


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will be analyzed according to the treatment to which they were exposed longer in duration. The 
SAF will be used for all safety analyses.
2.2.1
Subgroup of interest
Only protocol specified subgroup analyses will be covered in the CSR. Subgroup analyses on 
the pooled study data for submission purpose are out of the scope of this SAP but will be 
specified in the relevant submission plan document (e.g., Clinical Summary Preparation 
Document (CSPD)). As subgroup analyses do not control for either type I or type II error, they 
should be considered as hypothesis generating in nature with the purpose of examining potential 
inconsistencies of a treatment among the many subgroups being examined. All confidence 
intervals and p-values for subgroup analysis will be presented without multiplicity adjustments.
Subgroups for efficacy analyses:

NfL level (high:>median, low:<=median), where the median is defined based on all patients 
in the FAS of the combined data from both ASCLEPIOS studies.

NfL levels (<Q1; >=Q1 but <Q2; >=Q2 but < Q3; >=Q3; where Q1, Q2 and Q3 are first, 
second and third quartiles of baseline neurofilament levels in all patients from studies 
G2301 and G2302 combined)

Vitamin D levels ( <Q1; >=Q1 but <Q2; >=Q2 but < Q3; >=Q3; where Q1, Q2 and Q3 are 
first, second and third quartiles of baseline vitamin D levels in all patients from studies 
G2301 and G2302 combined)

Newly diagnosed (within 3 years prior to the screening visit) and treatment-naïve (no prior 
MS DMT) patients
These subgroups will be used for selected exploratory analyses as described in Section 2.12.
Subgroups for safety analyses:

Age at baseline (<18, 18-30, 31-40, 41-55, >55)

Gender (male, female)

Gender x Age: 10 subgroups defined by age and gender: female & age <18; female & age 
of 18-30; female & age  of 31-40; female & age of 41-55; female & age >55; male & <18; 
male & age of 18-30; male & age of 31-40; male & age of 41-55; male & age >55;

Gender x body weight (by quartile): 8 subgroups defined by gender and baseline body 
weight: female & weight <Q1; female & weight >=Q1 but <Q2; female & weight >=Q2 but 
< Q3; female & weight >=Q3; male & weight <Q1; male & weight >=Q1 but <Q2; male & 
weight >=Q2 but < Q3; male & weight >=Q3; where Q1, Q2 and Q3 are first, second and 
third quartiles of baseline weight in all patients from studies G2301 and G2302 combined 

Race (White, Asian, Black or African Americian, Other)
o
White: those who selected “Caucasian” as race on demography CRF
o
Asian: those who selected “Asian” as race on demography CRF
o
Black or African American: those who selected “Black” as race on demography 
CRF


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o
Other: those who selected “Native American” or “Pacific Islander” or “Unknown” 
or “Other” as race on demography CRF

*Patients who accidentally received both investigational drug and active comparator during 
the study

**Patients in SAF who had data reported after date of last administration of study drug

**Patients in SAF who had at least one eCSSRS performed after the date of last 
administration of study drug

**Patients in SAF who had B-cell count data after the date of last administration of study 
drug

**Patients in SAF who had teriflunomide data
*This subgroup will be used for exploratory analysis described in Section 2.8.1. **These 
subgroups will be used for corresponding safety follow up data analysis described in Section 
2.8.7. Rest of the subgroups will be used for patient-year summaries described in Section 2.4.1.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number and percentage of patients who were screened but did not continue into the 
treatment period will be presented, along with the reason for discontinuation. Data collected on 
the screening phase disposition CRF page will be used to summarize this information. The 
summary will be on the SCR set.
The number and percentage of patients who completed the study on treatment or prematurely 
discontinued study drug will be presented, along with the primary reason for discontinuation. 
Data collected on the end of study treatment CRF page will be used to summarize this 
information. The summary will be on the FAS.
The number and percentage of patients who completed the study (i.e., treatment epoch) or 
prematurely discontinued study prior to the end of the treatment epoch will be presented, along 
with the primary reason for discontinuation. Data collected on the study phase completion CRF 
page will be used to summarize this information. The summary will be on the FAS.
Time to study drug discontinuations and time to study discontinuations by treatment group will
be presented using Kaplan-Meier estimates in survival curves and in summary tables, along 
with the p-value from the log-rank test. Time to study drug discontinuation in (days) will be 
derived as [last dose date – first dose date + 1]. Time to study discontinuation (in days) will be 
derived as [date of discontinuation/study phase completion” for the treatment epoch – first dose 
date + 1]. The event flag for analysis of time to study drug discontinuations is set to 1 for patients 
who answered “No” to question “did the subject complete study treatment” as recorded on End 
of Study Treatment CRF page or 0 otherwise. The event flag for analysis of time to study 
discontinuations is set to 1 for patients whose “subject status” is not “completed” as recorded 
on Study Phase Completion CRF page or 0 otherwise. These analyses will be on the FAS.


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The number and percentage of patients in each analysis set will be presented by treatment group. 
Protocol deviations will be summarized by deviation categories and treatment for the FAS. In 
addition, protocol deviations that led to exclusion from the analysis set will be summarized by 
deviation category, deviation terms and treatment groups for the FAS.
Patients exclusion from PPS will be listed for all patients with reasons for exclusion (i.e. 
including both protocol and non-protocol deviations).
2.3.2
Background and demographic characteristics
Background characteristics include recipient demographic characteristics (gender, race and 
ethnicity collected on the Demography CRF), age, height, body weight, BMI and employment 
status at baseline.
Age will be calculated from date of first administration of study drug and date of birth. Derived 
baseline height, body weight and BMI will be presented. These variables will be summarized
by treatment group for the FAS using frequency distributions (for categorical variables) and 
descriptive statistics of mean, standard deviation, minimum, median and maximum (for 
continuous variables). 
Demography will be presented by study but also side-by-side for the two studies in the 
combined report to evaluate poolability of the two ASCLEPIOS trials.
2.3.3
MS baseline disease characteristics
MS baseline characteristics, MS disease history and MS medication history will be summarized 
by treatment group for the FAS in the individual study reports but also side-by-side for the two 
studies in the combined report to evaluate poolability of the two ASCLEPIOS trials.
MS baseline characteristics include baseline EDSS, 9HPT, T25FW, SDMT, and key MRI 
parameters (e.g., number of Gd-enhancing T1 lesions, T2 lesion volume, and normalized brain 
volume). 
MS disease history includes duration of MS since diagnosis (years), duration of MS since first 
symptom (years), number of relapses in the last 12 months prior to screening, number of 
relapses in the 12 to 24 months prior to screening, type of MS at study entry (i.e., RRMS or 
SPMS), time since onset of SPMS, and time since onset of most recent relapse (months) prior 
to screening. 
Duration of MS since diagnosis (years) will be derived [(first dose date – MS diagnosis start 
date + 1)/365.25]; duration of MS since first symptom (years) will be derived as [(first dose 
date – first MS symptom date +1)/365.25]; time since onset of SPMS (years) will be derived as 
[(first dose date – conversion to SPMS date +1)/365.25]; and time since onset of most recent 
relapse (months) will be derived as [(first dose date – most recent relapse onset date + 
1)/(365.25/12)]. In these calculations, partial dates if any will be imputed according to the rules 
specified in Section 5.1.3.3.
MS medication history of previous disease-modifying drugs (coded by WHO drug dictionary) 
will be summarized by preferred term (PT) and treatment group. The number and proportion of 
treatment-naïve patients (i.e., patients who have not been treated with any disease- modifying 
drug before study enrolment) will also be presented.


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2.3.4
Medical history
Medical history will be summarized by treatment group for the FAS. Any condition entered on 
the Medical History (MH) CRF will be coded using the MedDRA dictionary. The medical 
history will be summarized by primary system organ class (SOC), preferred term (PT) and 
treatment group.
The MH conditions captured on the eCRF “Protocol solicited medical history or medical history 
possibly contributing to liver dysfunction” will be tabulated in the regular MH table for level 2 
drugs (because the solicited events are captured for all patients) and shown and flagged in the 
regular MH listing. There is no separate deliverable required.
2.3.5
Smoking history and alcohol history
Data collected on smoking history and alcohol history CRF pages will be listed as appropriate.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Exposure to study treatment / compliance / time at risk
Duration of exposure to study drug will be derived as follows:

For patients whose actual treatment (Section 2.2 Safety set) is teriflunomide, duration 
of exposure will be calculated as (last dose date – first dose date +1- Ʃ [number of days 
with temporary study drug interruption]), which is the number of days between the first 
and the last day of study drug administration, excluding the number of days with 
temporary study drug interruption (as patients are scheduled to take the oral study 
medication once daily).

For patients whose actual treatment is ofatumumab, duration of exposure will be 
calculated as (last injection date – first injection date + 31 – Ʃ [(j+1)th injection date –
jth injection date -31]), where j and j+1 refer to consecutive injections with injection 
dates more than 31 days apart (as patients are scheduled to take the subcutaneous 
injections every 28 +/- 3 days).
Duration of exposure to study drug will be summarized descriptively on SAF set by treatment 
group and duration category (i.e., ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 12 
weeks, ≥ 24 weeks, ≥ 36 weeks, ≥48 weeks, ≥ 60 weeks, ≥ 72 weeks, ≥ 84 weeks, ≥ 96 weeks, 
≥ 108 weeks, ≥120 weeks, ≥ 132 weeks, ≥ 144 weeks, ≥ 156 weeks, ≥ 168 weeks). Descriptive 
statistics of duration in days will also be provided by treatment group.
For each treatment group, the number of patient-years is calculated as (the sum of the number 
of days of exposure for all patients in the group)/365.25 and will be summarized by age and 
gender, by gender and weight, as well as by race. Cutoffs for age subgroups and weight 
subgroups are defined in Section 2.2.1.
Time at risk is the censoring time used for estimating exposure adjusted incidence rate of SAEs 
or AEs in patients who did not experience the event of interest. For patients who have 
experienced the event of interest, the actual date of the SAE, or AE onset will be used. Details 


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about the calculation of exposure adjusted incidence rate of adverse events are described in 
Section 5.7.2. Time at risk also corresponds to the time period used for adverse event reporting.

Time at risk for AE is defined as the number of days spent in the study, from first to 
last administration of study drug, plus the safety data cut-off of 100 days. Time at risk 
for AE will be used for tables reporting AEs (including both SAE and non-SAE). If the 
corresponding last day of time at risk for AE is after the analysis cut-off date, then it
will be truncated by the analysis cut-off date as defined in Section 2.1.

Time at risk for SAE is defined as the number of days spent in the study from the day 
of first administration of study drug to the end of study date (including safety follow up 
epoch). Time at risk for SAE will be used only for tables reporting SAEs. If a patient is 
still in safety follow up epoch at the time of reporting, time at risk for SAE is the number 
of days from the day of first administration of study drug to the analysis cut-off date as 
defined in Section 2.1.
Time at risk for AE and time at risk for SAE will be summarized in a similar way to duration 
of exposure to study drug.
Compliance to the study drug administration schedule will be calculated as duration of 
exposure to study drug in (days)/duration of on-treatment period (as defined in Section 2.1.1) 
in (days) ×100%. This rule means that compliance will be measured during the time interval 
the patient took study medication: premature discontinuation from study drug will not be 
considered non-compliance. Compliance to study drug administration will be summarized 
descriptively on SAF by treatment group. In addition, compliance will be summarized with 
cumulative number and percentage of patients in each compliance category (i.e., ≥ 20%, ≥ 30%, 
≥ 40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, ≥98%, =100%).
2.4.2
Prior, concomitant and post therapies
Analyses described in this section will be performed on the SAF.
2.4.2.1
Concomitant medication
Records on the Prior and Concomitant Medications CRF page will be coded using the WHO
drug dictionary. All medications will be classified as prior, concomitant or post study drug 
discontinuation medication as follows:

Prior medications are defined as drugs taken and stopped prior to first dose of study 
medication.

Concomitant medications are defined as drugs taken at least once between first dose and 
last dose of study medication (including those which were started prior to first dose and 
continued into the treatment period).

Post-study drug discontinuation medications will be drugs started after the discontinuation 
of randomized study medication.
Medications will be categorized into one (and only one) of above classes based on recorded or 
imputed start and end dates. When incomplete or missing, dates will be imputed according to 
Novartis standards (details will be given in programming datasets specifications (PDS) 
document). If both start date and end date are completely missing and medication was not 


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collected on the “Previous MS Disease Modifying Treatment” page, medication will be 
classified into concomitant medication category.
Medications in each of these 3 categories will be summarized separately by treatment group, 
ATC code and preferred term. ATC level 1 and level 3 (e.g., M [Musculo-skeletal system], 
M01A [anti-inflammatory and anti-rheumatic products, non steroids], etc.) will be used.
Data collected from the Previous MS disease modifying treatment pages or as "Injection related 
premedication" in the concomitant medication pages will not be included in this summary.
2.4.2.2
Surgical and medical procedures
Records on the surgical and medical procedures CRF page will be coded using the MedDRA 
dictionary. All procedures will be classified as prior, concomitant or post-study drug 
discontinuation procedure, in the same way as done for concomitant medications.  Surgical and 
medical procedures in each of these 3 categories will be summarized separately by system organ 
class, preferred term and treatment group.
Imputation rules for start and end dates will follow the same rule as for the concomitant 
medications.
2.4.2.3
Injection related premedication
Injection related premedication will be identified by subcategory “Injection related 
premedication” in concomitant medication data set. Injection related premedication will also be 
summarized separately for each injection up to injection 10 and cumulatively for all injections.
For injection 1 summary, the injection related premedication with either start date or end date 
on the same day as the first injection date will be included and summarized for each of the three
protocol specified types and for each combination of the specified types (type 1+ type 2, type 
1+ type 3, type 2+ type 3, type 1+ type 2+ type 3). The three protocol specified types are steroids
(type 1), antihistamines (type 2) , and antipyretics/analgesics (type 3) (corresponding to 
“Acetaminophen” as specified in the table shell for this summary). The steroids (type 1) will be 
identified by category “Steroid”. The antihistamines (type 2) will be identified by ATC level 3 
“antihistamines for systemic use”. The antipyretics/analgesics (type 3) will be identified by 
ATC level 3 “other analgesics and antipyretics” and “anti-inflammatory and anti-rheumatic 
products, non-steroids”. In summaries for each combination of the specified types, the number 
and proportion of patients who took both (or all 3) types of injection related premedication at 
specified injection will be provided.
Rest injection specific summaries or cumulatively summaries will be reported similarly.
2.4.2.4
Previous MS disease modifying treatment
Data collected from the Previous MS disease modifying treatment pages will be summarized 
separately.


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2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary endpoint is the annualized relapse rate (ARR), which is defined as the number of 
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 (NB) model by using 
individual relapse count as the response variable with natural log of time in study in years 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. All confirmed relapses with a start date on or after the date 
of first administration of study drug and prior to or on the end of treatment epoch date 
will be included in the analysis. Additional details are provided in Section 5.1.3.4.
o
The definition of a confirmed MS relapse is one accompanied by a clinically 
relevant change in the EDSS assessment, i.e. an increase of at least 0.5 points on 
the EDSS (total) score, or an increase of at least 1 point on at least two Functional 
scores (FSs), or an increase of at least 2 points on at least one FS, excluding 
changes involving bowel/bladder or cerebral FS, compared to the last EDSS
assessment taken in the absence of (confirmed or unconfirmed) relapse and prior 
to the current relapse. EDSS obtained on the date as indicated on the Summary 
of MS Relapse eCRF page will be used. If such EDSS assessment is missing or 
not meeting the criteria to confirm the relapse, all other EDSS assessments taken 
within 30 days from the relapse start date (i.e., EDSS assessment date – relapse 
start date <=30) and before the relapse end date (EDSS assessment date < relapse 
end date) will be checked. If at least one of such available EDSS assessments 
meets the criteria, the relapse is a confirmed relapse. Otherwise, the relapse is 
considered an unconfirmed relapse.

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. 
Time in study for ARR will be calculated as (end of treatment epoch date – first dose 
date+1)/365.25.
2.5.2
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no difference in the ARR between ofatumumab 20mg 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 two treatment groups. 
Superiority of ofatumumab 20mg sc over teriflunomide 14 mg po will be concluded if the 
observed ARR on ofatumumab 20mg 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 


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EDSS, baseline number of T1 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. 
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 if that is indicated based on 
statistical criteria (e.g. non-convergence of models). 
2.5.3
Multiplicity adjustment
The planned submission consists of two studies of identical design (G2301 and G2302), 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 2-1 will be implemented. 


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Figure 2-1
Multiple testing procedure
Testing procedure and type-I-error control in the planned ofatumumab submission which consists of 
studies G2301 and G2302 (both with identical design). Hypotheses can only be tested in sequential 
order as indicated by the arrows. The number 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 two 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 2-1). 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-


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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 G2301 and G2302, at the submission level. Disability endpoints will be tested 
in hierarchical order as indicated by arrows in (Figure 2-1). 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.
2.5.4
Handling of missing values/censoring/discontinuations
The primary NB 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, patients who discontinue study 
treatment should remain in the study and follow the assessment schedule. The primary analysis 
will use all available data up to the end of treatment epoch date, irrespective of on or off 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).
2.5.5
Supportive analyses
The primary analysis will be repeated to analyze all reported MS relapses (confirmed or 
unconfirmed).
The primary analysis will also be repeated using the per-protocol set to provide an analysis of 
on-treatment data from patients who have no major protocol violations (refer to Section 5.6 for 
details of how per-protocol set flag is derived for each patient). Only relapses with a start date 
during the on-treatment period (as defined in Section 2.1.1) will be included and natural 
log(time on study drug in years) rather than natural log(time in 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 20mg sc once monthly 
and teriflunomide 14 mg po once daily during the initial “onset of action” period of 8 week 
(≤56 days=8*7 days), and relapse rates and the treatment effect thereafter (>56 days; long-term 
efficacy) a sensitivity analysis will be conducted on the FAS. This analysis will be implemented 


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as a piecewise negative binomial model assuming different event rates and ARR-ratios before 
and after week 8, but constant dispersion and covariates adjustment (as in the primary analysis 
model). Details of the statistical model and implementation of the model are provided in Section 
5.5.3.1.
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 20mg 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 on 
the FAS. 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. For patients with at least one 
relapse, the time to first relapse will be calculated as (start date of first relapse - date of first 
administration of study drug+1). For patients without relapses, they are censored with censored 
time as time in study (as defined in Section 2.5.1).
2.6
Analysis of the key secondary objectives
2.6.1
Key secondary endpoints
2.6.1.1
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. Analogously, a 6-month confirmed disability 
worsening (6mCDW) is defined as an increase from baseline in EDSS sustained for at least 6 
months. This means that after a scheduled or unscheduled visit at which the patient fulfills the 
disability worsening criterion as defined in Table 2-13, 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 in the absence of (confirmed or unconfirmed) 
relapse 3 months/90 days (or 6 months/166 days) after the onset of the worsening, or later.
In the time to event (3mCDW or 6mCDW) analysis, time will be calculated as (the date of 
EDSS assessment at onset of the event – date of first administration of study drug+1) for patients 
with the events. Censoring occurs in those patients who did not experience an event in the study 
(during the treatment epoch), this includes 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 calculated as (the date of last EDSS assessment during the treatment epoch – date of 
first administration of study drug+1). Additional details are provided in footnote of Table 2-13.
Table 2-13
Criterion for disability worsening based on change in EDSS score
Total EDSS at baseline* 
“Disability worsening” criterion
0
≥ +1.5


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0.5 to 5
≥ +1
≥5.5
≥ +0.5
A 3-month confirmed disability worsening 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 in the absence of 
(confirmed or unconfirmed) relapse 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 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 in the absence 
of (confirmed or unconfirmed) relapse if, over a period of 6 months (≥166 days=6*30-14 [visit window]) 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. The time will be calculated as (date of EDSS 
assessment at a tentative onset of the event – date of first administration of study drug+1) or (date of death –
date of first administration of study drug + 1) if a tentative onset date does not exist. Note: Death for other reasons 
than MS (i.e. not EDSS=10) will not be considered a disability worsening.
*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)
2.6.1.2
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. This means that after a scheduled or unscheduled visit at 
which the patient fulfills the disability improvement criterion as defined in Table 2-14, all EDSS 
assessments (scheduled or unscheduled) need to also fulfill the improvement criteria until the 
improvement (“the event”)  can be confirmed at the first scheduled visit that occurs 6
months/166 days after the onset of the improvement, or later. In the time to event (6mCDI) 
analysis, time will be calculated as (the date of EDSS assessment at onset of the event – date of 
first administration of study drug+1) for patients with the events. Censoring occurs in those
patients who did not experience a 6mCDI event in the study (during the treatment epoch), this 
includes patients who had a “tentative” disability improvement that could not be confirmed due 
to an early discontinuation or any another reason. The censoring time is calculated as (the date 
of last EDSS assessment during the treatment epoch – date of first administration of study 
drug+1).
Table 2-14
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
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.
*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


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2.6.1.3
Number of Gd-enhancing lesions per scan
Number of Gd-enhancing lesions will be obtained from each MRI scan per protocol assessment 
schedule. To estimate the number of Gd-enhancing lesions per scan, below variables will be 
derived: 
o
The total number of Gd-enhancing lesions during the treatment epoch will be 
derived by taking the sum of numbers of Gd-enhancing lesions from all scheduled 
MRI scans during the treatment epoch. MRI scans taken within 30 days after the 
termination of steroid therapy will not be included in analysis of Gd lesion related 
endpoint.
o
The number of MRI scans will be derived by counting the number of scheduled MRI 
scans with non-missing values for the number of Gd-enhancing lesions during the 
treatment epoch.
2.6.1.4
Annualized rate of new or enlarging T2 lesions
The number of new or enlarging T2 lesions as compared to the baseline MRI scan will be 
obtained from each MRI scan per protocol assessment schedule. To estimate the annualized rate 
of new or enlarging T2 lesions, below variables will be derived:
o
The total number of new or enlarging T2 lesions during the treatment epoch will be 
derived by taking the number of new or enlarging T2 lesions from the last scheduled 
MRI scan with a non-missing value during the treatment epoch.
o
The time (in years) from screening scan will be calculated as (date of last scheduled 
MRI scan with a non-missing value for the number of new or enlarging T2 lesions 
during the treatment epoch – date of screening scan +1)/365.25.
2.6.1.5
Neurofilaments light chain (NfL)
The NfL concentration in serum will be collected per protocol assessment schedule. To estimate 
the geometric mean of NfL, below variable will be derived:
o
The log-transformed value of NfL at each time point will be derived by taking the 
natural logarithm of the NfL concentraction values.
2.6.1.6
Brain volume loss
The normalized brain volume will be obtained at baseline MRI scan and percent change from 
baseline in brain volume will be obtained from each MRI scan per protocol assessment schedule. 
To estimate the annual rate of percent change from baseline in brain volume, all available 
scheduled MRI assessments taken during the treatment epoch will be used and the below 
variable will be derived for each assessment. 

Time of MRI assessment from screening scan will be calculated as (date of the 
scheduled MRI scan – date the screening scan +1)/365.25.


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2.6.2
Statistical hypothesis, model, and method of analysis
2.6.2.1
Disability worsening (3-month or 6-month confirmed)
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 
20mg sc and teriflunomide 14 mg po 

Superiority of ofatumumab 20mg 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 2.5.3 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 
G2301 and G2302. 
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. For 
confirmatory purposes the hazard ratio between ofatumumab and teriflunomide will be 
esitmated with 95% confidence interval and p-value from the combined data from both studies 
in this meta-analysis. In addition, an expanded model with a treatment-by-study interaction will 
be fit to the data and 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 expanded model 
with corresponding 95% confidence intervals and p-values. 
Supportive analysis: The confirmatory analysis of time to 3mCDW will also be done in a 
meta-analysis based on the combined per-protocol sets from G2301 and G2302.
Kaplan-Meier curves (and/or cumulative incidence plots) will be provided by treatment for the 
combined study populations to present the time-dependent cumulative probability of patients 
reaching 3mCDW. Kaplan-Meier curves (and/or cumulative incidence plots) and KM estimates 
by treatment will also be provided by study. 
By-treatment Kaplan-Meier (KM) estimates (and/or 1-KM estimates) will be calculated for the 
combined study data at month 18 and month 24, with 95% confidence intervals. Similar 
estimates will be provided by study. 
The log-rank test stratified by study will be performed for the combined study data as a 
supportive analysis. The log-rank test for each study data will also be performed for information 
only.
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-


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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. Details of the statistical model and 
implementation of the model are provided in Section 5.5.3.2. 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 will be performed similarly to the confirmatory analysis but patients who 
prematurely discontinued study with reason being “Lack of efficacy” as recorded in study phase 
completion CRF page and all patients who died during the treatment epoch (regardless whether 
due to MS or not) are considered having the disability worsening (3mCDW or 6mCDW) and 
time will be calculated based on a tentative onset date if it exists or on the study discontinuation 
date or death date as applicable (i.e., date of EDSS assessment at a tentative onset/EOS date/date 
of death- date of first administration of study drug+1).
An additional sensitivity analysis will be performed in which patients who prematurely 
discontinued study due to “Lack of efficacy” or died (due to any reason) during the treatment 
epoch will be considered having the disability worsening (3mCDW or 6mCDW) if patients 
were randomized to the ofatumumab treatment group.
2.6.2.2
Disability improvement (6-month confirmed)
Hypothesis and Analysis of disability improvement (6mCDI)
The null hypothesis is that there is no difference in the time to 6mCDI between ofatumumab 
20mg sc and teriflunomide 14 mg po 

Superiority of ofatumumab 20mg sc over teriflunomide 14 mg po will be concluded if 
there is an improved change 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 2.5.3
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 G2301 
and G2302. 
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. 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, an expanded model with a treatment-by-study interaction will 
be fit to the data and 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 expanded model 
with corresponding 95% confidence intervals and p-values.
Supportive analysis: 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 


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combined study data at month 18 and month 24, with 95% confidence intervals. Similar 
estimates will be provided by study.
The log-rank test stratified by study will be performed for the combined study data as a 
supportive analysis. The log-rank test for each study data will also be performed for information 
only.
2.6.2.3
Number of Gd-enhancing lesions per scan
The null hypothesis is that there is no difference in the number of Gd-lesion per scan between 
ofatumumab 20mg sc and teriflunomide 14 mg po 

Superiority of ofatumumab 20mg sc over teriflunomide 14 mg po will be concluded if 
there are fewer Gd-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-sided 
significance level of 0.05. The multiplicity adjustment explained in Section 2.5.3 applies.
Confirmatory analysis of the number of Gd-lesions per scan: The confirmatory analysis of 
the number of Gd-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 T1 lesions (derived 
as in Section 2.6.1.3) will be used as the response variable, and the natural log of the number of 
MRI-scans (derived as in Section 2.6.1.3) 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 T1 lesions at baseline as continuous covariates. 
The number of Gd-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-lesion per scan will be computed 
as one (1) minus the rate-ratio and expressed as a percentage.
Supportive analysis: The number of Gd-lesions will be summarized descriptively by visit-
window and treatment group.
2.6.2.4
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 20mg sc and teriflunomide 14 mg po 

Superiority of ofatumumab 20mg 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 2.5.3
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 (derived as in Section 


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2.6.1.4) will be used as the response variable, and the natural log of the time (in years) of the 
MRI assessment from the baseline scan (as defined in Section 2.6.1.4) 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 one (1) minus the rate-ratio and expressed as 
a percentage.
Supportive analysis: The number of new or enlarging T2 lesions collected at each visit will be 
summarized descriptively by treatment group.
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 
based on the new or enlarging T2 lesions between the Month 12 scan and the End of Study scan.
2.6.2.5
Neurofilament light chain (NfL)
The null hypothesis is that there is no difference in NfL between ofatumumab 20 mg sc and 
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 2.5.3 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 
natural log will be used). The response variable is the log-transformed values of the NfL 
level as the NfL level is expected to follow log-normal distribution. The exponentiated 
treatment differences are the geometric mean ratios (GMR) which will be reported by visit 
window with 95% confidence intervals and p-values. 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 visit window 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 model will also 
include a treatment-by-timepoint interaction to allow the treatment effect to vary over time.
The treatment effect of ofatumumab versus teriflunomide will be visualized in a line plot 
with 95% confidence intervals.
Supportive analysis: If ofatumumab significantly reduces NfL as compared with teriflunomide, 
the following additional analyses will be performed. In all patients (FAS), and additionally in
the subgroup of newly diagnosed (within 3 years prior to the screening visit) and treatment-


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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, higher brain volume loss and tend to have a worse disease course on EDSS during 
the study compared with patients with low (≤median) NfL concentration at baseline. The 
median will be estimated from all patients in the combined ASCLEPIOS I and ASCLEPIOS II 
patients and then applied in all analyses.

The T2 lesion rate will be estimated using a negative binomial model similar to the one
specified in Section 2.6.2.4. In addition, the model will include NfL baseline category and 
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. From the same model the high vs low NfL contrasts will be estimated with 95% 
confidence intervals. 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 2.5.2. In addition, the model will include NfL baseline category and 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. From the 
same model the high vs low NfL contrasts will be estimated with 95% confidence intervals.
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. In addition the model will include a treatment-by-NfL interaction term. 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. It is
acknowledged that the study will not be powered to show an effect on disability outcomes
in subgroups. Kaplan-Meier curves will be produced with by treatment and NfL high or low 
category.

The brain volume loss rate will be estimated using a random coefficient model similar to 
the one specified in Section 2.6.2.6. In addition, the model will include NfL baseline 
category and a treatment by time by NfL baseline category interaction as well as the 3 
corresponding 2-way interactions. The annual rate of brain volume change will be estimated 
by treatment within baseline NfL category. The treatment effect will be expressed as an 
rate-ratio with 95% confidence interval, for low and high baseline NfL category, 
respectively. From the same model the high vs low NfL contrasts will be estimated with 95% 
confidence intervals. The statistical hypothesis test with regards to the prognostic value of 


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NfL for on-study brain volume loss will be based on the high vs low baseline NfL category 
contrast in the teriflunomide group.

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,
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
by SOC and PT as well as by predefined adverse events as defined in the latest version of 
case retrieval sheet (eCRS) at the time of analysis implementation (i.e., study database lock).
2.6.2.6
Brain volume loss
The null hypothesis is that there is no difference in brain volume change between ofatumumab 
20mg sc and teriflunomide 14 mg po 

Superiority of ofatumumab 20mg 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 2.5.3 applies.
Confirmatory analysis of brain volume loss: The percentage change from baseline in brain 
volume will be estimated on the basis of all scheduled 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 and treatment by time interaction. 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 approximates 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 Months 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. 
Supportive analysis: Additionally, brain volume change and the annualized rate of brain 
atrophy (ARBA) will be summarized by visit. Calculation of ARBA is provided in Section 2.7.1. 
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 


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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 scheduled scans up to the last available MRI scan that evaluated percentage brain volume 
change relative to baseline in a repeated measures model. The unstructured covariance matrix 
will be used. The model will include treatment and scanning time point as factors (Month 12 
and Month 24), 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 Months 12 (Week 48) and 24 (Week 96) 
as defined in Table 2.5. The comparison of treatment differences in mean at Month 12 and 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.
2.6.3
Handling of missing values/censoring/discontinuations
2.6.3.1
Disability related endpoints (3mCDW, 6mCDW and 6mCDI)
Patients discontinuing study treatment should remain in the study and continue to follow the 
assessment schedule. The primary analysis of the time to 3-month/6-month confirmed disability 
worsening or the time to 6-month confirmed improvement uses all the available data up to the 
end of treatment epoch date, irrespective of on or off study treatment.
All patients in FAS will be included in the primary analysis. Patients who do not reach the 
endpoint by the end of treatment epoch date will be censored at date of last EDSS assessment 
during the treatment epoch.A per-protocol analysis of time to 3mCDW and time to 6mCDW 
will be performed to analyze on-treatment data (on-treatment period as defined in Section 2.1.1) 
from patients who have no major protocol deviations. 
2.6.3.2
MRI endpoints
The primary analysis will use all available data up to the end of treatment epoch date, 
irrespective of on or off study treatment.
For the number of Gd-enhancing lesions and the number of new or enlarging T2 lesions, the 
primary NB model with an offset for the total number of scans or for the time from screening 
scan respectively adjusts for missing information (drop-out) under the assumption of non-
informative drop-out, information is missing at random, and constant intensity (#lesion/time) 
of lesion formation over time. 
For the percent change from baseline in brain volume, the primary analysis of random 
coefficient model will include longitudinal data from all scheduled post-baseline MRI scans as 
response. Under the assumption of linearity of the percentage brain volume change over time, 
the model corrects for missing values.


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2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
Other secondary efficacy endpoints include:

Time to first confirmed relapse: For patients with at least one confirmed relapse, the time 
to first confirmed relapse will be calculated as (start date of first confirmed relapse - date of 
first administration of study drug+1). For patients without confirmed relapses, they are 
censored with censored time as time in study (as defined in Section 2.5.1).

ARR > 8 weeks after the onset of treatment (estimated from sensitivity analysis of primary 
endpoint) (details as described in Section 5.5.3.1).

Risk of a 3mCDW > 8 weeks after the onset of treatment (estimated from sensitivity analysis 
of corresponding key secondary endpoint) (details as described in Section 5.5.3.2).

Risk of a 6mCDW > 8 weeks after the onset of treatment (estimated from sensitivity analysis 
of corresponding key secondary endpoint) (details as described in Section 5.5.3.2).

Time to 6-month confirmed cognitive decline on SDMT (6mCCD): similar to definition of 
6mCDW (Section 2.6.1.1) but replacing the worsening criteria by at least an increase by 4 
points from baseline in SDMT oral score. Patients who do not reach the endpoint by the end 
of treatment epoch date will be censored at date of last SDMT assessment during the 
treatment epoch.

Time to 6mCDW or 6mCCD: defined as either a 6-month confirmed disability worsening, 
or a 6-month confirmed cognitive worsening, whichever is first. If a patient has both events 
achieved, time variables for this composite endpoint will be the same as the event occurred 
earlier. If 6mCDW is achieved but 6mCCD is not, the time variables for this composite 
endpoint will be the same as the time to 6mCDW event. If 6mCCD is achieved but 6mCDW 
is not, the time variables for this composite endpoint will be the same as the time to 6mCCD 
event. If neither events achieved, the patient is censored. The time variable will take the 
larger value in the censoring times corresponding to these 2 individual events.

SDMT oral score by visit-window

Time to 6-month confirmed worsening of at least 20% in the timed 25-foot walk test 
(T25FW): similar to definition of 6mCDW (Section 2.6.1.1) but replacing the worsening 
criteria by at least 20% increase from baseline in T25FW score. Patients who do not reach 
the endpoint by the end of treatment epoch date will be censored at date of last T25FW 
assessment during the treatment epoch.

Time to 6-month confirmed worsening of at least 20% in the 9-Hole Peg Test (9HPT):
similar to definition of 6mCDW (Section 2.6.1.1) but replacing the worsening criteria by at 
least 20% increase from baseline in 9HPT score in at least one hand. Patients who do not 
reach the endpoint by the end of treatment epoch date will be censored at date of last 9HPT 
assessment during the treatment epoch.


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
6mCDI sustained until EOS: same as 6mCDI except that the rest EDSS scores (scheduled 
or unscheduled) after the confirmation visit of the 6mCDI during the treatment epoch have 
to meet the disability improvement criteria as well.

Disability status during the study (classified as improved, stable, or worsened): patients will 
be classified as improved if 6mCDI sustained until EOS was met (regardless whether 
6mCDW status was met at an earlier time point); or classified as stable if 6mCDW was not 
met & 6mCDI sustained until EOS was not met; or classified as worsened if 6mCDW was 
met & 6mCDI sustained until EOS was not met.

MS relapse characteristics include severity, recovery, hospitalization, and steroid treatment. 
The severity of MS relapses will be derived according to the criteria in Table 2-15. All 
relapses (confirmed or unconfirmed) will be considered. For confirmed relapses, the EDSS 
used to confirm the relapse (as specified in Section 2.5.2) will be used to determine the 
severity. For unconfirmed relapses, all EDSS assessments taken within 30 days from the 
relapse start date and before the relapse end date will be checked among which the most 
severe case will be selected to determine the severity. If no such EDSS assessment is 
available, the severity will be set to “missing EDSS”. If none of such EDSS assessments 
meet the mild, moderate or severe conditions, the severity will be set to “no worsening in 
EDSS”.
Table 2-15
Severity of MS relapse 
Mild relapse
Moderate relapse
Severe relapse
EDSS increase of 0.5 point
EDSS increase of 1 or 2 points
Exceeding Moderate criteria 
or
or
or
1 point FS change in one to 
three systems
2-point FS change in one or 
two systems
Exceeding Moderate criteria
or
or
1-point change in four or more 
systems
Exceeding Moderate criteria
Definition is based on the EDSS obtained to confirm the relapse as compared to the last EDSS
(scheduled or unscheduled) taken in the absence of (confirmed or unconfirmed) relapse and prior 
to the current relapse.
EDSS refers to total score; FS refers to functional score; all of the 7 functional scores are 
considered in this derivation.
[Panitch et al 2002]

ARR time-based and ARR patient based: ARRs using a “time-based approach” are 
calculated by taking the total number of relapses observed for all patients within a treatment 
group divided by the total number of days in study of all patients within the treatment group 
and multiplied by 365.25 days. Also a “patient-based approach” is presented, where 
individual ARRs are computed and summarized over patients within a treatment group. For 
above ARR calculations, one analysis will consider confirmed relapses only. Another 
analysis will consider both confirmed and unconfirmed relapses together. T2 lesion volume
and its change from baseline MRI scans by visit-window


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
Number of new or enlarging T2 lesions on MRI between Month 12 and EOS: The number 
of new T2 lesions on the EOS scan relative to the Month 12 scan will be collected; The time 
(in years) from the Month 12 scan to the EOS MRI scan will be calculated as (date of EOS 
MRI scan – date of Month 12 MRI scan +1)/365.25.

Number of new or enlarging T2 lesions on MRI at yearly visits relative to screening scan: 
The number of new T2 lesions at yearly visit scans relative to the screening scan will be 
collected; The time (in years) from the screening scan to the yearly MRI scan will be 
calculated as (date of yearly MRI scan – date of screening MRI scan +1)/365.25.

Annualized rate of brain atrophy (ARBA) by visit-window: ARBA describes the “averaged 
annual percentage change” in brain volume. It is designed to adjust for differences in the 
time spent between two scans that are compared by standardizing the percentage change in 
brain volume (PBVC) 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 two 
scans that are being compared. Days are calculated as post-baseline MRI scan date-
screening MRI scan date +1.

Proportion of patients free of clinical and MRI disease activity (No evidence of disease 
activity; NEDA-4): NEDA-4 is defined as no 3mCDW, no confirmed MS relapse, no new 
or enlarging T2 lesions on any MRI scan (scheduled or unscheduled) compared to baseline, 
and brain volume change >-0.4%/year on all MRI scans (scheduled and unscheduled; brain 
volume as measured by ARBA). The main analysis will consider only those patients who 
were 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. For the derivation of NEDA-4, data up to day 365.25 will be considered in the year 
1 analysis and data up to day 730.5 will be considered in the year 2 analysis.

EDSS total score by visit-window

The 25-foot Timed Walking Test (T25FW) score by visit-window: two trials will be 
performed at each scheduled visit. The average scores of the two trials per visit will be 
calculated as 


2
1
score
T25FW
T25FW
2
1
T25FW


. In case of missing data, the average 
of the non-missing values will be taken.

The 9-Hole Peg Test (9HPT) score by visit-window: four trials (two of each arm) will be 
performed at each scheduled visit. The 9HPT score per visit will be calculated for the 
dominant and the non-dominant hands separately and then for the average of both hands. In 
case of missing data, the average of the non-missing values will be taken.
o
9HPTdominant hand=(9HPTdominant hand, trial 1 + 9HPTdominant hand, trial 2)/2
o
9HPTnon-dominant hand=(9HPTnon-dominant hand, trial 1 + 9HPTnon-dominant hand, trial 2)/2
o
9HPTtotal=(9HPnon-dominant hand + 9HPdominant hand)/2. 

NfL related secondary hypotheses are specified in Section 2.6.2.5 as ‘supportive analysis’ 
for the key-secondary endpoint NfL.


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2.7.2
Statistical model and method of analysis
Methods of analyses for efficacy endpoints defined in Section 2.7.1 are described below.

The analysis of “Time of first relapse” and “Annualized relapse rates > 8 weeks after the 
onset of treatment” is described in (Section 2.5.5) as sensitivity analysis to the primary 
analysis.

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 2.6.2.1) 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 G2301 and G2302, in 
a Cox proportional hazards model with study as stratum, treatment, and region as factors 
and baseline SDMT-result as a continuous covariate. By study analysis will be performed 
for information only.

Time to 6mCDW or 6mCCD (composite endpoint) will be analyzed in the combined FAS 
from studies G2301 and G2302, in a Cox proportional hazards model with study as stratum, 
treatment, and region as factors and baseline EDSS and baseline SDMT scores as 
continuous covariates. By study analysis will be performed for information only.

SDMT scores and change from baseline will be summarized by visit-window and treatment
in the combined FAS from studies G2301 and G2302. For the change from baseline values, 
a repeated measures mixed effects analysis adjusted for study, treatment, region, and SDMT 
baseline scores will be performed.

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 G2301 and G2302, in a Cox 
proportional hazards model with study as stratum, treatment, and region as factors and the 
baseline T25FW-result as a continuous covariate. By study analysis will be performed for 
information only.

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 G2301 and G2302, in a Cox proportional 
hazards model with study as stratum, treatment, and region as factors and baseline 9HPT-
result as a continuous covariate. By study analysis will be performed for information only.

The 6mCDI sustained until EOS will be analyzed in the same way as for the 6mCDI (as 
described in Section 2.6.2.2)

The disability status during the study will be summarized descriptively by treatment group 
(i.e., number and percent of patients improved, stable or worsened will be provided) and 
compared between treatment groups via a Chi-square test.

For MS relapse characteristics, summary statistics will be presented. The proportion of 
patients hospitalized for relapse and the proportion of patients with severe relapses will be 
compared between treatment groups using a Chi-square test.

For the presentation of descriptive statistics, ARR time based and ARR patient based will
be reported by treatment group.


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
Change in T2 lesion volume on MRI will be summarized by visit-window. 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 EOS and Month 12 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) from the Month 12 scan to the EOS MRI scan will serve as the 
offset variable.

Number of new or enlarging T2 lesions on MRI at yearly visits relative to baseline 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 
yearly MRI scan relative to the screening scan will be used as the response variable. The 
natural log of the time (in years) from the screening scan to the yearly MRI scan will serve 
as the offset variable. Due to the variable length of patient study participation, this analysis 
will only be performed for visits where there are at least a total of 100 patients with non-
missing data on this endpoint. In case of non-convergence, region will be removed from the 
regression model.

The analysis of ARBA is described in (Section 2.6.2.6) as supportive analysis to the key 
secondary endpoint of brain volume change.

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. 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. 

EDSS, T25FW, 9HPT: The scores and their change from baseline values will be 
summarized by visit-window and treatment in the combined FAS from studies G2301 and 
G2302. For the change from baseline values, a repeated measures mixed effects analysis 
adjusted for study, treatment, region, and corresponding baseline values will be performed.

NfL related secondary hypotheses are specified in Section 2.6.2.5 as ‘supportive analysis’ 
for the key-secondary endpoint NfL.
2.7.3
Handling of missing values/censoring/discontinuations
As a general rule, missing data will not be imputed in any secondary endpoint analyses. All the 
available data up to the end of treatment epoch date, irrespective of on or off study treatment 
will be used as applicable. Details of handling discontinuations or censoring are provided in the 
relevant endpoints or analysis of endpoints sections (Section 2.7.1 and/or Section 2.7.2). 
2.8
Safety analyses
Safety analyses will be conducted using the safety (SAF) set. Patients will be grouped by the 
actual treatment received. If patients received both investigational drug and active comparator 


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accidentally during the study, they will be analyzed according to the treatment to which they 
were exposed longer in duration. Unless explicitly stated otherwise, only data up to and 
including the safety cut-off of 100 days after last administration of study drug 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 cut-off of 100 days (5 x 20 days) takes the long half-life of both the 
investigational and 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.
2.8.1
Adverse events (AEs)
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation of a patient after providing written informed consent for participation in 
the study. That means that a patient can report AEs before having started study medication. For 
reporting purposes, the main focus will be on treatment emergent adverse event (TEAE), 
defined as any adverse event which started on or after the day of first dose of study medication. 
Except for serious TEAES and death, only TEAEs up to and including safety cut-off of 100 
days after last administration of study drug will be included in the analyses. All serious TEAES 
and death will be included, regardless of safety cut-off.
AEs will be reported by primary system organ class (SOC) and preferred term according to the 
Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for 
reporting the study will be described in a footnote.
The number and percentage of patients reporting any TEAEs (referred to as incidence of any 
TEAEs later) will be summarized by primary SOC, preferred term and treatment. Separate 
summaries will be provided for serious TEAEs, drug related TEAEs, TEAEs leading to 
permanent discontinuation of study drug, TEAEs causing study drug interruption, and most 
common TEAEs (2% in any of the treatment groups). Additionally, incidence of any TEAEs 
will also be summarized by SOC, preferred term, and maximum CTCAE grade. Missing 
CTCAE grade will not be imputed..
Odds ratios (investigational drug vs. control) with 95% confidence intervals will be presented 
along with the summary of any TEAEs and the summary of serious TEAEs. Details in 
calculations of odds ratios and their 95% confidence intervals are provided in Section 5.7.1. 
Incidence of any TEAEs will be plotted by SOC, along with the odds ratio (and corresponding 
95% confidence interval) for TEAEs in each SOC. Odds ratios provide appropriate inferences 
for events that are likely to occur at certain times (e.g., injection related reactions) while no 
constant risk over time is expected.
Given the flexible duration of patients follow-up in the study, any TEAEs and serious TEAEs 
will also be summarized by reporting exposure-adjusted incidence rates (assuming a Poisson-
process for adverse events), by primary SOC, preferred term and treatment. The analysis will 


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take into account the time-at-risk as defined in Section 2.4.1 for each patient. The incidence rate 
ratios (investigational drug vs. control) and corresponding 95% confidence intervals will be 
presented along with this summary. Details in calculations of incidence rates and their 95% 
confidence intervals as well as incidence rate ratios and their 95% confidence intervals are 
provided in Section 5.7.2. The exposure adjusted incidence rates provide appropriate inferences 
for events that are likely to occur at any time during the observation period with constant risk 
over time (e.g., infection or cancer).
If a patient reported more than one adverse event within the same primary system organ class, 
the patient will be counted only once with the maximum CTCAE grade at the system organ 
class level, where applicable. 
All AEs will be presented in listings.
For the subgroup of patients who accidentally received both investigational drug and active 
comparator during the study, a listing of adverse events along with drug administration 
information will be provided.
2.8.1.1
Selected AEs of special interest / grouping of AEs
Selected tables will be produced for Adverse Events of Special Interest (AESI) (i.e., risks) 
defined in the latest version of case retrieval sheet (eCRS) at the time of analysis 
implementation (i.e., study database lock). Specifically, incidence of TEAEs that fulfill the risk 
search terms as defined in eCRS will be summarized by risk name, preferred term and treatment 
with odds ratios and 95% confidence intervals presented. The exposure-adjusted incidence rate 
of TEAEs that fulfill the risk search terms as defined in eCRS will also be summarized by risk 
name, preferred term and treatment with incidence rate ratios and 95% confidence intervals 
presented. Similarly, separate summaries will be provided for serious TEAEs that fulfill the risk 
search terms as defined in eCRS. Additionally, incidence of any TEAEs that fulfill the search 
terms as defined in eCRS will also be summarized by risk name, preferred term, and maximum 
CTCAE grade.
2.8.1.1.1 Injection reaction related AEs
Incidence of injection site reaction AEs and injection systemic reaction AEs as collected in the 
relevant CRF pages will be reported as part of the AE summary tables as two preferred terms 
respectively. For summaries of injection systemic reaction AEs specified in this section, , 
reaction/symptom start date and time will be compared with the injection date and time. Only 
reactions/symptoms within 24 hours after injections will be included (i.e., time to onset of 
reaction <= 24 hours). The time to onset of reaction will be derived as (reaction start date/time
– injection date/time) and rounded to the closest integer in hours.
Symptoms listed in the injection site reaction or injection systemic reaction CRF pages will be 
summarized by providing the number and percentage of patients with each of the symptoms 
and pre-specified grouping of symptoms as well as overall. These summaries will be provided 
for each injection up to injection 10 and cumulatively for all injections.
For the injection site reaction, no grouping of symptoms will be specified. For the injection 
systemic reaction, symptoms will be grouped under 6 categories as defined below and the 


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number and percentage of patients with at least one symptom reported under the category will 
be provided for each category.
•
Skin/mucosal tissue symptoms: Rash, Urticaria, Pruritus general, Flushing 
•
Respiratory compromise: Dyspnea, Bronchospasm, Chest discomfort, Cough 
•
Related to change in vital signs: Hypotension, Hypertension, Dizziness, Tachycardia
•
Gastrointestinal symptoms: Nausea, Vomiting, Abdominal pain, Diarrhea
•
Musculoskeletal/connective tissue symptoms: Arthralgia, Myalgia, Back pain
•
Other manifestations: Fever, Headache, Chills, Asthenia, Fatigue, and Other
For the injection systemic reaction, time to onset of the first symptoms after each injection will 
be summarized by cumulative hour intervals (i.e., 0 to 1, 0 to 2, 0 to 3, etc. until 0 to 24 hours).
These summaries will be provided for each injection up to injection 10 and cumulatively for all 
injections.
The proportion of patients with injection site reactions and the proportion of patients with
injection systemic reactions will be plotted by treatment group against the injection sequence 
numbers (injections 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10).
For the first 3 injections, additional summaries will be provided by category of injection related 
premedication. Specifically, 9 categories are defined as 1) no injection related premedication, 
2) type 1, 3) type 2, 4) type 3, 5) type 1+ type 2, 6) type 1+ type 3, 7) type 2+ type 3, 8) type 
1+ type 2+ type 3, 9) Any injection related premedication. The types 1 to 3 refer to protocol 
specified three types of injection related premedication as stated in Section 2.4.2.3.
A separate listing for injection site reaction AEs and injection systemic reaction AEs will be 
provided where all reported injection related reactions (IRR) (regardless of timing) will be listed 
along with the corresponding injection sequence number and time to onset from the most recent 
injection as well as from Day 1. The listing will be sorted by injection of first occurrence of 
symptoms. Specifically, under the first injection, patients whose first IRR was associated with
the first injection will be listed; within a patient all IRRs to all injections will be listed 
chronologically. Under the second injection, patients whose first IRR was associated with the 
second injection will be listed; similarly, within a patient all IRRs to all injections will be listed 
chronologically. The listing will continue with subsequent injections until all patients with IRRs 
are included in the listing.
2.8.1.1.2 Liver safety related AEs
Standardized MedDRA Queries (SMQs) are groupings of terms from one or more MedDRA 
SOCs that relate to a defined medical condition or area of interest. They are intended to aid in 
case identification.
SMQ Table: The number and percentage of patients experiencing adverse events categorized 
under the SMQ module drug-related hepatic disorders – comprehensive search (SMQ code 
20000006, broad search) and its SMQ sub-modules will be reported. 


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SMQ-PT Table: The more detailed SMQ-PT table including the respective preferred term 
frequencies falling under the SMQ drug-related hepatic disorders – comprehensive search  
(SMQ code 20000006, broad search) and its SMQ sub-modules will be provided.
2.8.1.1.3 Other analyses
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on non-
serious treatment emergent adverse events with an incidence greater than 5% and on treatment 
emergent serious adverse events and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
•a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•more than one occurrence will be counted if there is > 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Deaths
Death, if meaningful number of cases reported (i.e., 5 or more cases), will be summarized by 
providing the number and percentage of patients by treatment group. All deaths as recorded in 
the final database (i.e., up to database lock) will be included.
2.8.3
Laboratory data
Data summaries will be provided in SI units. The summary of laboratory evaluations will be 
presented for three groups of laboratory tests: Hematology, Chemistry and Urinalysis. On 
presenting summary statistics, laboratory data will be grouped and displayed in an alphabetical 
order within the Hematology and Chemistry groups and subgroups. Refer to Section 5.3.1 for 
subgroup definitions.
Descriptive summary statistics (mean, median, standard deviation, Min and Max) of the change 
from baseline in the laboratory result to each study visit-window by treatment group will be 
presented. Change from baseline will only be summarized for patients with both baseline and 
post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the post-baseline values. For the shift tables, the grade level 
based on CTC grade (as defined by CTCAE as listed in Section 5.3.3) will be used to evaluate 
whether a particular laboratory test value was Grade 0, 1, 2, 3, or 4 relative to whether or not 


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the baseline value was Grade 0, 1, 2, 3 or 4. These summaries will be presented by laboratory 
test and treatment group. Shift table will also be provided for urinalysis results to compare 
baseline to post-baseline extreme values (negative, +, 2+, 3+, or 4+).
The number and percentage of patients with new or worsening laboratory abnormalities based 
on CTC grade (as defined by CTCAE as listed in Section 5.3.3) in each visit-window and at 
any time post baseline will be presented. Patients with specific laboratory abnormalities 
(defined by CTC grade 3 and 4) will be listed. 
Number of patients with newly occurring liver enzymes abnormalities will be summarized. 
Newly occurring liver enzymes abnormalities are defined in Section 5.3.2.
Liver function tests will also be presented graphically as matrix plots of each of the parameters 
(ALT, AST, TBIL, ALP) maximum post-baseline/ULN normalized. 
For the shift tables, abnormalities based on CTC grades tables and liver frequency distribution 
tables, all applicable post-baseline values will be checked against the respective criteria and the 
rules for handling multiple laboratory assessments within visit windows will not be applied. 
For continuous variables databased as <lower limit, these will be imputed as being half of the 
lower limit.
All above summaries include only data up to and including safety cut off. 
2.8.3.1
Liver events
Detailed information will be captured for patients with a reported liver event. For most studies 
patient listings may be appropriate because only a few liver events are expected, if any. 
However, respective tables with descriptive statistics may be provided if the number of liver 
events allows a meaningful interpretation, specifically if the number of liver events are greater 
than or equal to 10.
2.8.3.2
Renal events
Detailed information will be captured for patients with a reported renal event. The overall 
frequency and percentage of patients with confirmed renal events will be summarized by 
treatment group. Answers to “Event first identified through”, “Renal event associated signs and 
symptoms”, and “Any alternative diagnoses” (collected on diagnosis, follow up and overview 
pages) will also be summarized descriptively by treatment group. All data collected on the 
standard renal events CRF pages will be listed appropriately. 
2.8.3.3
Serology at screening
Collected data of laboratory serology to determine patient’s eligibility includes parameters with 
respect to hepatitis and HIV viruses. Parameters with respect to hepatitis include 1) anti-
hepatitis A virus IgM; 2) hepatitis B surface antigen and anti-hepatitis B core antigen IgM/IgG; 
3) anti-hepatitis C virus antibody; 4) anti-hepatitis E virus IgM.
The result of each serology parameter is a categorical value. The number and percentage of 
patients with values in each of the categories will be provided by treatment group for all above 
mentioned parameters. Serology test should be performed once at screening. For patients with 


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multiple assessments, the latest result will be used in the summary. Additional serology data 
with numerical values may be collected but will not be reported.
2.8.3.4
Other special lab results
Other non-routine laboratory data include pregnancy test results, B-cell counts, teriflunomide 
plasma levels, total IgG, total IgM, 
 
. All data will be listed appropriately.
The B-cell counts, total IgG, total IgM, neurofilaments
will be summarized 
using descriptive statistics by treatment group and visit-window.
In addition, number and percentage of patients with B-cells < the lower limit of normal (LLN) 
value (i.e., B-cell depleted) will be presented by treatment group and visit-window. Graphic 
presentation of B-cell counts distribution will also be provided by treatment group and visit-
window. All B-cell summaries defined in this section will include data up to the end of the on-
treatment period (i.e., last dose date + 30). This is to provide more accurate information about 
B-cell depletion because fast B-cell repletion is expected after study drug discontinuation and 
applying the safety cutoff (i.e., last dose date +100) would mix repletion and depletion to some 
degree.
Number and percentage of patients meeting the notable low level criteria in IgG or IgM at least 
once will be provided by treatment group. A notably low IgG level is defined as a level that is 
20% below the LLN and a notably low IgM level is defined as a level 10% below the LLN.
2.8.4
ECG data
ECG data will be collected at baseline visit, EOT visit and EOS visit. Clinically significant 
findings from ECG evaluations will be reported as AEs and included in the analysis of AEs. 
ECG parameters include max heart rate, mean PR duration, mean QT duration, mean QRS 
duration, and QT corrected using Fridericia’s correction formula (all as collected on the ECG
CRF). Descriptive statistics of each ECG parameter will be provided by treatment group for 
baseline and for the 2 nominal visits (i.e., EOT and EOS visits).
The number and percentage of patients meeting the criteria defined in Table 2-16 will be 
provided for each criterion by treatment group for baseline and for the 2 nominal visits.
Table 2-16
Criteria for relevant ECG absolute or change from baseline values
Absolute values criteria: 
Changes from baseline criteria:
Heart rate:  HR <40 or HR > 120 beats/min
QRS complex : increase > 25% compared to baseline
Pulse rate: PR <110 or PR >200 msec
QTcF > 500 msec and QTcF increase > 60 msec
QRS complex: < 70 msec or > 120 msec
QTcF < 350 or > 450 msec (males)
QTcF <360 or > 460 msec (females)


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2.8.5
Vital signs
Vital sign measurements include sitting systolic and diastolic blood pressures, sitting pulse, 
body temperature, height and body weight.
Three sitting measurements of blood pressure (SBP and DBP) and pulse will be taken at each 
vital sign assessment.
For post-baseline assessments, the blood pressure and pulse values will be the average of the 
non-missing values of the 3 measurements. If more than one blood pressure/pulse assessment 
(scheduled or unscheduled) exists in a particular visit-window (as defined in Section 2.1.2.1),
derivation should follow the rules as defined in Section 2.1.2.3. Derivation of baselines for 
blood pressure and pulse are provided in Section 2.1.1.
Height will be collected at screening visit only and will be summarized in the baseline 
characteristic summary only.
Analyses of vital sign measurements (excluding data collected on Day 1, Day 7, Day 14 and 
Month 1 protocol scheduled visit) using descriptive summary statistics (mean, median, standard 
deviation, min, max) for the change from baseline for each post-baseline visit-window will be 
performed. These descriptive summaries will be presented by vital sign parameter and treatment 
group. Change from baseline will only be summarized for patients with both baseline and post-
baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of patients with clinically notable vital signs will be presented. For 
clinical notable vital signs values, refer to Section 5.4. 
For vital signs data collected on Day 1, Day 7, Day 14 and Month 1 protocol scheduled visit, 
pre and post-injection vital signs data including temperature, pulse rate and blood pressure are 
collected. Change from pre-injection to post-injection in these 3 parameters will be summarized 
by nominal visit.
All above summaries include only data up to and including safety cut off. 
2.8.6
Suicidality evaluations
The Columbia Suicide Severity Rating Scale (C-SSRS) questionnaire will be administered 
electronically (eC-SSRS), via an interactive voice response (IVR) system. However, as per 
internal Novartis guidelines, a CRF page ‘Supplemental Data for Suicidal Ideation and 
Behavior Categories’ is also used as an unplanned/unscheduled visit for those cases when the 
subject did not conduct the phone interview because, e.g. the subject was hospitalized and 
unable to conduct the interview or the subject refused to conduct the interview/withdrew from 
the study and external information on suicidal ideation and behavior (SIB) is required. In such 
cases, SIB information will still be collected from external parties (spouse, caregiver, nurse, 
investigator, etc.) through means of this CRF page. Further, for deaths due to suicide, the site 
should fill out the Supplemental Data CRF (“completed suicide” tickbox) to ensure accurate 
reporting of such cases. When reporting the SIB data, data from both sources (IVR eC-SSRS 
and Supplemental CRF) will be used in a pooled manner and no distinction will be made 
between the two. 


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Table 2-17
Standard SIB events as categorized by C-SSRS 
Category 
number
C-SSRS category
Suicidal Ideation
1
   Wish to be dead
2
   Non-specific active suicidal thoughts
3
   Active suicidal ideation with any methods (not plan) without intent to act
4
   Active suicidal ideation with some intent to act, without specific plan
5
   Active suicidal ideation with specific plan and intent
Suicidal behavior
6
   Preparatory acts or behavior
7
   Aborted attempt
8
   Interrupted attempt
9
   Actual attempt
10
   Completed suicide
Self-injurious behavior, without suicidal intent
11
   Non-suicidal self-injurious behavior
Definition of ‘all prior history’ and ‘recent history’ 
SIB will be collected once before randomization, either at screening or at baseline visits. SIB 
assessments obtained before the first dose of study drug will be defined by two components: all 
prior history and recent history.
All prior history will be defined as the SIB results obtained from the lifetime assessment, and
recent history will be defined as the SIB results obtained from the pre-defined period (i.e., past 
6 months or 24 months) assessment of the screening or baseline visit. In case multiple 
assessments collected before first dose of study drug, results should be derived as the worst case 
value per the reporting timeframe. Worst case is defined by an answer ‘yes’ to the SIB category.
Data summaries 
SIB data will be summarized for the Safety set. The number and percentage of subjects with 
suicidal ideation, suicidal behavior and self-injurious behavior without suicidal intent will be 
presented by analysis-period (recent history, all prior history and any time post-baseline) and 
treatment group. The following 14 events will be included in the summary table:

Each of the 11 categories listed in Table 2-17, separately 

Any suicidal ideation or behavior (a ‘yes’ answer  to at least one of the 10 suicidal 
ideation and behavior questions in analysis-period of interest)

Any suicidal ideation (answered ‘yes’ to at least one of the 5 suicidal ideation questions 
in analysis-period of interest)

Any suicidal behavior (answered ‘yes’ to at least one of the 5 suicidal behavior 
questions in analysis-period of interest)
In addition, the number and percentage of subjects with the following post-baseline events will be 
presented (Nilsson et al. 2013):


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Note: in these definitions, a category of 0 is assigned to a subject without suicidal ideation (i.e. 
a ‘no’ answer to all suicidal ideation categories)

Worsening suicidal ideation compared to recent history: An increase in the maximum 
suicidal ideation category at any time post-baseline from the maximum suicidal ideation 
category during pre-treatment recent history. 

Worsening serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation category to 4 or 5 at any time post-baseline from not having 
serious suicidal ideation (categories of 0-3) during pre-treatment recent history. 

Emergence of serious suicidal ideation compared to recent history: A maximum suicidal 
ideation category of 4 or 5 at any time post-baseline from no suicidal ideation (category 0) 
during pre-treatment recent history.

Improvement in suicidal ideation at last on-treatment measurement compared to recent 
history: A decrease in suicidal ideation score at last on-treatment measurement from pre-
treatment recent history.   

Emergence of suicidal behavior compared to all prior history: The occurrence of suicidal 
behavior (Categories 6-10) at any time post-baseline from not having suicidal behavior 
(Categories 6-10) prior to treatment (includes “lifetime” and any other assessments prior to 
treatment taken prior to treatment). 
For those analyses, each subject can only be counted once for each event. However, a subject 
can be counted in several different events.
Suicidal ideation and behavior data will be listed. Detailed answers to C-SSRS items will be 
listed separately for subjects with any suicidal ideation at any time post-baseline (i.e. a ‘yes’ 
answer to at least one of the five suicidal ideation questions at any time post-baseline) and for 
a subject with any suicidal behavior at any time post-baseline (i.e. a ‘yes’ answer to at least one 
of the five suicidal behavior questions at any time post-baseline).
2.8.7
Safety evaluation during the Safety follow-up
Safety data collected after last administration of study drug includes adverse events, vital signs,
routine laboratory parameters, laboratory assessments to measure total IgG, total IgM, B-cell 
repletion and residual teriflunomide PK levels, and eCSSRS. No safety cutoff date will be 
applied in the analyses defined in this section. Safety data within the safety cutoff date but after 
last administraction of study drug will also be included.
The number and percentage of patients with at least one TEAEs that started after the date of last 
administration of study drug will be reported by SOC, preferred term, and treatment group. The 
subset of patients in SAF who had data reported after the date of last administration of study 
drug will be included in the analysis and the number of patients in this subset will be the 
denominator in calculating the percentage. 
The vital signs data collected after study drug discontinuation will be summarized as summary 
statistics of the vital sign measures and of the change from baseline in the vital sign measures 
by treatment group for each visit-window after study drug discontinuation (as defined in Section 
2.1.2.2). The SAF will be used for these analyses.


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The B-cell counts and its change from baseline values will be summarized by treatment group 
for each visit-window after study drug discontinuation. In addition, the change from last 
assessment on study drug in B-cell count will also be summarized similarly. Graphic 
presentation of B-cell counts distribution will also be provided by treatment group for each
visit-window after study drug discontinuation. Additionally, number and percentage of patients
with B-cells within 10%, 10 to 20%, 20 to 50%, 50% to 80%, 80 to 100% of baseline, or with 
B-cells < the lower limit of normal (LLN), or with B-cell repletion will be presented by 
treatment group for each visit-window after study drug discontinuation. B-cell repletion is 
defined as B-cell counts having returned to their baseline value or to LLN (i.e., >=100% of 
baseline or >=LLN). The analysis will be limited to the subset of patients in SAF who had B-
cell count data after the date of last administration of study drug; the number of patients in this 
subset will be the denominator in calculating the percentage.
Patients with teriflunomide plasma data will be listed as only small percentage of patients are 
expected to have such data.
The eCSSRS data collected after study drug discontinuation will be summarized similarly as in 
Section 2.8.6. The subset of patients in SAF who had at least one eCSSRS performed after the 
date of last administration of study drug will be included in the analysis and the number of 
patients in this subset will be the denominator in calculating the percentage.
As stated in Section 2.1, the registration CSR will contain only partial data collected from the 
Safety FU epoch because the registration CSR cutoff date will depend on EOS date of the study. 
A complete analysis of the post-treatment safety follow-up will be provided in the final CSR
when all patients have completed the Safety FU epoch.
2.9
Pharmacokinetic endpoints  
2.9.2
Immunogenicity assessment
Samples will be analyzed for 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. All 
patients in FAS with non-missing values will be included in these analyses.
2.10
PD and PK/PD analyses and modelling
PK concentration data summarized by visit together with by-patient listings will be provided in 
the study report. All patients in FAS with non-missing values will be included in these analyses.


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2.11
Patient-reported outcomes
For patient-reported outcomes, data from unscheduled visits will not be summarized but will 
be listed only. The FAS will be used for all analyses of patient reported outcomes.
2.11.1
MSIS-29
The Multiple Sclerosis Impact Scale version 2 (MSIS-29 v2) is a 29-item, self-administered 
questionnaire that includes two domains, physical and psychological. 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 
two weeks. Each of the 29 items will be given a score between 1 (not at all) and 4 (extremely) 
(MSIS-29 v2 guidelines). The physical impact score is computed by summing up Items 1-20 
(resulting in a score between 20 and 80). The psychological impact score is computed by 
summing up Items 21-29 (resulting in a score between 9 and 36).
For ease of interpretation, these scores are transformed to a scale of 0-100 using the following 
formula: 100 x (observed score minus lowest possible score) / (highest possible score minus 
lowest possible score). The higher the score, the greater is the degree of disability.
In case of missing item scores, the following rule applies: if more than 50% (i.e., more than 10 
for the physical scale and more than 4 for the psychological scale) of the item scores are missing, 
the scale score will not be calculated and set to missing. If no more than 50% of the item scores 
are missing, the scale score will be imputed as the average of the non-missing item scores 
multiplied by the number of items in the scale (20 for the physical scale and 9 for the 
psychological scale).
Both the MSIS-29 physical impact score and the psychological impact score and the 
corresponding changes from baseline will be summarized by visit-windows. The change from 
baseline at post-baseline visit-windows will be compared between treatment groups using a 
repeated measures mixed effects analysis adjusted for treatment, visit-windows (as class 
variable), region, and the corresponding baseline score.


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2.14
Interim analysis
Two separate SAPs will be developed to document methodology details, one for analyses that 
will be performed for DMC (as mentioned in Section 2.14.2), the other for analyses that will be 
performed for blinded data reviews (as mentioned in Section 2.14.3).
2.14.1
Unblinding interim analysis
No unblinding interim efficacy analysis is planned for this study. 
2.14.2
Analysis for Data Monitoring Committee (DMC)
Regular interim analyses on risk-benefit evaluation 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 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.
2.14.3
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-estimation: relapse (and disability) related assumptions (primary 
endpoint) 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 EOS: data collected by the study on relapse rates and disability 
worsening events will be monitored. EOS will be declared only once when sufficient 


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information has been collected to address the study’s primary and key secondary 
objectives.  
Details of the statistical analysis plan with respect to blinded data reviews are provided in the 
BSSR SAP.
3
Sample size calculation
Sample size requirements for this study are primarily driven by the disability-related key-
secondary endpoints. A total of 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.
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 2.5.3. 

3mCDW: A total sample size of 1800 patients across two studies of identical design is 
sufficient to provide ≥90% power and for the demonstration of superiority based on the 
3mCDW.

6mCDW & 6mCDI: A total sample size of 1800 patients across two 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 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.


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3.1.1
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. The same sample size, with the same assumptions 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 two 
studies of identical design. The formula proposed by Keene et al. 2007 was used for the sample 
size calculation for the primary endpoint.
3.1.1.1
Justification of assumptions for the 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’Connor et al. 2011). In 
an additional phase 3 study of teriflunomide versus Interferon beta-1a, patients treated with 
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 ofatumubab 
but is administered as infusion. In the ocrelizumb 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), ocrelizumba 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. 


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The dispersion parameter of k=0.82 is assumed based on the values observed for relapse data 
in the fingolimod phase III 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. For instance, if all other 
assumptions were kept fixed but patients were followed for only 1 year instead of 1.5 years, the 
power in each cohort would drop to approximately 78%. If, on the other hand, patients were 
followed up for 2 years, the power for the primary endpoint would increase to approximately 
95%.
3.1.2
Sample size the number of GdT1 lesions per scan
We assume a negative binomial distribution of the number of Gd-T1 lesions per scan. Assuming 
0.26 Gd-T1 lesions per scan for teriflunomide and a 90% relative reduction with ofatumumab 
(i.e. 0.026 Gd-T1 lesions per scan for ofatumumab), and a dispersion parameter κGd=5.3 (as 
observed in the combined FREEDOMS and FREEDOMS II studies for 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.
3.1.3
Sample size for the annualized rate of new or enlarging T2 lesions
We assume a negative binomial distribution of the number of T2 lesions. Assuming 2.1 new or 
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), an average follow-up of 1.5 
years, 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 66 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 84 randomized 
patients (42 per arm) is required for this endpoint.
3.1.4
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 


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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.
3.1.5
Sample size for the 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 ofatumubab (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). 
3.1.6
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 two 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-
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). 
3.1.7
Sample size for 6-month confirmed disability worsening (6mCDW)
The cumulative event probability over two 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). 


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3.1.8
Sample size for 6-month confirmed disability improvement (6mCDI)
The cumulative event probability over two 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.
4
Change to protocol specified analyses
Changes to protocol specified analyses are in Section 2.6.2.5 NfL and Section 2.12 Biomarkers.
All changes are listed below: 

Protocol (Section 9.5.1.2) specified analysis for NfL high vs. low subgroup on selected 
efficacy endpoints where brain volume was not included; the final analysis plan in NfL 
section includes the brain volume endpoint for this subgroup analysis.
 
 
 
 
 
All changes are made to be consistent with the NfL high vs. low subgroup analyses and/or to 
align with NfL pre-submission meeting briefing book submitted to FDA on Feb 8th 2019. 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing or partial dates are not allowed in completing the study drug administration CRF pages. 
The end date of study drug will be the last end date or last injection date for patients randomized 
to teriflunomide or ofatumumab, respectively.


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5.1.2
AE date imputation
For the start and end dates of the adverse event records, when incomplete or missing, dates will 
be imputed according to Novartis standards (details will be given in programming datasets 
specifications (PDS) document).
5.1.3
Concomitant medication date imputation
For the start and end dates of the concomitant medication records, when incomplete or missing, 
dates will be imputed according to Novartis standards (details will be given in programming 
datasets specifications (PDS) document).
5.1.3.1
Prior therapies date imputation
Same as above.
5.1.3.2
Post therapies date imputation
Same as above.
5.1.3.3
Relapse date imputation
Missing or partial dates are not expected for the start and end dates of relapses on the MS 
relapses CRF pages. In case partial dates (unknown day with month and year available) exist in
the final database, the following rules will apply:

For start date, it will be imputed by the first day of the month or the first dose date if it 
occurs in the same month as the first dose date.

For end date, it will be imputed by the last day of the month or truncated to have a 
duration of maximally 90 days.
5.1.3.4
Other imputations
For the calculation of duration or time since relevant history events as specified in Section 2.3.3
(MS disease baseline characteristics), partial dates will be imputed for the MS diagnosis start 
date, the first MS symptom date, the conversion to SPMS date, and the most recent relapse 
onset date via below imputation rules.

If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be imputed as 
missing.

If the year is not missing and possible, but the month is impossible or missing (e.g. 17-
XXX-2010), then the year will be kept and date will be imputed as July 1st (e.g., 1-July-
2010).

If the year and the month are not missing and possible, but the day is impossible or 
missing (e.g. 31-FEB-2009), then the year and month will be kept, and date will be 
imputed as 15th (e.g., 15-FEB-2009).

The imputed dates should be prior to the screening visit date. That is, if imputed dates 
are on or after the screening visit date, the dates will be imputed to be one day before 
the screening visit date.


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5.1.3.5
Data handling for relapses within 30 days of onset of previous 
relapses or relapses with duration beyond 90 days
According to protocol definition of MS relapses, the start date of a new relapse has to be at least 
30 days after the start date of a previous relapse (i.e., start date of a new relapse – start date of 
a previous relapse >=30). If a relapse is recorded with a start date less than 30 days after the 
start date of a previous relapse, below data manipulation will be done to combine them into a 
single relapse by creating a new relapse record with the following information.

Start date: take the earliest start date.

End date: take the latest end date. If one of the end dates is missing, set it to missing.

Date of EDSS intended to confirm the relapse:
o
Take the date of EDSS by which the relapse can be confirmed.
o
If more than one EDSS assessments meet the above criteria, take the date of 
EDSS by which the worst severity value is derived.
o
If no EDSS assessment meets the above criteria, take the earliest date of EDSS 
as captured on the relapse CRF page.

Severity: take the value representing the worst case (severe>moderate>mild>missing)

“Did the relapse affect daily activities?”, “Hospitalization?”, “Steroid used?”, 
“Recovery status”: for each of these characteristics, take the value representing the worst 
case (yes>no for first 3 questions; no>partial>complete recovery for last question).
According to CRF completion guidelines, maximum duration of a relapse is 90 days. If a relapse 
is recorded with a duration longer than 90 days, the end date will be truncated to have a duration 
of exactly 90 days. This applies also to the artificial record created by above procedure. Missing 
end date of relapse is not allowed. In the rare cases that missing end date exist in the final 
database, it will be imputed so that the duration of relapse is exactly 90 days.
5.2
AEs coding/grading
AEs are coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
The latest MedDRA version will be used and will be described in the footnote of relevant 
outputs.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE). 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). The CTCAE grade of 5 (death) 
is not used; rather, ‘fatal’ is collected as AE outcome and death information is also collected on 
a separate (e)CRF page.


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5.3
Laboratory parameters derivations
For each patient, the estimated creatinine clearance values (without collecting urine) will be 
calculated using the Cockcroft-Gault formula (as specified in Table 5-1). In these calculations, 
the body weight is the last measurement collected on or before the day when the patient takes 
the laboratory test and age should also be calculated based on the time when the patient takes 
the laboratory test. 
If the creatinine value is collected in the unit µmol/L (SI unit), it will be converted to mg/dL in 
order to use the formulas. The conversion is via the equation below:

mg/dL = 88.4 µmol/L (e.g., creatinine = 2.0 mg/dL = 176.8 µmol/L).
Table 5-1
Creatinine clearance calculation
Variable
Formula
Creatinine clearance [mL/min] 
using Cockcroft-Gault formula 
(Cockcroft and Gault 1976)
= (140 – A) W  / (72 C) G
    Where
A is age [years]
W is body weight [kg]
C is the serum concentration of creatinine [mg/dL]
G is a constant: G=1 for males and G=0.85 for females.
The estimated creatinine clearance will be included as one of the laboratory parameters.
5.3.1
Laboratory test groups and subgroups
On presenting lab results, grouping parameters by family will ease the review. Table below 
shows a possible set of lab parameters and their corresponding classification. 
Table 5-2
Laboratory tests
Order
Laboratory Group
Subgroups
Tests [SI unit]
1
Hematology
    Red Blood Cells
   
    White Blood Cell Differential
Hematocrit [%]
Hemoglobin [g/L]
Platelets [10E9/L]
Red cell count [10E12/L]
Absolute Basophils [10E9/L]
Absolute Eosinophils [10E9/L]
Absolute Lymphocytes [10E9/L]
Absolute Monocytes [10E9/L]
Absolute Neutrophils [10E9/L]
Basophils [%]
Eosinophils [%]
Lymphocytes [%]
Monocytes [%]
Neutrophils [%]
White Cell Count [10E9/L]


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Order
Laboratory Group
Subgroups
Tests [SI unit]
    B-cells
    Immunoglobulin
CD19+ B-cell counts[cells/µL]
Total IgG [g/L]
Total IgM [g/L]
2
Chemistry 
    Renal Function
    Liver Function Tests
    Other Enzymes
   Lipids
    Other
    Electrolytes / Metabolism Tests
Creatinine [umol/L]
Blood urea nitrogen [mmol/L]
ALT [U/L]
Albumin [g/L]
Alkaline Phosphatase [U/L]
AST [U/L]
Bilirubin (direct/conjugated) [umol/L]
GGT [U/L]
Total Bilirubin [umol/L]
Total protein [g/L]
Amylase [U/L]
Cholesterol HDL [mmol/L]
Cholesterol LDL [mmol/L]
Triglycerides [mmol/L]
Total Cholesterol [mmol/L]
Random glucose [mmol/L]
C-Reactive protein (CRP) [mg/L]
Bicarbonate [mmol/L]
Calcium [mmol/L]
Chloride [mmol/L]
Magnesium [mmol/L]
Phosphate [mmol/L]
Potassium [mmol/L]
Sodium [mmol/L]
3
Urinalysis
Blood
Glucose
Specific gravity
Albumin
Protein


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5.3.2
Newly occurring liver enzymes abnormalities
Below lists the criteria for “events” of newly occurring liver enzymes abnormalities:

ALT > 3, 5, 10, 20x ULN                                                                           

ALT or AST > 3, 5, 8, 10, 20x ULN                                 

ALT or AST > 3x ULN & TBIL > 1.5x ULN                

ALT or AST > 3x ULN & TBIL > 2x ULN                  

ALP > 1.5, 2, 5x ULN                                      

TBIL > 1, 1.5, 2x ULN                                        

ALP > 3, 5x ULN & TBL > 2x ULN                                                  

ALT or AST > 3x ULN & TBIL > 2x ULN  & ALP ≤ 2x ULN

ALT or AST > 3x ULN & (nausea or vomiting or fatigue or general malaise or abdominal 
pain or (rash and eosinophilia))      
When a criterion contains multiple laboratory parameters (e.g., ALT > 3xULN & 
TBL > 2xULN), unless otherwise requested by the project clinical team/Brand Safety Leader 
(BSL), the criterion should be only considered to be met when the elevation in both parameters 
occurs on the same sample day (as evidenced by the same date that the lab samples were taken).
The “events” are defined in the Novartis safety guideline on hepatotoxicity (Novartis: Philippe 
Close 2011), section: Safety parameters for special liver event analyses.
5.3.2.1
Definition of characteristics for liver event overview summary
Characteristics: Liver events are categorized based on ALT and ALP measurements using the 
closest lab assessment +/- 7 days from the onset of the liver event into the following 
characteristics ‘Hepatocellular’ (ALT  > 2xULN or ALT/ULN:ALP/ULN > 5), ‘Cholestatic’ 
(ALP > 2xULN or ALT/ULN:ALP/ULN ≤ 2), ‘Mixed’ (ALT > 2xULN and ALP > ULN and 
2  < ALT/ULN:ALP/ULN ≤ 5), ‘None’ (if none of the three above qualifies), and ‘Unknown’ 
(in case of a missing ALT or ALP values). Note that the categories are not mutually exclusive.
The definition is consistent with Novartis safety guideline on hepatotoxicity.
5.3.3
CTCAE grades for laboratory parameters
Table 5-3 CTCAE grades for laboratory parameters (CTCAE Version 5)
Grade
Abnormality
Lab 
parameter
1
2
3
4
Hematology
Anemia
Hemoglobin
(g/L)
<LLN - 100 g/L
<100 - 80 g/L
<80 g/L
transfusion 
indicated


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Grade
Abnormality
Lab 
parameter
1
2
3
4
Platelet 
count 
decreased
Platelets 
(thrombocytes) 
(109/L)
<LLN-75.0 
x 
109/L
<75.0 -
50.0 x 
109/L
<50.0 - 25.0 x 109/L
<25.0 x 109/L
White 
blood 
cell 
decreased
Leukocytes 
(WBCs)
(109/L)
<LLN -
3.0 x 
109/L
<3.0 - 2.0 x109/L
<2.0 - 1.0 x 109/L
<1.0 x 109/L
Neutrophil 
count 
decreased
Absolute 
neutrophil 
count 
(109/L)
<LLN 
-
1.5 
x109/L
<1.5 - 1.0 x109/L
<1.0 - 0.5 x109/L
<0.5 x109/L
Lymphocyte 
count 
decreased
Absolute 
lymphocyte 
count
(109/L)
<LLN x 0.8 -
109/L 
<0.8 - 0.5 x 109/L
<0.5 - 0.2 x 109/L 
<0.2 x 109/L
Lymphocyte 
count 
increased
Absolute 
lymphocyte 
count
(109/L)
>4 – 20 x 109/L
> 20 x 109/L
Chemistry
Liver function
Alanine 
aminotransferase 
increased
ALT (SGPT)
(U/L)
>ULN – 3.0 x 
ULN if baseline 
was 
normal; >1.5 –
3.0 x baseline if 
baseline was 
abnormal
>3.0 – 5.0 x ULN 
if baseline was 
normal; >3.0 –
5.0 x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Aspartate 
aminotransferase 
increased
AST (SGOT)
(U/L)
>ULN – 3.0 x 
ULN if baseline 
was normal; 1.5 
– 3.0 x baseline 
if baseline was 
abnormal
>3.0 – 5.0 x ULN 
if baseline was 
normal; >3.0 –
5.0 x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Blood
bilirubin 
increased
Bilirubin
(µmol/L)
>ULN – 1.5 x 
ULN if baseline 
was 
normal; >1.0 –
1.5 x baseline if 
baseline was 
abnormal
>1.5 – 3.0 x ULN 
if baseline was 
normal; >1.5 –
3.0 x baseline if 
baseline was 
abnormal
>3.0 – 10.0 x ULN 
if baseline was 
normal; >3.0 –
10.0 x baseline if 
baseline was 
abnormal
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal
GGT increased
Gamma-
glutamyl 
transferase 
(GGT) (U/L)
>ULN – 2.5 x 
ULN if baseline 
was normal; 2.0 
– 2.5 x baseline 
if baseline was 
abnormal
>2.5 – 5.0 x ULN 
if baseline was 
normal; >2.5 –
5.0 x baseline if 
baseline was 
abnormal
>5.0 – 20.0 x ULN 
if baseline was 
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Alkaline phosphatase 
increased
Alkaline 
Phosphatase 
>ULN - 2.5 x 
ULN if baseline 
>2.5 - 5.0 x ULN 
if baseline was 
>5.0 - 20.0 x ULN 
if baseline was 
>20.0 x ULN if 
baseline was 


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Grade
Abnormality
Lab 
parameter
1
2
3
4
(U/L)
was normal; 2.0 
– 2.5 x baseline 
if baseline was 
abnormal
normal; >2.5 –
5.0 x baseline if 
baseline was 
abnormal
normal; >5.0 –
20.0 x baseline if 
baseline was 
abnormal
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Renal function Note: A semi-colon (;) indicates ‘or’ within the description of the grade.
Creatinine increased*
Creatinine 
(µmol/L)
>ULN -
1.5 x 
ULN
>1.5 
-
3.0 
x 
baseline;
>1.5 - 3.0x ULN
>3.0 baseline;
>3.0 - 6.0 x ULN
>6.0 x ULN
Other enzymes
Serum 
amylase 
increased
Amylase 
(U/L)
>ULN -
1.5 x 
ULN
>1.5 - 2.0 x ULN;
>2.0 - 5.0 x ULN 
and 
asymptomatic
>2.0 - 5.0 x ULN
with signs or 
symptoms; >5.0 x 
ULN and 
asymptomatic
>5.0 x ULNand 
with signs or 
symptoms
Serum 
amylase** 
increased
Amylase 
(U/L)
>ULN -
1.5 x 
ULN
>1.5 - 2.0 x ULN;
>2.0 - 5.0 x ULN 
>5.0 x ULN
Lipids
Cholesterol high
Cholesterol 
Total 
(mmol/L)
>ULN-
7.75 
mmol/L
>7.75-10.34 
mmol/L
>10.34-12.92 
mmol/L
>12.92 mmol/L
Hypertriglyceridemia
Triglycerides
(mmol/L)
1.71 
-
3.42 
mmol/L
>3.42 
-
5.7 
mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Highest grade will be assigned if more than one grade criteria are met for an observed value of a patient.
**CTCAE 4.03 definition. For reporting in CSR, the grade definition per CTCAE 4.03 will be used for this parameter only.
5.4
Clinical notable vital signs 
Clinically notable vital sign values to be used for this study are listed below.
Table 5-4
Vital signs clinically notable values
Vital Sign
Notable criteria
Pulse (beats/min, bpn)
>120 bpm 
Or <50 bpm
Systolic Blood Pressure (mmHg)
≥160 mmHg 
Or <90 mmHg


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Vital Sign
Notable criteria
Diastolic Blood Pressure
≥100 mmHg 
Or <50 mmHg
Temperature (°C)
>38.3 °C (>101 °F) 
Body weight (kg)
≥7% from baseline weight 
5.5
Statistical models
5.5.1
Primary analysis
The null hypothesis is that there is no difference in the ARR between ofatumumab 20mg 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 two treatment groups. H0: ARRo /ARRt = 1 vs. Ha: ARRo /ARRt<1. Where ARRo
and ARRt are ARR of ofatumumab and ARR of teriflunomide respectively.
The null hypothesis will be tested 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 T1 Gd-enhancing lesions and the patient’s age at baseline as covariates. 
The SAS procedure GENMOD will be used to conduct the analysis. In GENMOD, the log of 
the dispersion parameter will be used (lognb) as an option in model statement. The natural log
of time in year is used as an offset by specifying offset option in the model statement.
5.5.2
Key secondary analysis
For disability related key secondary endpoints, the Cox proportional hazard model will be the 
key secondary analysis to test H0: λo/λt = 1 vs. Ha: λo/λt < 1. Where λo and λt are hazard of 
disability events in ofatumumab and teriflunomide treatment groups respectively. A stratified 
Cox proportional hazards model with study as stratum, treatment, and region as factors and 
baseline EDSS at baseline as a continuous covariate. The model will contain a treatment-by-
study interaction.
The Cox proportional hazard (PH) model assumes that the effect of each covariate is the same 
at all points in time. To check the PH assumption for the treatment covariate, a plot of log-log 
survivor function vs. time for each treatment group will be used. If the hazards are proportional, 
the log-log survivor functions should be parallel. Approximate parallelism between the curves 
for the treatment groups will provide supportive evidence of the proportional hazards 
assumption.
If the assumption of proportional hazards is questionable based on graphical analyses, then the 
interpretation of the estimated hazard ratio will need to be done with caution. 
The SAS procedure PHREG will be used to conduct the Cox PH analysis. The SAS procedure 
LIFETEST will be used to conduct the KM analysis.


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For the key secondary endpoints related to Gd lesions and T2 lesions, mathematical details are 
similar to the ones for primary analysis described in Section 5.5.1 as the negative binomial 
models will be used.
For the key secondary endpoint related to brain volume change, a random coefficients model 
will be used to test H0: βo - βt = 0 vs. Ha: βo < βt. Where βo and βt are annual rate of percent 
change from baseline in brain volume in ofatumumab and teriflunomide treatment groups 
respectively. 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 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 annual rate of percent change from baseline in brain volume is approximates as the 
population slope within the treatment group. 
Percent brain volume change was approximately linear over time and approximately normally 
distributed in 3 independent studies of the fingolimod phase 3 program. Data collected from 
this study will be checked descriptively by plotting the population mean percent change from 
baseline against time before database lock in a blinded fashion (pooling all patients).
The SAS procedure MIXED will be used to conduct the analysis. Unstructured covariance will 
be assumed.
5.5.3
Important supportive analysis of primary or key secondary endpoints
5.5.3.1
Supportive analysis of primary endpoint: 
To estimate the ARR and the treatment effect during the initial “onset of action” period of 8 
week (≤56 days=8*7 days), and the ARR and the treatment effect thereafter (>56 days; long-
term efficacy) a sensitivity analysis will be conducted on the FAS. The number of confirmed 
relapses for the ith patient from treatment group j who spent ti years in the study Nij(ti) is assumed 
to follow a piecewise constant negative binomial distribution with different ARR before and 
after day 56 but with a constant dispersion k.












56
56
),
,
*
(
~
)
(
56
),
,
*
(
~
)
(
)
(
)
(
)
(
2
2
2
2
1
1
1
1
2
1
i
i
i
i
j
i
ij
i
i
j
i
ij
i
ij
i
ij
i
ij
t
for
t
t
k
t
NegBin
t
N
t
k
t
NegBin
t
N
where
t
N
t
N
t
N


In the above notation, ti1 and ti2 are the times spent in the study before and after day 56
respectively. The total time in study ti=ti1 + ti2.
5.5.3.1.1 Implementation in SAS
The piecewise constant negative binomial regression model can be re-written as a Poisson-
Gamma mixture model which can be implemented in SAS via NLMIXED procedure. 
Specifically, let Nij(ti)|Ui denote a Poisson distributed random variable where Ui is a Gamma 
distributed random variable with mean 1 and variance 1/α=k. The model assumed for the mean 
of Nij(ti)|Ui is expressed by time period, before or after day 56 respectively:


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


















days
t
and
t
t
t
U
x
trt
t
U
t
N
E
days
t
U
x
trt
t
U
t
N
E
i
i
i
i
i
T
i
j
i
i
i
ij
i
i
T
i
j
i
i
i
ij
56
,
)
exp(
)
|)
(
(
56
,
)
exp(
)
|)
(
(
1
2
2
2
2
1
2
1
1
1
1
1
1






Where 
denotes the vector of covariates for subject , and trtj is an indicator variable which is 
one for all patients assigned to ofatumumab and zero for those assigned to teriflunomid, exp()
quantifies the effect of the covariates. Thus, 
1
1and 
2
1represent the ARR for teriflunomid up 
to day 56 and thereafter, respectively. The treatment effect (ARR-ratio) is exp(θ1) during the 
first 56 days, and exp(θ2) thereafer. Hence, the ARR on ofatumumb is 
1
2=
1
1exp(θ1) during 
the first 56 days, and 
2
2=
2
1exp(θ2) thereafter.
In case of non-convergence of this model, all covariates will be dropped from the model.
As the annualized relapse rate is to be estimated, time will be divided by 365.25 (as in year 
scale) for implementation in SAS. The data set will be prepared in such a way that there will be 
2 records, one for period ≤56 days and the other for period >56 days, for patients whose actual 
time in study is greater than 56 days. For period ≤56 days, the number of confirmed relapses 
with relapse starting date on or before day 56 will be calculated and the time in study variable 
will be set to 56/365.25. For period >56 days, the number of confirmed relapses with relapse 
starting date after day 56 will be calculated and the time in study variable will be set to (value 
of time in study overall-56 then divided by 365.25). The time period indicator variable will be 
populated for both records appropriately (e.g., 0 for period ≤56 days and 1 for period >56 days). 
For patients whose actual time in study variable is ≤56 days, the observed record (i.e., same as 
the overall number of confirmed relapses and time in study) will be populated with time period 
indicator as ≤56 days. Table 5-5 provides an example of the data set where other covariates are 
to be added accordingly.
Table 5-5
Key data structure for piecewise NB model
Patient
Treatment
Treatment 
code
Period 
code
Time 
in 
study
(total)
Time 
in 
study (by 
period)
No. 
of 
confirmed 
relapses 
(total)
No. 
of 
confirmed 
relapses 
(by 
period)
1
OFA20
1
0
100/365.25
56/365.25
3
1
1
OFA20
1
1
100/365.25
44/365.25
3
2
2
TER14
0
0
45/365.26
45/365.26
2
2
Additional patient level variables will be derived to be used as covariates in this model.
Continuous covariates will be centered by the mean. For example, age will be centered by 
subtracting the mean of age as (age – mean(age)). The mean will be calculated based on all 
patients in the study.
Factors will be dummy coded. There are 3 factors in the model, i.e. treatment, period, and 
region. Treatment code and Period code as shown in Table 5-5 can be considered as dummy 


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coded variables as each factor has 2 levels only where the reference level will have a value of 
0. Region will have 5 levels (as in Section 5.8) so that 4 dummy coded region variables will be 
derived. The reference region will be the “North America and AUS” region. The rest 4 regions 
will each have a dummy coded variable with value of 1 if patients are in this region or 0 if 
patients are not in this region. Patients in the reference region will have 0 values in all 4 region 
dummy coded variables.
5.5.3.2
Supportive analysis of key secondary endpoints (3mCDW and 
6mCDW):
To estimate the hazard ratio between treatment groups 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 for the 3mCDW and 6mCDW. A stratified Cox proportional hazards 
model simililar to that for the main analysis will be used with study and time period indicator 
as strata, treatment and region as factors and baseline EDSS as a continuous covariate. The 
model will also contain an interaction term of time period indicator by treatment.
The SAS procedure PHREG will be used to conduct the analysis.
The data set for Cox’s PH model will include a time to event variable and event status variable 
(0 as censored) as usual. To fit the above mentioned stratified Cox’s PH model, an artificial 
record will be created for patients whose actual time to event variable is >56 days. This artificial 
record will set the time to event variable equal to 56 days and event status variable as censored.
A time period indicator variable will be populated for all records as 0 if the time to event
variable ≤56 days and 1 if the time to event variable >56 days. Table 5-6 provides an example 
of the data set where other covariates are to be added accordingly. Bolded records are artificial 
records.
Table 5-6
Key data structure for stratified Cox’s PH model
Patient
Treatment
Treatment 
code
Period 
code
Time to event
Event status
1
OFA20
1
0
56
0
1
OFA20
1
1
100
1
2
TER14
0
0
45
1
3
OFA20
1
0
56
0
3
OFA20
1
1
155
0
5.6
Rule of exclusion criteria of analysis sets 
Patient classification in the analysis sets is entirely based on protocol deviation and non-
protocol deviation criteria. Details are provided in Table 5-7 and Table 5-8.


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Table 5-7
Protocol deviations that cause patients to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analysis sets
EXCL01
Patients with primary progressive MS 
or non-relapsing/no MRI activity-
SPMS
Excluded from PPS
EXCL02
Patients meeting criteria for 
neuromyelitis optica
Excluded from PPS 
EXCL03
Disease duration of more than 10 years 
in patients with EDSS score of 2 or less
Excluded from PPS 
EXCL08
Patients with an active chronic disease 
(or stable but treated) of the immune 
system other than MS or with a known 
immunodeficiency syndrome
Excluded from PPS 
EXCL19
Teriflunomide (if discontinued for 
reasons related to safety or lack of 
efficacy) at any time prior to 
randomization
Excluded from PPS 
EXCL25B
Patients currently treated with 
leflunomide
Excluded from PPS
EXCL49
History of clinically significant CNS 
disease (e.g. stroke, traumatic brain or 
spinal injury, history or presence of 
myelopathy) or neurological disorders 
which may mimic MS
Excluded from PPS 
EXCL52
History of hypersensitivity to any of 
the study drugs or excipients (including 
lactose intolerance) or to drugs of 
similar chemical classes
Excluded from PPS
INCL01
Informed consent obtained = 'No' or 
missing
Excluded from all analysis 
sets
INCL03
No diagnosis of MS as defined by 2010 
revised McDonald criteria
Excluded from PPS 
INCL06
Neurologically stable within 1 month 
prior to randomization
Excluded from PPS 
WITH11
Patient diagnosed with PML and study 
treatment was not discontinued
Excluded from PPS 
TRT01
Patient received incorrect study drug
Excluded from PPS 
TRT02
Patient received damaged or expired 
study drug
Excluded from PPS 
COMD01
Immunosuppressive/chemotherapeutic 
medications or procedures, including 
Excluded from PPS 


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Deviation 
ID
Description of Deviation
Exclusion in Analysis sets
cyclosporine, azathioprine, 
methotrexate, cyclophosphamide, 
mitoxantrone, lymphoid irradiation and 
hematopoietic stem cell transplantation 
while taking double-blind treatment
COMD02
Monoclonal antibodies targeting the 
immune system, including but not 
limited to natalizumab, alemtuzumab, 
and B-cell depleting agents such as 
rituximab, ocrelizumab and 
obinutuzumab while taking double-
blind treatment
Excluded from PPS 
COMD03
Any other immunomodulatory or 
disease- modifying MS treatment, 
including but not limited to, 
fingolimod, interferon beta, glatiramer 
acetate, dimethyl fumarate or systemic 
corticosteroids (except when given for 
MS Relapse treatment) while taking 
double-blind treatment
Excluded from PPS 
COMD04
Leflunomide while taking double-blind 
treatment
Excluded from PPS 
COMD06
Daclizumab while taking double-blind 
treatment
Excluded from PPS
OTH01
EDSS rater acted as a treating 
physician or treating physician acted as 
EDSS rater
Excluded from PPS 
OTH02
Not following per protocol blinding 
procedures such that the integrity of the 
study is compromised  
Excluded from PPS 
Table 5-8
Patient Classification
Analysis Set
PD ID that cause patients to 
be excluded
Non-PD criteria that cause 
patients to be excluded
SCR
NA
NA
FAS
INCL01
Not assigned a valid randomization number
Mis-randomized patients who didn’t take 
study drug
PPS
As listed in Table 5.7
Not in FAS;  


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Analysis Set
PD ID that cause patients to 
be excluded
Non-PD criteria that cause 
patients to be excluded
Compliance to study drug administration < 
80%
EDSS baseline value >=7.0
SAF
INCL01
No double-blind study drug taken
5.7
Statistical method details for TEAEs
5.7.1 Odds ratios and 95% confidence interval
For an investigational drug group with n1 patients at risk, independent from the control group 
with n0 patients at risk, of whom x1 and x0 experience a certain event with probability π1 and π0
respectively, the odds ratio (OR) is estimated as
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p


  with p1= x1/n1 and p0=x0/n0, simplifying to 
)
(
)
(
1
1
0
0
0
1
x
n
x
x
n
x




.  
The OR and a conditional exact 95% confidence interval will be obtained by using the SAS 
procedure PROC FREQ with statement EXACT OR. The data set will include a patient level 
response variable indicating whether a patient has at least one AE of a specific type (1=yes, 
0=no).
By default SAS sets the OR to missing if the odds for one of the treatments cannot be calculated 
(no infinity in SAS). This is problematic as infrequent but very serious adverse events that 
happen exclusively on active treatment can easily be missed if the OR for such highly 
imbalanced advents is set to missing and sorted last. To ensure that potentially important 
imbalances appear at the top of a table if it is sorted by OR, the following additional rules are 
applied (considering the numerator and the denominator of the OR that would lead to divisions 
by zero):

NO CASE CLAUSE [0/0]: If (x1=0 and x0=0) or (x1=n1 and x0=n0), i.e. there are either 
no events in both treatment groups, or all patients in both treatment groups had the event, 
then the OR cannot be estimated. The OR can be left missing for the sorting, but should 
be displayed on the output as “N.E.” indicating not estimable (if it has to be shown on 
the table, in this case it needs to be explained in the footnote).

SAFETY CLAUSE[~/0]: If (x0=0 and x1≠0) or (x0≠n0and x1=n1), i.e. there are no events 
on control, but some on investigational drug, or everyone on investigational drug 
experienced the event, but not everyone on control, then OR will be imputed as 100000 
for the sorting (so that it comes up top if sorted by the OR). On the output present the 
OR as “>100”.

EFFICACY CLAUSE[0/~]: If (x1=0 and x0 ≠0) or (x1≠n1 and x0 =n0), i.e. there are no 
events on investigational drug, but some on control, or, everyone on control experienced 
the event, but not everyone on investigational drug, then OR will be imputed as 


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1/100000 for the sorting (so that it comes prior to the missing ones). On the output 
present the OR as “<1/100”.
5.7.2 Exposure adjusted incidence rate and 95% confidence interval 
It will be assumed that for each of n patients in a clinical trial the time tj (j=1,...,n) to the first 
incidence of a certain event is observed, or if the event was not experienced, the time is censored
at the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process θ with constant intensity λ. The rate 
parameter λ will be estimated by 
T
D

ˆ
, where 



n
j
jt
T
1
and D is the number of patients with 
at least one event. Conditionally on T, an exact 95% confidence interval for a Poisson variable 
with parameter θT and observed value D can be obtained based on (Garwood, 1936), from 
which an exact 95% confidence interval for 
T
D

ˆ
will be derived as follows (Sahai, 1993; Ulm, 
1990):
Lower confidence limit   
T
c
L
D
2
,
2
/
5.0


for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D
2
2
,
2
/
1
5
.
0




where
k
c ,
is the αth quantile of the Chi-square distribution with k degrees of freedom.
The SAS procedure GENMOD will be used to fit a Poisson regression model with only 
treatment as factor, the log-link and natural logarithm of time as the offset variable. The 
incidence rate (and 95% confidence intervals) are obtained as the exponentiated estimates by 
treatment (e.g. obtained by statement LSMEANS with option EXP). The data set will include a 
patient level response variable indicating whether the patient experienced at least one event of 
a specific type (1=yes, 0=no) and a patient level time variable which is derived as follows: 

For patients who had at least one event of that type: time is calculated as (start day of the 
first event - date of first administration of study drug+1). 

For patients who did not have an event of that type: time at risk as defined in Section 2.4.1  
will be used.
The time will be divided by 365.25 before taking the logarithm transformation as offset variable 
so that the estimated incidence rate corresponds to an annualized rate.
5.8
Regions for randomization stratification
Regions
G2301
G2302
Western Europe
Austria
x
Belgium
x
x
Denmark
x


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Finland
x
France
x
x
Germany
x
x
Greece
x
Italy
x
x
Netherlands
x
Norway
x
Portugal
x
x
Spain
x
x
Sweden 
x
Switzerland
x
x
United Kingdom
x
x
Eastern Europe
Bulgaria
x
x
Croatia
x
x
Czech Republic
x
x
Estonia
x
Hungary
x
x
Latvia
x
Lithuania
x
Poland
x
x
Romania
x
x
Slovakia
x
x
Turkey
x
x
North America and AUS
Australia
x
x
Canada
x
x
United States
x
x
Asia Pacific
India
x
x
South Korea
x
Taiwan
x
Thailand
x
Latin America
Argentina
x
x
Brazil
x


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Chile
x
Mexico
x
x
Peru
x
Others
Egypt
x
Israel
x
Kuwait
x
Lebanon
x
Saudi Arabia
x
Russia Federation
x
x
South Africa
x
United Arab Emirates
x


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6
References
Cockcroft DW, Gault MJ (1976) Prediction of creatinine clearance from serum creatinine. 
Nephron; 16:31-41
Confavreux C, O'Connor P, Comi G, et al. (2014) Oral teriflunomide for patients with relapsing 
multiple sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol: 
Mar;13(3):247-56
Garwood F. (1936) Fiducial Limits for the Poisson Distribution. Biometrika 28, 437-442.
Gassmann-Mayer et al. (2011) Clinical and statistical assessment of suicidal ideation and 
behavior in pharmaceutical trials, Clinical Pharmacology & Therapeutics 90 4, 554–560.
Hauser SL, Comi GC, Hartung HP et al. (2015) Efficacy and safety of ocrelizumab in relapsing 
multiple sclerosis - results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA 
I and II studies. ECTRIMS Online Library. Hauser S. Oct 9, 2015; 116634
Kappos L, Li D, Calabresi PA et al. (2011) Ocrelizumab in relapsing-remitting multiple 
sclerosis: a phase 2, randomized, placebo-controlled, mutlicentre trial. Lancet; 378: 1779-87
Keene ON, Jones MRK, Lane PW, Anderson J. (2007) Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharmaceutical 
Statistics; 6: 89-97
O’Connor P, Wolinsky JS, Confavreux C et al. (2011) Randomized Trial of Oral Teriflunomide 
for Relapsing Multiple Sclerosis. N Engl J Med; 365:1293-303
Panitch H, Goodin DS, Francis G, et al. (2002) Randomized, comparative study of interferon 
beta-1a treatment regimens in MS. The EVIDENCE trial. Neurology. 2002;59:1496–506.
Novartis: Philippe Close (2011): Hepatotoxicity: Clinical Development Safety Guideline. 
Novartis: COMB157G SAP for BSSR: statisticial analysis plan for blinded sample size re-
estimation
Sahai H, Khurshid A (1993). Conﬁdence intervals for the ratio of two Poisson means. The 
Mathematical Scientist, 18, 43–50.
Ulm K (1990). A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology 1990;131(2):373-375.