Clinical trial NCT04869358
Conditions: Relapsing Multiple Sclerosis
Keywords: COVID-19 SARS-CoV-2 mRNA vaccine immune response Ofatumumab Relapsing Multiple Sclerosis RMS adult MS
Sponsor: Novartis Pharmaceuticals
Start date: 2021-05-27; Completion date: 2023-06-13
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aimed to understand whether patients with relapsing multiple sclerosis (RMS) can mount an immune response to SARS-CoV-2 mRNA vaccines (initial vaccinations or booster vaccines) when vaccinated either before initiation of ofatumumab treatment or at least 4 weeks after commencing ofatumumab treatment.

Detailed description:
This was a four cohort, multicenter, open-label, prospective study of 34 (optionally up to 60) patients who had relapsing multiple sclerosis (RMS) planning to undergo a SARS-CoV-2 mRNA vaccination (initial vaccinations or booster vaccines) as part of clinical routine. The maximal duration of the study for an individual patient was 22 months.

* The first cohort was RMS patients receiving SARS-CoV-2 mRNA vaccine (initial vaccinations or booster vaccines) as part of clinical routine prior to starting ofatumumab treatment.
* The second cohort was participants receiving SARS-CoV-2 mRNA vaccine (initial vaccinations or booster vaccines) as part of clinical routine while already stable on ofatumumab treatment for at least 4 weeks (since first dose).

Cohort 1a - Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment.

Cohort 1b - Patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.

Cohort 2a - Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

Cohort 2b - Patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

Development of SARS-CoV-2 specific T-cells and functional anti-SARS-CoV-2 antibodies were investigated for up to 18 months after the participants' vaccination.

Arms: arm 1: Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment. arm 2: Patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment. arm 3: Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose). arm 4: Patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).
Interventions: intervention 1: Ofatumumab
Intervention descriptions: intervention 1: Ofatumumab 20 mg s.c. on days 1, 7, 14, week 4 and every 4 weeks thereafter

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
Ofatumumab (OMB157) 
Synopsis/Clinical Trial Protocol COMB157GDE01 / NCT04869358
Tracking the immune response to SARS-CoV-2 modRNA 
vaccines in an open-label multicenter study in participants 
with relapsing multiple sclerosis treated with ofatumumab 
s.c. (KYRIOS)
Document type: 
Amended Protocol Version 
EUDRACT number: 
2021-000307-20 
Version number: 
03 
Clinical Trial Phase: 
IV 
Release date: 
28-Mar-2022
Property of Novartis Pharma Vertriebs GmbH  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ............................................................................................................. 2 
List of tables ................................................................................................................... 4 
List of figures .................................................................................................................. 5 
List of abbreviations ........................................................................................................ 6 
Glossary of terms ............................................................................................................ 7 
Amendment 2.................................................................................................................. 9 
Amendment 1................................................................................................................ 17 
Protocol summary ......................................................................................................... 21 
1 
Introduction .................................................................................................................. 24 
1.1 
Background ....................................................................................................... 24 
1.2 
Purpose .............................................................................................................. 26 
2 
Objectives and endpoints ............................................................................................... 26 
2.1 
Primary estimands ............................................................................................. 28 
2.2 
Secondary estimands .......................................................................................... 29 
3 
Study design ................................................................................................................. 29 
4 
Rationale ....................................................................................................................... 34 
4.1 
Rationale for study design .................................................................................. 34 
4.2 
Rationale for dose/regimen and duration of treatment ........................................ 35 
Ofatumumab ................................................................................................................. 35 
Vaccination ................................................................................................................... 35 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs .................................................................................................................. 35 
4.4 
Purpose and timing of interim analyses/design adaptations ................................ 36 
4.5 
Risks and benefits .............................................................................................. 36 
4.5.1 
Blood sample volume ........................................................................ 37 
5 
Study Population ........................................................................................................... 37 
5.1 
Inclusion criteria ................................................................................................ 37 
5.2 
Exclusion criteria ............................................................................................... 38 
6 
Treatment ...................................................................................................................... 38 
6.1 
Study treatment .................................................................................................. 38 
6.1.1 
Investigational and control drugs........................................................ 38 
6.1.2 
Supply of study treatment .................................................................. 39 
6.1.3 
Treatment arms/group ........................................................................ 39 
6.2 
Other treatment(s) .............................................................................................. 39 
6.2.1 
Concomitant therapy .......................................................................... 39 
6.2.2 
Prohibited medication ........................................................................ 39 


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6.3 
Participant numbering, treatment assignment, randomization ............................. 39 
6.3.1 
Participant numbering ........................................................................ 39 
6.3.2 
Treatment assignment, randomization ................................................ 40 
6.4 
Treatment blinding............................................................................................. 40 
6.5 
Dose escalation and dose modification ............................................................... 40 
6.6 
Additional treatment guidance ........................................................................... 40 
6.6.1 
Treatment compliance ........................................................................ 40 
6.7 
Preparation and dispensation .............................................................................. 40 
6.7.1 
Handling of study treatment and additional treatment ......................... 41 
7 
Informed consent procedures ......................................................................................... 41 
8 
Visit schedule and assessments...................................................................................... 42 
8.1 
Screening ........................................................................................................... 51 
8.1.1 
Eligibility screening ........................................................................... 51 
8.1.2 
Information to be collected on screening failures ............................... 51 
8.2 
Participant demographics/other baseline characteristics ..................................... 51 
8.3 
Efficacy ............................................................................................................. 51 
8.3.1 
Efficacy assessment 1 ........................................................................ 51 
8.3.2 
Efficacy assessment 2 ........................................................................ 51 
8.3.3 
Appropriateness of efficacy assessments ............................................ 52 
8.4 
Safety ................................................................................................................ 52 
8.4.1 
Laboratory evaluations ....................................................................... 53 
8.4.2 
Pregnancy and assessments of fertility ............................................... 53 
8.5 
Additional assessments ...................................................................................... 54 
9 
Study discontinuation and completion ........................................................................... 54 
9.1 
Discontinuation and completion ......................................................................... 54 
9.1.1 
Study treatment discontinuation and study discontinuation ................. 54 
9.1.2 
Withdrawal of informed consent ........................................................ 55 
9.1.3 
Lost to follow-up ............................................................................... 55 
9.1.4 
Early study termination by the sponsor............................................... 56 
9.2 
Study completion and post-study treatment ........................................................ 56 
10 Safety monitoring and reporting .................................................................................... 56 
10.1 
Definition of adverse events and reporting requirements .................................... 56 
10.1.1 
Adverse events ................................................................................... 56 
10.1.2 
Serious adverse events ....................................................................... 58 
10.1.3 
SAE reporting .................................................................................... 59 
10.1.4 
Pregnancy reporting ........................................................................... 59 


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10.1.5 
Reporting of study treatment errors including misuse/abuse ............... 60 
10.2 
Additional Safety Monitoring ............................................................................ 60 
11 Data Collection and Database management ................................................................... 61 
11.1 
Data collection ................................................................................................... 61 
11.2 
Database management and quality control ......................................................... 61 
11.3 
Site monitoring .................................................................................................. 61 
12 Data analysis and statistical methods ............................................................................. 62 
12.1 
Analysis sets ...................................................................................................... 62 
12.2 
Participant demographics and other baseline characteristics ............................... 62 
12.3 
Treatments ......................................................................................................... 63 
12.4 
Analysis of the primary endpoint(s)/estimand(s) ................................................ 63 
12.4.1 
Definition of primary endpoint(s)/estimand(s) .................................... 63 
12.4.2 
Statistical model, hypothesis, and method of analysis ......................... 63 
12.4.3 
Handling of remaining intercurrent events of primary estimand ......... 63 
12.4.4 
Supportive analyses ........................................................................... 64 
12.5 
Analysis of secondary endpoints/estimands ........................................................ 64 
12.5.1 
Safety endpoints ................................................................................ 64 
 
 65 
12.7 
Interim analyses ................................................................................................. 65 
12.8 
Sample size calculation ...................................................................................... 65 
12.8.1 
Primary endpoint(s) ........................................................................... 65 
13 Ethical considerations and administrative procedures .................................................... 66 
13.1 
Regulatory and ethical compliance ..................................................................... 66 
13.2 
Responsibilities of the investigator and IRB/IEC ............................................... 66 
13.3 
Publication of study protocol and results ............................................................ 66 
13.4 
Quality Control and Quality Assurance .............................................................. 67 
14 Protocol adherence ........................................................................................................ 67 
14.1 
Protocol amendments ......................................................................................... 67 
15 References .................................................................................................................... 68 
 
List of tables 
Table 2-1 
Objectives and related endpoints ........................................................ 26 
Table 6-1 
Investigational and control drug ......................................................... 38 
Table 8-1 
Assessment schedule cohort 1a .......................................................... 43 
Table 8-2 
Assessment schedule cohort 1b .......................................................... 45 
PPD


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Table 8-4 
Assessment schedule cohort 2b .......................................................... 49 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ...................................................................................... 60 
List of figures 
Figure 3-1 
Study design ...................................................................................... 30 
 


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List of abbreviations 
 
AE 
Adverse Event 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
DQF 
Data Query Form 
ELISpot 
Enzyme-linked immunospot 
eSource 
Electronic Source 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Nab 
Neutralizing antibody 
QMS  
Quality Management System 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TD 
Study Treatment Discontinuation 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
 
 
 
 


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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 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
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 
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 


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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 
Run-in Failure 
A participant who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to participant’s intervention or 
other treatment) 
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 3 
Amendment Summary:  
Main changes in the amendment include termination of recruitment, addition of a study visit 
and omitting of study exclusion after use of prohibited medication. 
 
Termination of recruitment: With the advancement of the vaccination efforts in Germany 
participating centers of this study report that there are no more suitable MS patients for this 
study who have not yet received their initial or booster SARS-CoV-2 vaccination and fit the 
inclusion/exclusion criteria (especially “no known prior COVID-19 infection”). Therefore, 
recruitment will be officially stopped with the approval of this amendment. 
Addition of study visit: An additional visit will be performed 1 month after the second booster 
vaccine. Assessment of the immune response at the same time point after two consecutive 
vaccinations is necessary to draw conclusions on the formation of a memory immune response. 
In order to collect this information, an additional study visit is necessary. 
 
Prohibited medication: Non-mRNA vaccines will still be listed as prohibited medication but 
patients receiving this kind of vaccine will no longer be excluded from the study. So far, there 
is only very limited information available with regards to the immune response in ofatumumab 
treated patients after SARS-CoV-2 vaccination. It is therefore essential to capture as much 
information about maintenance of immune response in this vulnerable patient cohort as possible 
in order to provide the best guidance for patients and physicians. As vaccination is the main 
tool to fight the pandemic, all patients are encouraged to receive booster vaccines. It is not 
planned that these boosters are non-mRNA vaccines but if it happens, this should not lead to 
study continuation but will instead be reflected in the analysis.   
 
 
Changes to the protocol: 
Section 3: Study design: 
- 
Foot note below study design was changed to reflect that an additional visit should be 
performed after the second booster vaccine. 
- 
Specification that patients in cohorts 1b and 2b have to receive their first SARS-CoV-2 
mRNA booster during the study. 
 
Section 6.2.2: Prohibited medication: 
- 
Vaccination with non-mRNA vaccines won’t lead to exclusion of these patients 
 
Section 8: Visit schedule and assessments 


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- 
Visit schedules for all cohorts  were updated to reflect additional visits after the second 
booster vaccine. 
 
Section 12.4.4: Supportive analyses: 
- 
Sentence was added to describe that it will be reflected in the analysis if patients should 
receive a non-mRNA vaccine as booster. 
 
 
 
Amendment 2 
Amendment Summary:  
Main changes in the amendment include splitting of each cohort into two subcohorts, 
corresponding changes in the treatment schedule, adaption of the primary endpoint and the 
exclusion criteria as well as addition of an interim analysis. 
 
Study design: Based on current discussions about the necessity of SARS-CoV-2 booster 
vaccines in immunocompromised patients, the immune response of patients with MS after 
booster vaccines should be investigated. The existing cohorts that receive SARS-CoV-2 
vaccination either before or after starting ofatumumab treatment, were therefore divided into 
two subcohorts each: the first subcohort (cohort 1a and 2a) will receive their initial SARS-CoV-
2 vaccination (1st and 2nd vaccine) within the study while the other subcohort (cohort 1b and 
2b) will receive a booster shot during the study. 
 
Primary endpoint: The primary endpoint was adjusted to reflect the new study design. In order 
to have comparable data after the initial vaccination cycle and the booster vaccine, the primary 
endpoint will be measured 1 month after either the 2nd SARS-CoV-2 vaccine (cohort 1a and 2a) 
or the booster vaccine (cohort 1b and 2b).  
 
Exclusion criteria: As fully vaccinated patients are now allowed to be recruited to the study 
(into cohort 1b and 2b), the exclusion criteria were amended to exclude patients that have 
received any non-mRNA SARS-CoV-2 vaccination before the study 
 
Interim analysis: In order to provide fast guidance on the currently discussed booster vaccines, 
an additional interim analysis should be performed when at least 10 patients have been 
vaccinated while being on stable ofatumumab treatment (cohort 2) or on January 10th 2022, 
whichever comes first. 
 


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Changes to the protocol: 
List of abbreviations 
- 
Deletion of unused abbreviations 
 
Protocol Summary 
- 
Change of primary endpoint 
- 
Addition of secondary endpoint (level of T-cell response) 
- 
Complement of secondary objective, which was added by amendment 1 
- 
Addition of exclusion criterion (no previous non-mRNA vaccine) 
- 
Study treatment was adjusted to new subcohorts 
 
Section 1.1: Background 
- 
Typo was corrected 
 
Section 1.2: Purpose 
- 
specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
- 
patients will be monitored for up to 18 months after initial vaccination (Amendment1) 
 
Section 2: Objectives and endpoints 
- 
Primary objective and endpoint were adjusted to updated study design 
- 
New subcohorts were included in all secondary objectives and endpoints 
- 
New secondary endpoint to investigate T-cell levels 
 
 
 
Section 2.1: Primary estimands 
- 
specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
- 
explanation was added for how the new cohorts 1b and 2b answer the primary question 
of the study 
- 
“developing” was replaced by “having developed” to adjust for new study design 
- 
population was adjusted to reflect new study design (integration of cohort 1b and 2b) 
- 
variable was updated to reflect new study design (integration of cohort 1b and 2b) 


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- 
intercurrent events were updated with conditions for the new subcohorts 1b and 2b 
 
Section 3: Study design 
- 
specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
- 
Description of the new subcohorts 1b and 2b were added 
- 
Figure 3-1 was adjusted to reflect new study design (one figure each for cohort 1a/2a 
and cohort 1b/2b) 
- 
Sentences were added to specify that remote phone calls 1 week, 2 weeks and 4 weeks 
after first ofatumumab dosing should be used to ensure that the application of the first 
ofatumumab doses are performed according to SmPC 
- 
Baseline visit in cohort 2 should be approx. one week before the first vaccination and 
not “at least” one week 
- 
Specification that “1 month” equivalates 4 weeks. 
- 
Description of run-in period and study period was updated and now describes procedure 
for all subcohorts 
- 
Typos were corrected 
 
Section 4.1: Rationale for study design 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 4.2: Rationale for dose/regimen and duration of treatment 
- 
Start of ofatumumab treatment for all subcohorts was specified 
 
Section 4.4: Purpose and timing of interim analyses/design adaptations 
- 
Section was adjusted to the new primary endpoint. 
- 
Additional interim analysis was added. 
 
Section 4.5: Risks and benefits 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
Section 4.5.1: Blood sample volume 
- 
Reference to new assessment tables was added 


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Section 5.1: Inclusion criteria 
- 
As ofatumumab SmPC is final, the expected date was deleted 
- 
SARS-CoV-2 vaccines (initial vaccination cycle and booster shots) should be done 
according to respective SmPC and local regulations 
 
Section 5.2: Exclusion criteria 
- 
Addition of new criterion that no previous non-modRNA SARS-CoV-2 vaccines are 
allowed 
 
Section 6.1: Study treatment 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 6.1.3: Treatment arms/group 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 6.3.2: Treatment assignment, randomization 
- 
Description of subcohorts was added 
 
Section 8: Visit schedule and assessments 
- 
Visit schedules for cohort 1b (Table 8-2) and cohort 2b (Table 8-4) were added 
- 
Visit schedules for cohort 1a (Table 8-1) and cohort 2a (Table 8-3) were updated to 
reflect new optional booster vaccine and a corresponding additional visit. 
 
Section 8.1: Screening 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 8.: Efficacy 
- 
Reference to assessment schedules was updated 
- 
“Pharmacodynamic samples” was replaced with “blood samples” 
 


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Protocol No. COMB157GDE01 
 
Section 8.3.1: Efficacy assessment 1 
- 
Text was updated to reflect new primary endpoint 
 
Section 8.3.2: Efficacy assessment 2 
- 
Complement of efficacy assessments, which have already been added by amendment 1 
- 
Endpoints of cohorts 1b and 2b were added to existing endpoints 
 
Section 8.3.3: Appropriateness of efficacy assessments 
- 
Text was adapted to reflect new primary endpoint 
 
Section 8.4: Laboratory evaluatins 
- 
Reference to assessment schedules was updated 
 
Section 9.1.1: Replacement policy 
- 
Patients with a confirmed COVID-19 disease after screening do not have to be excluded 
from the study and replaced. 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
- 
 
Section 9.1.2: Withdrawal of informed consent 
- 
Sentence was adjusted to reflect that after withdrawal of consent, patients can decide if 
their stored and not yet analyzed blood samples should be destroyed or can still be used 
by Novartis. 
 
Section 9.1.4: Early study termination by the sponsor  
- 
Typo was corrected 
 
Section 10.1.3: SAE Reporting 
- 
SAE follow-up information need to be submitted immediately, without undue delay, 
and under no circumstances later than within 24 hours of the investigator receiving the 
follow-up information 
 
Section 12.1: Analysis set 
- 
The efficacy analysis set was adapted to new visit schedule. 


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Section 12.2: Population demographics and other baseline characteristics 
- 
Update of cohorts to new study design 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 12.4: Analysis of the primary endpoint(s)/estimand(s) 
- 
Specification that SARS-CoV-2 vaccines can be the initial vaccination or a booster 
vaccine 
 
Section 12.4.1: Definitin of primary endpoint(s)/estimand(s) 
- 
Primary endpoint was adjusted to include patients from new cohorts (1b and 2b). In 
order to have comparable date between new and old cohorts, “one month” was chosen 
as best timepoint. 
 
Section 12.4.3: Handling of remaining intercurrent events of primary estimand 
- 
Addition of an intercurrent event in new cohorts 1b and 2b. 
 
Section 12.4.3: Supportive analyses 
- 
Addition of an sentence that patients receiving their initial vaccine vs. patients receiving 
booster vaccines will also be described separately. 
 
Section 12.7: Interim analysis 
- 
Definition of second interim analysis 
 
Table 2.1: Objectives 
- 
Typos were corrected 
 
Table 6-1 
- 
New cohorts were added to table 
 
 
Table 8.1/8.2/8.3/8.4: Treatment schedule 


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- 
Cohort 1a and cohort 2a: a new optional remote visit was added in case patients in this 
cohort receive booster vaccinations. In that case, an additional visit (A2) should be 
performed 1 month after the booster (including blood sampling) in order to assess the 
immune reaction towards booster vaccines. 
- 
Table 8.2 and 8.4 were added to describe treatment schedule for cohort 1b and cohort 
2b. Patients will follow a similar schedule as patients in cohort 1a and 2a. The main 
difference is that patients in cohort 1b and 2b receive booster vaccines instead of their 
initial SARS-CoV-2 vaccines. The immune response towards the booster will be 
measured 1, 6 and 12 months after the booster. 
- 
Footnotes were added to specify that remote phone calls 1 week, 2 weeks and 4 weeks 
after first ofatumumab dosing should be used to ensure that the application of the first 
ofatumumab doses are performed according to SmPC 
- 
Wording for timing of baseline visit in cohort 2 was specified: visit should be approx. 
one week before vaccination. 


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Amendment 1 
Amendment Summary: 
Main changes in this amendment include the inclusion of an additional interim analysis as well 
as prolongation of the study period in order to investigate sustainability of SARS-CoV-2 
vaccination induced immune reaction and reaction towards possible additional booster shots. 
 
 
Prolongation of study period: Maintenance of the immune response after SARS-CoV-2 
vaccination should be evaluated for at least 6 months after vaccination. As evidence grows for 
the possibility to sustained immunity beyond 6 months post-vaccination and a third booster shot 
for patients with immunocompromising treatments after 1 year is currently discussed in 
multiple countries, the investigational phase of this study should in total comprise 18 months 
after the initial vaccination cycle to ensure an at least 6-months follow-up after a possible 
booster vaccination. Patients in this study therefore will be specifically allowed to receive 
additional SARS-CoV-2 vaccines (either as additional booster or as yearly refresher) if 
suggested by local regulations and according to the physician's discretion. 
 
 
 
 
Interim analysis: An additional interim analysis will be performed once at least five patients 
have completed the primary endpoint or on September 1st 2021, whichever comes first, as proof 
of concept for the study. 
 
Changes to the protocol: 
Section 1.1: Background 
• Insertion of sentence that additional SARS-CoV-2 vaccines will be allowed within the 
study if suggested by local regulations. 
 
Section 3: Study design 
- 
Follow up phase will be replaced by extended study phase 
- 
Additional visits during study phase were added 
- 
Sentence was added that during the study, additional SARS-CoV-2 vaccines can be 
received according to physician’s discretion if suggested by local regulations 
 
Section 4.2: Rationale for dose/regimen and duration of treatment 
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- 
Description of vaccination was amended to specify that vaccines will be received 
according to respective SmPC or following local regulations provided e.g. by German 
health authorities and additional SARS-CoV-2 vaccines can be received if suggested by 
local regulations. 
 
Section 4.4: Interim analysis 
- 
An additional interim analysis was added as proof of concept for the study 
 
Section 4.5.1: Blood sample volume  
- 
Time frame in which blood samples are collected was adapted from 9 to 23 months due 
to extension of study phase 
 
Section 5: Study population 
- 
Wording was updated due to addition of an earlier interim analysis 
 
Section 8.3.1: Efficacy assessment 2 
- 
The cell surface marker CD45R0 for immunophenotyping of SARS-CoV-2 reactive T-
cells was replaced with CD27 
 
Section 8.4: Safety 
- 
Vital signs were added to the description of a full physical exam 
 
Section 8.4.1: Laboratory assessments 
- 
Paragraph about central laboratory was added 
- 
ELISpot assays will be performed for IFN-γ and IL-2  
- 
Inclusion of standard hematology tests 
- 
Inclusion of B-cell count 
 
Section 9.1.1.1: Replacement policy 
- 
Vaccination was specified as mRNA vaccination 
- 
Only patients with confirmed COVID-19 disease should be excluded and replaced 
 
Section 10.1.1: Adverse events 


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- 
Adverse event monitoring should continue until 30 days after the last dose of study 
treatment  
 
Section 10.1.3: SAE Reporting 
- 
Specification that MS relapses will be reported in the MS relapse eCRF instead of SAE 
forms unless they are unusually severe or unexpected. 
 
Section 12.1: Analysis sets 
- 
Sentence was deleted because a more detailed description is given in the following 
paragraph. 
 
Section 12.5.1: Safety endpoints 
- 
Treatment period was specified to last from first intake of study medication to 30 days 
after the last study visit. 
 
Section 12.7: Interim analysis 
- 
An additional interim analysis was added 
 
 
Figure 3-1 Study design 
- 
Figure was adapted to new study design with 18-months study phase 
- 
Vaccination will be given according to respective SmPC or local regulations provided 
e.g. by German health authorities 
 
 
 
Table 6-1: Study drug 
- 
admin. route of mRNA vaccines was changed to i.m. 
 
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Table 8-1 and Table 8-2: 
- 
For cohort 2, no blood analysis will be necessary at screening. Reference values for 
cellular and humoral immune responses will be measured at Baseline (visit 4). 
- 
Two additional on site visits were added per cohort including blood sampling. 
- 
Status of MS- and concomitant medication should be assessed at all onsite and remote 
visits 
- 
A more detailed description of blood testing was included: standard hematology test and 
B-cell count 
- 
Note was added to specify that MS relapses within the last two years should be recorded 
- 
Note was added to amend that vaccination will be given according to respective SmPC 
or local regulations provided e.g. by German health authorities 
 
 
 


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Protocol No. COMB157GDE01 
 
Protocol summary 
 
Protocol 
number 
COMB157GDE01 
Full Title 
Tracking the immune response to SARS-CoV-2 modRNA vaccines in an open-
label multicenter study in participants with relapsing multiple sclerosis treated 
with ofatumumab s.c. (KYRIOS) 
Brief title 
Study to assess SARS-CoV-2 vaccination response in ofatumumab treated RMS 
patients  
Sponsor and 
Clinical Phase 
Novartis / clinical phase IV 
Investigation 
type 
Drug (Ofatumumab (OMB157)) 
Study type 
Low-intervention, 2 cohorts 
Purpose and 
rationale 
A major concern about B-cell depleting therapies in the context of vaccination is 
the potentially reduced immune response to vaccines. It has, however, been 
shown for the recently approved SARS-CoV-2 mRNA vaccines that they do not 
only induce a B-cell but also a functional T-cell response. For this purpose, we 
evaluate the proportion of patients that elicit humoral and specific T-cell 
responses upon vaccination with modRNA vaccines in patients receiving 
vaccination before initiation of ofatumumab treatment or at least 4 weeks after 
commencing ofatumumab treatment. The study will further follow the 
development of these immune responses for six months after vaccination.    
Primary 
Objective(s)  
To estimate the proportion of RMS patients having established SARS-CoV-2-
specific T cells after receiving a modRNA vaccine (initial vaccination cycle or 
booster vaccine) either before or after starting ofatumumab treatment.  
Secondary 
Objectives 
• 
To estimate the proportion of RMS patients maintaining for up to 6 months 
SARS-CoV-2-specific T cells after receiving a modRNA vaccine either before 
or after starting ofatumumab treatment.  
• 
To estimate the proportion of RMS patients achieving seroconversion (i.e. 
having SARS-CoV-2 serum neutralizing antibodies) after receiving a modRNA 
vaccine either before or after starting ofatumumab treatment.  
• 
To estimate the proportion of RMS patients maintaining for up to 6 months 
quantifiable levels of SARS-CoV-2 serum functional antibodies after receiving 
a modRNA vaccine either before or after starting ofatumumab treatment.  
• 
Describing phenotypically the cellular response after receiving a modRNA 
vaccine either before or after starting ofatumumab treatment. 
• 
Describing safety and tolerability, incl. patients developing coronavirus 
disease 2019 (COVID-19) 
• 
To estimate the proportion of RMS patients with quantifiable SARS-CoV-2-
specific T cells and functional antibodies after receiving an additional dose of 
modRNA vaccine (booster vaccine) 
Study design 
This is a two cohort, multicenter, open-label, prospective study of 40 (optionally up 
to 60) RMS patients. 


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Protocol No. COMB157GDE01 
 
• 
The first cohort will be RMS patients receiving modRNA vaccine as part of 
clinical routine prior to starting ofatumumab treatment.  
• 
The second cohort will be participants receiving modRNA vaccine as part of 
clinical routine while already stable on ofatumumab treatment for at least 4 
weeks (since first dose). 
Ofatumumab treatment initiation and maintenance will be performed as per 
approved SmPC. SARS-CoV-2 mRNA vaccination will be performed as part of 
clinical routine. 
Study 
population 
The study population will consist of females and males with relapsing MS. 
Key Inclusion 
criteria 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Patients eligible to start ofatumumab as per physician’s discretion and 
approved SmPC (exp. April, 2021; for cohort 2, patients may already be on 
ofatumumab, but most patients will start ofatumumab as part of this study). 
3. Patients willing and eligible to receive a modRNA vaccine against SARS-
CoV-2 as part of clinical routine 
Key Exclusion 
criteria 
1. History of known COVID-19 infection (assessed based on patient statements 
and/or medical history) or current COVID-19 symptoms 
2. Patients who previously received a BTK inhibitor or an antiCD20 therapy other 
than ofatumumab 
3. Patients likely not being able or willing to complete the study  
4. Use of other investigational drugs within 5 half-lives of enrollment/initiation of 
study treatment (e.g. small molecules) or until the expected 
pharmacodynamic effect has returned to baseline (e.g. biologics), whichever 
is longer 
5. Patients with any medical or psychological condition that, in the investigators 
opinion, renders the patient unable to understand the nature, scope, and 
possible consequences of the study 
6. No person directly associated with the administration of the study is allowed 
to participate as a study subject  
7. No family member of the investigational study staff is allowed to participate in 
this study 
8. No previous vaccination with a non-modRNA SARS-CoV-2 vaccine. 
Study 
treatment 
• 
Cohort 1: RNA vaccine will be received as part of clinical routine before 
starting Ofatumumab (OMB157) treatment 
o 
Cohort 1a: will receive their 1st and 2nd SARS-CoV-2 vaccines (and an 
optional booster vaccine) 
o 
Cohort 1b: will receive a booster vaccine 
• 
Cohort 2: RNA vaccine will be received as part of clinical routine while 
already stable on Ofatumumab (OMB157) treatment 
o 
Cohort 2a: will receive their 1st and 2nd SARS-CoV-2 vaccines (and 
an optional booster vaccine) 
o 
Cohort 2b: will receive a booster vaccine 


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Treatment of 
interest 
Ofatumumab (OMB157) / SARS-CoV-2 modRNA vaccine 
Efficacy 
assessments 
• 
Detection of SARS-CoV-2 specific T-cells  
• 
Detection of SARS-CoV-2 serum functional antibodies  
Key safety 
assessments 
Patients developing COVID-19 
Data analysis 
The primary analysis will not use any statistical testing or modelling. The 
absolute numbers and the proportion of participants achieving seroconversion 
within each cohort will be calculated. It will be augmented by a (descriptive) 95% 
confidence interval (exact Clopper-Pearson). All secondary endpoints will be 
summarized descriptively as frequencies and percentages, or, for continuous 
data, mean, standard deviation, median, minimum, and maximum will be 
presented. 
Key words 
COVID-19, SARS-CoV-2, RNA vaccine, ofatumumab, relapsing remitting 
multiple sclerosis, SARS-CoV-2 booster 


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1 
Introduction 
1.1 
Background 
Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread around the world and 
become a global pandemic. COVID-19 affects the health and social and economic life of 
millions of people. Especially the elderly and persons with preexisting conditions (e.g. asthma, 
diabetes, and heart disease) have an increased risk of a severe and potentially lethal course of 
the disease. With the nucleoside-modified RNA (modRNA) vaccine BNT162b2 (BioNTech 
SE/Pfizer), the first vaccine gained market authorization (e.g. in the UK, US, and EU) (Polack, 
Thomas et al. 2020). Similarly, mRNA-1273 (Moderna) has gained regulatory approval as 
SARS-CoV-2 vaccine, e.g. in UK, US, and EU. Most recently, Astra Zeneca’s vaccine received 
approval in the UK. More approvals for these and other vaccines around the world are expected 
for 2021.     
Multiple sclerosis (MS) is an autoimmune disease which causes demyelinisation and neuronal 
damage in the central nervous system. Worldwide, approximately 2.5 million people are 
affected by MS, most patients presenting with relapsing forms (RMS).  
Between 2016 and 2019, two phase III clinical trials (ASCLEPIOS I & II) showed that monthly 
subcutaneous injections of ofatumumab can reduce the annual relapse rate and probability of 
confirmed disability progression compared to teriflunomide (Hauser, Bar-Or et al. 2020). 
Ofatumumab is a fully human anti-CD20 monoclonal antibody that selectively depletes CD20+ 
B- and T-cells, which prevent migration to the CNS and the formation of inflammatory lesions. 
Since August 2020, ofatumumab (Kesimpta) is available as treatment for RMS patients in the 
US and EMA approval is expected by Q2 2021. 
A major concern about B-cell depleting therapies in the context of vaccination is the potentially 
reduced immune response to vaccines as seen e.g. in the VELOCE trial assessing the immune 
response in patients treated with the anti-CD20 monoclonal antibody ocrelizumab (Bar-Or, 
Calkwood et al. 2020). However, the average serum IgG levels in the ASCLEPIOS I and II 
trials remained well within the reference range over time and no association was observed 
between a decrease in immunoglobulin levels and the incidence of serious/non-serious 
infections in ofatumumab-treated patients (Wiendl 2020).  
Although B-cells have been assumed to be the major drivers for establishment of immunity 
after vaccination, it has recently been shown that T-cells might be equally important for 
vaccine-induced immunity especially against intracellular infections like viruses (Ahmed and 
Akondy 2011). It has been observed for previous coronavirus-caused disease that T-cell 
responses were better markers for prior coronavirus infections than antibodies as some COVID-
19 patients (especially with mild disease) don’t undergo seroconversion and T-cell responses 
can be detected for a longer time period (Hellerstein 2020). Immunological memory to SARS-
CoV-2 has been recently demonstrated for 8 months post infection (Dan, Mateus et al. 2021). 
Concomitant with these findings, it has been shown that 100% of all COVID-19 patients 
showed specific CD4+ and 70% showed specific CD8+ T-cell responses (Grifoni, Weiskopf et 
al. 2020). Furthermore, it was observed that upon contact with a confirmed COVID-19 patient, 
multiple persons developed disease symptoms and a T-cell mediated response without 


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seroconversion suggesting the importance of T-cell activation even in the absence of SARS-
CoV-2 neutralizing antibodies (Gallais, Velay et al. 2020). 
When looking into the immune responses after vaccination with the two newly approved 
modRNA vaccines it was shown that both, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 
(Moderna), not only induced an antibody-response against the SARS-CoV-2 spike protein but 
also functional CD4+ and CD8+ T-cell responses (Jackson, Anderson et al. 2020, Sahin, Muik 
et al. 2020).  
Especially in the context of ofatumumab treatment and the imminent B-cell depletion, the 
activation of CD4+ and CD8+ T-cells plays an even more important role for the development of 
vaccine-induced immunity. It is therefore essential to understand the impact of concomitant 
ofatumumab treatment on 
1) the cellular response, investigating the development of CD4+ and CD8+ T cell responses 
against the SARS-CoV-2 spike protein, which is necessary for infection of the target 
cell (Huang, Yang et al. 2020), and  
2) the humoral immune response, investigating SARS-CoV-2 serum neutralizing antibody 
levels. 
In recent publications describing SARS-COV-2 mRNA vaccines, functional T-cell responses 
were defined as interferon γ (IFNγ) secretion by T-cells measured by enzyme-linked immuno 
spot (ELISpot) assay after in vitro stimulation with a peptide mix resembling the SARS-CoV-
2 spike protein (Jackson, Anderson et al. 2020, Sahin, Muik et al. 2020). In this study, we will 
perform ELISpot assays followed by detailed immunophenotyping to further characterize the 
developed T-cell response. Furthermore, we will test for functional antibodies, i.e. antibodies 
that inhibit the binding of the viral spike protein to the human angiotensin-converting enzyme 
2 (ACE2) receptor, which is the first and necessarily required step during SARS-CoV-2 
infection (Yang et al, 2020). The detection of SARS-CoV-2 serum functional antibodies after 
vaccination in patients negative for this parameter at baseline is defined as seroconversion 
according to World Health Organization guidelines (WHO guideline, 2020).  
In this study, immune response to SARS-CoV-2 mRNA vaccines will be analyzed in patients 
receiving the vaccine before starting ofatumumab treatment (cohort 1) or during stable 
ofatumumab treatment (cohort 2).  
If suggested by local regulations, patients will be allowed to receive additional SARS-CoV-2 
vaccines (either as additional booster or yearly refresher) during the study according to the 
physician’s discretion and as part of the clinical routine. 
Data gathered within AMA-VACC (CBAF312ADE03) will serve to describe differences to 
other DMTs. In AMA-VACC, humoral and cellular immune response is assessed at identical 
timepoints as within this study in MS patients treated with siponimod, platform therapies 
(i.e. interferons, glatiramer acetate, teriflunomide, dimethyl fumarate), or currently without 
DMT.   
 


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1.2 
Purpose 
 
B-cell depleting therapies have in the past been shown to impair the immune response to 
conventional vaccines. The objective of this study is to assess whether participants treated with 
monthly s.c. injections of ofatumumab (20 mg) can mount an adequate immune response to the 
new class of SARS-CoV-2 modRNA vaccines (initial or booster) as measured by humoral and 
cellular responses. The study will further investigate the maintenance of SARS-CoV-2 specific 
responses for up to 18 months after the initial vaccination. 
 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
To estimate the proportion of RMS patients 
having established SARS-CoV-2-specific T 
cells after receiving a modRNA vaccine 
(initial vaccination or booster) either before or 
after starting ofatumumab treatment.  
 
Endpoint(s) for primary objective(s)  
• 
Proportion 
of 
RMS 
patients 
having 
established SARS-CoV-2-specific T cells as 
defined by detection of SARS-CoV-2 reactive 
T-cells, measured by e.g. enzyme-linked 
immunosorbent spot (ELIspot) assay from T-
cells that were stimulated with SARS-CoV-2 
peptide mix, either one month after second 
dose of vaccine or one month after booster 
vaccine in participants who received the 
respective vaccine before or after starting 
ofatumumab treatment (yes/no)  
 
Secondary Objective(s) 
• 
To estimate the proportion of RMS patients 
maintaining for up to 18 months SARS-CoV-
2-specific T cells after receiving a modRNA 
vaccine either before or after starting 
ofatumumab treatment.  
 
Endpoint(s) for secondary objective(s) 
• 
Proportion of RMS patients with detectable 
SARS-CoV-2 reactive T-cells one week, 6, 
12 and 18 months after second dose of 
vaccine or 6 and 12 months after booster 
vaccine in participants who received the 
vaccine before or after starting ofatumumab 
treatment (yes/no)  
• 
To estimate the increase in specific T-cells 
after receiving a modRNA booster vaccine 
either before or after starting ofatumumab 
treatment. 
• 
Fold change of SARS-CoV-2 specific T-cell 
levels one week, 1 month, 6 months, 12 
months and 18 months after the second dose 
of vaccine or 1 months, 6 months and 18 
months after a booster vaccine compared to 
the last timepoint before the respective 
vaccine 


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Objective(s) 
Endpoint(s) 
• 
To estimate the proportion of RMS patients 
achieving seroconversion (i.e. having SARS-
CoV-2 serum neutralizing antibodies) after 
receiving a modRNA vaccine either before or 
after starting ofatumumab treatment.  
• 
Proportion 
of 
RMS 
patients 
achieving 
seroconversion (i.e. having SARS-CoV-2 
serum neutralizing antibodies) after receiving 
a modRNA vaccine either before or after 
starting ofatumumab treatment (yes/no) 
• 
To estimate the proportion of RMS patients 
maintaining for up to 18 months quantifiable 
levels of SARS-CoV-2 serum functional 
antibodies after receiving a modRNA vaccine 
either before or after starting ofatumumab 
treatment.  
• 
Proportion of RMS patients with quantifiable 
levels of SARS-CoV-2 serum functional 
antibodies one week, 1, 6, 12 and 18  months 
after receiving the second dose of modRNA 
vaccine or 1, 6 and 12 months after a booster 
shot 
either 
before 
or 
after 
starting 
ofatumumab treatment (yes/no) 
 
• 
Describing 
phenotypically 
the 
cellular 
response after receiving a modRNA vaccine 
either before or after starting ofatumumab 
treatment. 
• 
Phenotypical characterization of peripheral 
blood mononuclear cells for CD45, CD3, 
CD4, CD8, CD62l, CD45RA, CD45R0, CCR7 
• 
Immunophenotyping 
for 
naive, 
central 
memory, effector memory, and effector cells 
on CD4+ and CD8+ cells 
• 
Measuring cells positive for intracellular 
cytokine-staining for interferon-gamma and 
interleukin-4 
• 
Describing safety and tolerability, incl. 
patients developing coronavirus disease 
2019 (COVID-19) 
• 
AEs, SAEs, incl. patients with clinical 
confirmed COVID-19  
 
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Objective(s) 
Endpoint(s) 
 
2.1 
Primary estimands 
The primary clinical question of interest is: What is the proportion of RMS patients having 
developed a specific immune response after receiving a SARS-CoV-2 mRNA vaccine (initial 
vaccination or booster vaccine) either before or after starting ofatumumab treatment. 
The justification for the primary estimand is that it will capture whether ofatumumab-treated 
patients will mount a specific T-cell response after receiving a SARS-CoV-2 mRNA vaccine 
assessed by enzyme-linked immunosorbent spot (ELISpot) assays from T-cells that were 
stimulated with SARS-CoV-2 peptide mix. 
Patients will receive either their initial vaccination (1st and 2nd SARS-CoV-2 vaccines) or a 
booster vaccine before or after starting ofatumumab treatment. In both cases we want to assess 
if ofatumumab initiation negatively affects or prevents the immune response. 
Since this is not a randomized trial, no randomization needs to be preserved and the ITT-
principle and the associated estimands framework do not apply. However, this protocol will 
keep as close as appropriate to the terminology and the definitions established within that 
framework. 
 
The primary estimand is described by the following attributes: 
1. Population: Patients with relapsing MS (RMS) divided in two cohorts, each receiving a 
SARS-CoV-2 mRNA vaccine as part of clinical routine: (1) vaccination before start of 
ofatumumab treatment, (2) vaccination after having been on stable ofatumumab treatment 
for at least 4 weeks. The SARS-CoV-2 mRNA vaccine can be either the initial vaccination 
cycle (for patient that are exposed to the vaccine for the first time; cohort 1a and cohort 
2a) or a booster vaccination (for patients that have already completed the initial 
vaccination cycle; cohort 1b and cohort 2b). Patients in cohort 1a or 2a who fail to receive 
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their second dose of vaccine for whatever reason will be included in the analysis as non-
responders. Patients in cohort 1a and 2a who did receive their second dose of vaccine and 
patients in cohort 1b and 2b who received their booster shot and do not have a valid 
determination of specific T-cell response to SARS-CoV-2 for whatever reason will be 
excluded from the analysis of vaccine efficacy. 
2. Variable: Receiving the second dose of mRNA vaccine (for cohort 1a and 2a) or a booster 
vaccination (cohort 1b and 2b) and mounting a specific T cell response one month after 
second dose of vaccine (cohort 1a and 2a) or booster vaccine (cohort 1b and 2b) defined by 
detection of SARS-CoV-2 specific T-cells by ELISpot assays after stimulation of T-cells 
with SARS-CoV-2 peptide mix (yes/no) 
3. Treatment of interest: ofatumumab treatment, which is started either before or after 
receiving a SARS-CoV-2 mRNA vaccine (initial vaccination cycle or booster vaccine) 
4. Intercurrent events:  
a. Vaccination with a non-mRNA vaccine: patients will be excluded from the study 
b. Failure to receive the second dose of vaccine (for cohort 1a and 2a): patients will be 
classified as non-responders 
c. Failure to initiate ofatumumab treatment within six weeks after completion of the 
vaccination cycle (cohort 1a) or of the booster vaccine (cohort 1b): patients will be 
excluded from the efficacy analyses 
d. Failure to complete ofatumumab initiation or interruption of ofatumumab treatment 
prior to first vaccination (cohort 2a) or prior to booster vaccination (cohort 2b): 
patents will be excluded from the study 
e. No valid detection of SARS-CoV-2 specific T-cells: patients will be excluded from 
the efficacy analyses if they received their second dose of vaccine (cohort 1a and 
2a) or booster vaccine (cohort 1b and 2b) and further analyses will be performed to 
confirm methodical reasons 
5. Summary measure: n.a., there will be no formal comparison between cohorts. Response 
rates will only be calculated within each cohort. 
 
 
2.2 
Secondary estimands 
Not applicable 
 
3 
Study design 
This is a two cohort, multicenter, open-label, prospective study of 20 RMS patients per 
treatment arm (optional increase to 30 depending on results of interim analysis) willing to start 
ofatumumab treatment and receive SARS-CoV-2 modRNA vaccination (initial vaccination or 
booster vaccine) as part of clinical routine. 


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• The first cohort will be RMS patients receiving modRNA vaccine as part of clinical 
routine prior to starting ofatumumab treatment. 
o Cohort 1a will receive their initial SARS-CoV-2 mRNA vaccines (vaccination 
1 and vaccination 2) before starting ofatumumab treatment  
o Cohort 1b will receive a booster vaccination before starting ofatumumab 
treatment 
 
• The second cohort will be participants receiving modRNA vaccine as part of clinical 
routine while already stable on ofatumumab treatment for at least 4 weeks (since first 
dose).  
o Cohort 2a will receive their initial SARS-CoV-2 mRNA vaccines (vaccination 
1 and vaccination 2) while being on stable ofatumumab treatment  
o Cohort 2b will receive a booster vaccination while being on stable ofatumumab 
treatment 
 
Initiation and maintenance of ofatumumab treatment in this study will be performed according 
to the approved SmPC. Especially for cohort 1, possible effects of the previous MS treatment 
on vaccination efficacy should be kept in mind when scheduling SARS-CoV-2 vaccination. The 
interventional part of KYRIOS is limited to the collection of blood samples at specified time-
points to analyze development of SARS-CoV-2 specific T-cells and neutralizing antibodies as 
response to the modRNA vaccination in clinical routine. 
 
Figure 3-1 
Study design 
Cohort 1a and cohort 2a: 


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PEP: primary endpoint; Vacc.= vaccination with modRNA vaccine;  
# Vaccination as part of clinical routine; required number of vaccinations and interval depends on SmPC 
of respective modRNA vaccines or local regulations provided e.g. by German health authorities. 
## Booster vaccination as part of clinical routine e.g. if suggested by German health authorities and at 
the physician’s discretion.  
* Ofatumumab treatment has to be initiated at least 4 weeks before Vacc.1,  
** Ofatumumab initiation doses can be omitted if patient already receives ofatumumab at the time of 
screening 
***Booster vaccination is optional can be performed any time after vacc.2. If a booster vaccination is 
given, an additional unscheduled visit should be performed 1 month after the booster vaccination in 
order to assess the immune reaction. If this unscheduled visit would be within 2 weeks of the next 
scheduled visit, the next scheduled visit can be omitted. This only applies for the first and second booster, 
there won’t be any additional visits for potential following boosters. 
 
Cohort 1b and cohort 2b: 
 


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PEP: primary endpoint; Vacc.= vaccination with modRNA vaccine;  
# Vaccination as part of clinical routine and before the study; required number of vaccinations and 
interval depends on SmPC of respective modRNA vaccines or local regulations provided e.g. by German 
health authorities. 
## First booster vaccination as part of clinical routine according to SmPC of respective vaccine or local 
regulations, e.g. German health authorities. Additional boosters can be performed any time during the 
study. 
* Screening can be performed any time after completion of the initial vaccination cycle (vacc.2). For 
cohort 2b, ofatumumab treatment has to be initiated at or after screening but at least 4 weeks before 
booster vaccination  
** Ofatumumab initiation doses can be omitted if patient already receives ofatumumab at the time of 
screening 
*** Additional booster vaccination is optional can be performed any time after the first booster. If a 
second booster vaccination is given, an unscheduled visit should be performed 1 month after the second 
booster vaccination in order to assess the immune reaction. If this unscheduled visit would be within 2 
weeks of the next scheduled visit, the next scheduled visit can be omitted. This only applies for the 
second booster, there won’t be any additional visits for potential following boosters. 
 
 
The study consists of 2 periods: run-in period and study period.  
 
The run-in period comprises the time from screening to vaccination, including the baseline 
visit (approx. one week before the first vaccination). Patient eligibility will be determined based 
on the screening and baseline assessments.  


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• For cohort 1a, screening and baseline can be performed on the same day, and have to be 
performed before the first vaccination. Possible effects of the previous MS treatment on 
vaccination efficacy should be kept in mind when scheduling SARS-CoV-2 vaccination. 
For cohort 1b, screening and baseline can be performed any time after completion of the 
initial vaccination cycle and should be approx. 1 week before the first SARS-CoV-2 
booster vaccine. Possible effects of the previous MS treatment on booster vaccine 
efficacy should be kept in mind when scheduling SARS-CoV-2 booster vaccination. 
 
• For cohort 2a and 2b, the run-in period includes initiation of ofatumumab treatment as 
per approved SmPC and lasts for at least 4 weeks after the first ofatumumab dosing. For 
cohort 2a and 2b, additional visits during the run-in period will be necessary: one visit 
to start ofatumumab treatment (can be performed at screening), three remote visits (e.g. 
phone calls) 1, 2 and 4 weeks after the first ofatumumab dose to ensure the application 
of the first ofatumumab doses according to SmPC, and the baseline visit approx. 1 week  
o before the first vaccine (cohort 2a). 
o before the first booster vaccination (cohort 2b)  
Patients that have already been on stable ofatumumab treatment for at least 4 weeks 
before the screening visit will follow the run-in period assessment schedule for cohort 
1: no additional visits except screening/baseline will be needed. Assessments during the 
study period will be performed as defined for cohort 2.   
 
 
The study period starts for cohorts 1a and 2a with the first SARS-CoV-2 modRNA vaccination 
and ends 18 months after the second vaccination (EOS). All patients will return to the study site 
1 week, 1 month, 3 months, 6 months, 12 months and 18 months after the second vaccination 
for study visits. During the study, patients are allowed to receive additional SARS-CoV-2 
vaccines (as booster shot or yearly refresher) if suggested by local regulations and as per 
physician’s discretion.  
For cohorts 1b and 2b, the study period starts with the first booster vaccination and patients will 
return to the study site 1 month (equivalates 4 weeks), 3 months, 6 months and 12 months (EOS) 
after the booster vaccine. 
• For cohort 1a, ofatumumab treatment will be initiated as per approved SmPC during 
visit 2 (4 weeks after receiving the second SARS-CoV-2 modRNA vaccine). 
Ofatumumab treatment can be started earlier if medically indicated but at the earliest 
two weeks after the second mRNA vaccine. If ofatumumab treatment can’t be started 4 
weeks after the second vaccine, the Novartis Medical Advisor should be contacted to 
discuss further proceeding.  
• For cohort 1b, ofatumumab treatment will be initiated as per approved SmPC during 
visit 1 (4 weeks after receiving the first SARS-CoV-2 modRNA booster vaccine). 
Ofatumumab treatment can be started earlier if medically indicated but at the earliest 


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two weeks after the booster vaccine. If ofatumumab treatment can’t be started 4 weeks 
after the booster vaccine, the Novartis Medical Advisor should be contacted to discuss 
further proceeding.  
Cohort 1a and 1b will have three additional remote visits (e.g. phone contact) 1 week, 2 
weeks and 4 weeks after the initial ofatumumab dosing in order to ensure application of 
the first ofatumumab doses according to SmPC.  
• Cohort 2a will receive both initial vaccinations while continuing on stable ofatumumab 
treatment.  
• Cohort 2b will receive first booster vaccination while continuing on stable ofatumumab 
treatment. 
 
 
4 
Rationale 
4.1 
Rationale for study design 
 
A two-cohort, multicenter, open-label, prospective design has been selected to generate data in 
a timely manner in order to provide a guidance for physicians and patients on the timing of 
initial and booster SARS-CoV-2 vaccination and the start of ofatumumab treatment in RMS 
patients. The study will assess two main questions: 
a) Can patients mount an immune response towards SARS-CoV-2 modRNA vaccines 
(initial vaccination or booster) when starting ofatumumab treatment after vaccination? 
b) Can patients mount an immune response towards SARS-CoV-2 modRNA vaccines 
(initial vaccination or booster) when receiving the vaccination while on stable 
ofatumumab treatment (for at least 4 weeks after the first ofatumumab dosing)? 
A non-randomized design has been chosen to enable feasible recruitment as the patient’s wish 
as well as the physician’s discretion have to be taken into consideration when deciding on the 
timing of the vaccine and start of ofatumumab treatment. 
 
Rationale for study population 
Initiation and maintenance of ofatumumab treatment in this study will be performed as per 
approved SmPC. No inclusion/ exclusion criteria regarding age or disease severity were 
implemented in this study in order to reflect the clinical routine of ofatumumab patients in 
Germany as closely as possible. Therefore, all patients eligible for ofatumumab treatment and 
a SARS-CoV-2 modRNA vaccine may be suitable for KYRIOS as long as all other 
inclusion/exclusion criteria are met. In order to assess whether ofatumumab patients can mount 
an immune response after vaccination, patients with previous known COVID-19 disease will 
be excluded from the study. 


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Rationale for chosen endpoints 
Recent publications about the immune responses after vaccination with the new SARS-CoV-2 
modRNA vaccines show that both, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 
(Moderna), not only induced an antibody-response against the SARS-CoV-2 spike protein but 
also functional CD4+ and CD8+ T-cell responses (Jackson, Anderson et al. 2020, Sahin, Muik 
et al. 2020).  
Especially in the context of ofatumumab treatment and the imminent B-cell depletion, the 
activation of CD4+ and CD8+ T-cells plays a very important role for the development of 
vaccine-induced immunity. The primary endpoint in this study was therefore chosen in analogy 
to the recently completed trials and in-depth analyses of the modRNA vaccines BNT162b2 
(ClinicalTrials.gov Identifier: NCT04368728, (Sahin, Muik et al. 2020, Walsh, Frenck et al. 
2020)) and mRNA-1273 (ClinicalTrials.gov Identifier: NCT04283461, (Jackson, Anderson et 
al. 2020)).   
 
 
4.2 
Rationale for dose/regimen and duration of treatment 
Ofatumumab 
All patients in this study will be treated with ofatumumab (20 mg s.c.) according to approved 
SmPC to be as close to the clinical routine as possible. Cohort 1 will start ofatumumab treatment 
four weeks after the second SARS-CoV-2 modRNA vaccination (1a) or four weeks after SARS-
CoV-2 booster vaccination (1b), cohort 2 will already have been on stable ofatumumab 
treatment at the start of the study or will start ofatumumab treatment at least 4 weeks before the 
first vaccination (2a) or before booster vaccination (2b) and will remain on stable treatment 
until completion of the study. 
Vaccination 
In this study, patients will receive a modRNA vaccine at the discretion of the treating physician 
as part of the clinical routine and according to the respective SmPC or local regulations provided 
e.g. by German health authorities. If suggested by local regulations, patients are allowed to 
receive additional SARS-CoV-2 vaccines (as booster or yearly refresher) as per physician’s 
discretion. 
 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
 


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4.4 
Purpose and timing of interim analyses/design adaptations 
The first interim analysis is planned when at least five patients per cohort have completed the 
study visit one week after the second SARS-CoV-2 modRNA vaccination or on September 1st 
2021, whichever comes first. The data gathered at this time point will be examined as a 
preliminary evaluation of proof of concept.  
The second interim analysis is planned when at least 10 patients that were vaccinated during 
stable ofatumumab-treatment have passed the primary endpoint, 1 month after the 2nd 
vaccination or after booster or on January 10th 2022, whichever comes first. The data gathered 
at this time point will be examined as a preliminary evaluation of proof of concept for the new 
study design. 
An additional interim analysis is planned after all participants have completed the study visit 1 
month after the second SARS-CoV-2 modRNA vaccination or one month after the booster 
vaccine, respectively. The data gathered at this time point will be the basis for the primary 
endpoint of this study. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study including an increase in participants (from 40 to 60), the sponsor’s clinical 
development projects in general, or in case of any safety concerns. 
Additional information is presented in the interim analysis section. 
 
4.5 
Risks and benefits 
This study does not interfere with clinical routine treatment of MS patients with ofatumumab 
or SARS-CoV-2 vaccinations. The only intervention is the blood sampling at specific time-
points in the course of this trial. 
As blood draw is also regularly performed in the clinical routine, the procedure of additional 
drawings of blood (venous puncture) within this study for antibody- and T-cell response 
measurements only bear minimal risk for the patient.  
Participation in this study might delay initiation of ofatumumab treatment (for patients in cohort 
1) or SARS-CoV-2 vaccination (for patients in cohort 2). Duration of the delay depends on 
multiple parameters:  
• 
For cohort 1, the delay of ofatumumab initiation depends on a) time between screening 
and appointment for vaccination (1-12 weeks), b) type of vaccination and resulting 
interval between vaccination one and two (e.g. 3 weeks for BioNTech/Pfizer or 4 weeks 
for Moderna) and c) on the physician’s discretion on how long to wait between last 
vaccination and ofatumumab initiation (2-4 weeks). In total, the delay will be a 
minimum of six weeks.  
• 
For cohort 2, the delay of SARS-CoV-2 vaccination will be 4-12 weeks after 
screening/ofatumumab initiation depending on the physician’s discretion.    
The overall risks associated with this study are therefore comparable to those in usual clinical 
practice. Patients will most likely not have a direct benefit from participating in this study except 


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receiving information about whether SARS-CoV-2 specific antibodies and T-cells can be 
detected after vaccination.  
The results of this study will, however, contribute to a better understanding of the immune 
responses to modRNA vaccines (initial vaccination and booster) in ofatumumab treated RMS 
patients. Findings may also provide guidance for the timing of modRNA vaccines and the start 
of ofatumumab treatment and inform patients and physicians if risk management might be 
needed. 
 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of up 
to 23 months, from each participant as part of the study. Additional samples may be required 
for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1, 8-2, 8-
3 and Table 8-4). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual. 
Blood samples will be stored until the end of the study in case measurements need to be repeated 
or confirmed. 
 
 
5 
Study Population 
The study population will consist of 40 female and male RMS patients that are planned to be 
treated in clinical routine with Ofatumumab as per approved SmPC. There is an optional 
increase to 60 patients after the interim analyses.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Patients eligible to start ofatumumab as per physician’s discretion and approved SmPC (for 
cohort 2, patients may already be on ofatumumab, but most patients will start 
ofatumumab as part of this study). 
3. Patients willing and eligible to receive a modRNA (according to respective SmPC and local 
regulations) vaccine against SARS-CoV-2 (initial vaccination cycle or booster shot) as 
part of clinical routine.  
 


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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. History of known COVID-19 infection (assessed based on patient statement and/or medical 
history) or current COVID-19 symptoms. 
2. Participants who previously received a BTK inhibitor or an antiCD20 therapy other than 
ofatumumab 
3. Patients likely not being able or willing to complete the study.  
4. Use of other investigational drugs within 5 half-lives of enrollment/initiation of study 
treatment (e.g. small molecules) or until the expected pharmacodynamic effect has 
returned to baseline (e.g. biologics), whichever is longer 
5. Patients with any medical or psychological condition that, in the investigators opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of 
the study 
6. No person directly associated with the administration of the study is allowed to participate 
as a study subject  
7. No family member of the investigational study staff is allowed to participate in this study 
8. No previous vaccination with a non-modRNA SARS-CoV-2 vaccine. 
 
6 
Treatment 
6.1 
Study treatment 
The SARS-CoV-2 modRNA vaccine (initial vaccination or booster) will be received as part of 
clinical routine. Ofatumumab initiation and treatment in this study will be performed as per 
approved SmPC to resemble clinical routine as closely as possible.  
6.1.1 
Investigational and control drugs 
Table 6-1 merely serves as overview on the different treatments investigated in individual 
cohorts. This is not a guidance for treatment as all treatments are performed as part of clinical 
routine. 
Table 6-1 
Investigational and control drug 
Treatment 
Arm 
Type of Study 
Drug 
Compound 
Min Dose 
Max Dose 
Frequency 
Admin. Route 
Cohort 1a, 1b, 
2a and 2b 
investigational 
modRNA 
Clinical routine 
Clinical routine 
Clinical routine 
i.m. 
investigational 
ofatumumab 
20 mg 
20 mg 
monthly 
sc 
 


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6.1.2 
Supply of study treatment 
Ofatumumab is supplied during the study while modRNA vaccines are part of clinical routine 
and there will be no supply. 
 
6.1.3 
Treatment arms/group 
Participants will be assigned at screening to one of the following “2” treatment arms in a ratio 
of “1:1” at the discretion of the physician. There is no randomization within the trial. 
• 
The first treatment arm will be RMS patients receiving modRNA vaccine (either initial 
vaccination cycle or a booster) as part of clinical routine prior to starting ofatumumab 
treatment.   
• 
The second treatment arm will be participants receiving modRNA vaccine (either initial 
vaccination cycle or a booster) as part of clinical routine while already stable on 
ofatumumab treatment for at least 4 weeks (since first dose).   
 
6.2 
Other treatment(s) 
Not applicable. 
6.2.1 
Concomitant therapy 
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 Case Report Forms. 
 
6.2.2 
Prohibited medication 
The use of non-mRNA SARS-CoV-2 vaccines is prohibited in this study.   
Further prohibited medication applies according to approved Ofatumumab SmPC.  
 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
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. 


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6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of a participant to a particular 
cohort will be coordinated by the sponsor.  
Cohort 1: will be RMS patients receiving modRNA vaccine as part of the clinical routine prior 
to starting ofatumumab treatment (Cohort 1a: patients that receive their first SARS-CoV-2 
vaccination within the study and cohort 1b: patients that have already completed their initial 
vaccination cycle and will receive a booster vaccine within the study)  
Cohort 2: will be participants receiving modRNA vaccine as part of clinical routine while 
already stable on ofatumumab treatment for at least 4 weeks (since the first dose) (Cohort 2a: 
patients that receive their first SARS-CoV-2 vaccination within the study and cohort 2b: 
patients that have already completed their initial vaccination cycle and will receive a booster 
vaccine within the study).  
 
6.4 
Treatment blinding 
Not applicable. 
 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
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. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log. 
 
6.7 
Preparation and dispensation 
Each study site will be supplied with ofatumumab in packaging as described under 
investigational and control drugs section.  
SARS-CoV-2 modRNA vaccines will be received as part of clinical routine and will not be 
provided. 


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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
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 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. 
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. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-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 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/IEC. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 


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8 
Visit schedule and assessments 
The Assessment Schedule (cohort 1a: Table 8-1 and cohort 1b: Table 8-2, cohort 2a; Table 8-3 
and cohort 2b: Table 8-4) lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(cohort 1a: Table 8-1, cohort 1b: Table 8-2, cohort 2a: Table 8-3 and cohort 2b: Table 8-4) or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Participants who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF. 


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Table 8-1 
Assessment schedule cohort 1a 
 
Period 
Run-in 
Investigational   
Visit 
Screening/ 
Baseline 
Vaccina
tion 1# 
Vaccina
tion 2# 
1 
On 
site 
A1** 
(onsite, 
only if 
medically 
indicated) 
2 
On 
site 
3 
remote 
4 
remot
e 
5 
remote 
6 
On site 
Booster 
vacc. 
**** 
remote 
A2**** 
(onsite, 
only if 
booster 
vacc.) 
7 
On site 
 
8 
On site 
9 
On site 
(end of 
study) 
Day/Week/ 
Month 
1-12 
weeks 
before 
vacc.1 
Day 1 
Day 
22/29* 
+1  
week 
after 
vacc. 
2 
2-4  
weeks 
after 
vacc. 2 
+4  
weeks 
after 
vacc.
2  
+5   
weeks 
after 
vacc.2 
+6 
weeks 
after 
vacc.2  
+8  
weeks 
after 
vacc.2 
+3 
months 
after 
vacc. 2 
after 
vacc.2 
+1 
month 
after 
booster 
+6 
months 
after 
vacc.2 
+12 
months 
after 
vacc.2 
+ 18 
months 
after 
vacc.2 
Obtain 
informed 
consent 
 X 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
Inclusion/excl
usion criteria 
 X 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
Anamnesis, 
Demography, 
Relevant 
medical and 
MS history 
 X 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
Physical 
exam 
 F 
  
  
 S 
S 
S 
  
 
 
 
 
S 
S 
S 
F 
Blood 
sampling 3 
 X 
  
  
 X 
 
X 
  
 
 
 
 
X 
X 
X 
X 
MS relapse4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status MS 
and 
concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local urine 
and 
X 
 
 
 
X 
X*** 
 
 
 
 
 
 
 
 
 


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pregnancy 
test 1 
Administratio
n of study 
drug at site 
 
 
 
 
X 
X*** 
 
 
 
 
 
 
 
 
 
Self-injection 
training 1 
 
 
 
 
X 
X*** 
 
 
 
 
 
 
 
 
 
Study drug 
dispension 
 
 
 
 
X 
X*** 
 
 
 
X 
 
 
X 
X 
 
Contact after 
modRNA 
vaccination 2 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Documentati
on SARS-
CoV-2 
vaccination 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Telephone 
contact 
  
  
  
  
 
 
X  
X 
X 
 
 
 
 
 
 
AE/SAE 
X  
 X 
 X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
White color: timing of visits depends on vaccination date 
Light grey color: optional visits 
Dark grey color:  Timing of visits depends on start of ofatumumab treatment and timelines have to be adjusted if ofatumumab treatment is initiated at visit A1 instead of visit 2. Visit 3: 1 week 
after start of ofatumumab treatment, visit 4: two weeks after start of ofatumumab treatment and visit 5: 4 weeks after start of ofatumumab treatment. Remote visits should be used to ensure 
that the first ofatumumab doses are applied according to SmPC. 
 
A = additional visit; vacc. = Vaccination with modRNA vaccine, 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
F = full assessment, S = short medical exam 
# modRNA vaccination independent of study site at designated vaccination centers as part of clinical routine and depending on federal regulations 
* Number of required vaccinations and interval depends on the SmPC of the respective modRNA vaccination and on local guidelines provided e.g. by the responsible health authorities 
** If medically indicated, ofatumumab treatment might be started at an additional visit (A1) before visit 2 but at the earliest two weeks after the last vaccination.  
*** Assessments don’t have to be performed on visit 2 if ofatumumab treatment has already been initiated at visit A1. 
**** Patients are allowed to receive SARS-CoV-2 booster vaccines any time after vacc. 2 according to respective SmPCs or local regulations, as part of clinical routine and at the physician’s 
discretion. If patients receive a booster vaccination, additional visit 2 (A2) should be performed 1 month (4 weeks) after the booster vaccination to collect a blood sample and assess immune 
response. If the next scheduled visit falls within two weeks of visit A2, the scheduled visit can be omitted. This only applies for the first and second booster. All potential following boosters should 
be documented but there won’t be any additional visits afterwards. 


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1 According to approved SmPC requirements 
2 Contact can be on site, virtual or via phone according to physician’s choice. 
3 Laboratory test includes a standard hematology set, B-cell count, detection and characterization of SARS-CoV-2 specific T cells and neutralizing antibodies; if no SARS-CoV-2 specific T-cells 
can be detected, HLA-haplotyping will be considered to exclude methodical reasons. Blood samples will be stored.  
4 MS relapses within the last two years should be reported 
 
Table 8-2 
Assessment schedule cohort 1b 
Period 
Run-in 
Investigational   
Visit 
Screening 
On site 
Booster 
vacc. 
# 
A1* 
(onsite, 
only if 
medically 
indicated) 
1 
On site 
2 
remote 
3 
remote 
4 
remote 
Booster 
vacc. 
*** 
remote 
A2*** 
(onsite, 
only if 
booster 
vacc.) 
5 
On site 
6 
On site 
 
7 
On site 
(end of study) 
Day/Week/ 
Month 
Approx. 1 
week 
before 
booster 
Day 1 
2-4  weeks 
after 
booster 
+1 
month 
after 
booster 
+5   
weeks 
after 
booster 
+6 
weeks 
after 
booster 
+8  
weeks 
after 
booster 
any 
time 
+1 
month 
after 
booster 
+3 
months 
after 
booster 
+6 
months 
after 
booster 
+12  
months  
after booster 
Obtain 
informed 
consent 
 X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/excl
usion criteria 
 X 
 
 
 
 
 
 
 
 
 
 
 
Anamnesis, 
Demography, 
Relevant 
medical and 
MS history 
 X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam 
 F 
 
S 
S 
 
 
 
 
S 
 
S 
F 
Blood 
sampling 3 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
MS relapse4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status MS 
and 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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concomitant 
medication 
Local urine 
and 
pregnancy 
test 1 
X 
 
X 
X** 
 
 
 
 
 
 
 
 
Administratio
n of study 
drug at site 
 
 
X 
X** 
 
 
 
 
 
 
 
 
Self-injection 
training 1 
 
 
X 
X** 
 
 
 
 
 
 
 
 
Study drug 
dispension 
 
 
X 
X** 
 
 
 
 
 
X 
X 
 
Contact after 
modRNA 
vaccination 2 
 
X 
 
 
 
 
 
X 
 
 
 
 
Documentati
on SARS-
CoV-2 
vaccination 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Telephone 
contact 
 
 
 
 
X  
X 
X 
 
 
 
 
 
AE/SAE 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
White color: timing of visits depends on vaccination date 
Grey color:  Timing of visits depends on start of ofatumumab treatment and timelines have to be adjusted if ofatumumab treatment is initiated at visit A1 instead of visit 1. Visit 2: 1 week after 
start of ofatumumab treatment, visit 3: two weeks after start of ofatumumab treatment and visit 4: 4 weeks after start of ofatumumab treatment. Remote visits should be used to ensure that the 
first ofatumumab doses are applied according to SmPC. 
 
A = additional visit; vacc. = Vaccination with modRNA vaccine, 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
F = full assessment, S = short medical exam 
# First booster vaccination; can be performed any time after termination of the initial SARS-CoV-2 vaccination cycle (vacc.2) as part of clinical routine independent of the study, e.g. at 
designated vaccination centers according to respective SmPCs or local/federal regulations and at the physician’s discretion. Additional booster shots can be performed any time during the 
study and should be documented, however, there won’t be any additional visits afterwards.  
* If medically indicated, ofatumumab treatment might be started at an additional visit (A1) before visit 1 but at the earliest two weeks after the booster vaccination.  
** Assessments don’t have to be performed on visit 1 if ofatumumab treatment has already been initiated at visit A1. 


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*** Patients are allowed to receive additional SARS-CoV-2 booster vaccines any time after their first booster according to respective SmPCs or local regulations, as part of clinical routine and at 
the physician’s discretion. If patients receive a second booster vaccination, additional visit 2 (A2) should be performed 1 month (4 weeks) after the second booster vaccination to collect a blood 
sample and assess immune response. If the next scheduled visit falls within two weeks of visit A2, the scheduled visit can be omitted. This only applies for the second booster. All potential 
following boosters should be documented but there won’t be any additional visits afterwards. 
 
1 According to approved SmPC requirements 
2 Contact can be on site, virtual or via phone according to physician’s choice. 
3 Laboratory test includes a standard hematology set, B-cell count, detection and characterization of SARS-CoV-2 specific T cells and neutralizing antibodies; if no SARS-CoV-2 specific T-cells 
can be detected, HLA-haplotyping will be considered to exclude methodical reasons. Blood samples will be stored.  
4 MS relapses within the last two years should be reported 
 
Table 8-3 
Assessment schedule cohort 2a 
Phase 
Run-in phase 
Investigational phase 
Visit  
Screening 
on site 
1* 
remote 
2* 
remote 
3* 
remote 
4 
Baseline 
on site 
Vacc. 1# Vacc. 2# 
5 
on site 
6 
on site 
Booster 
vacc. 
*** 
 
A1*** 
(onsite, 
only if 
booster 
vacc.) 
7 
on site 
8  
on site 
 
9  
on site 
10 
On site 
(end of 
study) 
Time of Visit 
4-12 
weeks 
before 
vacc. 1 
+ 1 week 
after 
screening 
+ 2 weeks 
after 
screening 
+ 4 weeks 
after 
screening 
approx. 1 
week 
before 
vacc. 1 
day 1 
day 
22/29** 
+ 1  
week 
after 
vacc. 2 
+ 1 
month 
after 
vacc. 2 
after 
vacc.2 
+ 1 
month 
after 
booster 
+ 3 
months 
after 
vacc. 2 
+ 6 
months 
after    
vacc. 2 
+ 12 
months 
after    
vacc. 2 
+ 18 
months 
after 
vacc.2 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information & 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anamnesis, 
demographics, MS 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MS relapse 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status MS and 
concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Physical exam 
F 
 
 
 
S 
 
 
S 
S 
 
S 
 
S 
S 
F 
Blood sample 3 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
Local urine 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
study drug at site* 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-injection 
training* 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
dispension 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Contact after 
modRNA 
vaccination 2 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone contact 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
White color: timing of visits depends on vaccination date 
Light grey color: optional visits 
Dark grey color:  timing of visits depends on start of ofatumumab treatment. Remote visits should be used to ensure that the first ofatumumab doses are applied according to SmPC 
Vacc. = Vaccination with modRNA vaccine 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
F = full assessment, S = short medical exam 
# modRNA vaccination independent of study site at designated vaccination centers as part of clinical routine and depending on federal regulations.  
* If patient is already on stable ofatumumab treatment at the time of screening, the marked assessments as well as visits 1, 2 and 3 are not necessary. In that case, screening and baseline visit 
can be performed at the same day approx. one week before the first vaccination (similar to cohort 1). 
** Number of required vaccinations and interval depends on the SmPC of the respective modRNA vaccination and on local guidelines provided e.g. by the responsible health authorities 
*** Patients are allowed to receive SARS-CoV-2 booster vaccines any time after vacc.2. If patients receive a booster vaccination, an additional visit (A1) should be performed 1 month (4 weeks) 
after the booster vaccination to collect a blood sample and measure immune response. If the next scheduled visit falls within two weeks of visit A1, the scheduled visit can be omitted. This only 
applies for the first and second booster. All potential following boosters should be documented but there won’t be any additional visits afterwards. 
† Phone contact to follow up on the occurrence of COVID-19 cases 
1 According to approved SmPC requirements 
2 Contact can be on site, virtual or via phone according to physician’s choice. 
3 Laboratory test includes a standard hematology set, B-cell count, detection and characterization of SARS-CoV-2 specific T cells and neutralizing antibodies; if no SARS-CoV-2 specific T-cells 
can be detected, HLA-haplotyping will be considered to exclude methodical reasons. Blood samples will be stored. 4 MS relapses within the last two years should be reported 


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Table 8-4 
Assessment schedule cohort 2b 
Period 
Run-in 
Investigational   
Visit 
Screening 
On site 
1* 
remote 
2* 
remote 
3* 
remote 
Baseline* 
On site 
Booster 
vacc. 
# 
4 
On site 
Booster 
vacc. 
** 
 
A1** 
(onsite, 
only if 
booster 
vacc.) 
5 
On site 
6 
On site 
 
7 
On site 
(end of 
study) 
Day/Week/Month 
min. 4 
weeks 
before 
booster 
+ 1 week 
after 
screening 
+ 2 weeks 
after 
screening 
+ 4 weeks 
after 
screening 
Approx. 1  
week 
before 
booster  
Day 1 
+1 
month 
after 
booster 
after 
vacc.2 
+ 1 
month 
after 
booster 
+3 
months 
after 
booster 
+6 
months 
after 
booster 
+12 months 
after 
booster 
Obtain informed 
consent 
 X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 X 
 
 
 
 
 
 
 
 
 
 
 
Anamnesis, 
Demography, 
Relevant medical 
and MS history 
 X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 F 
 
 
 
S 
 
S 
 
S 
 
S 
F 
Blood sampling 3 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
MS relapse4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status MS and 
concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local urine and 
pregnancy test 1 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
study drug at site * 
X 
 
 
 
 
 
 
 
 
 
 
 
Self-injection 
training * 1 
X 
 
 
 
 
 
 
 
 
 
 
 


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Study drug 
dispension 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Contact after 
modRNA 
vaccination 2 
 
 
 
 
 
X 
 
X 
 
 
 
 
Documentation 
SARS-CoV-2 
vaccination 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Telephone contact 
 
X  
X 
X 
 
 
 
 
 
 
 
 
AE/SAE 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
White color: timing of visits depends on vaccination date 
Grey color:  Timing of visits depends on start of ofatumumab treatment. Remote visits should be used to ensure that the first ofatumumab doses are applied according to SmPC. 
 
A = additional visit; vacc. = Vaccination with modRNA vaccine, 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
F = full assessment, S = short medical exam 
# First booster vaccination; can be performed any time after termination of the initial SARS-CoV-2 vaccination cycle (vacc.2) as part of clinical routine independent of the study, e.g. at 
designated vaccination centers according to respective SmPCs or local/federal regulations and at the physician’s discretion. Additional booster shots can be performed any time during the 
study and should be documented, however, there won’t be any additional visits afterwards.   
* If patient is already on stable ofatumumab treatment at the time of screening, the marked assessments as well as visits 1, 2 and 3 are not necessary. In that case, screening and baseline visit 
can be performed at the same day approx. one week before the booster vaccine (similar to cohort 1b). 
*** Patients are allowed to receive SARS-CoV-2 booster vaccines any time after their first booster. If patients receive a second booster vaccination, an additional visit (A1) should be performed 
1 month (4 weeks) after the second booster vaccination to collect a blood sample and measure immune response. If the next scheduled visit falls within two weeks of visit A1, the scheduled visit 
can be omitted. This only applies for the second booster. All potential following boosters should be documented but there won’t be any additional visits afterwards. 
 
1 According to approved SmPC requirements 
2 Contact can be on site, virtual or via phone according to physician’s choice. 
3 Laboratory test includes a standard hematology set, B-cell count, detection and characterization of SARS-CoV-2 specific T cells and neutralizing antibodies; if no SARS-CoV-2 specific T-cells 
can be detected, HLA-haplotyping will be considered to exclude methodical reasons. Blood samples will be stored.  
4 MS relapses within the last two years should be reported 


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8.1 
Screening 
Re-screening is permitted if the patient is not eligible for SARS-CoV-2 vaccination (initial 
vaccination or booster vaccine) by local regulation within 12 weeks after screening. In this case 
the Novartis Medical Advisor should be contacted to discuss further proceeding. 
8.1.1 
Eligibility screening 
At screening, patients will be asked about previous COVID-19 disease. If a patient has had 
COVID-19 disease before screening, the patient is not eligible to further participate in the study. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, 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). 
 
8.2 
Participant demographics/other baseline characteristics 
Anamnesis, participant demographics (year of birth, sex, race) and relevant medical 
history/current medical conditions including MS disease and current treatment will be 
documented. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start and during the study must be documented. See the protocol Section 6.2.1 Concomitant 
Therapy for further details on what information must be recorded on the appropriate page of the 
eCRF. 
 
8.3 
Efficacy 
Blood samples will be collected at the timepoints defined in the Assessment Schedule (cohort 
1a: Table 8-1, cohort 1b: Table 8-2, cohort 2a: Table 8-3, cohort 2b: Table 8-4). Follow 
instructions outlined in the Laboratory manual regarding sample collection, numbering, 
processing, and shipment. 
8.3.1 
Efficacy assessment 1 
SARS-CoV-2 vaccination efficacy is defined as detection of SARS-CoV-2 specific T-cells one 
month after completion of the initial vaccination cycle or 1 month after a booster vaccination.  
8.3.2 
Efficacy assessment 2 
Additional efficacy assessments are: 


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• Longitudinal follow-up of SARS-CoV-2 specific T-cells one week, one month, six 
months, 12 months and 18 months after second dose of vaccine as well as 6 months and 
12 months after booster vaccine 
• Longitudinal follow-up of SARS-CoV-2 serum functional antibody levels one week, 
one month, six months, 12 months and 18 months after second dose of vaccine as well 
as 6 months and 12 months after booster vaccine 
• Phenotypical characterization of peripheral blood mononuclear cells for CD45, CD3, 
CD4, CD8, CD62l, CD45RA, CD27, CCR7 
• Immunophenotyping for naive, central memory, effector memory, and effector cells on 
CD4+ and CD8+ cells 
• Measuring cells positive for intracellular cytokine-staining for interferon-gamma and 
interleukin-4 
 
 
 
 
 
 
8.3.3 
Appropriateness of efficacy assessments 
Efficacy assessments in KYRIOS are based on the study set up of the phase II clinical trial 
NCT04380701 (EudraCT: 2020-001038-36) for the SARS-CoV-2 vaccination candidate 
BNT162b2 (Sahin, Muik et al. 2020). This study reports SARS-CoV-2 specific T-cell responses 
one week after completion of the vaccination cycle measured by ex vivo IFNγ ELISPOT assay. 
Sahin et al. further characterized the T cells involved in the T cell response with regards to 
surface markers and Th1/Th2 polarization and reported stable IgG levels from one week after 
the second vaccine for up to 60 days. Comparable results were also reported for mRNA-1273 
by Jackson et al, 2020.  
The detection of SARS-CoV-2 reactive T-cells one month after completion of the vaccination 
cycle was chosen as a primary endpoint in this study to assess efficacy. 
Further characterization of the T-cell response as well as measurement of IgG antibodies as 
reported by Sahin et al. will be performed as secondary assessments.   
 
 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
 


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Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of 
vital signs (blood pressure [SBP and DBP] and pulse), general 
appearance, height, weight, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, 
and pelvic exams will be performed. 
A short physical exam will include the examination of general 
appearance and vital signs (blood pressure [SBP and DBP] and 
pulse).  
Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings 
that are present prior to signing informed consent must be 
recorded on the appropriate CRF that captures medical history. 
Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an 
adverse event. 
 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual.  
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered clinically 
significant. 
Special clinical laboratory evaluations 
 
Test Category 
Test Name 
SARS-CoV-2 vaccination 
antibody response 
Serum functional SARS-CoV-2 antibodies 
SARS-CoV-2 vaccination 
T-cell response 
Ex vivo IFNγ and IL-2 enzyme-linked immunosorbent spot (ELISpot)  
Hematology 
Blood samples will be collected according to the schedule in Table 8-1, 
8-2, 8-3 and Table 8-4. 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) 
B cell count 
CD19+/CD20+ B-cell counts. Samples will be collected according to 
the schedule in Table 8-1, Table 8-2, Table 8-3 and Table 8-4. 
8.4.2 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 


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8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration 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. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of 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 assessments indicated in the Assessment Schedule. 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 study treatment discontinuation, 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 (including COVID-19 disease) 
 


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9.1.1.1 
Replacement policy 
Patients successfully screened who do not receive a SARS-CoV-2 mRNA vaccination or a 
booster vaccine within 3 months after screening will be excluded from the study and be replaced 
unless the patient is currently not eligible for SARS-CoV-2 vaccination by local regulation. In 
this case the Novartis Medical Advisor should be contacted to discuss further proceeding.  
 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
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 his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of 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. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
The patient can decide if Novartis is allowed to retain and use all research results (data) that 
have already been collected for the study evaluation or if stored blood samples need to be 
destroyed. 
 
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 or withdraw, 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 or until the end of the study. 


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9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
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 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/IECs of the early termination of the trial.  
 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
 
10 
Safety monitoring and reporting 
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 (version 5 or higher): 
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version. CTCAE grade 5 will be used to capture death 
information within the eCRF. 
 
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 if the event is ongoing, an outcome of not 
recovered/not resolved 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/withdrawn 
6. Its outcome (i.e. recovery status or whether it was fatal) 
 
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 
Investigator's Brochure (IB). 


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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.  
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 and has not worsened since signing the informed consent 
• 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). 


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All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
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. MS relapses are exempt from SAE 
reporting although they may meet the SAE definition on the basis that they are considered 
medically significant and are frequently associated with hospitalization. These events will be 
reported on the MS relapse eCRF instead of the SAE form. However, if in the judgement of the 
Investigator, a MS relapse is unusually severe or unexpected and warrants specific notification, 
then an SAE form must be completed and submitted according to SAE reporting procedures 
outlined above. Detailed instructions regarding the submission process and requirements 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 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a 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 EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
 
Any SAEs experienced after the 30 day period 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 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 


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Doctor ask about her 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 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 study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
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. 
 
10.2 
Additional Safety Monitoring 
Not applicable. 
 


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11 
Data Collection and Database management 
11.1 
Data collection 
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 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 and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
 
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. eSource DDE or 
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/delegated CRO/CRA organization. Additionally, 


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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 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received.  
The safety analysis set will include all participants that received any study drug. 
The efficacy analysis sets at one week, one month,six months, 12 months and 18 months after 
the second SARS-CoV-2 vaccine and 1, 6 and 12 months after a booster vaccine, respectively, 
will include all participants who have a valid determination of SARS-CoV-2 reactive T-cells at 
that time point plus those who failed to receive their second dose of vaccine for whatever reason. 
The latter will be counted as non-responders. Patients completing vaccination but fail to provide 
a blood sample at one week after the second vaccination will be excluded from the study and 
analysis. 
 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group (Cohort 1 and 2) for the FAS. 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 


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For Cohort 1, the time between second vaccination (cohort 1a) or booster vaccination (cohort 
1b) and start of ofatumumab treatment will be presented. For Cohort 2, the time from first 
ofatumumab dose to first vaccination (cohort 2a) or booster vaccination (cohort 2b) will be 
summarized. For both cohorts, continuous ofatumumab intake will be presented.  
 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in days to Ofatumumab will be summarized by means of descriptive 
statistics using the safety set. 
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, by cohort. 
 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The primary clinical question of this study is to estimate the proportion of RMS patients 
mounting an immune response after receiving a modRNA vaccine (initial vaccination or 
booster) either before or after starting ofatumumab treatment. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary endpoint of this study is the proportion of RMS patients having established SARS-
CoV-2-specific T cells as defined by detection of SARS-CoV-2 reactive T-cells, measured by 
e.g. enzyme-linked immunosorbent spot (ELISpot) assay from T-cells that were stimulated with 
SARS-CoV-2 peptide mix, one month after second dose of vaccine or one month after booster 
vaccine in participants who received the respective vaccine before or after starting ofatumumab 
treatment (yes/no). 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will not use any statistical testing or modelling. The absolute numbers and 
the proportion of participants with detectable SARS-CoV-2 reactive T-cells within each cohort 
will be calculated. It will be augmented by a (descriptive) 95% confidence interval (exact 
Clopper-Pearson). 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Cohort 1a and cohort 2a: Patients who fail to receive their second dose of vaccine for whatever 
reason will be included in the analysis as non-responders. Patients who did receive their second 
dose of vaccine and do not have a valid determination of reactive T-cells to SARS-CoV-2 for 
whatever reason will be excluded from the analysis of vaccine efficacy. 


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Patients in cohort 1b and 2b who did receive a booster vaccine and do not have a valid 
determination of reactive T-cells to SARS-CoV-2 for whatever reason will be excluded from 
the analysis of vaccine efficacy. 
12.4.4 
Supportive analyses 
Patient demographics and baseline characteristics among both cohorts will be compared in the 
data analysis. Additionally, patients receiving their initial vaccination (cohorts 1a and 2a) vs. a 
booster shot (cohort 1b and 2b) will be analyzed separately. If patients received a non-mRNA 
vaccine as booster, this would be reflected in the analysis. 
 
12.5 
Analysis of secondary endpoints/estimands 
All secondary endpoints will be summarized descriptively as frequencies and percentages, or, 
for continuous data, mean, standard deviation, median, minimum, and maximum will be 
presented. 
12.5.1 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the last study visit. 
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 (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by cohort, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 


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A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group (cohort 1 and 2), participant, and visit/time 
and if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time.  
 
 
 
 
 
 
 
12.7 
Interim analyses 
The first interim analysis will be performed when at least 5 participants per cohort have 
completed the study visit one week after a complete SARS-CoV-2 vaccination cycle or on 
September 1st 2021, whichever comes first. 
The second interim analysis will be performed when at least 10 patients in cohort 2 have 
completed the primary endpoint, 1 month (4 weeks) after the second vaccine (2a) or the booster 
vaccine (2b) or on January 10th 2022, whichever comes first. 
An additional interim analysis will be performed when all participants have completed study 
visit 1 (one week after SARS-CoV-2 vaccination cycle completion) as this reflects the primary 
endpoint and whenever deemed necessary. As all analyses in this study are purely descriptive, 
there is no need for any statistical adjustments. 
 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size of 20 participants per arm is selected based on need for early availability of 
results for the current covid-19 pandemic and the feasibility to recruit sufficient participants. 
This sample size of 20 subjects will provide estimates of proportion responded 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 subjects 
will be enrolled in each arm. In case of fast recruitment the sponsor is allowed to increase 
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sample size in each arm by up to 10 additional patients to support the generation of meaningful 
data in a larger sample size. 
 
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/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, 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, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
 
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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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/IEC 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/IEC 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/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any 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/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Ahmed, R. and R. S. Akondy (2011). "Insights into human CD8(+) T-cell memory using the 
yellow fever and smallpox vaccines." Immunol Cell Biol 89(3): 340-345. 
Bar-Or, A., J. C. Calkwood, C. Chognot, J. Evershed, E. J. Fox, A. Herman, M. Manfrini, J. 
McNamara, D. S. Robertson, D. Stokmaier, J. K. Wendt, K. L. Winthrop and A. Traboulsee 
(2020). "Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The 
VELOCE study." Neurology 95(14): e1999-e2008. 
Dan, J. M., J. Mateus, Y. Kato, K. M. Hastie, E. D. Yu, C. E. Faliti, A. Grifoni, S. I. Ramirez, 
S. Haupt, A. Frazier, C. Nakao, V. Rayaprolu, S. A. Rawlings, B. Peters, F. Krammer, V. 
Simon, E. O. Saphire, D. M. Smith, D. Weiskopf, A. Sette and S. Crotty (2021). 
"Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection." 
Science. 
Gallais, F., A. Velay, M.-J. Wendling, C. Nazon and ... (2020). "Intrafamilial Exposure to 
SARS-CoV-2 Induces Cellular Immune Response without Seroconversion." medRxiv 
preprint. 
Grifoni, A., D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. 
Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, 
A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty and A. Sette 
(2020). "Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-
19 Disease and Unexposed Individuals." Cell 181(7): 1489-1501 e1415. 
Hauser, S. L., A. Bar-Or, J. A. Cohen, G. Comi, J. Correale, P. K. Coyle, A. H. Cross, J. de 
Seze, D. Leppert, X. Montalban, K. Selmaj, H. Wiendl, C. Kerloeguen, R. Willi, B. Li, A. 
Kakarieka, D. Tomic, A. Goodyear, R. Pingili, D. A. Haring, K. Ramanathan, M. 
Merschhemke, L. Kappos, I. Asclepios and A. I. T. Groups (2020). "Ofatumumab versus 
Teriflunomide in Multiple Sclerosis." N Engl J Med 383(6): 546-557. 
Hellerstein, M. (2020). "What are the roles of antibodies versus a durable, high quality T-cell 
response in protective immunity against SARS-CoV-2?" Vaccine X 6: 100076. 
Huang, Y., C. Yang, X. F. Xu, W. Xu and S. W. Liu (2020). "Structural and functional 
properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-
19." Acta Pharmacol Sin 41(9): 1141-1149. 
Jackson, L. A., E. J. Anderson, N. G. Rouphael, P. C. Roberts, M. Makhene, R. N. Coler, M. 
P. McCullough, J. D. Chappell, M. R. Denison, L. J. Stevens, A. J. Pruijssers, A. McDermott, 
B. Flach, N. A. Doria-Rose, K. S. Corbett, K. M. Morabito, S. O'Dell, S. D. Schmidt, P. A. 
Swanson, 2nd, M. Padilla, J. R. Mascola, K. M. Neuzil, H. Bennett, W. Sun, E. Peters, M. 
Makowski, J. Albert, K. Cross, W. Buchanan, R. Pikaart-Tautges, J. E. Ledgerwood, B. S. 
Graham, J. H. Beigel and R. N. A. S. G. m (2020). "An mRNA Vaccine against SARS-CoV-2 
- Preliminary Report." N Engl J Med 383(20): 1920-1931. 
Polack, F. P., S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. 
Perez Marc, E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. 
Koury, P. Li, W. V. Kalina, D. Cooper, R. W. Frenck, Jr., L. L. Hammitt, O. Tureci, H. Nell, 


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A. Schaefer, S. Unal, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Sahin, K. U. Jansen, W. 
C. Gruber and C. C. T. Group (2020). "Safety and Efficacy of the BNT162b2 mRNA Covid-
19 Vaccine." N Engl J Med. 
Sahin, U., A. Muik, I. Vogler, E. Derhovasessian and L. M. Kranz (2020). "BNT162b2 
induces SARS-CoV-2-neutralising antibodies and T cells in humans." medRxiv preprint. 
Walsh, E. E., R. W. Frenck, Jr., A. R. Falsey, N. Kitchin, J. Absalon, A. Gurtman, S. 
Lockhart, K. Neuzil, M. J. Mulligan, R. Bailey, K. A. Swanson, P. Li, K. Koury, W. Kalina, 
D. Cooper, C. Fontes-Garfias, P. Y. Shi, O. Tureci, K. R. Tompkins, K. E. Lyke, V. Raabe, P. 
R. Dormitzer, K. U. Jansen, U. Sahin and W. C. Gruber (2020). "Safety and Immunogenicity 
of Two RNA-Based Covid-19 Vaccine Candidates." N Engl J Med. 
Wiendl, H. (2020). "Serum immunoglobulin levels and infection risk in the Phase 3 trials of 
ofatumumab in relapsing multiple sclerosis." Poster Presentation at the 8th Joint ACTRIMS-
ECTRIMS Meeting, MSVirtual2020, September 11-13, 2020. 
 

SAP_001.pdf: 
Clinical Development
Ofatumumab (OMB157)®
COMB157GDE01 1&7
Tracking the immune response to SARS-CoV-2 modRNA 
vaccines in ab open-label multicenter study in participants 
with relapsing multiple sclerosis treated with ofatumumab
s.c. (KYRIOS)
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Clinical Trial Head, Dr. 
CRO Statistician,
Document type:
SAP Documentation
Document status:
Final 4.0
Release date:
13 Nov 2023
Number of pages:
21
Property of Novartis 
For business use only
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis
PPD
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SAP Version Final 4.0 
For business use only 
Page 2 
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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and 
title impacted 
(Current) 
17- 
JUN- 
2021 
Prior to FPFV 
Creation of 1st draft 
version (0.1) 
For Sponsor review 
NA 
14- 
07- 
2021 
After 
recruitment of 4 
patients/ before 
DBL 
Review of CTH 
and TS 
Second draft 
NA 
22- 
JUL- 
2021 
After 
recruitment of 5 
patients/ before 
DBL 
Finalization after 
review 
Final version 
NA 
07- 
DEC- 
2021 
After 1st interim 
analysis 
2nd Protocol 
Amendment 
Version 2.0 of SAP and TFLs 
all 
15- 
JUN- 
2022 
After 2nd 
interim analysis 
After protocol 
amendment No. 3 
Version 3.0 of SAP and 
Version 7 of TFLs 
all 
13 
Nov 
2023 
After DB- 
closure 
Correction of 
analysis data 
Note to file dated 29 Sep 2023 
and 20 Oct 2023 (Correction 
of invalid quantitative values 
and spots of IFNg and IL-2 
(towards SARS-CoV-2 and 
towards PAN coronavirae) – 
in 
case 
of 
qualitative 
assessment “not evaluable” or 
 “missing” 
5.1 


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SAP Version Final 4.0
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Signature Page
Clinical Trial Leader
Trial Statistican
CRO Statistican
Digitally signed by
DN: dc=com, dc=novartis, 
ou=people, ou=PH, 
serialNumber=687758, cn=
 
Date: 2023.11.13 12:50:19 +01'00'
Digitally signed by
DN: dc=com, dc=novartis, ou=people, ou=PH,
serialNumber=2363440, cn
Date: 2023.11.13 10:15:47 +01'00'
PPD
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PP
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Page 4 
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Table of contents 
Signature Page ............................................................................................................................ 3 
Table of contents .................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction .......................................................................................................................... 7 
1.1 
Study design ............................................................................................................. 7 
1.2 
Study objectives and endpoints ................................................................................ 8 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information .......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.1.2 
Handling with unscheduled vitis ........................................................... 11 
2.1.3 
Visits relevant for efficacy analyses ...................................................... 11 
2.2 
Analysis sets ........................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 12 
2.3 
Patient disposition, demographics and other baseline characteristics .................... 12 
2.3.1 
Patient disposition ................................................................................. 12 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 13 
2.5.1 
Primary endpoint ................................................................................... 13 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ........................ 15 
2.5.4 
Supportive analyses ............................................................................... 15 
2.6 
Analysis of the key secondary objective ................................................................ 16 
2.7 
Analysis of secondary efficacy objective(s) ........................................................... 16 
2.7.1 
Secondary endpoints .............................................................................. 16 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.7.3 
Handling of missing values/censoring/discontinuations ........................ 17 
 
 17 
2.9 
Safety analyses ....................................................................................................... 17 
2.9.1 
Adverse events (AEs) ............................................................................ 17 
2.9.2 
Deaths .................................................................................................... 18 
2.9.3 
Laboratory data ...................................................................................... 18 
2.9.4 
Other safety data .................................................................................... 18 
2.10 
Pharmacokinetic endpoints .................................................................................... 19 
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2.11 
PD and PK/PD analyses ......................................................................................... 19 
2.12 
Patient-reported outcomes ...................................................................................... 19 
2.13 
Biomarkers ............................................................................................................. 19 
2.14 
Other Exploratory analyses .................................................................................... 19 
2.15 
Interim analysis ...................................................................................................... 19 
3 
Sample size calculation ...................................................................................................... 19 
4 
Change to protocol specified analyses ............................................................................... 19 
5 
Appendix ............................................................................................................................ 19 
5.1 
Imputation rules ..................................................................................................... 19 
5.2 
Treatment-emergent adverse events ....................................................................... 20 
5.3 
Statistical models ................................................................................................... 20 
5.3.1 
Primary analysis .................................................................................... 20 
5.3.2 
Secondary analysis ................................................................................ 21 
5.4 
Rule of exclusion criteria of analysis sets .............................................................. 21 
6 
Reference ........................................................................................................................... 21 
 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
CI 
Confidence interval 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
eCRF 
Electronic Case Report Form 
EAS 
Efficacy Analysis Set 
DMT 
Disease modifying therapy 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MNC 
Mononuclear cells 
MS 
Multiple sclerosis 
RAP 
Report and Analysis Process 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAE 
Serious adverse event 
SOC 
System Organ Class 
SmPC 
Summary of Procduc Characteristics 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes how the statistical analyses of this study will be 
implemented. Based on the tables/listings/figures (TFL) of resulting from this SAP the Clinical 
Study Report (CSR) will be written. The TFLs will be attached in section 14 of the CSR. 
In addition this SAP describes which patient Data Listings to be attached in section 16.2.1 of 
the CSR will be generated. 
This SAP is not used for other analyses or studies. 
It is based on the Amended Study Protocol (CSP), Version 3 dated 28-MAR-2022 
1.1 
Study design 
This is a two cohort, multicenter, open-label, prospective study of 40 patients (optionally up to 
60) suffering from relapsing multiple sclerosis (RMS). 
• The first cohort will be RMS patients receiving modRNA vaccine as part of clinical 
routine prior to starting ofatumumab treatment. 
Cohort 1a: will receive their 1st and 2nd SARS-CoV-2 vacines (and an optional booster 
vaccine) 
Cohort 1b: will receive a booster vaccine 
• The second cohort will be participants receiving modRNA vaccine as part of clinical 
routine while already stable on ofatumumab treatment for at least 4 weeks (since first 
dose). 
Cohort 2a: will receive their 1st and 2nd SARS-CoV-2 vaccines (and an optional booster 
vaccine) 
Cohort 2b: will receive a booster vaccine 
Ofatumumab treatment initiation and maintenance will be performed as per approved SmPC. 
SARS-CoV-2 mRNA vaccination will be performed as part of clinical routine. 
The first interim analysis is planned when at least five patients per cohort have completed the 
study visit one week after the second SARS-CoV-2 modRNA vaccination or on September 1st 
2021, whichever comes first. The data gathered at this time point will be examined as a 
preliminary evaluation of proof of concept. 
The second interim analysis is planned when at least 10 patients that were vaccinated during 
stable ofatumumab-treatment have passes the primary endpoint, 1 month after the 2nd 
vaccination or after booster or on January 10th 2022, whichever comes first. The data gathered 
at this time point will be examined as a preliminary evaluation of proof of concept for the new 
study design. 
An additional interim analysis is planned after all participants have completed the study visit 1 
month after the second SARS-CoV-2 modRNA vaccination or booster vaccination, respectively. 
The data gathered at this time point will be the basis for the primary endpoint of this study. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study including an increase in participants (from 40 to 60), the sponsor’s clinical 
development projects in general, or in case of any safety concerns. 


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1.2 
Study objectives and endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
To estimate the proportion of RMS 
patients having established SARS-CoV- 
2-specific T-cells after receiving a mod 
RNA vaccine (initial or booster) either 
before or after starting ofatumumab 
treatment. 
Endpoint(s) for primary objective(s) 
Proportion of RMS patients having established 
SARS-CoV-2-specific T-cells as defined by 
detection of SARS-CoV-2 reactive T-cells, 
measured by e.g. enzyme-linked immunosorbent 
spot (ELIspot) assay from T-cells that were 
stimulated with SARS-CoV-2 peptide mix, either 
one month after second dose of vaccine or one 
month after booster vaccine in participants who 
received the respective vaccine before or after 
starting ofatumumab treatment (yes/no) 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
To estimate the proportion of RMS 
patients maintaining for up to 18 months 
SARS-CoV-2-specific 
T 
cells 
after 
receiving a modRNA vaccine either 
before or after starting ofatumumab 
treatment. 
Proportion of RMS patients with detectable 
SARS-CoV-2 reactive T-cells one week, 6 and 
18 months after second dose of vaccine or 6 and 
12 months after booster vaccine in participants 
who received the vaccine before or after starting 
ofatumumab treatment (yes/no) 
To estimate the increase in specific T-cells 
after receiving a modRNA booster vaccine 
either before or after starting ofatumumab 
treatment. 
Fold change of SARS-CoV-2 specific T-cell levels one 
week, 1 month, 6 months, 12 months and 18 months 
after the second dose of vaccine or 1 months, 6 
months and 18 months after a booster vaccine 
compared to the last timepoint before the respective 
vaccine 
To estimate the proportion of RMS 
patients achieving seroconversion (i.e. 
having SARS-CoV-2 serum neutralizing 
antibodies) after receiving a modRNA 
vaccine either before or after starting 
ofatumumab treatment. 
Proportion 
of 
RMS 
patients 
achieving 
seroconversion (i.e. having SARS-CoV-2 serum 
neutralizing 
antibodies) 
after 
receiving 
a 
modRNA vaccine either before or after starting 
ofatumumab treatment (yes/no) 
To estimate the proportion of RMS 
patients maintaining for up to 18 months 
quantifiable 
levels 
of 
SARS-CoV-2 
serum 
functional 
antibodies 
after 
receiving a modRNA vaccine either 
before  or  after  starting  ofatumumab 
treatment. 
Proportion of RMS patients with quantifiable 
levels 
of 
SARS-CoV-2 
serum 
functional 
antibodies one week, 1, 6, 12, and 18 months after 
receiving the second dose of modRNA vaccine or 
1, 6, and 12 months after a booster shot either 
before or after starting ofatumumab treatment 
(yes/no) 


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Describing phenotypically the cellular 
response after receiving a modRNA 
vaccine either before or after starting 
ofatumumab treatment. 
- 
Phenotypical 
characterization 
of 
peripheral blood mononuclear cells for 
CD45, 
CD3, 
CD4, 
CD8, 
CD62l, 
CD45RA, CD27, CCR7 
- 
Immunophenotyping for naive, central 
memory, effector memory, and effector 
cells on CD4+ and CD8+ cells 
- 
Measuring cells positive for intracellular 
cytokine-staining for interferon-gamma 
and interleukin-4 
 
Describing safety and tolerability, incl. 
patients developing coronavirus disease 
2019 (COVID-19) 
 
AEs, SAEs, incl. patients with clinical confirmed 
COVID-19 
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2 
Statistical methods 
2.1 
Data analysis general information 
Data analysis will be performed by the CRO 
. The software SAS, 
version 9.2 or higher is used. 
Categorical data will be summarized as frequencies and percentages. According to the small 
sample size of this study, percentages are presented without decimal places, i.e. as integers 
without digits. 
For continuous data, mean, standard deviation, median, minimum, and maximum will be 
presented. 
All listings and tables will be presented by cohort. 
2.1.1 
General definitions 
Study treatments 
The modRNA vaccine and the ofatumumab treatment are defined both as study treatments. The 
ofatumumab treatment which is started either before or after receiving a SARS-CoV-2 mRNA 
vaccine (either initial or booster) is considered as treatment of interest. 
Screening failure 
A screening failure is a patient not eligible for the study. Screening failures are identified by: 
- 
any inclusion criterion is violated or 
- 
any exclusion criterion applies 
2.1.2 
Handling with unscheduled vitis 
In this study unscheduled visits may be performed for various reasons. If laboratory data (i. e. 
the primary and secondary parameters) are available for unscheduled visits it will be checked 
if the unscheduled visit replaces a scheduled visit. This will be done before analysis in the data 
review meeting and documented in the minutes. 
2.1.3 
Visits relevant for efficacy analyses 
The following table shows which visits in each cohort are relevant for efficacy analysis and 
how they are numbered1: 
 
Baseline 
Week 1 
Month 1 
Month 6 
Month 12 
Month 18 
Cohort 1a 
(Ofatumumab 
after initial 
vaccination) 
Screening/ 
Baseline 
(101; 10) 
Visit 1 
 
(104; 1000) 
Visit 2 
 
(105; 1010) 
Visit 7 
 
(110; 1060) 
Visit 8 
 
(112; 1120) 
Visit 9 
 
(113; 1180) 
 
 
1 The first number indicates the visit number of raw data. This visit number deviates in the different cohorts. The 
second number ist the visit number used in the analysis data. this number was assigned uniformly across all 
cohorts 
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Cohort 1b 
(Ofatumumab 
after booster 
vaccination) 
Screening 
(701; 10) 
n.a. 
Visit 1 
(705; 1010) 
Visit 6 
(710; 1060) 
Visit 7 
(713; 1120) 
n.a. 
Cohort 2a 
(Ofatumumab 
before initial 
vaccination) 
Baseline 
(Visit 4) 
(205, 10) 
Visit 5 
(208, 1000) 
Visit 6 
(209, 1010) 
Visit 8 
(213, 1060) 
Visit 9 
(214, 1120) 
Visit 10 
(215; 1180) 
Cohort 2b 
(Ofatumumab 
before booster 
vaccination) 
Baseline 
(808; 10) 
n.a. 
Visit 4 
(809, 1010) 
Visit 6 
(811; 1060) 
Visit 7 
(812; 1120) 
n.a. 
 
 
2.2 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment received. 
The Safety Analysis Set (SAF) will include all participants that received any study drug. 
The Efficacy Analysis Set (EAS) will include all patients of the Safety Set who received a mRNA 
vaccine. Patients who failed their second dose of mRNA vaccine are included in the Efficacy 
Analysis Set, but counted as non-responders. Patients with invalid or missing efficacy parameter at 
a respective time point are included in the EAS, but excluded from the denominator for that time 
point when calculating responder-rates. 
2.2.1 
Subgroup of interest 
In general no subgroups are displayed. In selected tables (see Tables/Listings/Figures-Shells) 
the data are displayed separately for the subcohorts 1a, 1b, 2a, and 2b. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group (ofatumumab before versus after vaccination) for the SAF and 
the Efficacy Analysis Set. 
If major imbalance in relevant demographic or other baseline charateristics are discovered, the 
study results will be interpreted with more caution and post-hoc supportive analyses may be 
conducted to adjust for the imbalance. 
2.3.1 
Patient disposition 
Patient disposition displays the absolute and relative frequency of screening failures, the 
number of patients included in the different analysis sets. 
The reasons for screening failure, for missed study visits, for exclusion from analysis 
populations and for premature drop-out are described by frequency tables as well as protocol 
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The duration of intervals between relevant study visits are displayed by sample statistics. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The absolute and relative frequency of performed study visits (restricted to visits which are 
relevant for efficacy analysis) and performed vaccinations are presented. Sample statistics for 
the duration of intervals between screening and 1st resp. booster vaccination, 1st and 2nd 
vaccination, 2nd resp. booster vaccination and Week 1/Month 1/Month 6/ Month 12 after 
Vaccination 2 resp. booster vaccination are displayed. Here always the exact date of the 
respective vaccination is used but not the date of study visit called “Vaccination 1” or 
“Vaccination 2” or “Booster Vaccination” which displays the date of phone contact with the 
patient. 
Two types of investigational study drugs are used in this study: 
1. Ofatumumab for treatment of MS 
2. mRNA vaccine 
The interval of ofatumumab start is displayed relatively to the 1st resp. booster vaccination for 
cohort 2, and relatively to the 2nd resp. booster vaccination for cohort 1. Sample statistics are 
provided for these intervals. The frequencies of patients with temporary interruption 
respectively permanent discontinuation until each efficacy assessment time point (Week 1, 
Month 1, 6, 12, and 18) are provided. 
The different vaccines are displayed by a frequency table separately for 1st and 2nd vaccination. 
2.4.2 
Prior, concomitant and post therapies 
The number and types of all pretreatments for multiple sclerosis prior to screening are displayed. 
Here, all MS-therapies except ofatumumab which are starting before screening and ongoing 
after screening are included into counts. 
The last disease modifying drug before ofatunumab respectively the number of treatment-naïve 
patients is displayed in a frequency table. 
Concomitant medications are coded by WHO Drug-dictionary. Frequencies of Anatomic 
Therapeutical Chemical (ATC) categories and Preferred Names are presented. Here, a 
medication with multiple entries is counted only once in a ATC category respectively a 
preferred name category. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary clinical question of interest is: What is the proportion of RMS patients having 
developed a specific immune response after receiving a modRNA vaccine (either initial 
vaccination or booster) either before or after starting ofatumumab treatment. The justification 
for the primary estimand is that it will capture whether ofatumumab-treated patients will mount 


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a specific T-cell response after receiving a SARS-CoV-2 mRNA vaccine assessed by enzyme- 
linked immunosorbent spot (ELISpot) assays from T-cells that were stimulated with SARS- 
CoV-2 peptide mix. Patients will receive either their initial vaccination (1st and 2nd SARS-CoV- 
2 vaccines) or a booster vaccine before or after starting ofatumumab treatment. In both cases 
we want to assess if ofatumumab initiation negatively affects or prevents the immune response. 
Since this is not a randomized trial, no randomization needs to be preserved and the ITT- 
principle and the associated estimands framework do not apply. However, this protocol will 
keep as close as appropriate to the terminology and the definitions established within that 
framework. 
 
The primary estimand is described by the following attributes: 
1. Population: Patients with relapsing MS (RMS) divided in two cohorts, each receiving a 
SARS-CoV-2 mRNA vaccine as part of clinical routine: (1) vaccination before start of 
ofatumumab treatment, (2) vaccination after having been on stable ofatumumab treatment for 
at least 4 weeks. The SARS-CoV-2 mRNA vaccine can be either the initial vaccination cycle 
(for patient that are exposed to the vaccine for the first time; cohort 1a and cohort 2a) or a 
booster vaccination (for patients that have already completed the initial vaccination cycle; 
cohort 1b and cohort 2b). Patients in cohort 1a or 2a who fail to receive their second dose of 
vaccine for whatever reason will be included in the analysis as non-responders. Patients in 
cohorts 1a and 2a who did receive their second dose of vaccine and patients in cohorts 1b and 
2b who received their booster shot and do not have a valid determination of specific T-cell 
response to SARS-CoV-2 for whatever reason will be excluded from the analysis of vaccine 
efficacy. 
2. Variable: Receiving the second dose of mRNA vaccine (for cohort 1a and 2a) or a booster 
vaccination (cohort 1b and 2b) and mounting a specific T cell response2 one month after second 
dose of vaccine (cohort 1a and 2a) or booster vaccine (cohort 1b and 2b) defined by detection 
of SARS-CoV-2 specific T-cells by ELISpot assays after stimulation of T-cells with SARS- 
CoV-2 peptide mix (yes/no) 
3. Treatment of interest: ofatumumab treatment, which is started either before or after 
receiving a SARS-CoV-2 mRNA vaccine (initial vaccination cycle or booster vaccine) 
4. Intercurrent events: 
a. Vaccination with a non-mRNA vaccine: patients will be excluded from the study 
b. Failure to receive the second dose (for cohorts 1a and 2a) of vaccine: patients will be 
classified as non-responders 
c. Failure to initiate ofatumumab treatment within six weeks after completion of the 
vaccination cycle (cohort 1a) or of the booster vaccine (cohort 1b): patients will be excluded 
from the efficacy analyses 
 
 
 
2 See appendix 5.3.1 for derivation 


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d. Failure to complete ofatumumab initiation or interruption of ofatumumab treatment prior 
to first vaccination (cohort 2a) or prior to booster vaccination (cohort 2b): patents will be 
excluded from the study 
e. No valid detection of SARS-CoV-2 specific T-cells: patients will be excluded from the 
efficacy analyses if they received their second dose of vaccine (cohorts 1a and 2a) or booster 
vaccine (cohort 1b and 2b) and further analyses will be performed to confirm methodical 
reasons 
5. Summary measure: n.a., there will be no formal comparison between cohorts. Response 
rates will only be calculated within each cohort. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The efficacy analysis set is used for all analyses of the primary parameter. 
The primary analysis will not use any statistical testing or modelling. The absolute numbers and the 
proportion of participants achieving SARS-CoV-2-specific T-cell response within each cohort will 
be calculated. It will be augmented by a (descriptive) two-sided 95% confidence interval (exact 
Clopper-Pearson). 
2.5.3 
Handling of missing values/censoring/discontinuations 
Cohort 1a and cohort 2a: Patients who fail to receive their first dose of vaccine for whatever reason 
are excluded from the efficacy analysis Set(s). The number of these patients is displayed in the 
patient disposition table. 
Patients who fail to receive their second dose of vaccine for whatever reason will be included in the 
analysis as non-responders. The number of these patients is displayed in the analysis table. 
Patients who did receive their second dose of vaccine and do not have a valid determination of 
reactive T-cells to SARS-CoV-2 for whatever reason will be excluded from the analysis of vaccine 
efficacy at the respective time point. The number of these patients is displayed in the analysis table. 
Cohort 1b and cohort 2b: Patients who fail to receive their booster vaccination for whatever reason 
are excluded from the efficacy analysis Sets(s). The number of theses patients is displayed in the 
patient disposition table. 
Patients who did receive their booster vaccination and do not have a valid determination of reactive 
T-cells to SARS-CoV-2 for whatever reason will be excluded from the analysis of vaccine efficacy 
at the respective time point. The number of these patients is displayed in the analysis table. 
2.5.4 
Supportive analyses 
The reactivity towards SARS-CoV-2 and towards PAN coronaviridae is analysed by frequency 
tables presenting each investigational visit. This applies to the parameters: 
- 
IFNg (qualitative, i.e. reactive, equivocal, not reactive) 
- 
IL-2 (qualitative, i.e. reactive, equivocal, not reactive) 
The stimulation index towards SARS-CoV-2 and towards PAN coronaviridae is analysed by 
sample statistics and a boxplot graph for each investigational visit. This applies to the 
parameters: 


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- 
IFNg (quantitative) 
- 
IL-2 (quantitative) 
 
If relevant differences in demographic or other baseline chracteristics are observed post-hoc 
analysis will be performed to adjust the primary endpoint for theses inhomogeneities. A logistic 
regression model would be applied. 
2.6 
Analysis of the key secondary objective 
Not applicable, because no key secondary objectives are specified. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The secondary endpoints are analyzed descriptively within each cohort. The Efficacy Analysis 
Set is used for all analyses of the secondary parameters. 
The proportion of patients achieving seroconversion3 in SARS-CoV-2 neutralizing antibodies 
is presented for the time points Month 1, Month 6, and Month 12. Exact confidence intervals 
(95%, two-sided) are calculated by the Pearson-Clopper method. 
The phenotypical parameters are displayed by sample statistics and boxplots per time point 
(Screening, Month 1, Month 6, and Month 12) by cohort. For the baseline visit the subcohorts 
are presented. This applies to these parameters: 
- 
CD19+/CD20+ B cells (absolute and relative values) 
- 
CD4+ cells (% of mononuclear cells) 
- 
CD4: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD4 naïve: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD4 TCM: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD4 TEM CD27 – and CD27+: IL4 basal and stimulated, IFNg basal and stimulated 
(%) 
- 
CD8+ cells (% of mononuclear cells) 
- 
CD8: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD8 naïve: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD8 TCM: IL4 basal and stimulated, IFNg basal and stimulated (%) 
- 
CD8 TEM CD27 – and CD27+: IL4 basal and stimulated, IFNg basal and stimulated 
(%) 
 
 
 
3 For derivation of seroconversion see Appendix 5.3.2 


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All other laboratory data (e. g. number of basal/background spots, spots, quality, comments, 
mutations and hemotology) are listed only. 
The MS activity is measured by relapses. The crude annual relapse rate until end of study and 
the underlying sums (of relapses and patient-years) will be presented. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Not applicable due to descriptive analysis. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing values are not replaced. 
2.9 
Safety analyses 
All safety analyses are presented for the Safety Set (SAF). Descriptive statistics are presented 
within study treatment groups (cohorts 1 and 2). 
2.9.1 
Adverse events (AEs) 
According to the CSP all adverse events starting in the on-treatment period, i. e. the treatment- 
emergent AEs, are analyzed. 
The on-treatment period lasts from the date of first administration of study treatment4 after informed 
consent to 30 days after the last visit. 
 
4 Study treatment is ofatumumab as well as the modRNA vaccine. 
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The number (and percentage) of subjects with treatment-emergent adverse events will be 
summarized in the following ways: 
• by treatment group (cohort 1 and 2), primary system organ class and preferred term. 
• by treatment group (cohort 1 and 2), primary system organ class, preferred term and 
maximum severity 
• by type of modRNA (Biontech/Pfizer versus Moderna), primary system organ class and 
preferred term. 
A subject with multiple AEs within a MedDRA primary system organ class is only counted 
once towards the total of the primary system organ class. 
A subject with multiple AEs within a preferred term is only counted once towards the total of 
the preferred term class. 
Separate summaries will be provided for study medication related AEs, death, SAEs, AEs 
leading to discontinuation and adverse events leading to dose adjustment. 
The absolute and relative frequency of COVID-19 infections is presented. 
Deaths and serious adverse events are listed in addition. Deaths outside the on-treatment period 
are listed in addition. 
Rates of COVID-19 infections and the rate of COVID-19 infections starting >= 7 days after the 
2nd vaccination are displayed. Alle COVID-19 infections are listed with the dates of all COVID- 
19 vaccinations. 
2.9.1.1 
Adverse events of special interest / grouping of AEs 
Adverse events related to COVID-19 pandemic are listed. 
2.9.2 
Deaths 
Deaths are listed. A frequency table with absolute numbers, percentages and 95% confidence 
interval is presented. 
2.9.3 
Laboratory data 
Hematology is listed only. The analysis of other lab parameters are described in section 2.5 and 
section 2.7. 
2.9.4 
Other safety data 
2.9.4.1 
Physical examination 
Clinically significant findings which were not present at screening but at any later visits are 
displayed by a frequency table. 
2.9.4.2 
Vital signs 
The changes from screening to Week 1, to Month 1, to Months 6, to month 12, and to Month 18 
as well as differences between last and first value are displayed for pulse, systolic/diastolic 
blood pressure and body weight. 


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2.10 
Pharmacokinetic endpoints 
Not applicable. 
2.11 
PD and PK/PD analyses 
Not applicable. 
2.12 
Patient-reported outcomes 
Not applicable. 
2.13 
Biomarkers 
Not applicable. 
2.14 
Other Exploratory analyses 
Not applicable. 
2.15 
Interim analysis 
See section 1.1 Study design. 
3 
Sample size calculation 
The sample size of 20 participants per arm is selected based on need for early availability of results 
for the current covid-19 pandemic and the feasibility to recruit sufficient participants. This sample 
size of 20 subjects will provide estimates of proportion responded 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 subjects will be enrolled in each arm. 
In case of fast recruitment the sponsor is allowed to increase sample size in each arm by up to 10 
additional patients to support the generation of meaningful data in a larger sample size. 
 
4 
Change to protocol specified analyses 
The efficacy analysis set was defined in such a way that it can be applied to all efficacy analyses. 
With regard to the primary parameter, there is no change in content compared to the definition 
in the study protocol. 
 
 
5 
Appendix 
5.1 
Imputation rules 
No imputations will be done except: 
a. If differences between dates are calculated, partial dates are replaced by 15/6 for 
days/month. If negative date differences result from this replacement, the value is set to 
0. 


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b. According to the Note to File dated 29 September 2023 the quantitative values and spots 
of IFGg and IL-2 were corrected (i. e. set to a missing value) when the respective 
qualitative assessment was “not evaluable”. This applied both to parameters “PAN 
corona” and “SARS CoV-2. This correction was performed also when the value for 
qualitative assessments was “missing” (see Note to file dated 20 Oct 2023). 
 
 
5.2 
Treatment-emergent adverse events 
Treatment emergent AEs are those which start in the on-treatment period. The on-treatment 
period lasts from the date of first administration of study medication after informed consent to 
30 days after the last visit. 
The date of first administration of study medication is the date of 1st vaccination or the date of 
first ofatumumab at or after screening whichever is earlier. 
5.3 
Statistical models 
5.3.1 
Primary analysis 
The primary parameter “T-cell response” is derived from the laboratory data. Patients who have 
either SARS-CoV-2 reactive INFg-secreting T-cells or SARS-CoV-2 reactive IL-2 secreting T- 
cells (or both) are classified are responders. The assement “equivocal” is rated as reactive for 
this analysis, which is based on observations made during the validation of the assay. It was 
noticed that the positiv control of the ELISpot assay repeatedly provoked lower signals than 
seen in healthy volunteers, which led to the conclusion that T-cells from MS patients in general 
show lower reactivity in this assay. Consequently, the cut-offs for “reactive”/”equivocal” and 
“not reactive” defined by the kit-manufacturer have to be adjusted to these circumstances and 
results that would be classified as “equivocal” for healthy patients can be considered as signal 
and hence as “reactive” for MS patients. The following table presents the derivation of T cell 
response: 
 
Reactivity to INFg SARS-CoV-2 (quantitative) 
Reactivity towards IL-2 
SARS-CoV-2 
(quantitative) 
reactive 
equivocal 
Not reactive 
Missing 
value 
reactive 
response 
response 
response 
response 
equivocal 
response 
response 
response 
response 
Not 
reactive 
response 
response 
Non-response 
Non-response 
Missing 
value 
response 
response 
Non-response 
m.v. 
(not included in 
denominator) 


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5.3.2 
Secondary analysis 
A patient achieves sercoconversion when the neutralizing SARS-CoV-2 antibodies have 
changed from negative at screening/baseline to positive at the respective Visit. If the 
neutralizing SARS-CoV-2 antibodies are already positive at baseline (e.g. in patients of 
cohorts b who received their initial COVID-19 vaccine before the study) seroconversion cannot 
be derived for the post-baseline visits. These cases are displayed in addition in the tables 
as ”already seroconverted at baseline”. 
5.4 
Rule of exclusion criteria of analysis sets 
 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
I01 
Incl. crit. no. 1 (IFC) violated 
Excluded form all analysis 
Sets 
S02 
Different vaccines at first and 2nd 
vaccination 
Excluded form Efficacy 
Analysis Set 
 
Table 2 
Subject Classification 
Analysis Set 
PD ID that 
cause subjects to be excluded 
Non-PD criteria that cause 
subjects to be excluded 
SAF/Efficacy 
Analysis Set 
NA 
Not having any study treatment 
Efficacy 
Analysis Set 
NA 
No mRNA vaccine administered: 
- 
Patients of cohort 1a and 2a who 
missed the 1st vaccliation 
- 
Patients of cohort 1b and 2b who 
missed the (study) booster 
vaccination 
 
 
6 
Reference 
None.