Clinical trial NCT04878211
Conditions: Relapsing Multiple Sclerosis (RMS)
Keywords: Multiple Sclerosis Relapsing Multiple Sclerosis COVID COVID-19 Vaccine Coronavirus adult OMB157
Sponsor: Novartis Pharmaceuticals
Start date: 2021-06-10; Completion date: 2023-04-14
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated if relapsing multiple sclerosis (MS) participants treated with ofatumumab 20 mg subcutaneous (s.c.) administered once monthly could develop an adequate immune response to the COVID-19 mRNA vaccine compared to participants on an interferon or glatiramer acetate.

Detailed description:
This was a six-cohort, multicenter, prospective study planned for up to 88 relapsing multiple sclerosis (MS) participants. The study was intended to address two questions: 1) Can participants treated with ofatumumab develop an immune response if receiving a COVID-19 mRNA vaccine two weeks prior to ofatumumab start? 2) If receiving COVID-19 mRNA vaccine after introduction of ofatumumab treatment, can participants develop an immune response? Cohort 1: participants received an mRNA COVID-19 vaccine at least two weeks prior to ofatumumab start. Cohort 2: participants received an mRNA COVID-19 vaccine at least four weeks after beginning ofatumumab. Cohort 3: participants on an interferon or glatiramer acetate who received COVID-19 mRNA vaccine. Cohort 4: participants fully vaccinated with an RNA COVID-19 vaccine at least four weeks after ofatumumab start. Cohort 5: participants vaccinated with an RNA COVID-19 vaccine, with or without a booster dose, and on interferon or glatiramer acetate. Cohort 6: participants fully vaccinated with an RNA COVID-19 vaccine who received a booster dose at least four weeks after ofatumumab start. Participants obtained the COVID-19 mRNA vaccine from their HCP (private insurance) or appropriate federal, state or local program.

Participants in Cohort 1 received loading doses of ofatumumab and subsequent dosing was 20 mg s.c. administered monthly. All other cohorts continued current dosing schedule of either ofatumumab, glatiramer acetate or interferon. Participation in trial was maximum of 421 days which was dependent on the Cohort.

Arms: arm 1: Participants received non-live COVID-19 mRNA vaccine at least two weeks prior to start of ofatumumab (OMB157) (20 mg subcutaneous). arm 2: Participants received non-live COVID-19 mRNA vaccine at least four weeks after start of ofatumumab (OMB157) (20 mg subcutaneous). arm 3: Participants will receive non-live COVID-19 mRNA vaccine at least 4 weeks after start of prescribed interferon or glatiramer acetate arm 4: Participants fully vaccinated with a non-live COVID mRNA vaccine and on ofatumumab for at least 4 weeks (20 mg subcutaneous) arm 5: Participants fully vaccinated with a non-live COVID mRNA vaccine, without or without a booster, and on interferon or glatiramer acetate for at least 4 weeks. arm 6: Participants fully vaccinated with a non-live COVID mRNA vaccine with a booster and on ofatumumab for at least 4 weeks (20 mg subcutaneous)
Interventions: intervention 1: Ofatumumab intervention 2: mRNA COVID-19 vaccine intervention 3: interferon or glatiramer acetate
Intervention descriptions: intervention 1: 3 loading doses followed by monthly administrations intervention 2: Pfizer or Moderna mRNA Vaccine intervention 3: iDMT

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
OMB157G/Ofatumumab 
Synopsis/Clinical Trial Protocol COMB157GUS16 / NCT04878211
An open-label multicenter study to assess response to 
COVID-19 vaccine in participants with multiple sclerosis 
treated with ofatumumab 20 mg subcutaneously
Document type: 
Amended Protocol Version 
EUDRACT number: 
NA 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
IV 
Release date: 
26-May-2022
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis  
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 7 
Amendment 2 ...................................................................................................................... 9 
Amendment 1 .................................................................................................................... 10 
Protocol summary .............................................................................................................. 11 
1 
Introduction ....................................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.2 
Purpose .................................................................................................................. 15 
2 
Objectives, endpoints and estimands ................................................................................. 16 
2.1 
Primary estimands ................................................................................................. 17 
2.2 
Secondary estimands ............................................................................................. 17 
3 
Study design ...................................................................................................................... 18 
4 
Rationale ............................................................................................................................ 22 
4.1 
Rationale for study design ..................................................................................... 22 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 23 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 23 
4.4 
Purpose and timing of interim analyses ................................................................. 23 
4.5 
Risks and benefits .................................................................................................. 23 
4.5.1 
Blood sample volume ............................................................................ 24 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 24 
5 
Study Population ............................................................................................................... 25 
5.1 
Inclusion criteria .................................................................................................... 25 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Additional study treatments .................................................................. 30 
6.1.3 
Treatment cohorts .................................................................................. 30 
6.1.4 
Post-Trial Access .................................................................................. 30 
6.2 
Other treatment(s) .................................................................................................. 30 
6.2.1 
Concomitant therapy ............................................................................. 30 
6.2.2 
Prohibited medication ........................................................................... 31 


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6.2.3 
Recommended treatment of MS relapse ............................................... 32 
6.3 
Preparation and dispensation ................................................................................. 32 
6.3.1 
Handling of study treatment and other treatment .................................. 33 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 34 
6.4 
Participant numbering, treatment assignment, randomization .............................. 36 
6.4.1 
Participant numbering ........................................................................... 36 
6.5 
Treatment blinding................................................................................................. 37 
6.6 
Dose escalation and dose modification .................................................................. 37 
6.7 
Additional treatment guidance ............................................................................... 37 
6.7.1 
Treatment compliance ........................................................................... 37 
6.7.2 
Emergency breaking of assigned treatment code .................................. 37 
7 
Informed consent procedures ............................................................................................ 37 
8 
Visit schedule and assessments ......................................................................................... 38 
8.1 
Screening ............................................................................................................... 57 
8.1.1 
Eligibility screening .............................................................................. 57 
8.1.2 
Information to be collected on screening failures ................................. 57 
8.2 
Participant demographics/other baseline characteristics ....................................... 57 
8.3 
Efficacy .................................................................................................................. 57 
8.4 
Safety ..................................................................................................................... 57 
8.4.1 
Laboratory evaluations .......................................................................... 58 
8.4.2 
Pregnancy and assessments of fertility ................................................. 58 
8.5 
Additional assessments .......................................................................................... 58 
8.5.1 
Use of residual biological samples ........................................................ 59 
8.5.2 
Serum Immunoglobulins ....................................................................... 59 
8.5.3 
Bio-banked samples .............................................................................. 59 
9 
Discontinuation and completion ........................................................................................ 59 
9.1 
Discontinuation from study treatment and from study .......................................... 59 
9.1.1 
Discontinuation from study treatment ................................................... 59 
9.1.2 
Discontinuation from study ................................................................... 60 
9.1.3 
Lost to follow-up ................................................................................... 61 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 61 
9.3 
Study stopping rules .............................................................................................. 62 
9.4 
Study completion and post-study treatment .......................................................... 62 
9.5 
Early study termination by the sponsor ................................................................. 62 
10 Safety monitoring, reporting and committees ................................................................... 62 
10.1 
Definition of adverse events and reporting requirements ...................................... 62 


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10.1.1 
Adverse events ...................................................................................... 62 
10.1.2 
Serious adverse events .......................................................................... 64 
10.1.3 
SAE reporting ........................................................................................ 65 
10.1.4 
Pregnancy reporting .............................................................................. 65 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 66 
10.2 
Additional Safety Monitoring ................................................................................ 66 
11 Data Collection and Database management ...................................................................... 67 
11.1 
Data collection ....................................................................................................... 67 
11.2 
Database management and quality control ............................................................ 67 
11.3 
Site monitoring ...................................................................................................... 68 
12 Data analysis and statistical methods ................................................................................ 68 
12.1 
Analysis sets .......................................................................................................... 68 
12.2 
Participant demographics and other baseline characteristics ................................. 69 
12.3 
Treatments ............................................................................................................. 69 
12.4 
Analysis supporting primary objectives ................................................................ 69 
12.4.1 
Definition of primary endpoint(s) ......................................................... 69 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 69 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 69 
12.4.4 
Handling of missing values not related to intercurrent event ............... 69 
12.4.5 
Sensitivity analyses ............................................................................... 69 
12.4.6 
Supplementary analysis ......................................................................... 70 
12.5 
Analysis supporting secondary objectives ............................................................. 70 
12.5.1 
Safety endpoints .................................................................................... 70 
 
 71 
12.7 
Interim analyses ..................................................................................................... 71 
12.8 
Sample size calculation .......................................................................................... 72 
12.8.1 
Primary endpoint(s) ............................................................................... 72 
13 Ethical considerations and administrative procedures ...................................................... 72 
13.1 
Regulatory and ethical compliance ........................................................................ 72 
13.2 
Responsibilities of the investigator and IRB ......................................................... 72 
13.3 
Publication of study protocol and results ............................................................... 72 
13.4 
Quality Control and Quality Assurance ................................................................. 73 
14 Protocol adherence ............................................................................................................ 73 
14.1 
Protocol amendments ............................................................................................. 73 
15 References ......................................................................................................................... 74 
 


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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 16 
Table 6-1 
Investigational and control drug ............................................................ 29 
Table 6-2 
Prohibited medication ........................................................................... 31 
Table 6-3 
Dose and treatment schedule ................................................................. 36 
Table 8-1 
Assessment schedule for Cohort 1 (Pfizer vaccine) .............................. 40 
Table 8-2 
Assessment schedule for Cohort 1 (Moderna vaccine) ......................... 43 
Table 8-3 
Assessment schedule for Cohorts 2 and 3 (Pfizer vaccine) .................. 46 
Table 8-4 
Assessment schedule for Cohorts 2 and 3 (Moderna vaccine) ............. 48 
Table 8-5 
Assessment schedule for Cohorts 4, 5 and 6 (Pfizer vaccine) .............. 51 
Table 8-6 
Assessment schedule for Cohorts 4, 5 and 6 (Moderna vaccine) ......... 54 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 66 
List of figures 
Figure 3-1 
Study Design (Cohort 1, Pfizer) ............................................................ 19 
Figure 3-2 
Study Design (Cohort 1, Moderna) ....................................................... 19 
Figure 3-3 
Study Design (Cohorts 2 and 3, Pfizer) ................................................ 20 
Figure 3-4 
Study Design (Cohorts 2 and 3, Moderna) ............................................ 21 
Figure 3-5 
Study Design (Cohorts 4, 5, and 6, Pfizer) ........................................... 21 
Figure 3-6 
Study Design (Cohorts 4, 5, and 6, Moderna) ....................................... 21 
 


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List of abbreviations 
AE 
Adverse Event 
COVID-19 
Coronavirus 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
EDC 
Electronic Data Capture 
EOS 
End of Study 
 
 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
iDMT 
Injectable Disease Modifying Therapy 
  
 
IN 
Investigator Notification 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
mg 
milligram(s) 
ml 
milliliter(s) 
mAb 
monoclonal antibody 
QMS  
Quality Management System 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Control drug 
A study drug (active or placebo) 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 participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained  
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-enrolled 
participants 
Mis-enrolled participants are those who were not qualified for enrollment and 
who did not take study treatment, but have been inadvertently enrolled into 
the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 


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should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Participant number 
A unique identifier assigned to each screened participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant  
Study treatment 
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant 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 
This protocol has been amended to allow participants with a known diagnosis of COVID-19 
prior to starting in the study to be enrolled.  In this amendment we have also addressed 
inconsistencies and sought to make clarifications at certain points. 
Changes to the protocol 
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.  
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 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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Amendment 1 
Amendment Rationale 
This protocol has been amended to add 3 new cohorts comprised of participants who have 
completed a full course (two doses) of a COVID-19 mRNA vaccine.  Also, the sample size of 
the study is increased to enroll a reasonable number of participants in all six cohorts. Given the 
decline in the US vaccination rate, the decision to include participants who are fully vaccinated 
was made to increase the rate in which participants are enrolled and to capture additional data 
related to mounting an immune response.  The number of interim analysis is increased from one 
to three. In this amendment we have also addressed inconsistencies and sought to make 
clarifications at certain points. 
Changes to the protocol 
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.  
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 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 
COMB157GUS16 
Full Title 
An open-label multicenter study to assess response to COVID-19 vaccine in 
participants with multiple sclerosis treated with ofatumumab 20 mg 
subcutaneously 
Brief title 
A multicenter study to assess response to COVID-19 vaccine in multiple sclerosis 
participants treated with ofatumumab  
Sponsor and 
Clinical Phase 
Novartis  
Clinical phase IV 
Investigation 
type 
Biological/Vaccine 
Study type 
Interventional, 6-cohort   
Purpose and 
rationale 
The objective of this study is to assess whether participants treated with 
ofatumumab 20 mg subcutaneous (s.c.) administered once monthly can mount an 
adequate immune response to non-live COVID-19 mRNA vaccine as measured 
by humoral responses compared to participants on an interferon or glatiramer 
acetate.   
Primary 
Objective(s)  
To assess immune response to non-live mRNA COVID-19 vaccine in ofatumumab 
treated subjects 
Secondary 
Objectives 
• 
To assess immune conversion to non-live mRNA COVID-19 vaccine in 
ofatumumab treated subjects  
• 
To assess adverse events and serious adverse events 
Study design 
This is a 6-cohort, multicenter, prospective study of up to 88 relapsing MS 
participants.  
Cohort 
Brief Description 
1 
Vaccine naive, planning to start OMB 
2 
Vaccine naive, currently on OMB for ≥ 4 weeks 
3 
Vaccine naive, on interferon or glatiramer acetate for ≥ 4 weeks 
4 
Fully vaccinated, currently on OMB for ≥ 4 weeks 
5 
Fully vaccinated, on interferon or glatiramer acetate for ≥ 4 
weeks, +/- booster 
6 
Fully vaccinated, currently on OMB for ≥ 4 weeks, + booster 
All groups will undergo serologic testing.   
Participants will obtain the COVID-19 mRNA vaccine from their HCP (private 
insurance) or appropriate federal, state or local program.   
Study 
population 
Adult (ages 18-55) relapsing MS participants 
Key Inclusion 
criteria 
Patients eligible for inclusion in Cohort 1 of this study must fulfill the following 
criteria:  
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old inclusive at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 


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5. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) 
6. Eligible to receive and plan to be started on Ofatumumab according to the 
approved labeling  
7. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or 
latent infection 
8. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Patients eligible for inclusion in Cohort 2 of this study must fulfill the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed ofatumumab for ≥ 4 weeks for the 
treatment of RMS 
6. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) 
7. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or 
latent infection 
8. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Patients eligible for inclusion in Cohort 3 of this study must fulfill the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed interferon or glatiramer acetate for ≥ 4 
weeks for the treatment of RMS 
6. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) 
7. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Patients eligible for inclusion in Cohort 4 of this study must fulfill the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Completed a full course (two doses) of a COVID-19 mRNA vaccine at least 
≥ 4 weeks after start of commercially prescribed ofatumumab for the 
treatment of RMS 
6. Currently on commercially prescribed ofatumumab for ≥ 4 weeks for the 
treatment of RMS  
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 
2 weeks ago 
8. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or 
latent infection 
9. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
 
Patients eligible for inclusion in Cohort 5 of this study must fulfill the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed interferon or glatiramer acetate for ≥ 4 
weeks for the treatment of RMS 


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6. Completed a full course (two doses) of a COVID-19 mRNA vaccine after 
start of glatiramer acetate or interferon  
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 
2 weeks ago 
8. If the patient has received the mRNA booster, then the mRNA booster 
should be ≥ 2 weeks prior to enrollment  
9. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
 
Patients eligible for inclusion in Cohort 6 of this  study must fulfill the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed ofatumumab  
6. Completed a full course (two doses) of a COVID-19 mRNA vaccine at least 
≥ 4 weeks after start of commercially prescribed ofatumumab for the 
treatment of RMS 
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 
2 weeks ago 
8. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or 
latent infection 
9. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
10. Has received an mRNA booster ≥ 2 weeks prior to enrollment  
Key Exclusion 
criteria 
1. Already has received the J&J vaccine. 
2. Has a contraindication to receiving an mRNA COVID-19 vaccine 
3. Has an immediate allergic reaction to a past vaccine or injection 
4. Any safety finding including low immunoglobulin IgG and/or low 
immunoglobulin IgM levels requiring an ofatumumab treatment interruption 
within the 12 weeks immediately prior to vaccination as determined by the 
HCP 
5. Any major episode of infection requiring hospitalization or treatment with 
intravenous antibiotics within 4 weeks prior to the first vaccination visit or oral 
antibiotics within two weeks prior to the first vaccination visit 
6. Prior treatment with B-cell targeted therapies (e.g., rituximab or ocrelizumab), 
alemtuzumab, 
anti-CD4, 
cladribine, 
cyclophosphamide, 
mitoxantrone, 
azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body 
irradiation, or bone marrow transplantation 
7. Prior treatment with S1P agent within 2 months  at Screening 
8. Prior treatment with natalizumab within 6 months of study enrollment/Visit 2 
9. Since commercially prescribed ofatumumab is being used in the study, 
contraindications as per the USPI will be adhered to which include active 
infection hepatitis B infection, progressive multifocal leukoencephalopathy 
and pregnancy 
10. Participation in another interventional clinical trial within 14 days before 
enrollment 
Study 
treatment 
Participants in Cohort 1 (Pfizer vaccine): The first of three 20 mg sc ofatumumab 
loading doses will be administered on Day 36 or 2 weeks after receiving a full 
course (two doses) of COVID-19 vaccine. The 2nd and 3rd loading doses should 
be administered on Day 43 and Day 50 or 7 and 14 days respectively after the 1st 
loading dose.  Subsequent dosing includes 20 mg sc administered monthly 
starting at Day 64. 


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Participants in Cohort 1 (Moderna vaccine): The first of three 20 mg sc 
ofatumumab loading doses will be administered on Day 43 or 2 weeks after 
receiving a full course (two doses) of COVID-19 vaccine. The 2nd and 3rd loading 
doses should be administered on Day 50 and Day 57 or 7 and 14 days respectively 
after the 1st loading dose.  Subsequent dosing includes 20 mg sc administered 
monthly starting at Day 71. 
Participants in Cohort 2:  Will continue to take prescribed ofatumumab as per 
their current dosing schedule. 
Participants in Cohort 3: Will continue to take interferon or glatiramer acetate as 
per their current dosing schedule. 
Participants in Cohort 4: Will continue to take prescribed ofatumumab as per 
their current dosing schedule. 
Participants in Cohort 5: Will continue to take prescribed glatiramer acetate or 
interferon as per their current dosing schedule. 
Participants in Cohort 6: Will continue to take prescribed ofatumumab as per 
their current dosing schedule. 
Treatment of 
interest 
COVID-19 mRNA vaccine 
Efficacy 
assessments 
None 
Key safety 
assessments 
• 
SARS-CoV-2 qualitative/quantitative IgG antibody assay 
• 
Adverse events/serious adverse events 
 
  
 
 
 
 
 
 
 
Data analysis 
The primary endpoint is achieving immune response as defined by a positive 
SARS-CoV-2 qualitative IgG antibody assay 14 days after full course (two doses) 
vaccination (yes/no). 
The sample size of 20 participants per individual or combined cohort is selected 
based on budget and need for early availability of results. The sample size of 20 
participants will provide estimates with margin of error (half-width of a 95% 
confidence interval) of 20.1%, 19%, and 17.5% corresponding to immune 
response rates of 70%, 75%, and 80%, respectively. Adjusting for 10% drop-out, 
22 participants will be enrolled in Cohort 1. In combination, 22 participants will be 
enrolled in Cohorts 2 and 4.  In combination, 22 patients will be enrolled in Cohorts 
3 and 5.  In Cohort 6, 22 participants will be enrolled. 
The number and percentage of responders will be presented. The 95% confidence 
interval for the proportion of responders will be calculated by using exact method.  
Key words 
COVID-19, vaccine, ofatumumab, SARS-coV2, antibody, 
 open-label 


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1 
Introduction 
1.1 
Background 
Multiple sclerosis (MS) is a common cause of neurologic disability in young adults.  In this 
disease, damage is caused by an autoimmune attack of the central nervous system.  Recent phase 
3 trials have demonstrated that antibodies that bind and cause CD20 B cells apoptosis have a 
powerful anti-inflammatory effect as measured by relapse and MRI activity, and leave 
participants with less disability than active comparators (Hauser et al 2020 and Hauser et al 
2017). 
MS disease modifying treatments target the immune system and in so doing may diminish 
vaccine efficacy (Farez et al 2019).  Questions have arisen whether therapies that affect B cells 
might also abrogate vaccine response.  Though other medications also impact B cells, anti-
CD20 antibodies have the most selective and potent impact on B cells.  These antibodies impact 
memory B cells which are believed to be an important component in maintaining immunologic 
memory but also preserve immunoglobulin secreting plasma cells which function to recognize 
and remove pathogens.  Research with an anti-CD20 B cell agent, ocrelizumab, indicates that 
an immune response can occur after vaccination but that the proportion of participants with an 
adequate response is diminished relative to a control group (Bar-Or et al 2020).  
Ofatumumab is a subcutaneously administered anti-CD20 therapy that received FDA approval 
for treatment of relapsing forms of MS in August 2020.  Data is currently lacking regarding 
whether MS participants on ofatumumab can mount an appropriate immune response to 
vaccines, including the COVID-19 vaccine.  In this study, MS participants will receive the 
COVID-19 vaccination and follow-up assays to assess whether they are able to mount a 
response to the vaccine.  A reference cohort of participants on injectable disease modifying 
treatments (interferon or glatiramer acetate) is included.  In a prior study, interferon and 
glatiramer acetate did not diminish vaccine response (Olberg et al 2018). 
1.2 
Purpose 
An important safety concern for health care providers and patients is whether an MS disease 
modifying agent might compromise vaccine efficacy.  Ofatumumab is a human anti-CD20 
monoclonal antibody (mAb) that induces B-cell depletion.  An increased risk of infections has 
been observed with other anti-CD20 B-cell depleting therapies.  Ofatumumab has the potential 
for an increased risk of infections, including serious bacterial, fungal, and new or reactivated 
viral infections; some of these infections have been fatal in patients treated with other anti-
CD20 antibodies.  As such, participants on ofatumumab may have an increased risk of 
morbidity and mortality should they contract COVID-19.  Therefore, it is important to assess if 
participants treated with ofatumumab are able to mount protective immune responses against 
the COVID-19 vaccine. 
This study will aim to address the following: 
1. To define COVID vaccine response in patients receiving a full course mRNA 
vaccination and how treatment with ofatumumab effects response. 
2. To determine the impact of a booster dose on immune response. 


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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objectives 
• 
To assess immune response to non-live 
mRNA COVID-19 vaccine in ofatumumab 
treated participants  
Endpoint(s) for primary objective(s)  
• 
Achieving immune response as defined by 
positive SARS-CoV-2 qualitative IgG 
antibody assay ≥ 14 days after vaccination 
(yes/no) 
Secondary Objectives 
• 
To assess sustained immune response to 
non-live mRNA COVID-19 vaccine in 
ofatumumab treated participants 
Endpoint(s) for secondary objective(s) 
• 
Achieve immune response at other 
assessment time points (yes/no) 
 
• 
To assess immune conversion to non-live 
mRNA COVID-19 vaccine in ofatumumab 
treated participants 
 
• Immune conversion to non-live mRNA 
COVID-19 vaccine (yes/no) defined as : 
• 
For patients with serum available prior to 
vaccine: 
o 
Baseline absence of SARS-CoV-2 
spike IgG with post-vaccination 
SARS-CoV-2 positive qualitative  
antibody assay ≥ 14 days after full 
course (two doses) vaccination 
(yes/no) or 
o 
Baseline serum presence of SARS-
CoV-2 quantitative IgG antibody with 
post-vaccination ≥ 4-fold increase in 
SARS-CoV-2 quantitative antibody 
titer as determined by dilution assay 
≥ 14 days after vaccination (yes/no) 
• For patients with serum unavailable prior to 
vaccine but who have not received a booster 
(Cohorts 4 and 5): 
o 
Initial negative SARS-CoV-2 
nucleocapsid antibody with post-
vaccination SARS-CoV-2 positive 
qualitative  antibody assay ≥ 14 
days after full course (two doses) 
vaccination (yes/no) 
• 
To assess adverse events and serious 
adverse events 
• 
Adverse events/serious adverse events 


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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during the trial conduct which could impact the interpretation of the trial 
results (e.g., premature discontinuation of treatment). 
The primary clinical question of interest is: Do relapsing MS participants who receive 
ofatumumab treatment mount an immune response to non-live mRNA COVID-19 vaccine?   
The justification for the primary estimand is that it will capture whether ofatumumab treated 
participants generate antibodies to mRNA COVID-19 vaccines. 
The primary estimand is described by the following attributes: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. Relapsing MS participants subdivided into 6 cohorts. (1) Will receive  
a full course (two doses) of a COVID-19 mRNA vaccine two weeks prior to starting 
ofatumumab 20 mg subcutaneous treatment; (2) Will receive a full course (two doses) of a 
COVID-19 mRNA vaccine after at least 4 weeks of commercial ofatumumab 20 mg 
subcutaneous treatment  (3) Will receive a full course (two doses) of a COVID-19 mRNA 
vaccine after at least 4 weeks of  interferon or glatiramer acetate treatment (4) Completed 
a full course (two doses) of a COVID-19 mRNA vaccine after at least 4 weeks of 
commercial ofatumumab 20 mg subcutaneous treatment but has not yet received a 
COVID-19 mRNA booster (5) Completed a full course (two doses) of a COVID-19 
mRNA vaccine after at least 4 weeks of interferon or glatiramer acetate (may or may not 
have received at least 1 COVID-19 mRNA booster) (6) Completed a full course (two 
doses) of a COVID-19 mRNA vaccine after at least 4 weeks of commercial ofatumumab 
20 mg subcutaneous treatment and received at least 1 additional booster vaccine ≥ 14 days 
prior to Screening. 
• Variable:  Achieving immune response as defined by a positive SARS-CoV-2 qualitative 
IgG antibody assay ≥ 14 days after full course (two doses) vaccination (yes/no) 
• Treatment of interest: Non-live COVID-19 mRNA vaccine either two weeks prior to 
ofatumumab start or at least 4 weeks after ofatumumab start or while on interferon or 
glatiramer acetate 
• Intercurrent event: Discontinuation of treatment/study, or death 
• Summary measure: Proportion of participants achieving immune response 
2.2 
Secondary estimands 
Not applicable. 


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3 
Study design 
This is a 6-cohort, multicenter prospective study in up to 88 participants with relapsing multiple 
sclerosis. Up to 66 of the participants will begin treatment with ofatumumab or already be on 
commercial ofatumumab, the remaining 22 participants will remain on interferon or glatiramer 
acetate.  
In this study, participants must intend to receive or have received a full course of a non-live 
COVID-19 mRNA (Pfizer or Moderna) vaccine.  Participants also must meet inclusion criteria 
and not meet exclusion criteria. 
1. Screening Period:  
Participants will enter a Screening Period of up to 7 days to assess eligibility requirements.    
Participants in Cohort 1, 2, 4 and 6 without Hepatitis B virus (HBV) and total serum 
immunoglobulin results within the past 6 months prior to screening will require central labs 
drawn.  Participants with Hepatitis B virus (HBV) and total serum immunoglobulin results 
within the specified inclusion range the past 6 months prior to screening will not require the 
labs to be drawn.   
Participants in Cohort 3 and 5 without total serum immunoglobulin results within the past 6 
months prior to screening will require central labs drawn.  Participants with total serum 
immunoglobulin results within the specified inclusion range the past 6 months prior to screening 
will not require the labs to be drawn.     
1. Treatment Period: 
Participants will obtain the mRNA vaccine through their HCP (private insurance) or appropriate 
federal, state or local program.  Participants should be instructed to provide documentation of 
vaccine administration to the Study Doctor at the next scheduled on-site study visit. 
Cohort 1:   
For participants who receive the Pfizer vaccine, the first of three 20 mg s.c ofatumumab loading 
doses will be administered on Day 36 or 2 weeks after receiving a full course (two doses) of a 
COVID-19 vaccine. The 2nd and 3rd loading doses should be administered on Day 43 and  
Day 50 or 7 and 14 days respectively after the 1st loading dose.  Subsequent dosing includes 20 
mg s.c. administered monthly starting at Day 64. 
For participants who receive the Moderna vaccine, the first of three 20 mg s.c ofatumumab 
loading doses will be administered on Day 43 or 2 weeks after receiving a full course (two 
doses) of a COVID-19 vaccine. The 2nd and 3rd loading doses should be administered on Day 
50 and Day 57 or 7 and 14 days respectively after the 1st loading dose.  Subsequent dosing 
includes 20 mg s.c administered monthly starting at Day 71. 
Cohort 2: Will continue taking their prescribed ofatumumab as per their current dosing 
schedule.   
Cohort 3: Will continue administration of their prescribed interferon or glatiramer acetate as 
per their current dosing schedule.   


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Cohort 4: Will continue taking their prescribed ofatumumab as per their current dosing 
schedule and should adhere to the visit schedule as shown in either Table 8-5 (Pfizer) or Table 
8-6 (Moderna).  
Cohort 5: Will continue taking their prescribed glatiramer acetate or interferon as per their 
current dosing schedule and should adhere to the visit schedule as shown in either Table 8-5 
(Pfizer) or Table 8-6 (Moderna). 
Cohort 6: Will continue taking their prescribed ofatumumab as per their current dosing 
schedule and should adhere to the visit schedule as shown in either Table 8-5 (Pfizer) or Table 
8-6 (Moderna). 
Study design schematics for Cohorts 1, 2 and 3 are shown in Figure 3-1, Figure 3-2, Figure 3-
3, and Figure 3-4. Study design schemas for Cohorts 4, 5, and 6 are shown in Figure 3-5 and 
Figure 3-6.  
Figure 3-1 
Study Design (Cohort 1, Pfizer) 
 
Figure 3-2 
Study Design (Cohort 1, Moderna) 
 


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Figure 3-3 
Study Design (Cohorts 2 and 3, Pfizer)  
 
 


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Figure 3-4 
Study Design (Cohorts 2 and 3, Moderna) 
 
Figure 3-5 
Study Design (Cohorts 4, 5, and 6, Pfizer) 
 
 
Figure 3-6 
Study Design (Cohorts 4, 5, and 6, Moderna) 
 


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Remote procedures 
At the investigator's direction and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures according to the assessment schedules in Table 8-1, Table 8-2, Table 8-3, Table 8-
4, Table 8-5 and Table 8-6 performed from within their home. 
Such procedures will be performed remotely under the oversight of the Investigator, who retains 
accountability for the oversight and all efficacy and safety decisions with delegation of tasks to 
an off-site healthcare professional. Off-site healthcare professionals will be provided by a third-
party vendor sourced by Novartis or an agent for Novartis.  
In addition to procedures performed by the off-site healthcare professional, the on-site staff may 
perform certain procedures remotely using tele-visits. 
4 
Rationale 
4.1 
Rationale for study design 
A multicenter, 6-cohort, open-label, comparator design has been selected in order to render 
feasible recruitment given the study’s expedited schedule based on the importance of this 
dataset. The study will address two questions: 
1. Can participants treated with ofatumumab develop an immune response if receiving a 
COVID-19 mRNA vaccine two weeks prior to ofatumumab start?  
2. If receiving COVID-19 mRNA vaccine after introduction of ofatumumab treatment, can 
participants develop an immune response?  
Participant Cohorts 3 and 5 on interferon or glatiramer acetate are included as a comparator. 
Rationale of study population: 
The included population is selected to be consistent with the ofatumumab phase 3 trial program 
and within the parameters of use specified by FDA approval and United States Prescribing 
Information (USPI). Screening participants will be excluded if they possess contraindications 
to either receiving ofatumumab per prescribing information or they possess contraindications 
to receiving a COVID-19 mRNA vaccine.  Participants will also be excluded if there is clinical 
or serologic evidence, they have already contracted COVID-19. This is appropriate because the 
aim of the study is to assess whether a non-vaccinated ofatumumab treated individual can mount 
a response after COVID-19 mRNA vaccine. 
Rationale of chosen endpoints: 
Whether or not participants develop an immune response to the mRNA COVID-19 vaccine they 
receive will be determined by serum immune measures of humoral and cell mediated responses.  
Currently there is no consensus on which assays, and values would indicate seroprotection or 
seroconversion.  Notwithstanding this, testing is available to consider both arms of the immune 
response.  Here we propose to use a serum qualitative IgG SARS coV2 antibody assay to 
measure the humoral response.  The qualitative IgG SARS CoV2 assay has received an 
emergency use approval from the FDA.   


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4.2 
Rationale for dose/regimen and duration of treatment 
Ofatumumab dose 
The dose regimen for ofatumumab in this study is consistent with the FDA approved regimen 
in the prescribing information. 
Duration of treatment: 
The treatment duration is 382 days for those receiving the Pfizer mRNA vaccine and 389 days 
for those receiving the Moderna mRNA vaccine.  This duration is chosen to provide long term 
information regarding vaccine response and safety outcomes. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A reference cohort of participants on Injectable Disease Modifying Therapy (iDMT)) is 
included.  Permitted iDMTs include interferon or glatiramer acetate.  In a prior study, interferon 
and glatiramer acetate have been found to preserve vaccine responses (Olberg et al 2018). 
4.4 
Purpose and timing of interim analyses 
For the purpose of early dissemination of results, an interim analysis will be performed once 
Cohorts 2 and 4 in combination have at least 10 patients enrolled that have had their serum 
drawn ≥ 14 days after full vaccination (two dose) course. 
A second interim analysis will be performed once Cohort 6 has at least 10 participants.  A third 
interim analysis will be performed once Cohorts 2-5 have full enrollment with blood drawn ≥ 
14 days after full course (two doses) vaccination.   
4.5 
Risks and benefits 
There is no benefit expected for participants in this study. Their participation will help 
contribute to a better understanding of the immune response that occurs when participants 
receiving ofatumumab are given a COVID-19 mRNA vaccine. 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, avoidance of prohibited treatments and 
adherence to investigator guidance regarding specific safety areas. For further details about 
ofatumumab, please refer to the Investigator’s Brochure (IB) and USPI. 
Ofatumumab is approved for the treatment of RMS in several countries. Over 1500 RMS 
participants have been exposed to ofatumumab across phase 2 and phase 3 studies.  In the 


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pivotal Phase 3 studies COMB157G2301 and COMB157G2302, treatment with ofatumumab 
significantly lowered the annualized relapse rate (ARR; primary endpoint) compared to the 
active comparator teriflunomide by >50%. Ofatumumab also significantly reduced the risk of 
disability progression by >30% and showed significant suppression of both gadolinium (Gd)-
enhancing T1 lesions (>90%) and new/enlarging T2 lesions (>80%) on brain MRI compared to 
teriflunomide.  
The data from the ofatumumab program in MS indicates ofatumumab to have an acceptable 
safety profile and to be well tolerated at the recommended subcutaneous dose of 20 mg. Adverse 
reactions in the MS population included upper respiratory tract infections, decreased 
immunoglobulin M, injection site reaction, and injection related reactions. For further details 
about ofatumumab, please refer to the IB and USPI. 
Overall, the balance of benefit and risk supports the proposed clinical study to evaluate the 
potential of ofatumumab s.c as an effective and safe therapy to address the unmet medical need 
of participants with RMS. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
Novartis will supply participants in Cohort 1 with ofatumumab treatment as per the assessment 
schedules in Table 8-1 and Table 8-2.   
In the context of the COVID-19 pandemic, additional risks for participants taking part in any 
clinical trial cannot be excluded. Eligibility criteria for the study requires the Investigator to 
evaluate infections and exclude participants with ongoing infection. Additionally, this protocol 
includes home visits (Cohort 1 only) to minimize unnecessary risk that would be associated 
with on-site visits.  Other options like home nursing visits conducted by an off-site healthcare 
professional and shipment of IMP directly to participants’ home may be considered on a case-
by-case basis. 
4.5.1 
Blood sample volume 
Timings of blood sample collection are outlined in the assessment schedules (Table 8-1, Table 
8-2, Table 8-3, Table 8-4, Table 8-5 and Table 8-6). 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 


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5 
Study Population 
The study population will consist of male and female participants, ≥ 18 years of age to 55 years 
of age inclusive, with a diagnosis of relapsing MS.   
The study aims to enroll up to 88 participants at up to 30 centers in the United States.  Since a 
25% screen failure rate is expected, approximately 117 participants will be screened. 22 
participants will be enrolled in Cohort 1.  In combination, 22 participants will be enrolled in 
Cohorts 2 and 4.  In combination, 22 patients will be enrolled in Cohorts 3 and 5.  In Cohort 6, 
22 participants will be enrolled. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in Cohort 1 of this study must meet all of the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old inclusive at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) at least two 
weeks prior to starting ofatumumab 
6. Eligible to receive and plan to be started on ofatumumab according to the approved 
labeling  
7. Pre-ofatumumab serology with Hepatitis B testing not indicative of active or latent 
infection 
8. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Participants eligible for inclusion in Cohort 2 of this study must meet all of the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old inclusive at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) 
6. Currently on commercially prescribed ofatumumab for ≥ 4 weeks for the treatment of 
RMS 
7. Pre-ofatumumab serology with Hepatitis B testing not indicative of active or latent 
infection 
8. Total serum immunoglobulin IgG ≥ 400mg/dl at Screening 
Participants eligible for inclusion in Cohort 3 of this study must meet all of the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old inclusive at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 


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4. Must be willing to comply with the study schedule 
5. Will be receiving an mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) 
6. Currently on commercially prescribed interferon or glatiramer acetate for ≥ 4 weeks for 
the treatment of RMS 
7. Total serum immunoglobulin IgG ≥ 400mg/dl at Screening 
Participants eligible for inclusion in Cohort 4 of this study must meet all of the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Completed a full course (two doses) of a COVID-19 mRNA vaccine at least ≥ 4 weeks 
after start of commercially prescribed ofatumumab for the treatment of RMS  
6. Currently on commercially prescribed ofatumumab for ≥ 4 weeks for the treatment of 
RMS 
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 2 weeks ago 
8. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or latent 
infection 
9. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Patients eligible for inclusion in Cohort 5 of this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed interferon or glatiramer acetate for ≥ 4 weeks for 
the treatment of RMS 
6. Completed a full course (two doses) of a COVID-19 mRNA vaccine after start of 
glatiramer acetate or interferon  
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 2 weeks 
ago 
8. If the patient has received the mRNA booster, then the mRNA booster should be ≥ 2 
weeks prior to enrollment. 
9. 
Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
Patients eligible for inclusion in Cohort 6 of this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Age 18-55 years old at Screening 
3. Diagnosis of relapsing MS by 2017 revised McDonald criteria 
4. Must be willing to comply with the study schedule 
5. Currently on commercially prescribed ofatumumab for ≥ 4 weeks for the treatment of 
RMS 


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6. Completed a full course (two doses) of a COVID-19 mRNA vaccine at least ≥ 4 weeks 
after start of commercially prescribed ofatumumab for the treatment of RMS 
7. Received two dose mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) ≥ 2 weeks ago 
8. Pre-ofatumumab serologies with Hepatitis B testing not indicative of active or latent 
infection 
9. Total serum immunoglobulin IgG ≥ 400 mg/dl at Screening 
10. Has received an mRNA booster ≥ 2 weeks prior to enrollment 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study: 
1. Already has received the J&J vaccine. 
2. Has a contraindication to receiving an mRNA COVID-19 vaccine 
3. Has an immediate allergic reaction to past vaccine or injection 
4. Any safety finding including low immunoglobulin IgG and/or low immunoglobulin IgM 
levels requiring an ofatumumab treatment interruption within the 12 weeks immediately 
prior to vaccination as determined by the HCP 
5.  Any major episode of infection requiring hospitalization or treatment with intravenous 
antibiotics within 4 weeks prior to the first vaccination visit or oral antibiotics within two 
weeks prior to the first vaccination visit 
6. Prior treatment with B-cell targeted therapies (e.g., rituximab or ocrelizumab), 
alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone 
marrow transplantation 
7. Prior treatment with S1P agent within 2 months  at Screening 
8. Prior treatment with natalizumab within 6 months of study enrollment 
9. Since commercially prescribed ofatumumab is being used in the study, contraindications as 
per the USPI will be adhered to which include active infection hepatitis B infection, 
progressive multifocal leukoencephalopathy and pregnancy. 
10. Participation in another interventional clinical trial within 14 days before enrollment. 
11. Use of other investigational drugs at the time of enrollment (Screening) or within the prior 
30 days, or five elimination half-lives, or until the expected pharmacodynamic effect has 
returned to baseline, whichever is longer. 
12. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
13. Have been treated with any of the medications listed below within the time specified: 
 
Medication 
Exclusionary if used within the  timeframe 
specified below 
Intravenous, oral, intra-articular or intramuscular 
corticosteroids, adrenocorticotropic hormone 
30 days prior to Screening 


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Medication 
Exclusionary if used within the  timeframe 
specified below 
Immunosuppressive, chemotherapeutic medications 
(e.g. mitoxantrone, cyclophosphamide, cladribine, 
S1P modulators) 
2 months prior to first study drug 
administration 
Natalizumab 
Within 6 months of study enrollment/Visit 2 
Mitoxantrone (with evidence of cardiotoxicity 
following treatment or cumulative life-time dose > 
60mg/m2) 
Alemtuzumab 
Lymphoid irradiation; bone marrow transplantation 
Other strongly immunosuppressive treatments (with 
effects potentially lasting over 6 months) 
Ofatumumab 
aCD20+ monoclonal antibodies in development 
(e.g. ublituximab or obinutuzumab) 
Daclizumab 
Anytime 
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception while taking 
study treatment and for 6 months after stopping medication. Effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. 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 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception. 
• Barrier methods of contraception: Condom or Occlusive cap (e.g. diaphragm or 
cervical/vault caps).  
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 treatment. 
Women are considered post-menopausal and not of childbearing 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 bilateral tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 


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confirmed by follow up hormone level assessment is she considered not of childbearing 
potential. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF). 
6 
Treatment 
6.1 
Study treatment 
Novartis will supply the following study treatment: 
• Cohort 1: Open-label ofatumumab in an auto-injector containing 20 mg s.c ofatumumab (20 
mg/0.4ml) for subcutaneous administration as per the assessment schedules in Table 8-1 
and Table 8-2.   
Participants in Cohort 2 will continue on their commercially prescribed ofatumumab treatment. 
Participants enrolled in Cohort 3 will continue on their commercially prescribed interferon or 
glatiramer acetate treatment. 
Participants in Cohort 4 will continue on their commercially prescribed ofatumumab treatment. 
Participants in Cohort 5 will continue on their commercially prescribed interferon or glatiramer 
acetate treatment. 
Participants in Cohort 6 will continue on their commercially prescribed ofatumumab. 
Participants will obtain a COVID-19 mRNA vaccine from their HCP (private insurance) or 
appropriate federal, state or local program. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug  
Route of 
Administration 
Supply Type 
Supplied by 
OMB157 20mg/0.4mL 
Subcutaneous Use 
Open-label auto-
injectors (Cohort 1); 
commercially prescribed 
(Cohorts 2, 4 and 6) 
Sponsor (Cohort 
1) or 
commercially 
prescribed 
(Cohorts 2, 4 and 
6) 
Interferon or glatiramer 
acetate 
Subcutaneous or 
intramuscular use 
Commercially prescribed 
Commercially 
prescribed 
COVID-19 mRNA 
vaccine (Pfizer or 
Moderna) 
Intramuscular  
Commercially supplied 
HCP/private 
insurance, or 
appropriate 
federal, state or 
local program 


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6.1.1.1 
Decentralized Clinical Trial Model (US sites only) 
The study medication and all required clinical study supplies may be distributed via direct-to-
participant shipment utilizing an extension of the IND for compliance purposes. 
6.1.2 
Additional study treatments  
No other treatment beyond investigational drug are included in this trial. 
6.1.3 
Treatment cohorts 
• Cohort 1: RMS participants receiving non-live COVID-19 mRNA vaccine at least two 
weeks prior to ofatumumab start.   
• Cohort 2:  RMS participants receiving non-live COVID-19 mRNA vaccine at least 4 
weeks after ofatumumab start.   
• Cohort 3: RMS participants receiving non-live COVID-19 mRNA vaccine at least 4 
weeks after start of prescribed interferon or glatiramer acetate.   
• Cohort 4:  RMS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥ 4 weeks after ofatumumab start.   
• Cohort 5:  RMS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥ 4 weeks after glatiramer acetate or interferon start.   
• Cohort 6:  RMS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥ 4 weeks after ofatumumab start and having received a 
booster ≥ 14 days prior to screening  
6.1.4 
Post-Trial Access 
Participants in Cohort 1 will be referred to the commercial participant services hub for post-
trial continuity of treatment, where the benefit/risk is acceptable and discussed with the 
participant, investigator and if applicable, the participant’s treating physician.  Participants who 
do not complete the study or withdraw due to an ofatumumab related AE or SAE should follow-
up with their treating physician for continued treatment options. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The Investigator should instruct the participant to notify the study site about any new 
medications he/she takes after study enrollment. All medications, procedures, and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
participant was enrolled into the study must be recorded on the appropriate electronic Case 
Report Forms (eCRFs). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis Medical Director before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 


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Premedication prior to subcutaneous injection 
Premedication is not required. Premedication with acetaminophen and/or antihistamines (or 
equivalent) is optional and may be administered at the discretion of the Investigator.  If 
Investigators choose to administer premedication, it should be administered 30 to 60 minutes 
prior to study drug injection. 
Any administrations of premedication must be recorded in the appropriate eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis Medical Director before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in Table 6-2 is NOT allowed for any study cohort in 
combination with study drug, due to increased risk of immunosuppression and confounding of 
efficacy evaluations. 
Exclusionary medications for study eligibility are listed in the exclusion criteria (Section 5.2). 
Use of excluded medications is not allowed for any study cohort while the participant is on 
study medication.   
Table 6-2 
Prohibited medication 
Medication 
Action taken 
Immunosuppressive/chemotherapeutic 
medications (including herbal) or procedures, 
including but not limited to cyclosporine, 
azathioprine, leflunomide, methotrexate, 
cyclophosphamide, mitoxantrone, lymphoid 
irradiation and hematopoietic stem cell 
transplantation 
Discontinue participant from study 
Monoclonal antibodies targeting the immune 
system, including but not limited to 
natalizumab, alemtuzumab, daclizumab and 
B-cell depleting agents under investigation, 
such as but not limited to ublituximab and 
obinutuzumab 
Discontinue participant from study 
Any other immunomodulatory or disease 
modifying MS treatment, including but not 
limited to fingolimod, interferon beta, 
glatiramer acetate, dimethyl fumarate, 
intravenous immunoglobulin, plasmapheresis 
or systemic corticosteroids (except for when 
given for MS relapse treatment as defined in 
Section 6.2.3) 
Discontinue participant from study. 
Administration of any live or live attenuated 
vaccine (including for measles) is prohibited 
while participants are exposed to study drug 
They may be administered when 
participants are no longer exposed to 


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Medication 
Action taken 
(long lasting effects of the study drugs should 
be taken into  consideration) 
study drug. Consider risk/benefit and 
follow local labels. 
6.2.3 
Recommended treatment of MS relapse 
An MS relapse is defined as an 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 (Polman et al 2011). The 
abnormality must have been present for at least 24 hours and occurred in the absence of fever 
(< 37.5°C) or a known infection. 
The decision to treat MS relapses should be based on the Investigator's judgement and/or local 
clinical practice. Standard of care will be followed during treatment as per local clinical 
practice. Taper with oral steroids is not permitted. Plasmapheresis may be used only if 
participant does not respond to standard treatment with corticosteroids. 
If MS relapses require treatment, the standard treatment should consist of a short course of 
corticosteroids of 3-5 days and up to 1000mg methylprednisolone/day or equivalent on an 
inpatient or outpatient basis. Standard of care will be followed during treatment as per local 
clinical practice. 
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration. Use of steroids for treatment of MS attack/relapse must be recorded on the 
Concomitant Medications eCRF. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the Interactive Response Technology (IRT) and obtaining the medication number(s).  
Special notes regarding dispensing treatment to Cohort 1 
Participants have the option to take home multiple doses of study drug for administration at 
home between office visits or they may return to the study site between office visits for 
administration of study drug onsite.  To facilitate this, Study Staff will have the option to either 
dispense multiple kits of study drug in IRT by selecting “home visit” or dispense 1 study drug 
kit for office administration by selecting “office visit”.  Example: 
• At Visit 4 (office visit), if “home visit” is selected in IRT, sufficient study drug will be 
dispensed for administration during the Visit 4 office visit  plus sufficient study drug for 
at-home administrations until the participant returns for the Visit 8 office visit.  If “office 
visit” is selected, the system will only dispense study drug for administration in the office 
during Visit 4.  In this case, the patient will need to return to the site a week later to 


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receive their next scheduled dose at which time the Study Staff will need to contact IRT 
again to dispense treatment and select either “home visit” or “office visit”.  
• At Visit 9 (office visit), participants will not receive a dose of study drug in the office but 
will receive sufficient study drug to cover monthly, at-home administrations of study drug 
until the Visit 10 office visit. 
• At Visit 10 (office visit), participants will not receive a dose of study drug in the office 
but will receive sufficient study drug to cover the next 3 monthly, at-home administrations 
of study drug. 
If a participant in Cohort 1 is unable to travel to the investigative site for their study visit, 
shipment of study treatment from the site to the participant’s home may be an option. As per 
Section 4.6, during a Public Health emergency as declared by Local or Regional authorities i.e. 
pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery of 
IMP directly to a participant's home may be permitted (if allowed by Local or Regional Health 
Authorities and Ethics Committees as appropriate) in the event the Investigator has decided that 
an on-site visit by the participant is no longer appropriate or possible, and that it is in the interest 
of the participant's health to administer the study treatment even without performing an on-site 
visit. The dispatch of IMP from the site to the participant’s home remains under the 
accountability of the Investigator. Regular phone calls or virtual contacts every month should 
occur between the site and the participant for instructional purposes, safety monitoring, 
investigation of any adverse events, ensuring participants continue to benefit from treatment, 
and discussion of the participant's health status until the participants can resume visits at the 
study site. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
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 designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the treatment labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
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 participant except for the medication number. 
Participants in Cohort 1 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. 
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.  
At the conclusion of the study, the site may destroy and document destruction of unused study 
treatment, drug labels and packaging as appropriate in compliance with site processes, 


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monitoring processes, and per local regulation/guidelines after approval from the Novartis 
Clinical Lead. Otherwise, the investigator will return all unused study treatment, packaging, 
drug labels, and a copy of the completed drug accountability log to the Novartis or its agent. 
The study treatment and all required clinical study supplies will be distributed direct to the 
participant utilizing an extension of the IND for compliance purposes. 
6.3.2 
Instruction for prescribing and taking study treatment 
COVID-19 mRNA vaccine 
The vaccine should be obtained through the HCP (private insurance) or appropriate federal, 
state or local program.  
Participants in Cohort 1 
Ofatumumab will be provided in an auto injector for subcutaneous administration containing 
20 mg ofatumumab (20 mg/0.4 ml). Treatment should be administered after study assessments 
have been completed for the visit. 
Cohort 1 should receive their first loading dose of ofatumumab at Visit 4 which should be held 
2 weeks after receiving their 2nd COVID-19 vaccine dose.   
Site staff should remove the study treatment from the refrigerator and allow the auto injector 
pen to reach room temperature in their unopened box (approximately 15-30 minutes) before 
self-injection by the participant. Used syringes should be disposed of immediately after use in 
a sharps container. 
A different body site (front of thighs, lower abdomen) should be chosen each time a dose is 
administered to reduce the risk of an injection-site reaction; investigator/qualified site 
staff/caregiver can also inject the study treatment in the outer upper arms. Each new injection 
should be given at least one inch from the previously used site. If administration is in the 
abdomen, the 2-inch area around navel should be avoided. Study treatment should also not be 
injected into areas where the skin is tender, bruised, red, or hard, or where the participant has 
scars or stretch mark 
As participants must self-administer ofatumumab, site personnel will provide training on the 
correct procedure for injection technique of the ofatumumab subcutaneous injections to enable 
the participant and/or a caregiver to administer from home in-between scheduled office visits. 
Documentation of the participant or caregiver understanding the correct administration 
procedure must be documented in the source document.  Participants will be instructed to 
contact the investigator/site staff prior to self-administration at home if they are experiencing 
any AE/SAEs or have any concerns.  
Site personnel will make remote contact with participants in Cohort 1 on/around the time of the 
2nd loading dose to query about any new or worsening symptoms warranting an unscheduled 
visit, compliance with study treatment, injection reactions, and compliance with contraception 
requirements when applicable.  
Additional remote contacts should be conducted on/around the time participants are due to 
administer treatment at home. The method of contact with each participant can be the personal 


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preference of the individual between telephone contacts, email contact or text messages, 
however, the site staff must be able to provide suitable source documentation of each contact 
regardless of the method of contact.   
Participants will be asked to complete a participant diary to record doses of home 
administrations of ofatumumab. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Participants in Cohort 2 
Upon enrollment, participants already receiving prescribed ofatumumab will continue to take 
prescribed treatment as per their current dosing schedule. 
Participants will be asked to complete a participant diary to record doses of ofatumumab 
administered while in the study. 
Participants in Cohort 3 
Upon enrollment, participants in Cohort 3 will continue to take their interferon or glatiramer 
acetate as per their current dosing schedule. 
Participants will be asked to complete a participant diary to record doses of their interferon or 
glatiramer acetate taken during the study. 
Participants in Cohort 4 
Upon enrollment, participants will continue to take prescribed ofatumumab treatment as per 
their current dosing schedule.  
Participants will be asked to complete a participant diary to record doses of ofatumumab 
administered while in the study. 
Participants in Cohort 5 
Upon enrollment, participants will continue their prescribed interferon or glatiramer acetate 
treatment as per their current dosing schedule.   
Participants will be asked to complete a participant diary to record doses of ofatumumab 
administered while in the study. 
Participants in Cohort 6 
Upon enrollment, participants will continue their prescribed ofatumumab treatment as per their 
current dosing schedule.   
Participants will be asked to complete a participant diary to record doses of ofatumumab 
administered while in the study. 


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Table 6-3 
Dose and treatment schedule 
 
Investigational Drug 
Frequency and/or Regimen 
Cohort 1 
OMB157 20mg/0.4mL 
Day 36, 43, 50, 64 and monthly 
thereafter for participants that 
receive the Pfizer vaccine.  Day 
43, 50, 57, 71 and monthly 
thereafter for participants that 
receive the Moderna vaccine. 
Cohort 2 
OMB157 20mg/0.4mL 
Monthly as prescribed 
Cohort 3 
Interferon or glatiramer acetate 
As prescribed 
Cohort 4 
OMB157 20mg/0.4mL 
As prescribed 
Cohort 5 
Interferon or glatiramer acetate 
As prescribed 
Cohort 6 
OMB157 20mg/0.4mL 
As prescribed 
6.4 
Participant numbering, treatment assignment, randomization  
6.4.1 
Participant numbering  
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
At the Screening Visit (Visit 1/Day -7), the Investigator or his/her staff will contact the 
Interactive Response Technology (IRT) system and provide the assigned participant study 
identification number along with the requested identifying information to register the 
participant into IRT. The site must use the eCRF with the matching participant number from 
the electronic data capture (EDC) system to enter data. 
Once assigned to a participant, a participant number will not be reused. If a participant fails to 
be enrolled for any reason, the IRT system must be notified within 2 days and the reason for 
not being enrolled will be entered on the Screening Phase Disposition Form and the appropriate 
eCRF(s) pages should also be completed. 
6.4.1.1 
Treatment assignment, randomization  
No randomization will be performed in this study. The assignment of a participant to a cohort 
will be determined by inclusion/exclusion criteria. 
An IRT system will be used to track participant visits and status.  IRT will also be used to 
dispense treatment to Cohort 1 as indicated in the assessment schedules in  
Table 8-1 and Table 8-2.   
At dosing visits, the system will specify unique medication numbers that will correspond to 
open-label treatment to be dispensed.   


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6.5 
Treatment blinding 
Not applicable. 
6.6 
Dose escalation and dose modification 
Dose adjustments and/or interruptions are not permitted. 
6.7 
Additional treatment guidance 
Not applicable. 
6.7.1 
Treatment compliance 
Participant compliance with treatment should be at least 80%. The Investigator and/or study 
personnel will counsel the participant if compliance is below 80%. The investigator must 
promote compliance by instructing the participant to take the study treatment exactly as 
prescribed and by stating that compliance is necessary for the participant’s safety and the 
validity of the study. The participant must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using information provided by the 
participant. This information should be captured in the source document at each visit for Cohort 
1 and in the eCRF for Cohorts 2, 3, 4, 5 and 6.  
All study treatment dispensed and returned must be recorded in the Drug Accountability Log. 
6.7.2 
Emergency breaking of assigned treatment code  
Since this study is open-label, emergency breaking of assigned treatment codes is not 
applicable. 
7 
Informed consent procedures  
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the IRB/. 
Information about common side effects already known about the investigational treatment can 
be found in the IB and USPI. This information will be included in the participant informed 
consent and should be discussed with the participant during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 


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an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also included:  
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB 
approval. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g. the presence of an 
impartial witness, sign/dating separate ICFs by trial participant and person obtaining informed 
consent, etc.). 
8 
Visit schedule and assessments 
The below Assessment Schedules (Table 8-1, Table 8-2, Table 8-3, Table 8-4, Table 8-5 and 
Table 8-6) list all assessments with an X when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation.  The “X” in the table 
denotes the assessments to be recorded in the clinical database or received electronically from 
a vendor. The “S” in the table denotes the assessments that are only in the participant’s source 
documentation and do not need to be recorded in the clinical database. 
Participants should be seen for all visits/assessments as outlined in the assessment schedules or 
as close to the designated day/time as possible. The Investigator should promote compliance by 
instructing the participant to attend the study visits as scheduled and by stating that compliance 
is necessary for the participant’s safety and the validity of the study. Missed or rescheduled 
visits should not lead to automatic discontinuation. The participant should be instructed to 
contact the Investigator if he/she is unable for any reason to attend a study visit as scheduled or 
if he/she is unable for any reason to take the study treatment as prescribed.  
Participants who prematurely discontinue the study should be scheduled for the End of Study 
(EOS) visit within 7 days. At this final visit, all the assessments mentioned under EOS visit 
should be performed, all dispensed investigational product should be reconciled, and the 


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adverse event and concomitant medications recorded on the CRF.  Participants that prematurely 
discontinue should also have a remote follow-up safety visit performed 30 days after the EOS 
visit. 
Special guidance regarding the scheduling of visits for Cohorts 1, 2 and 3 
• The study site will need to perform Vaccine Status Check-ins (make remote contact with 
participant) to confirm when the 1st and 2nd COVID-19 vaccinations are scheduled in order 
to schedule Visit 4. 
• The date of the 2nd COVID-19 vaccine dose will determine the date of Visit 4 and all other 
remaining study visits. 
• Visits 2 and 3 should always occur prior to administration of the mRNA vaccine.  
• The Visit 4 lab samples should be collected 14 days after a participant has received their 
2nd COVID-19 vaccine dose. 
Home study visits (Cohort 1) 
Home (remote) study visits are planned at Visits 5, 6 and 7 for participants in Cohort 1.   
To facilitate this, at Visit 4, sufficient study drug can be supplied to the participant to cover all 
home administrations of study drug until the Visit 8 in-person, clinic visit.  Refer to Section 6.7 
for additional information.  
Participants and/or caregivers trained to administer the ofatumumab subcutaneous injections 
will need to administer treatment at home study visits. Refer to Table 8-1 and Table 8-2. 
The option for a participant to return to the clinic for administration of treatment at Visits 5, 6 
and 7 is available if that is his/her preference. 
Unscheduled visits 
In addition to the scheduled visits, participants may have unscheduled visits due to a MS relapse, 
an acute illness of undetermined cause, for other reasons, or at the discretion of the Investigator. 
Data collected during unscheduled visits will be recorded in the unscheduled visits CRF.


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Table 8-1 
Assessment schedule for Cohort 1 (Pfizer vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office visit) 
Visit 10 
(office visit) 
Visit 11/ End 
of Study – 
EOS (office 
visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 43 
Day 50 
Day 64 
Day 92 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusio
n criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
Non-drug 
therapies and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Serum Pregnancy 
Test1 
S 
 
 
 
 
 
 
 
S 
 
 
Hepatitis B virus 
(HBV) 2 
X 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office visit) 
Visit 10 
(office visit) 
Visit 11/ End 
of Study – 
EOS (office 
visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 43 
Day 50 
Day 64 
Day 92 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
SARS CoV2 
qualitative 
antibody 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Serum 
Immunoglobulin2 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
CD 19+ B cells 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
X 
 
 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
X 
 
 
 
 
 
 
 
Vaccine 
Administration 
Form 
 
X 
X 
 
 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Self-Injection 
Training  
 
 
 
S 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office visit) 
Visit 10 
(office visit) 
Visit 11/ End 
of Study – 
EOS (office 
visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 43 
Day 50 
Day 64 
Day 92 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Office 
administration of 
study drug  
 
 
 
X 
 
X 
 
 
 
 
 
Dispense study 
drug for future 
home 
administration 
 
 
 
X 
 
X 
X 
X 
 
 
 
Home 
administration of 
study drug 
 
 
 
 
X 
 
 
 
 
 
 
Patient Diary/Drug 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
 
 
 
 
X 
S 
 
Vaccine check-in 
contacts4 
 
S 
S 
 
 
 
 
 
 
 
 
Remote check-in5 
 
 
 
 
S 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 


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Page 43 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses.  
4 Vaccine check-ins (remote contacts) by site staff to confirm participant has received the COVID-19 vaccine and to collect any AEs/SAEs. 
5 Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs, changes in con meds and compliance with current 
treatment.  Method of contact can be via telephone, email or text message depending on the preference of each participant. 
Table 8-2 
Assessment schedule for Cohort 1 (Moderna vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office 
visit) 
Visit 10 
(office 
visit) 
Visit 11/ End of 
Study – EOS 
(office visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 50 
Day 57 
Day 71 
Day 99 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
Non-drug therapies 
and procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Serum Pregnancy 
Test1 
S 
 
 
 
 
 
 
 
S 
 
 


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Page 44 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office 
visit) 
Visit 10 
(office 
visit) 
Visit 11/ End of 
Study – EOS 
(office visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 50 
Day 57 
Day 71 
Day 99 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Hepatitis B virus 
(HBV)2 
X 
 
 
 
 
 
 
 
 
 
 
SARS CoV2 
qualitative antibody 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Serum 
Immunoglobulin2 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
CD 19+ B cells 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
X 
 
 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
X 
 
 
 
 
 
 
 
Vaccine 
Administration 
Form 
 
X 
X 
 
 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Novartis 
Confidential 
Page 45 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
(home 
visit) 
Visit 3 
(home 
visit) 
Visit 4 
(office 
visit) 
Visit 5  
Visit 6 
Visit 7 
(home 
visit) 
Visit 8 
(office 
visit) 
Visit 9 
(office 
visit) 
Visit 10 
(office 
visit) 
Visit 11/ End of 
Study – EOS 
(office visit) 
Visit 12 / 
Safety 
(remote 
contact) 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 50 
Day 57 
Day 71 
Day 99 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Self-Injection 
Training  
 
 
 
S 
 
 
 
 
 
 
 
Office 
administration of 
study drug  
 
 
 
X 
 
X 
 
 
 
 
 
Dispense study 
drug for future 
home 
administration 
 
 
 
X 
 
X 
X 
X 
 
 
 
Home 
administration of 
study drug 
 
 
 
 
X 
 
 
 
 
 
 
Patient Diary/Drug 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
 
 
 
 
X 
S 
 
Vaccine check-in 
contacts4 
 
S 
S 
 
 
 
 
 
 
 
 
Remote check-in5 
 
 
 
 
S 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 


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Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses.  
4 Vaccine check-ins (remote contacts) by site staff to confirm participant has received the COVID-19 vaccine and to collect any AEs/SAEs. 
5 Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs.  Method of contact can be via telephone, email or text 
message depending on the preference of each participant. 
 
Table 8-3 
Assessment schedule for Cohorts 2 and 3 (Pfizer vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
 
 
Non-drug therapies 
and procedures 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Serum Pregnancy 
Test1 
S 
 
 
 
 
 
S 
 
 


Novartis 
Confidential 
Page 47 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Hepatitis B virus 
(HBV) 
(Cohort 2 only)2 
X 
 
 
 
 
 
 
 
 
SARS CoV2 
qualitative antibody 
 
X 
X 
X 
X 
X 
X 
 
 
Serum 
Immunoglobulin 2 
 
X 
 
 
 
X 
 
X 
 
 
CD 19+ B cells 
(Cohort 2 only) 
X 
X 
X 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
X 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
X 
 
 
 
 
 
Vaccine 
Administration Form 
 
X 
X 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
X 
X 
 
 
Drug Accountability 
 
S 
S 
S 
S 
S 
S 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
 
 
X 
S 
 


Novartis 
Confidential 
Page 48 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 22 
Day 36 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Vaccine check-in 
contacts4 
 
S 
S 
 
 
 
 
 
 
Remote check-in5 
 
 
 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses.  
4 Vaccine check-ins (remote contacts) by site staff to confirm participant has received the COVID-19 vaccine and to collect any AEs/SAEs. 
5 Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs.  Method of contact can be via telephone, email or text 
message depending on the preference of each participant. 
Table 8-4 
Assessment schedule for Cohorts 2 and 3 (Moderna vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 49 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Non-drug therapies 
and procedures 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Serum Pregnancy 
Test1 
S 
 
 
 
 
 
S 
 
 
Hepatitis B virus 
(HBV) 
(Cohort 2 only)2 
X 
 
 
 
 
 
 
 
 
SARS CoV2 
qualitative antibody 
 
X 
X 
X 
X 
X 
X 
 
 
Serum 
Immunoglobulin 2 
 
X 
 
 
 
X 
 
X 
 
 
CD 19+ B cells 
(Cohort 2 only) 
X 
X 
X 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
X 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
X 
 
 
 
 
 


Novartis 
Confidential 
Page 50 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7/End of 
Study (EOS) 
Visit 8 / 
Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 29 
Day 43 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
 
+3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Vaccine 
Administration Form 
 
X 
X 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
X 
X 
 
 
Drug Accountability 
 
S 
S 
S 
S 
S 
S 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
 
 
X 
S 
 
Vaccine check-in 
contacts4 
 
S 
S 
 
 
 
 
 
 
Remote check-in5 
 
 
 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses.  
4 Vaccine check-ins (remote contacts) by site staff to confirm participant has received the COVID-19 vaccine and to collect any AEs/SAEs. 
5 Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs.  Method of contact can be via telephone, email or text 
message depending on the preference of each participant. 
 


Novartis 
Confidential 
Page 51 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Table 8-5 
Assessment schedule for Cohorts 4, 5 and 6 (Pfizer vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5/End of Study 
(EOS) 
Visit 6 / Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
Non-drug therapies 
and procedures 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
S 
X 
Local Serum 
Pregnancy Test1 
S 
 
 
 
S 
 
 
Hepatitis B virus 
(HBV) 
(Cohort 4 and 6 
only)2 
X 
 
 
 
 
 
 
SARS CoV2 
qualitative antibody 
 
X 
X 
X 
X 
 
 
SARS-CoV-2 
nucleocapsid 
antibody 
 
X 
 
 
 
 
 


Novartis 
Confidential 
Page 52 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5/End of Study 
(EOS) 
Visit 6 / Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 202 
Day 292 
Day 382 
Day 412 
 
Visit Window 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Serum 
Immunoglobulin 2 
X 
 
X 
 
X 
 
 
CD 19+ B cells 
(Cohort 4 and 6 
only) 
X 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
 
 
 
 
Vaccine 
Administration Form   
X 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
 
 
Drug Accountability 
 
S 
S 
S 
S 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
X 
S 
 
Remote check-in4 
 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 


Novartis 
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Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses.  
4Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs.  Method of contact can be via telephone, email or text message 
depending on the preference of each participant. 
 


Novartis 
Confidential 
Page 54 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Table 8-6 
Assessment schedule for Cohorts 4, 5 and 6 (Moderna vaccine) 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5/End of Study 
(EOS) 
Visit 6 / Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Obtain informed 
consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Relevant medical 
history/current 
medical history 
X 
 
 
 
 
 
 
Non-drug therapies 
and procedures 
X 
X 
X 
X 
X 
S 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
S 
X 
MS Relapse 
X 
X 
X 
X 
X 
S 
X 
Local Serum 
Pregnancy Test1 
S 
 
 
 
S 
 
 
Hepatitis B virus 
(HBV) 
(Cohort 4 and 6 
only)2 
X 
 
 
 
 
 
 
SARS CoV2 
qualitative antibody 
 
X 
X 
X 
X 
 
 
SARS-CoV-2 
nucleocapsid 
antibody 
 
X 
 
 
 
 
 


Novartis 
Confidential 
Page 55 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5/End of Study 
(EOS) 
Visit 6 / Safety 
Unscheduled 
Day/Week/Month 
Day -7 
Day 1 
Day 209 
Day 299 
Day 389 
Day 419 
 
Visit Window 
 
 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
 
Serum 
Immunoglobulin 2 
X 
 
X 
 
X 
 
 
CD 19+ B cells 
(Cohort 4 and 6 
only) 
X 
X 
X 
X 
X 
 
 
Biobanked serum 
sample3 
X 
 
 
 
 
 
 
Biobanked whole 
blood sample3 
X 
 
 
 
 
 
 
Vaccine 
Administration Form   
X 
 
 
 
 
 
 
IRT Transaction  
X 
X 
X 
X 
X 
 
 
Drug Accountability 
 
S 
S 
S 
S 
 
 
Adverse Events / 
Serious Adverse 
Events 
X 
X 
X 
X 
X 
S 
X 
Subject disposition 
X 
 
 
 
X 
S 
 
Remote check-in4 
 
 
 
 
 
S 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor 


Novartis 
Confidential 
Page 56 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
S = assessment to be recorded in the source documentation only 
1 Serum pregnancy should be performed locally for all sites except those unable to use a local lab.  Sites unable to perform locally should send sample to the central lab. 
2 Participants with lab results within the past 6 months prior to screening will not require labs drawn at screening visit.  Local labs should be documented in the source. 
Participants without lab results from the past 6 months prior to screening will require central labs drawn at the screening visit to be entered into the clinical database. 
3 Sample will be bio-banked for yet to be identified analyses. 
4Remote contact with participants by site staff. The contact should query about receipt any new AEs or SAEs.  Method of contact can be via telephone, email or text message 
depending on the preference of each participant.


Novartis 
Confidential 
Page 57 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
8.1 
Screening 
Rescreening is not permitted. 
8.1.1 
Eligibility screening 
8.1.1.1 
Hepatitis screen 
Hepatitis B virus (HBV) will be performed at Visit 1/Screening for participants in Cohort 1, 2, 
4 and 6 that do not have test results in their medical history within 6 months prior to the 
Screening Visit/Day -7. 
8.1.1.2 
Serum Immunoglobulins 
Total serum immunoglobulins will be performed at Visit 1/Screening for all participants that 
do not have test results in their medical history within 6 months prior to the Screening Visit/Day 
-7.   
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to enrollment will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, cohort, Protocol Amendment log and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event during the screening phase (see SAE section for reporting details). If the participant fails 
to be enrolled, the IRT must be notified within 2 days of the screen fail that the participant was 
not enrolled. 
Participants who are enrolled and fail to start treatment, e.g. participants enrolled in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic data and baseline characteristics to be collected on the participants 
include: age, sex, race and ethnicity. Relevant medical history/current medical condition data 
includes data collected up to the point in which informed consent is signed. Where possible, 
diagnoses, and not symptoms will be recorded. Investigators will have the discretion to record 
abnormal test findings on the CRF capturing medical history whenever in their judgment, the 
test abnormality occurred prior to the informed consent signature. 
8.3 
Efficacy 
Not applicable. 
8.4 
Safety 
For details on AE collection and reporting, refer to AE section. 


Novartis 
Confidential 
Page 58 of 74 
Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
8.4.1 
Laboratory evaluations 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
A central laboratory will be used for analysis of all specimen collected listed below with the 
exception of the serum pregnancy test. Details on the collection, shipment of samples and 
reporting of results by the central laboratory are provided to investigators in the central 
laboratory manual. 
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator (in 
consultation with the sponsor) and shall be based, in part, upon the nature and degree of the 
observed abnormality. The assessment may be repeated once prior to enrollment/Visit 2. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
Follow instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing, and shipment. 
8.4.2 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. A serum 
pregnancy test will be performed for all women of child-bearing potential at Screening 
Visit/Day -7 and the End of Study Visit.  Serum pregnancy should be performed locally for all 
sites except those unable to use a local lab.  Sites unable to perform locally should send sample 
to the central lab.   
Additional pregnancy testing might be performed if requested by local requirements. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 


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8.5.1 
Use of residual biological samples 
 
 
 
 
 
8.5.2 
Serum Immunoglobulins 
In Cohort 1, total serum immunoglobulin IgG will be obtained 14 days, 70 days, 180 days, and 
360 days after full course (second) vaccination.  In Cohort 2, total serum immunoglobulin IgG 
will be obtained 180 days and 360 days after full course (second) vaccination.  In Cohorts 4 and 
6, total serum immunoglobulin IgG will be obtained ≥ 180 days and ≥ 360 days after full course 
(second) vaccination.  If serum immunoglobulin IgG obtained is below 400mg/dl the patient 
will be withdrawn from the study. 
8.5.3 
Bio-banked samples 
As new and relevant assays are validated during this study and after its completion, (1) whole 
blood and (1) serum sample will be collected at Screening and Visit 4 for Cohorts 1, 2 and 3 to 
be bio-banked for yet to be identified analyses.  For Cohorts 4, 5, and 6, (1) whole blood and 
(1) serum sample will be collected at Screening Visit/Visit 1 only. 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study  
9.1.1 
Discontinuation from study treatment  
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Total serum immunoglobulin IgG < 400mg/dl after Visit 2 
• Use of prohibited treatment as per recommendations as per the USPI 
• Any situation in which study participation might result in a safety risk to the participant 
• Diagnosis of PML 
• Participants with active serious infections or reactivation 


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• 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 ofatumumab 
• Protocol violation that results in a significant risk to the participant's safety 
• Emergence of certain adverse events, such as malignancy (except successfully treated 
basal cell carcinoma, in situ squamous cell carcinoma and in situ carcinoma of cervix of 
uterus), liver failure or serious chronic infection (such as human immunodeficiency virus 
(HIV)) 
• Severe hyperproteinemia 
• Non-compliance with study drug or study procedures 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2 'Withdrawal of Informed Consent' section). Where possible, 
they should return for the EOS Visit. At EOS visits all dispensed study drug to participants 
in Cohort 1 should be reconciled and the adverse event and concomitant medications should be 
recorded on the CRF (for participants in both cohorts). If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.2 
Discontinuation from study  
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
Participants must be discontinued from the study under the following circumstances: 
• Failure to receive a complete COVID-19 mRNA (Pfizer or Moderna) vaccination course (2 
doses) 
• IgG ≤ 400mg/dl  


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If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table under the End of Study Visit (refer to 
Section 8). 
9.1.3 
Lost to follow-up  
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples  
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table under the EOS Visit (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 


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9.3 
Study stopping rules 
Not applicable.  
9.4 
Study completion and post-study treatment  
Study completion is defined as when the last participant completes the EOS Visit. 
9.5 
Early study termination by the sponsor  
The study can be terminated by Novartis at any time. 
Reasons for early termination may include: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Practical reasons 
• Regulatory or medical reasons 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible for an End 
of Study Visit within 7 calendar days and treated as a prematurely withdrawn participant. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the participant’s interests. The investigator 
or sponsor depending on local regulation will be responsible for informing IRBs of the early 
termination of the trial.   
10 
Safety monitoring, reporting and committees  
10.1 
Definition of adverse events and reporting requirements  
10.1.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 


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Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (1-5)  
• 1 = mild: usually transient in nature and generally not interfering with normal 
activities 
• 2 = moderate: sufficiently discomforting to interfere with normal activities 
• 3 = severe: prevents normal activities 
• 4 = life threatening 
• 5 = death 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB or 
USPI. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 


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• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
10.1.2 
Serious adverse events  
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect  
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred as per Section 10.1.5. 
10.1.3 
SAE reporting  
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis Safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site. 
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.  
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 using the Serious 
Adverse Event Report Form. 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. 
If the SAE is not previously documented in the IB or USPI (new occurrence) and is thought to 
be related to the study treatment, a CMO & PS Department associate may urgently require 
further information from the investigator for health authority reporting. Novartis may need to 
issue an Investigator Notification (IN) to inform all investigators involved in any study with the 
same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries. 
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting  
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 


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followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
Reporting of study treatment errors including misuse/abuse  
10.1.5 
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, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1). 
10.2 
Additional Safety Monitoring 
Not applicable. 


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11 
Data Collection and Database management  
11.1 
Data collection  
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control  
Novartis personnel or designated Contract Research Organization (CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions, non-
drug therapies/procedures and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. 
Dates of study visits, screen failures and study completion, as well as treatment codes and data 
about all study treatment (s) dispensed to participants in Cohort 1 will be tracked using an 
Interactive Response Technology (IRT). The system will be supplied by a vendor, who will also 
manage the database. The data will be sent electronically to Novartis at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for analysis. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for analysis. Any changes to the 


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database after that time can only be made after written agreement by Novartis development 
management. 
11.3 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The analysis will be conducted on all participant data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis prior to 
publication or presentation. 
Categorical variables will be presented as counts and percentages. For continuous variable, 
mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum 
will be presented.  All summaries will be presented for Cohort 1, Cohorts 2 and 4, Cohorts 3 
and 5, and Cohort 6. 
12.1 
Analysis sets 
The Safety Set comprises all participants who signed informed consent and met all entry 
criteria.  


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The Safety Set will be used for the summary of demographic and baseline characteristics as 
well as for all safety analyses. 
12.2 
Participant demographics and other baseline characteristics  
Demographics and other baseline characteristics will be summarized descriptively. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.  
12.3 
Treatments  
The duration of study in days will be summarized descriptively. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system (if applicable) and preferred term. 
12.4 
Analysis supporting primary objectives 
The primary objective of this study is to characterize those achieving immune response after 
receiving vaccination of non-live mRNA COVID-19 vaccine (Pfizer or Moderna vaccine) in 
subjects treated with ofatumumab 20 mg s.c. once monthly.  This will be achieved by estimating 
the immune response rate using the Safety Set. 
An immune responder is a participant achieving immune response as defined by a positive 
SARS-CoV-2 qualitative antibody assay after vaccination. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is achieving immune response as defined by a positive SARS-CoV-2 
qualitative antibody assay 14 days after vaccination (yes/no). 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The number and percentage of responders will be presented. The 95% confidence interval for 
the proportion of responders will be calculated by using exact method.  
12.4.3 
Handling of intercurrent events of primary estimand 
Non-responder imputation approach will be applied to missing postvaccination antibody assay 
regardless of intercurrent events.    
12.4.4 
Handling of missing values not related to intercurrent event 
Non-responder imputation approach will be applied to missing postvaccination antibody assay. 
12.4.5 
Sensitivity analyses  
Not applicable. 


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12.4.6 
Supplementary analysis  
Similar analyses will be performed by using valid assessments of antibody assay without 
imputation of missing data. 
12.5 
Analysis supporting secondary objectives 
In addition to assess immune response at other than ≥14 days after full course, the following 
variables will also be evaluated.  
• Immune conversion is defined as:   
• Baseline absence of SARS-CoV-2 qualitative IgG antibody with post-vaccination 
SARS-CoV-2 qualitative IgG antibody assay 14 days after full course (two doses) 
vaccination (yes/no); or 
• Baseline serum presence of SARS-CoV-2 quantitative antibody with post-vaccination 
≥ 4-fold increase in SARS-CoV-2 quantitative antibody titer as determined by 
dilution assay 14 days after full course (two doses) vaccination (yes/no).  
• Initial negative SARS-CoV-2 nucleocapsid antibody with post-vaccination SARS-
CoV-2 positive qualitative antibody assay ≥ 14 days after vaccination (yes/no) 
(Applicable to Cohorts 4 and 5.) 
Those variables will be summarized by frequency count and percentage together with the 95% 
confidence intervals for the proportion of responders obtained using exact method. 
Both non-responder imputation of missing data and observed case approach (no imputation for 
missing data) will be used in the above analyses.  
Participants may be enrolled after receiving at least 1 or more mRNA booster or may receive a 
booster during the trial.  This group will be segregated for further analysis. 
12.5.1 
Safety endpoints  
All listings and tables will be presented by cohort.  
In particular, summary tables for adverse events (AEs) will summarize only on-treatment 
events, which started or worsened during the on-treatment period (treatment-emergent AEs).  
Adverse events 
All information obtained on adverse events will be displayed by cohort and participant. 
The number (and percentage) of participants with treatment emergent adverse events will be 
summarized in the following ways: 
• by cohort, primary system organ class and preferred term. 
• by cohort, primary system organ class, preferred term and maximum severity. 
• by cohort, preferred term in descending order 
Separate summaries will be provided for study medication related adverse events, serious 
adverse events, and other significant adverse events leading to discontinuation. 


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In addition, a separate listing of death including on treatment and post treatment deaths will be 
provided. 
Clinical laboratory evaluations 
All laboratory data will be listed by cohort, participant, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by cohort. Shift 
tables using the low/normal/high/ (low and high) classification will be used to compare baseline 
to the worst on-treatment value. 
12.7 
Interim analyses 
For the purpose of early dissemination of results, an interim analysis will be performed once 
Cohorts 2 and 4 in combination have at least 10 patients enrolled that have had their serum 
drawn ≥ 14 days after full vaccination (two dose) course.   
A second interim analysis will be performed once Cohort 6 has at least 10 participants.   
The third interim analysis will be performed once Cohorts 2-5 have full enrollment with blood 
drawn ≥ 14 days after full course (two doses) vaccination.   
The following variables (but not limited to) will be summarized for each interim analysis 
mentioned above: 
• Demographics 
• Baseline characteristics 
• Immune response related variables 
• AE, SAE, AEs leading to study discontinuation and death 
Since there will be no hypothesis testing involved, statistical adjustment for the interim analysis 
will not be made at the stage of final analyses. 


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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size of 20 participants per cohort is selected based on budget and need for early 
availability of results. This sample size of 20 participants will provide estimates of proportion 
of responders with margin of error (half-width of a 95% confidence interval) of 20.1%, 19%, 
and 17.5% corresponding to response rates of 70%, 75%, and 80%, respectively.  Adjusting for 
10% drop-out, 22 participants will be enrolled in Cohort 1.  In combination, 22 participants will 
be enrolled in Cohorts 2 and 4.  In combination, 22 patients will be enrolled in Cohorts 3 and 
5.  In Cohort 6, 22 participants will be enrolled. 
13 
Ethical considerations and administrative procedures  
13.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB  
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board (IRB) for the trial protocol, written informed consent form, 
consent form updates, participant recruitment procedures (e.g., advertisements) and any other 
written information to be provided to participants. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBss, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately that this request has been made. 
13.3 
Publication of study protocol and results  
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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Amended Protocol Version 02 Clean 
 
Protocol No. COMB157GUS16 
 
13.4 
Quality Control and Quality Assurance  
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB at the study site should be informed according to local 
regulations. 


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Protocol No. COMB157GUS16 
 
15 
References  
References are available upon request. 
Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in 
participants with multiple sclerosis: The VELOCE study Neurology. 
2020;10.1212/WNL.0000000000010380 
Farez MF, Correale J, Armstrong MJ, et al. Practice guideline update summary: Vaccine-
preventable infections and immunization in multiple sclerosis: Report of the Guideline 
Development, Dissemination, and Implementation Subcommittee of the American Academy 
of Neurology. Neurology. 2019;93(13):584-594. 
Grifoni A, Weiskopf D, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in 
Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020 Jun 25;181(7):1489-
1501. 
Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus Teriflunomide in Multiple 
Sclerosis. N Engl J Med. 2020;383(6):546-557.  
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing 
Multiple Sclerosis. N Engl J Med. 2017;376(3):221-234.  
Olberg HK, Eide GE, et al. Antibody response to seasonal influenza vaccination in patients 
with multiple sclerosis receiving immunomodulatory therapy. Eur J Neurol. 2018 
Mar;25:527-534.   
Tan CW, Chia WN, et al. A SARS-CoV-2 surrogate virus neutralization test based on 
antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol. 
2020;38:1073-1078.) 

SAP_001.pdf: 
Clinical Development
OMB157G/Ofatumumab
COMB157GUS16 / NCT04878211
An open-label multicenter study to assess response to COVID-19 
vaccine in participants with multiple sclerosis treated with ofatumumab 
20 mg subcutaneously
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Final 2.0, Amendment 1
Release date:
28-Jun-2023
Number of pages:
32
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021


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SAP Amendment 1
Study No. COMB157GUS16
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
28-
May-
2021
Prior to 
clinical 
DB lock
Creation of 
final version
NA - first version
NA
28-
Jun-
2023
Prior to 
clinical 
DB lock
Creation of 
Amendment 
1
1.
Updated to align with protocol 
version 01 (amended protocol) 
dated 29-Sep-2021: added 3 
new cohorts; increased sample 
size; included participants who 
are fully vaccinated; increased 
number of interim analyses; 
addressed inconsistencies and 
made clarifications
2.
Updated list of abbreviations
3.
Clarified primary analysis time 
point for Cohorts 4-6 as Visit 2
 
 
 
5.
Updated definition of immune 
conversion to account for 
participants with serum 
unavailable prior to vaccine but 
who have not received a 
booster (Cohorts 4 and 5)
6.
Indicated that 95% CIs for 
point estimates of mean or 
proportion will be provided
7.
Clarified that summarization of 
data will be done via cohort 
groupings: Cohort 1, Cohorts 2 
and 4, Cohorts 3 and 5, and 
Cohort 6
8.
Changed baseline to pre-
vaccination and post-baseline 
to post-vaccination
9.
Modified definition of safety 
analysis set to include 
participants who signed 
1.
Section 1 Introduction; 
Section 1.1 Study design; 
Section 1.2 Study 
objectives, endpoints and 
estimands; Section 1.2.1 
Primary estimand(s); 
Section 2.1.1 General 
definitions; Section 2.5.1 
Primary endpoint(s); 
Section 2.13 Interim 
analysis; Section 3 
Sample size calculation
2.
List of abbreviations 
table
3.
Section 1.1 Study design
 
 
5.
Section 1.2 Study 
objectives, endpoints and 
estimands; Section 2.6.1 
Secondary endpoint(s)
6.
Section 2.1 Data analysis 
general information
7.
Section 2.1 Data analysis 
general information
8.
Section 1.2 Study 
objectives, endpoints and 
estimands; Section 2.1.1 
General definitions; 
Section 2.6.1 Secondary 
endpoint(s)
9.
Section 2.2 Analysis sets
10. Section 2.3.1 Patient 
disposition
11. Section 2.3.3 MS history


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SAP Amendment 1
Study No. COMB157GUS16
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
informed consent and met all 
entry criteria
10. Removed disposition event of 
Safety follow-up
11. Added section to address 
summarization of MS history
12. Clarified that medical history 
will be summarized with 
frequency counts and 
percentages
13. Added variables for time 
between points of interest; 
indicated that MS treatment 
compliance will be listed
14. Made updates to visit windows 
based on protocol amendment 
and review of data
15. Clarified that non-drug 
therapies/procedures will be 
coded per MedDRA 
terminology and summarized 
by primary SOC and PT; 
indicated that prior MS DMTs 
will be summarized by PT
16. Clarified that the primary 
analysis will be conducted 
using the safety analysis set
17. Added supplemental analysis in 
which primary analysis is 
repeated using data from 
Cohort 6 participants and any 
participants in Cohorts 1-5 who 
received a booster during the 
study
18. Added supplemental analysis in 
which analysis of secondary 
endpoints is repeated using data 
from Cohort 6 participants and 
any participants in Cohorts 1-5 
who received a booster during 
the study
19. Removed reference to CTC AE 
grades
20. Added descriptive summary of 
laboratory assessments
12. Section 2.3.4 Medical 
history
13. Section 2.4.1 Study 
treatment / compliance
14. Section 2.4.1.1 Visit 
windows
15. Section 2.4.2 Prior, 
concomitant and post 
therapies
16. Section 2.5 Analysis 
supporting primary 
objective(s)
17. Section 2.5.6 
Supplementary analyses
18. Section 2.6.6 
Supplementary analyses
19. Section 2.7.1 Adverse 
events (AEs)
20. Section 2.7.3 Laboratory 
data
21. Section 2.7.4.1 MS 
relapse
24. Section 5.1.2 AE date 
imputation; Section 5.1.3 
Concomitant medication 
date imputation
25. Section 5.1.3.3 Other 
imputations


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SAP Amendment 1
Study No. COMB157GUS16
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
21. Modified the categories for 
summary of number of relapses
24. Replaced AE and medication 
partial date imputation rules 
with 
 standard rules
25. Added imputation rule for 
partial relapse start dates


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SAP Amendment 1
Study No. COMB157GUS16
Table of contents
Table of contents...................................................................................................................5
List of abbreviations..............................................................................................................7
1
Introduction...........................................................................................................................8
1.1
Study design..............................................................................................................8
1.2
Study objectives, endpoints and estimands.............................................................12
1.2.1
Primary estimand(s).....................................................................................13
1.2.2
Secondary estimand(s).................................................................................14
2
Statistical methods ..............................................................................................................14
2.1
Data analysis general information...........................................................................14
2.1.1
General definitions ......................................................................................14
2.2
Analysis sets............................................................................................................16
2.2.1
Subgroup of interest.....................................................................................16
2.3
Patient disposition, demographics and other baseline characteristics.....................16
2.3.1
Patient disposition........................................................................................16
2.3.2
Demographics and other baseline characteristics........................................16
2.3.3
MS history ...................................................................................................17
2.3.4
Medical history............................................................................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance).........................................................................................................................17
2.4.1
Study treatment / compliance ......................................................................17
2.4.2
Prior, concomitant and post therapies..........................................................23
2.5
Analysis supporting primary objective(s)...............................................................23
2.5.1
Primary endpoint(s) .....................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis ................................24
2.5.3
Handling of intercurrent events ...................................................................24
2.5.4
Handling of missing values not related to intercurrent event......................25
2.5.5
Sensitivity analyses......................................................................................25
2.5.6
Supplementary analyses ..............................................................................25
2.6
Analysis supporting secondary objectives ..............................................................25
2.6.1
Secondary endpoint(s) .................................................................................25
2.6.2
Statistical hypothesis, model, and method of analysis ................................26
2.6.3
Handling of intercurrent events ...................................................................26
2.6.4
Handling of missing values not related to intercurrent event......................26


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SAP Amendment 1
Study No. COMB157GUS16
2.6.5
Sensitivity analyses......................................................................................26
2.6.6
Supplementary analyses ..............................................................................26
2.7
Safety analyses........................................................................................................26
2.7.1
Adverse events (AEs) ..................................................................................26
2.7.2
Deaths ..........................................................................................................27
2.7.3
Laboratory data............................................................................................27
2.7.4
Other safety data..........................................................................................27
2.8
Pharmacokinetic endpoints .....................................................................................27
2.9
PD and PK/PD analyses..........................................................................................27
2.10
Patient-reported outcomes.......................................................................................27
2.11
Biomarkers..............................................................................................................27
27
2.13
Interim analysis.......................................................................................................28
3
Sample size calculation.......................................................................................................29
4
Change to protocol specified analyses................................................................................29
5
Appendix.............................................................................................................................29
5.1
Imputation rules ......................................................................................................29
5.1.1
Study drug....................................................................................................29
5.1.2
AE date imputation......................................................................................29
5.1.3
Concomitant medication date imputation....................................................30
5.2
AEs coding/grading.................................................................................................32
5.3
Laboratory parameters derivations..........................................................................32
5.4
Statistical models ....................................................................................................32
5.4.1
Analysis supporting primary objective(s)....................................................32
5.4.2
Analysis supporting secondary objective(s)................................................32
5.5
Rule of exclusion criteria of analysis sets...............................................................32
6
Reference ............................................................................................................................32


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SAP Amendment 1
Study No. COMB157GUS16
List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
CDBL
Clinical Database Lock
CI
Confidence Interval
COVID-19
Coronavirus 2019
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
EOS
End of Study
HBV
Hepatitis B Virus
IA
Interim Analysis
IgG
Immunoglobulin G
LS
Least Squares
MedDRA
Medical Dictionary for Drug Regulatory Activities
mRNA
Messenger Ribonucleic Acid
MS
Multiple Sclerosis
NRI
Non-Response Imputation
PD
Pharmacodynamic
PK
Pharmacokinetic
PT
Preferred Term
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
s.c.
Subcutaneous
SOC
System Organ Class
WHO
World Health Organization


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SAP Amendment 1
Study No. COMB157GUS16
1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the statistical methods planned 
in Section 12 of the Clinical Study Protocol (CSP) version 01 (dated 29-Sep-2021) for the 
clinical trial COMB157GUS16 and any additional analyses, specifications or deviations from 
this planned protocol before clinical database lock (CDBL).
This SAP will be used to draft the Clinical Study Report (CSR) Section 9.7: Statistical methods.
1.1
Study design
This is a 6-cohort, multicenter prospective study in up to 88 participants with relapsing multiple 
sclerosis (MS). Up to 66 of the participants will begin treatment with ofatumumab or already be 
on commercial ofatumumab, the remaining 22 participants will remain on interferon or 
glatiramer acetate. 
In this study, participants must intend to receive or have received a full course (2 doses) of a 
non-live coronavirus 2019 (COVID-19) messenger ribonucleic acid (mRNA) (Pfizer or 
Moderna) vaccine. Participants also must meet inclusion criteria and not meet exclusion criteria.
The study consists of 2 periods as outlined below.
Screening period
Participants will enter a screening period of up to 7 days to assess eligibility requirements. 
Participants in Cohorts 1, 2, 4 and 6 without Hepatitis B virus (HBV) and total serum 
immunoglobulin results within the past 6 months prior to screening will require central labs to 
be drawn. Participants with HBV and total serum immunoglobulin results within the specified 
inclusion range the past 6 months prior to screening will not require the labs to be drawn.
Treatment period
Participants will obtain the mRNA vaccine through their HCP (private insurance) or appropriate 
federal, state or local program. Participants should be instructed to provide documentation of 
vaccine administration to the Study Doctor at the next scheduled on-site study visit.
Cohort 1: Relapsing MS participants receiving a full course (2 doses) of a non-live COVID-
19 mRNA vaccine ≥2 weeks prior to ofatumumab start.
For participants who receive the Pfizer vaccine, the first of three 20 mg subcutaneous (s.c) 
ofatumumab loading doses will be administered on Day 36 or 2 weeks after receiving a full 
course (two doses) of a COVID-19 vaccine. The 2nd and 3rd loading doses should be administered 
on Day 43 and Day 50 or 7 and 14 days respectively after the 1st loading dose. Subsequent dosing 
includes 20 mg s.c. administered monthly starting at Day 64.
For participants who receive the Moderna vaccine, the first of three 20 mg s.c ofatumumab 
loading doses will be administered on Day 43 or 2 weeks after receiving a full course (two doses) 
of a COVID-19 vaccine. The 2nd and 3rd loading doses should be administered on Day 50 and 
Day 57 or 7 and 14 days respectively after the 1st loading dose. Subsequent dosing includes 20 
mg s.c administered monthly starting at Day 71.


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SAP Amendment 1
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Cohort 2: Relapsing MS participants receiving a full course (2 doses) of a non-live COVID-
19 mRNA vaccine ≥4 weeks after ofatumumab start.
Will continue taking their prescribed ofatumumab as per their current dosing schedule.
Cohort 3: Relapsing MS participants receiving a full course (2 doses) of a non-live COVID-
19 mRNA vaccine ≥4 weeks after start of prescribed interferon or glatiramer acetate.
Will continue administration of their prescribed interferon or glatiramer acetate as per their 
current dosing schedule.
Cohort 4: Relapsing MS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥4 weeks after ofatumumab start.
Will continue taking their prescribed ofatumumab as per their current dosing schedule.
Cohort 5: Relapsing MS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥4 weeks after glatiramer acetate or interferon start.
Will continue taking their prescribed glatiramer acetate or interferon as per their current dosing 
schedule.
Cohort 6: Relapsing MS participants having completed a full course (2 doses) of a non-live 
COVID-19 mRNA vaccine ≥4 weeks after ofatumumab start and having received a booster 
≥14 days prior to screening.
Will continue taking their prescribed ofatumumab as per their current dosing schedule.
Study completion
According to the protocol, study completion is defined as when the last participant completes 
the end of study (EOS) visit. Participants who discontinue study treatment or who decide they 
do not wish to participate in the study further should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent. Where possible, they should return for the EOS 
visit.
Study design schematics for Cohorts 1, 2 and 3 are shown in Figures 1, 2, 3 and 4. Study design 
schematics for Cohorts 4, 5 and 6 are shown in Figures 5 and 6.


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Figure 1
Study Design (Cohort 1, Pfizer)
Figure 2
Study Design (Cohort 1, Moderna)
Figure 3
Study Design (Cohorts 2 and 3, Pfizer)


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SAP Amendment 1
Study No. COMB157GUS16
Figure 4
Study Design (Cohorts 2 and 3, Moderna)
Figure 5
Study Design (Cohorts 4, 5 and 6, Pfizer)
Figure 6
Study Design (Cohorts 4, 5 and 6, Moderna)
Primary analysis time point
The primary analysis time point is Visit 4 for Cohorts 1, 2 and 3, and Visit 2 for Cohorts 4, 5 
and 6.


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Interim analysis
For the purpose of early dissemination of results, an interim analysis (IA) will be performed 
once Cohorts 2 and 4 in combination have ≥10 participants enrolled that have had their serum 
drawn ≥14 days after full course (2 doses) vaccination.
A second IA will be performed once Cohort 6 has ≥10 participants. 
A third IA will be performed once Cohorts 2 – 5 have full enrollment with blood drawn ≥14 
days after full course (2 doses) vaccination.
1.2
Study objectives, endpoints and estimands
Study objectives and associated endpoints are shown in Table 1.
Table 1
Study objectives and endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
•
To assess immune response to non-live 
mRNA COVID-19 vaccine in ofatumumab-
treated participants
Endpoint(s) for primary objective(s) 
•
Achieving immune response as defined by 
positive severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) qualitative 
Immunoglobulin G (IgG) antibody assay ≥14 
days after full course (2 doses) vaccination 
(yes/no)
Secondary Objective(s)
•
To assess sustained immune response to 
non-live mRNA COVID-19 vaccine in 
ofatumumab-treated participants
Endpoint(s) for secondary objective(s)
•
Achieving immune response at other 
assessment time points (yes/no)
•
To assess immune conversion to non-live 
mRNA COVID-19 vaccine in ofatumumab-
treated participants
•
Immune conversion to non-live mRNA 
COVID-19 vaccine (yes/no) defined as:
•
For participants with serum available prior to 
vaccination:
o
Pre-vaccination absence of SARS-CoV-
2 spike IgG with post-vaccination SARS-
CoV-2 positive qualitative antibody 
assay ≥14 days after full course (2 
doses) vaccination (yes/no) or
o
Pre-vaccination serum presence of 
SARS-CoV-2 quantitative IgG antibody 
with post-vaccination ≥4-fold increase in 
SARS-CoV-2 quantitative antibody titer 
as determined by dilution assay ≥14 
days after full course (2 doses) 
vaccination (yes/no)
•
For participants with serum unavailable prior 
to vaccination and who have not received a 
booster (Cohorts 4 and 5):
o
Initial negative SARS-CoV-2 
nucleocapsid antibody with post-
vaccination SARS-CoV-2 positive 
qualitative antibody assay ≥14 days after 
full course (2 doses) vaccination (yes/no)


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Objective(s)
Endpoint(s)
•
To assess adverse events and serious 
adverse events
•
Adverse events/serious adverse events
1.2.1
Primary estimand(s)
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during the trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment).
The primary clinical question of interest is: Do relapsing MS participants who receive 
ofatumumab treatment mount an immune response to non-live mRNA COVID-19 vaccine?
The justification for the primary estimand is that it will capture whether ofatumumab-treated 
participants generate antibodies to mRNA COVID-19 vaccines.
The primary estimand is described by the following attributes:
•
Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. Relapsing MS participants subdivided into 6 cohorts. (1) Will 
receive a full course (2 doses) of a COVID-19 mRNA vaccine ≥2 weeks prior to starting 
ofatumumab 20 mg s.c. treatment; (2) Will receive a full course (2 doses) of a COVID-
19 mRNA vaccine after ≥4 weeks of commercial ofatumumab 20 mg s.c. treatment (3) 
Will receive a full course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of 
interferon or glatiramer acetate treatment (4) Completed a full course (2 doses) of a 
COVID-19 mRNA vaccine after ≥4 weeks of commercial ofatumumab 20 mg s.c. 
treatment but has not yet received a COVID-19 mRNA booster (5) Completed a full 
course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of interferon or 
glatiramer acetate (may or may not have received a COVID-19 mRNA booster) (6) 
Completed a full course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of 
commercial ofatumumab 20 mg s.c. treatment and received an additional booster vaccine 
≥14 days prior to screening
•
Variable: Achieving immune response as defined by a positive SARS-CoV-2 qualitative 
IgG antibody assay ≥14 days after full course (2 doses) vaccination (yes/no)


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•
Treatment of interest: Non-live COVID-19 mRNA vaccine either ≥2 weeks prior to 
ofatumumab start or ≥4 weeks after ofatumumab start or while on interferon or glatiramer 
acetate
•
Intercurrent event: Discontinuation of treatment/study, or death
•
Summary measure: Proportion of participants achieving immune response
1.2.2
Secondary estimand(s)
There are no secondary estimands specified for this study.
2
Statistical methods
2.1
Data analysis general information
The statistical analysis outlined in this SAP will be performed by 
, 
a Novartis-designated Contract Research Organization (CRO), using SAS® version 9.4 or higher.
For continuous variables, descriptive statistics will include number of participants (n), mean, 
standard deviation, minimum, maximum, median and 25th and 75th percentiles. For categorical 
variables, frequency counts and percentages will be reported. Where appropriate, 2-sided 95% 
confidence intervals (CIs) for point estimates of the mean or proportion will be provided.
Unless otherwise stated, all data summaries will be presented by cohort group (see below) and 
on all participants in the respective analysis set.
•
Cohort 1
•
Cohorts 2 and 4 combined
•
Cohorts 3 and 5 combined
•
Cohort 6
All data will be listed appropriately.
2.1.1
General definitions 
Treatment of interest
The treatment of interest will refer to the administration of a COVID-19 mRNA vaccine (either 
Pfizer or Moderna) to participants in each of the 6 cohorts. Participants will obtain a COVID-19 
mRNA vaccine from their HCP (private insurance) or appropriate federal, state or local program.
Additional treatment
•
Ofatumumab provided by Novartis in an auto-injector containing 20 mg s.c. ofatumumab 
(20 mg/0.4ml) for s.c. administration to participants in Cohort 1 as per the assessment 
schedule.
•
Commercially prescribed ofatumumab treatment for participants in Cohort 2 as per their 
current dosing schedule.


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Study No. COMB157GUS16
•
Commercially prescribed interferon or glatiramer acetate treatment for participants in 
Cohort 3 as per their current dosing schedule.
•
Commercially prescribed ofatumumab treatment for participants in Cohort 4 as per their 
current dosing schedule.
•
Commercially prescribed interferon or glatiramer acetate treatment for participants in 
Cohort 5 as per their current dosing schedule.
•
Commercially prescribed ofatumumab treatment for participants in Cohort 6 as per their 
current dosing schedule
Study day, onset day, and event duration
The study day of an assessment will be derived relative to the date of Visit 2 (Study Day 1), 
primarily for use in the derivation of analysis visits using visit windows (see Section 2.4.1.1). 
For data including but not limited to adverse events, medications, medical history, non-drug 
therapies/procedures and MS relapses, the onset day will be derived relative to the date of Visit 
1 (Screening) as described below.
For event dates on or after the date of Visit 1, the day of the event will be calculated as follows:
•
(date of event − date of Visit 1) + 1
For event dates prior to the date of Visit 1, the day of the event will be calculated as follows:
•
(date of event − date of Visit 1)
The duration of an event in days will be calculated as follows:
•
(event end date − event start date) + 1
Screening
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to Visit 2 (Study Day 1) unless otherwise specified. Per protocol, participant informed 
consent must be obtained prior to performing any study related activity. The date of signing of 
informed consent is the start date of the screening period. Any assessment obtained during the 
screening period will be labelled as a screening assessment.
Pre-vaccination
Unless otherwise specified, pre-vaccination is the last non-missing assessment (including 
unscheduled assessments) obtained prior to the first dose of the COVID-19 vaccine. Pre-
vaccination is only applicable to Cohorts 1, 2 and 3. All assessments obtained after the first dose 
of the COVID-19 vaccine are considered post-vaccination assessments unless otherwise 
specified.
Nominal visits
Nominal visits are defined as all scheduled visits as per the clinical study protocol including the 
EOS visit. The definition of nominal visit excludes unscheduled visits.


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2.2
Analysis sets 
The Safety Analysis Set (SAF) comprises all participants who signed informed consent and met 
all entry criteria.
Unless otherwise specified the SAF will be used for all summary tables and listings.
2.2.1
Subgroup of interest
There is no subgroup analysis planned for this study.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Participant disposition will be summarized for the following disposition events using all 
screened participants:
•
Screening
•
Treatment
•
End of study
Participants who have discontinued from the study will be listed as appropriate along with the 
primary reason for discontinuation.
The number and percentage of screen failures and the reason for screen failure will be presented 
for all screened participants.
For each protocol deviation, the number and percentage of participants for whom the deviation 
applies will be summarized by cohort group.
2.3.2
Demographics and other baseline characteristics
The following demographic variables will be summarized descriptively by cohort group:
Continuous variables
•
Age (years)
Categorical variables
•
Sex (Male, Female)
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown)
•
Race (White, Black or African American, Asian [Chinese, Indian, Japanese, Korean, 
Vietnamese], Native Hawaiian or Other Pacific Islander, American Indian or Alaska 
Native, Multiple)


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2.3.3
MS history
The number and percentage of participants with a relapse in the last 90 days prior to screening 
will be presented by cohort group.
The following variable will be summarized descriptively as a continuous variable by cohort 
group:
•
Time (days) from onset of most recent relapse (in the last 90 days prior to screening) to 
Visit 1 (Screening), in participants with a relapse in the last 90 days prior to screening
2.3.4
Medical history
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The MedDRA version used for reporting the study will be indicated in a footnote 
on relevant outputs.
Medical history will be summarized with frequency counts and percentages by cohort group, 
primary system organ class (SOC) and preferred term (PT). Tables will show the overall number 
and percentage of participants with at least one reported medical history event in a particular 
primary SOC and at least one reported medical history event in a particular PT.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Participants in all cohorts must intend to receive or have received both doses of a COVID-19 
mRNA vaccine.
The following variables will be summarized descriptively as continuous variables by cohort 
group unless otherwise specified:
•
Time (days) from first dose of ofatumumab to last dose of ofatumumab for Cohort 1 
participants
•
Time (days) from first dose of earliest MS DMT to:
o
first dose of COVID-19 vaccine
o
primary analysis time point (see Section 1.1)
•
Time (days) from first dose of most recent MS DMT to:
o
first dose of COVID-19 vaccine
o
primary analysis time point (see Section 1.1)
MS treatment compliance will be listed by individual cohort and participant.
Study duration
Study duration in days will be calculated as [(date of last contact/EOS – date of Visit 1) + 1] and 
summarized descriptively as a continuous variable by cohort group.


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2.4.1.1
Visit windows
Visit windows will be used for data that are summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. When visit 
windows are used, all visits, including unscheduled visits, will be re-aligned (i.e., they will be 
mapped into one of the visit windows). In the case of major deviations from the visit schedule, 
or due to unscheduled visits, several assessments for a participant may fall in a particular visit 
window (either scheduled or unscheduled). Approaches for handling multiple assessments in a 
visit window are outlined below.
The following steps are used to determine the cut-offs for visit windows:
•
The visit window associated with the previous assessment ends prior to the middle point; 
the visit window associated with the latter assessment begins after the middle point. In 
case the middle point is an exact study day, it will belong to the previous assessment.
•
The visit window of the first post-vaccination assessment starts the day after the second 
dose of the COVID-19 vaccine for Cohorts 1 – 5, and the day after the COVID-19 
vaccine booster for Cohort 6, unless otherwise specified.
Tables 2 – 10 provide visit windows for applicable parameters.
Table 2
Cohort 1 visit windows for SARS-CoV-2 qualitative 
antibody / CD19+ B cells / T cell
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study  days)
Pfizer vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 36
36
(vaccine day + 1) to 64
70 days post-vaccination
Day 92
92
65 to 147
180 days post-vaccination
Day 202
202
148 to 247
270 days post-vaccination
Day 292
292
248 to 337
360 days post-vaccination
Day 382
382
≥338
Moderna vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 43
43
(vaccine day + 1) to 71
70 days post-vaccination
Day 99
99
72 to 154
180 days post-vaccination
Day 209
209
155 to 254
270 days post-vaccination
Day 299
299
255 to 344
360 days post-vaccination
Day 389
389
≥345
Note:
- Pre-vaccination and study day are derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine.
- Assessments performed between the first and second doses of the COVID-19 vaccine are not 
assigned an analysis visit.


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Table 3
Cohort 1 visit windows for serum immunoglobulin 
(IgG, IgM)
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study days)
Pfizer vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 36
36
(vaccine day + 1) to 64
70 days post-vaccination
Day 92
92
65 to 147
180 days post-vaccination
Day 202
202
148 to 292
360 days post-vaccination
Day 382
382
≥293
Moderna vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 43
43
(vaccine day + 1) to 71
70 days post-vaccination
Day 99
99
72 to 154
180 days post-vaccination
Day 209
209
155 to 299
360 days post-vaccination
Day 389
389
≥300
Note:
- Pre-vaccination and study day are derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine.
- Assessments performed between the first and second doses of the COVID-19 vaccine are not 
assigned an analysis visit.


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Table 5
Cohorts 2 and 3 visit windows for SARS-CoV-2 qualitative
antibody / CD19+ B cells (Cohort 2 only) / T cell
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study  days)
Pfizer vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 36
36
(vaccine day + 1) to 119
180 days post-vaccination
Day 202
202
120 to 247
270 days post-vaccination
Day 292
292
248 to 337
360 days post-vaccination
Day 382
382
≥338
Moderna vaccine:
Pre-vaccination
Day 1
1
≤1
14 days post-vaccination
Day 43
43
(vaccine day + 1) to 126
180 days post-vaccination
Day 209
209
127 to 254
270 days post-vaccination
Day 299
299
255 to 344
360 days post-vaccination
Day 389
389
≥345
Note:
- Pre-vaccination and study day are derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine.
- Assessments performed between the first and second doses of the COVID-19 vaccine are not 
assigned an analysis visit.
Table 6
Cohorts 2 and 3 visit windows for serum immunoglobulin
(IgG, IgM)
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study  days)
Pfizer vaccine:
Pre-vaccination
Day 1
1
≤1
180 days post-vaccination
Day 202
202
(vaccine day + 1) to 292
360 days post-vaccination
Day 382
382
≥293
Moderna vaccine:
Pre-vaccination
Day 1
1
≤1
180 days post-vaccination
Day 209
209
(vaccine day + 1) to 299
360 days post-vaccination
Day 389
389
≥300
Note:
- Pre-vaccination and study day are derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine.
- Assessments performed between the first and second doses of the COVID-19 vaccine are not 
assigned an analysis visit.


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Table 8
Cohorts 4, 5 and 6 visit windows for SARS-CoV-2 
qualitative antibody / CD19+ B cells (Cohorts 4 and 6 only) /
T cell
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study  days)
Pfizer vaccine:
14 days post-vaccination
Day 1
1
(vaccine day + 1) to 1
180 days post-vaccination
Day 202
202
2 to 247
270 days post-vaccination
Day 292
292
248 to 337
360 days post-vaccination
Day 382
382
≥338
Moderna vaccine:
14 days post-vaccination
Day 1
1
(vaccine day + 1) to 1
180 days post-vaccination
Day 209
209
2 to 254
270 days post-vaccination
Day 299
299
255 to 344
360 days post-vaccination
Day 389
389
≥345
Note:
- Study day is derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine for Cohorts 4 and 5, and 
the study day of the COVID-19 vaccine booster for Cohort 6.


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Table 9
Cohorts 4, 5 and 6 visit windows for serum immunoglobulin
(IgG, IgM)
Analysis visit
Nominal time 
point
Scheduled visit day 
(target study day)
Visit window 
(study  days)
Pfizer vaccine:
14 days post-vaccination
Day 1
1
(vaccine day + 1) to 1
180 days post-vaccination
Day 202
202
2 to 292
360 days post-vaccination
Day 382
382
≥293
Moderna vaccine:
14 days post-vaccination
Day 1
1
(vaccine day + 1) to 1
180 days post-vaccination
Day 209
209
2 to 299
360 days post-vaccination
Day 389
389
≥300
Note:
- Study day is derived as outlined in Section 2.1.1.
- Vaccine day is the study day of the second dose of the COVID-19 vaccine for Cohorts 4 and 5, and 
the study day of the COVID-19 vaccine booster for Cohort 6.
Multiple assessments
When there are multiple assessments in a particular visit window, the rules outlined below are 
applied to select one value “representing” the participant in summary statistics for that visit 
window. All assessments will be displayed in listings.
•
Pre-vaccination (only applicable to Cohorts 1, 2 and 3): Pre-vaccination is derived as 
outlined in Section 2.1.1. In situations where the same assessment is performed more 
than once on Study Day 1 the repeated assessment will be used.
•
Post-vaccination: For post-vaccination visit windows, the following rules apply (unless 
otherwise specified): 
o
For continuous variables, the assessment with the study day that is closest to the 
target study day is selected. If two assessments are equidistant from the target study 


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day, the earlier assessment is selected (if one of the two equidistant assessments is an 
unscheduled assessment, it should be excluded from consideration).
o
For categorical variables, the assessment with the worst result is selected. 
If categorical variables are based on continuous variables, the analysis visit will be 
assigned to the continuous variable, and this analysis visit will be used for the derived 
categorical variable.
In situations where the same assessment is performed more than once on the same date 
the repeated assessment will be used.
2.4.2
Prior, concomitant and post therapies
Medications will be coded using the World Health Organization (WHO) Drug Dictionary. The 
WHO Drug Dictionary version used for reporting the study will be indicated in a footnote on 
relevant outputs.
Medications will be classified as prior or concomitant as follows:
•
Prior medications are defined as medications taken prior to the date of Visit 1 
(Screening). 
•
Concomitant medications are defined as medications taken on or after the date of Visit 1 
(Screening).
Medications will be categorized into the above classes based on recorded or imputed start and 
end dates (see Section 5.1.3).
Prior and concomitant medications will be summarized with frequency counts and percentages 
by cohort group, Anatomical Therapeutic Chemical (ATC) class and PT. Tables will show the 
overall number and percentage of participants receiving at least one medication of a particular 
ATC class and at least one medication of a particular PT. A separate summary of prior MS DMTs 
by PT will be provided.
 Non-drug therapies/procedures will be coded using MedDRA terminology. The MedDRA 
version used for reporting the study will be indicated in a footnote on relevant outputs. Non-drug 
therapies/procedures will be classified as prior or concomitant based on recorded or imputed 
start and end dates as outlined above for medications.
Prior and concomitant non-drug therapies/procedures will be summarized by cohort group, 
primary SOC and PT. Tables will show the overall number and percentage of participants with 
at least one non-drug therapy/procedure of a particular primary SOC and at least one non-drug 
therapy/procedure of a particular PT.
2.5
Analysis supporting primary objective(s)
The primary objective of this study is to characterize those achieving immune response after 
receiving a full course (2 doses) vaccination with a non-live mRNA COVID-19 vaccine (Pfizer 
or Moderna vaccine) in participants treated with ofatumumab 20 mg s.c. once monthly. This will 
be achieved by estimating the immune response rate using the SAF.


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An immune responder is a participant achieving immune response as defined by a positive 
SARS-CoV-2 qualitative IgG antibody assay after full course (2 doses) vaccination.
2.5.1
Primary endpoint(s)
The primary endpoint is achieving immune response as defined by a positive SARS-CoV-2 
qualitative IgG antibody assay ≥14 days after full course (2 doses) vaccination (yes/no).
The primary estimand is described by the following attributes:
•
Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population. Relapsing MS participants subdivided into 6 cohorts. (1) Will 
receive a full course (2 doses) of a COVID-19 mRNA vaccine ≥2 weeks prior to starting 
ofatumumab 20 mg s.c. treatment; (2) Will receive a full course (2 doses) of a COVID-
19 mRNA vaccine after ≥4 weeks of commercial ofatumumab 20 mg s.c. treatment (3) 
Will receive a full course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of 
interferon or glatiramer acetate treatment (4) Completed a full course (2 doses) of a 
COVID-19 mRNA vaccine after ≥4 weeks of commercial ofatumumab 20 mg s.c. 
treatment but has not yet received a COVID-19 mRNA booster (5) Completed a full 
course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of interferon or 
glatiramer acetate (may or may not have received a COVID-19 mRNA booster) (6) 
Completed a full course (2 doses) of a COVID-19 mRNA vaccine after ≥4 weeks of 
commercial ofatumumab 20 mg s.c. treatment and received an additional booster vaccine 
≥14 days prior to screening
•
Variable: Achieving immune response as defined by a positive SARS-CoV-2 qualitative 
IgG antibody assay ≥14 days after full course (2 doses) vaccination (yes/no)
•
Treatment of interest: Non-live COVID-19 mRNA vaccine either ≥2 weeks prior to 
ofatumumab start or ≥4 weeks after ofatumumab start or while on interferon or glatiramer 
acetate
•
Intercurrent event: Discontinuation of treatment/study, or death
•
Summary measure: Proportion of participants achieving immune response
2.5.2
Statistical hypothesis, model, and method of analysis 
The number and percentage of responders will be presented by cohort group and overall. The 2-
sided 95% CI for the proportion of responders will be calculated using an exact method (Clopper 
and Pearson, 1934).
2.5.3
Handling of intercurrent events 
Non-response imputation (NRI) approach will be applied to missing post-vaccination antibody 
assay regardless of intercurrent events.
NRI is a conservative imputation method for dichotomous variables. NRI assumes that a 
participant is a treatment failure if the participant discontinues the study prematurely. Hence, for 
missing data the primary endpoint will be imputed as “No”. Refer to Section 5.1.3.3.


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2.5.4
Handling of missing values not related to intercurrent event
NRI approach will be applied to missing post-vaccination antibody assay.
2.5.5
Sensitivity analyses 
There are no sensitivity analyses of the primary endpoint planned for this study. 
2.5.6
Supplementary analyses
A supplemental analysis of the primary endpoint will be performed using an observed case 
approach (completers) by using valid assessments of antibody assay without imputation of 
missing data. 
In addition, the primary analysis will be repeated using data from Cohort 6 participants and any 
participants in Cohorts 1 – 5 who received an mRNA booster during the study. Missing post-
vaccination antibody assay will be handled according to the NRI approach.
For each supplemental analysis the number and percentage of responders will be presented by 
cohort group and overall. The 2-sided 95% CI for the proportion of responders will be calculated 
using an exact method (Clopper and Pearson, 1934).
2.6
Analysis supporting secondary objectives 
Analysis of endpoints supporting secondary objectives is described in Sections 2.6.1 – 2.6.6 
below.
2.6.1
Secondary endpoint(s)
Secondary endpoints include the following:
•
Achieving immune response (responder) as defined by a positive SARS-CoV-2 
qualitative IgG antibody assay at other assessment time points ≥14 days after full course 
(2 doses) vaccination (yes/no).
•
Immune conversion (yes/no) which is defined as:
o
Pre-vaccination absence of SARS-CoV-2 qualitative IgG antibody with post-
vaccination positive SARS-CoV-2 qualitative IgG antibody assay at any assessment 
time point ≥14 days after full course (2 doses) vaccination (yes/no); or
o
Pre-vaccination serum presence of SARS-CoV-2 quantitative IG antibody with post-
vaccination ≥4-fold increase in SARS-CoV-2 quantitative antibody titer as 
determined by dilution assay at any assessment time point ≥14 days after full course 
(2 doses) vaccination (yes/no); or
o
Initial negative SARS-CoV-2 nucleocapsid antibody at Visit 2 (Day 1) with post-
vaccination positive SARS-CoV-2 qualitative IgG antibody assay at any post-Visit 2 
(Day 1) assessment time point ≥14 days after full course (2 doses) vaccination 
(yes/no) (Applicable to Cohorts 4 and 5.)


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2.6.2
Statistical hypothesis, model, and method of analysis
The number and percentage of responders will be presented by cohort group (and overall) and 
time point (where appropriate). The 2-sided 95% CI for the proportion of responders will be 
calculated using an exact method (Clopper and Pearson, 1934). Participants achieving immune 
conversion will be summarized in a similar fashion.
2.6.3
Handling of intercurrent events 
NRI approach will be applied to missing antibody assay regardless of intercurrent events.
2.6.4
Handling of missing values not related to intercurrent event
NRI approach will be applied to missing antibody assay.
2.6.5
Sensitivity analyses
There are no sensitivity analyses of secondary endpoints planned for this study. 
2.6.6
Supplementary analyses
A supplemental analysis of each secondary endpoint will be performed using an observed case 
approach (completers) by using valid assessments of antibody assay without imputation of 
missing data.
In addition, analysis of secondary endpoints will be repeated using data from Cohort 6 
participants and any participants in Cohorts 1 – 5 who received an mRNA booster during the 
study. Missing antibody assay will be handled according to the NRI approach.
The number and percentage of responders will be presented by cohort group and overall. The 2-
sided 95% CI for the proportion of responders will be calculated using an exact method (Clopper 
and Pearson, 1934). Participants achieving immune conversion will be summarized in a similar 
fashion.
2.7
Safety analyses
2.7.1
Adverse events (AEs)
Adverse events (AEs) will be coded using MedDRA terminology. The MedDRA version used 
for reporting the study will be indicated in a footnote on relevant outputs.
For reporting purposes, summary tables for AEs will summarize only on-study events, which 
started or worsened on or after the date of Visit 1 (Screening).
The number and percentage of participants with on-study AEs will be summarized in the 
following ways:
•
by cohort group, primary SOC and PT
•
by cohort group, primary SOC, PT and maximum severity
•
by cohort group and PT


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Separate summaries will be provided for MS treatment-related AEs (MS treatment includes 
ofatumumab, interferon and glatiramer acetate), serious adverse events (SAEs) and other 
significant AEs leading to discontinuation.
If a participant reported more than one AE with the same PT, the AE with the greatest 
severity/grade will be presented. A participant with multiple AEs within a primary SOC is only 
counted once towards the total of the primary SOC.
2.7.1.1
Adverse events of special interest / grouping of AEs
There are no AEs of special interest defined for this study.
2.7.2
Deaths
All deaths will be listed.
2.7.3
Laboratory data
Values and changes from pre-vaccination (where appropriate) in laboratory assessments will be 
summarized by cohort group and time point with descriptive statistics.
2.7.4
Other safety data
2.7.4.1
MS relapse
The number and percentage of participants with 0, 1, 2 or ≥3 confirmed relapses during the study 
will be presented by cohort group. In addition, the number and percentage of participants with 
at least 1 confirmed relapse during the study will be presented by cohort group.
2.8
Pharmacokinetic endpoints
There are no pharmacokinetic (PK) endpoints defined for this study. 
2.9
PD and PK/PD analyses
There are no pharmacodynamic (PD) or PK/PD analyses planned for this study. 
2.10
Patient-reported outcomes
There are no patient-reported outcome endpoints defined for this study. 
2.11
Biomarkers
There are no biomarker endpoints defined for this study. 


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2.13
Interim analysis
For the purpose of early dissemination of results, an IA will be performed once Cohorts 2 and 4 
in combination have ≥10 participants enrolled that have had their serum drawn ≥14 days after 
full course (2 doses) vaccination.
A second IA will be performed once Cohort 6 has ≥10 participants.
The third IA will be performed once Cohorts 2 – 5 have full enrollment with blood drawn ≥14 
days after full course (2 doses) vaccination.
The following variables (including but not limited to) will be summarized for each IA mentioned 
above:
•
Disposition
•
Demographics


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•
Baseline characteristics
•
Immune response-related variables
•
AEs, SAEs and AEs leading to study discontinuation
•
Deaths
Since there will be no hypothesis testing involved, statistical adjustment for the IA will not be 
made at the stage of final analyses.
3
Sample size calculation
The sample size of 20 participants per cohort is selected based on budget and need for early 
availability of results. This sample size of 20 participants will provide estimates of proportion 
of responders with margin of error (half-width of a 95% CI) of 20.1%, 19% and 17.5% 
corresponding to response rates of 70%, 75% and 80%, respectively. Adjusting for 10% drop-
out, 22 participants will be enrolled in Cohort 1. In combination, 22 participants will be enrolled 
in Cohorts 2 and 4. In combination, 22 participants will be enrolled in Cohorts 3 and 5. In Cohort 
6, 22 participants will be enrolled.
4
Change to protocol specified analyses
There are no changes to protocol specified analyses. 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
There will be no imputation rules for study drug detailed for this study.
5.1.2
AE date imputation
The following algorithm will be used to estimate AE start dates for which only partial 
information is known. Note that “index date” refers to the date of Visit 1 (Screening).
Missing day and month:
•
If the year is the same as the year of the index date, then the day and month of the 
index date will be assigned to the missing fields.
•
If the year is prior to the year of the index date, then December 31 will be assigned to 
the missing fields.
•
If the year is after the year of the index date, then January 1 will be assigned to the 
missing fields.
Missing month only:
•
Treat day as missing and replace both month and day according to the above procedure.


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Missing day only: 
•
If the month and year are the same as the year and month of the index date, then the 
index date will be assigned to the missing day. 
•
If the month and year are before the year and month of the index date, then the last day 
of the month will be assigned to the missing day.
•
If the month and year are after the year and month of the index date, then the first day 
of the month will be assigned to the missing day.
If the imputed start date result is after the stop date (and the stop date is complete), the imputed 
start date will be reset to the stop date.
The following algorithm will be used to estimate AE stop dates for which only partial 
information is known.
Missing year: 
•
Date left missing. 
Missing month: 
•
Impute ‘December’.
Missing day: 
•
Impute ‘last date of that month’.
5.1.3
Concomitant medication date imputation
The following algorithm will be used to estimate medication start dates for which only partial 
information is known. Note that “index date” refers to the date of Visit 1 (Screening).
Missing day and month:
•
If the year is the same as the year of the index date, then the day and month of the 
index date will be assigned to the missing fields.
•
If the year is prior to the year of the index date, then December 31 will be assigned to 
the missing fields.
•
If the year is after the year of the index date, then January 1 will be assigned to the 
missing fields.
Missing month only:
•
Treat day as missing and replace both month and day according to the above procedure.
Missing day only: 
•
If the month and year are the same as the year and month of the index date, then the 
index date will be assigned to the missing day. 
•
If the month and year are before the year and month of the index date, then the last day 
of the month will be assigned to the missing day.


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•
If the month and year are after the year and month of the index date, then the first day 
of the month will be assigned to the missing day.
If the imputed start date result is after the stop date (and the stop date is complete), the imputed 
start date will be reset to the stop date.
The following algorithm will be used to estimate medication stop dates for which only partial 
information is known.
Missing year: 
•
Date left missing. 
Missing month: 
•
Impute ‘December’.
Missing day: 
•
Impute ‘last date of that month’.
5.1.3.1
Prior therapies date imputation
Same as for medications above.
5.1.3.2
Post therapies date imputation
Same as for medications above.
5.1.3.3
Other imputations
Non-response imputation
NRI assumes that a participant is a non-responder if there are no valid immune response 
assessments after receiving both doses of the vaccine. Hence, for missing data the primary 
endpoint of achieving immune response as defined by a positive SARS-CoV-2 qualitative IgG 
antibody assay ≥14 days after full course (2 doses) vaccination (yes/no) will be imputed as “No”.
MS relapse date imputation
The following algorithm will be used to estimate relapse start dates for which only partial 
information is known. Note that “index date” refers to the date of Visit 1 (Screening).
Missing day only: 
•
The first day of the month will be assigned to the missing day. In case the relapse start 
date occurs in the same month as the index date, the relapse start date will be imputed 
as the index date.
The following algorithm will be used to estimate relapse stop dates for which only partial 
information is known.
Missing day only: 
•
The last day of the month will be assigned to the missing day or truncated to have a 
maximum duration of 90 days.


Novartis
Confidential
Page 32 of 32
SAP Amendment 1
Study No. COMB157GUS16
5.2
AEs coding/grading
Adverse events will be coded using the MedDRA terminology. The MedDRA version used for 
reporting the study will be indicated in a footnote on relevant outputs.
5.3
Laboratory parameters derivations
There are no laboratory parameter derivations for this study. 
5.4
Statistical models
5.4.1
Analysis supporting primary objective(s) 
There is no hypothesis testing planned for the analysis supporting the primary objective of this 
study.
5.4.2
Analysis supporting secondary objective(s)
There is no hypothesis testing planned for the analyses supporting the secondary objectives of 
this study.
5.5
Rule of exclusion criteria of analysis sets 
There are no rules of exclusion criteria of analysis sets for this study.
6
Reference
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934; 26:404-413.